CONGRESS OF NEUROLOGICAL SURGEONS SYSTEMATIC REVIEW AND EVIDENCE-BASED GUIDELINES UPDATE FOR THE ROLE OF EMERGING THERAPIES IN THE MANAGEMENT OF PATIENTS WITH METASTATIC BRAIN TUMORS

 NEUROSURGERY 2025

Sponsored by: Congress of Neurological Surgeons (CNS) and the Section on Tumors

 

Endorsed by: Reviewed for evidence-based integrity and endorsed by the American Association of Neurological Surgeons (AANS) and Congress of Neurological Surgeons (CNS)

 

Authors: Kristin Huntoon, PhD, DO¹,  J. Bradley Elder, MD², Guilherme Finger MD MSc², D. Ryan Ormond, MD, PhD³, Navid Redjal, MD^4,5, Mark E. Linskey, MD⁶, Jeffrey J. Olson, MD ⁷

 

Departmental and institutional affiliations:

1. Department of Neurosurgery at the University of Arizona and at Southern Arizona VA Health Care System, Tucson, AZ, USA
2. Department of Neurological Surgery, The Ohio State University, Columbus, OH, USA
3. Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA
4. Capital Institute for Neurosciences, Capital Health Pennington, NJ, USA
5. Department of Neurosurgery, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ, USA
6. Department of Neurological Surgery, University of California, Irvine, School of Medicine, Irvine, CA, USA
7. Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, USA

 

Corresponding Author contact information:

Kristin Huntoon, PhD, DO

University of Arizona Department of Neurosurgery

PO Box 245070

1501 N Campbell Avenue, Room 4303

Tucson, Arizona, 85724-5070

Tel: (520) 694-8888

kristinhuntoon@arizona.edu

No part of this article has been published or submitted for publication elsewhere.

 

Keywords: Brain metastases, targeted therapy, immunotherapy, leptomeningeal, laser interstitial thermal therapy, radiation sensitizer

 

Abbreviations:

CNS = central nervous system

GKRS = Gamma Knife Radiosurgery

HIFU = magnetic resonance imaging–guided focused ultrasound

ICI = immune checkpoint inhibitor

IT = intrathecal

LITT = laser interstitial thermal therapy

LM = leptomeningeal metastasis

MBT = metastatic brain tumors

NSCLC = non–small-cell lung carcinoma

OS = overall survival

PD-L1 = programmed death-ligand 1

PFS = progression-free survival

SRS = stereotactic radiosurgery

TKI = tyrosine kinase inhibitor

TPS = Tumor Proportion Score

WBRT = whole brain radiation therapy

 

 

ABSTRACT

Background: Patients with metastatic brain tumors (MBTs) require a multidisciplinary team-based approach to select the best diagnostic, surgical, and radiation interventions.

Objective: The aim of this guideline is to provide an update of the evidence-based recommendations of the guideline produced in 2019 regarding the use of emerging therapies for adult patients with MBTs.

Methods: PubMed and Embase were searched from January 1, 2016 through May 3, 2022 using search strategies pertinent to the therapeutic topics: targeted agents, immune modulating agents, interstitial modalities, radiosensitizers, laser interstitial thermal therapy (LITT), and magnetic resonance imaging–guided focused ultrasound (HIFU). The search results were screened using preestablished exclusion/inclusion criteria. Evidence tables were constructed using these data and the recommendations from the 2019 version were left unchanged, updated or, where appropriate, new recommendations were formulated.

Results: Of 6403 qualifying abstracts, 162 met the inclusion criteria and were included in the evidence tables. They provided 8 class I recommendations, 3 class II recommendations, and 17 class III recommendations. In 3 instances there was insufficient evidence to support a recommendation. The proliferation of qualifying literature since the end of 2015 was greatest regarding the topics related to targeted therapy and immunotherapy of MBTs. Fewer were available for LITT and radiosensitizers, but enough information was available to formulate recommendations on these 2 topics. For interstitial modalities and HIFU, insufficient qualifying data was identified to create recommendations.

Conclusion: This systematic review provides evidence-based recommendations for adult patients with MBTs regarding the use of therapies beyond standard surgical, radiation, and cytotoxic chemotherapy.

 

PICO QUESTIONS AND RECOMMENDATIONS

 

Target Population: Adults with MBTs

 

Question 1

In patients with parenchymal brain metastases, does the use of molecular targeted agents provide benefit in terms of local control, overall survival (OS), progression-free survival (PFS), performance status, or reduction in central nervous system (CNS) side effects compared to standard management with chemotherapy, immune modulators, stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), and surgical resection?

 

RECOMMENDATIONS

 

Unchanged Recommendation

 

Level I: The use of afatinib is not recommended in patients with brain metastasis due to breast cancer.

 

New Recommendations

 

Targeted Therapy for the Treatment of EGFR Mutant NSCLC Parenchymal Brain Metastases

 

Level I: In subjects with ≥3 untreated brain metastases from epidermal growth factor receptor (EGFR) mutant non–small-cell lung carcinoma (NSCLC), the use of icotinib and WBRT is recommended to improve intracranial PFS.

 

Level III: In subjects with brain metastases from EGFR mutant NSCLC, the addition of EGFR tyrosine kinase inhibitors to radiation therapy in the form of WBRT or SRS is suggested to improve OS, PFS, and intracranial PFS.

 

Targeted Therapy for the Treatment of ALK Mutation–Positive NSCLC Parenchymal Brain Metastases

 

Level I:  In patients with ALK mutation-positive NSCLC with untreated brain metastases the use of alectinib is recommended to delay time to intracranial tumor progression.

 

Level II:  In patients with untreated brain metastases from ALK mutation positive NSCLC lorlatinib is recommended to prolong intracranial tumor control and improve overall PFS.

 

Targeted Therapy for the Treatment of NSCLC Parenchymal Brain Metastases Not Assessed for EGFR and ALK Mutation Status

 

Level I: It is recommended that for patients with newly diagnosed brain metastases secondary to NSCLC not assessed for EGFR and ALK mutation status, and for whom WBRT is indicated, gefitinib be added to the treatment regimen to improve local tumor control and OS.

 

Level III: For individuals with brain metastases secondary to NSCLC not assessed for EGFR and ALK mutation status and for whom targeted therapy in the form of gefitinib or the combination of pemetrexed and platinum compounds are otherwise indicated, it is suggested that bevacizumab, when not contraindicated by other underlying medical conditions, be added to the treatment regimen to improve CNS control and to a lesser extent PFS and OS.

 

Targeted Therapy for the Treatment of EGFR Negative, ALK Negative NSCLC Parenchymal Brain Metastases

 

Level III: For individuals with brain metastases secondary to NSCLC that are EGFR and ALK mutation negative and for whom targeted therapy in the form of tyrosine kinase inhibitors (TKIs) are indicated, it is suggested that TKIs, when not contraindicated by other underlying medical conditions, be added to the treatment regimen, including radiation therapy, to improve CNS control and to a lesser extent PFS and OS.

 

Targeted Therapy for the Treatment of Melanoma Parenchymal Brain Metastases

 

Level I: It is recommended that for patients with newly diagnosed brain metastases secondary to melanoma that is BRAFV600E-positive, dabrafenib plus trametinib be added to the treatment regimen to obtain improved local tumor control.

 

Level III: For individuals with brain metastases secondary to BRAF-altered melanoma for whom targeted therapy in the form of BRAF inhibitors are indicated, it is suggested that immunotherapy, when not contraindicated by other underlying medical conditions, be added to the treatment regimen to improve CNS control and to a lesser extent PFS and OS.

 

Targeted Therapy for the Treatment of Breast Adenocarcinoma Parenchymal Brain Metastases

 

Level III: In adult patients with brain metastases from breast adenocarcinoma that are HER2-positive for whom radiation therapy is indicated, it is suggested that trastuzumab be added to the treatment regimen to improve PFS, median survival, and OS.

 

Level III: In adult patients with brain metastases from breast adenocarcinoma for whom SRS is indicated, it is suggested that lapatinib be added to that treatment to improve intracranial response rate and median survival.

 

Question 2

In patients with leptomeningeal brain metastases, does the use of molecular targeted agents provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, immune modulators, SRS, WBRT, and surgical resection?

 

New Recommendations

 

Level III: In individuals with leptomeningeal disease from NSCLC with EGFR mutations, it is suggested that EGFR TKIs be utilized to increase median survival, specifically the third-generation TKI osimertinib for patients with EGFR-mutant NSCLC and the second-generation ALK-TKI alectinib for the treatment of leptomeningeal metastases (LMs) in ALK-positive NSCLC.

 

Level III: In individuals with LMs from Her2 positive breast cancer, it is suggested that intrathecal (IT) trastuzumab be utilized to increase median survival.

 

Question 3

In patients with parenchymal brain metastases, does the use of immune modulators provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, molecular targeted agents, SRS, WBRT, and surgical resection?

 

New Recommendations

 

Level I: In individuals with active, untreated, asymptomatic parenchymal melanoma brain metastases (MBMs), ipilimumab plus nivolumab is recommended to increase median OS and be utilized without radiation to improve median OS.

 

Level III: In individuals with parenchymal brain metastases from NSCLC it is suggested that immune checkpoint inhibitors (ICIs) be utilized with radiation therapy to increase median survival, decrease incidence of local failure, increase intracranial PFS, and decrease distant intracranial failure.

 

Level III: In individuals with parenchymal brain metastases from NSCLC that are clinically stable for at least 4 weeks and with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) >50% it is suggested that ICIs be utilized without radiation to improve median OS.

 

Level III: In individuals with parenchymal brain metastases from breast cancer or colon carcinoma it is suggested that therapy with ICIs be considered alone or with radiation therapy to increase median survival and decrease incidence of local failure.

 

Question 4

In patients with leptomeningeal brain metastases, does the use of immune modulators provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, molecular targeted agents, SRS, WBRT, and surgical resection?

 

New Recommendation

 

There is insufficient evidence to make a recommendation regarding the use of immune modulators for the therapy of leptomeningeal brain metastases.   

 

Question 5

In patients with parenchymal brain metastases, does the use of interstitial modalities, in the form of interstitial chemotherapy or radiation (brachytherapy, intraoperative radiation therapy), provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, immune modulators and molecular targeted agents, SRS, WBRT, and surgical resection?

 

Unchanged Recommendation

 

There is insufficient evidence to make a recommendation regarding the use of interstitial modalities in the form of interstitial chemotherapy or radiation.

 

Question 6

In patients with parenchymal brain metastases, does the use of radiosensitizers provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, immune modulators and molecular targeted agents, SRS, WBRT, and surgical resection?

 

Unchanged Recommendations

 

Level I: The use of temozolomide as a radiation sensitizer is not recommended in the setting of whole-brain radiation therapy (WBRT) for patients with breast cancer brain metastases.

 

Level I: The use of chloroquine as radiation sensitizer is not recommended in the setting of WBRT for patients with brain metastases.

 

New Recommendations

 

Level II: When WBRT is utilized for brain metastases from NSCLC it is recommended that temozolomide be added to provide a smaller incidence of local failure, longer intracranial PFS, and longer OS.

 

Level III: For brain metastases from NSCLC with EGFR mutation positive status where WBRT or SRS is indicated, it is suggested that EFGR TKIs be added to that therapy to improved intracranial response rate and survival.

 

Question 7

In patients with parenchymal or leptomeningeal brain metastases, does the use of LITT provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, immune modulators and molecular targeted agents, SRS, WBRT, and surgical resection?

 

New Recommendations

 

Level III: For adults who have undergone SRS for brain metastases with subsequent imaging progression due to tumor progression it is suggested that LITT be considered as equivalent to craniotomy in terms of PFS and OS and the choice of management should be individualized based on the unique characteristics of the tumor location and the subject’s clinical status.

 

Level III: For adults who have undergone SRS for brain metastases with subsequent imaging progression due to radiation necrosis it is suggested that LITT be considered as equivalent to medical management for radiation necrosis and the choice of management should be individualized based on the unique characteristics of the tumor location and the subject’s clinical status.

 

Question 8

In patients with parenchymal or leptomeningeal brain metastases, does the use of HIFU provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, immune modulators and molecular targeted agents, SRS, WBRT, and surgical resection?

 

Unchanged Recommendation

 

There is insufficient evidence to make a recommendation regarding the use of HIFU for parenchymal and leptomeningeal brain metastases.

 

INTRODUCTION

Goals and Rationale

Advancements in the understanding of the biology of MBTs, the ability to create more sophisticated systemic treatments via improved pharmacologic chemistry, radiation therapy software and hardware advancements, and surgical equipment have yielded new information worthy of dissemination. As suggested by the Institute of Medicine, now the National Academy of Medicine, it is suggested that guidelines be updated in the range of every 5 years.¹ Thus, interval updates of the guideline on emerging therapies for MBTs published by the American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) in 2018 were planned to update the information in that publication.²

 

Objectives

This document seeks to update the recommendations for molecular and targeted agents, immune modulating agents, interstitial modalities, radiosensitizers, intraoperative radiation therapy, laser interstitial thermal therapy, and HIFU published in the 2018 guideline on emerging therapies for MBTs.² To accomplish this, the Joint Tumor Section of the AANS/CNS recruited representatives from the section to review and update the questions from the previous guideline to PICO (Patient \, Intervention, Comparison, Outcome) format, search the literature published regarding the items in each question since the search of the 2018 publication, and determine if that new information confirmed previous recommendations, required an update of previous recommendations, or new recommendations.

 

METHODOLOGY

Literature Search

To accomplish this update, new literature in PubMed and EMBASE from January 1, 2016 through May 3, 2022 was searched using the questions with their new PICO format, and data from the qualifying manuscripts for each topic was used to either confirm previous recommendations, update them, or create new ones. The search strategy used combinations of subheadings and key words and is documented in previous methodology papers. Search strategies for the root brain metastasis search as well as the 6 categories of emerging therapy (molecular and targeted agents, immune modulating agents, interstitial modalities, radiosensitizers, laser interstitial thermal therapy, and HIFU) can be found in Appendix I. Manuscripts selected for review upon screening of abstracts met the criteria described below. All citations were reviewed by 2 authors and acceptance or rejection recorded along with the reasons. When there was disagreement, the 2 reviewers met in live session to resolve the disagreement. The Guidelines Task Force used DistillerSR (which utilizes artificial intelligence) to cull, narrow, and aid its review of the relevant literature. All abstracts were reviewed, and relevant full text articles were retrieved and graded [by individuals on the Guidelines Task Force].

 

Inclusion/Exclusion Criteria

• Published in English
• Involves human patients with brain metastases
• Fully published primary study published between September 2008 and December 2015
• Paper evaluates ≥1 of the therapies in question:
• Molecular and targeted agents for parenchymal brain metastases
• Molecular and targeted agents for leptomeningeal brain metastases
• Immune modulating agents for parenchymal brain metastases
• Immune modulating agents for leptomeningeal brain metastases
• Interstitial modalities
• Radiosensitizers
• LITT
• HIFU
• Number of patients with brain metastases in the study ≥5 per study arm for ≥2 of the study arms for comparative studies, and ≥5 total patients if a noncomparative study

 

Data Collection Process

Manuscripts selected for review underwent full review by 2 authors to confirm that it met eligibility criteria; if not, the manuscript was rejected. As with the abstracts, when there was disagreement the 2 reviewers met in live session to resolve the disagreement. Data gleaned from the manuscript included type of study (e.g., phase 2 clinical trial, retrospective chart review, etc.), therapeutic agent evaluated, and the outcome measures and results yielded by the study.

 

Assessment for Risk of Bias

Each manuscript was evaluated by the writing group for bias, and the summation of different forms of bias are reflected in the data classification system. Inherent to emerging therapy agents, initial reports were noted to be in the form of small case series, anecdotal reports, and early phase clinical trials. As such, there is inevitable selection bias imposed by retrospective reviews and prospective studies with small numbers of patients. For example, patients selected for study, especially early phase trials, may have better medical status relative to patients not selected for study. In addition, small series of patients may have bias because of random variability. Our expectation is that the more promising techniques and agents mentioned in this guideline will be studied further as part of larger clinical trials which will eliminate some of the inherent bias of smaller, retrospective studies.

 

Rating Quality of Evidence and Recommendation Formulation

Each manuscript that met eligibility criteria and was found to have data relevant to the question was rated as providing class I, II, or III evidence based on the definitions provided in the AANS/CNS criteria. The pertinent classification levels and data for each paper were entered into an evidence table for each emerging therapy subtopic. The evidence tables were then validated among the writing group before the formulation of recommendations. The summation of the information from qualifying manuscripts was then synthesized and used to create level I, II, or III recommendations based on the classification of evidence on therapeutic effectiveness (Appendix II). An expanded description of the data classification system and translation to recommendation level designation is provided at Guideline Development Methodology - cns.org.

 

Revision Plans

In accordance with the National Academy of Medicine’s standards for developing clinical practice guidelines, the writers of the emerging therapies for MBTs task force will monitor related publications following the release of this document and will revise the entire document and/or specific sections “if new evidence shows that a recommended intervention causes previously unknown substantial harm; that a new intervention is significantly superior to a previously recommended intervention from an efficacy or harms perspective; or that a recommendation can be applied to new populations.”³ In addition, within 5 years from the date of publication the task force plans to assess the content this guideline to that it still reflects the clinical practice and treatment for patients with MBTs. In those cases where it does not, the recommendations will either be updated or new recommendations will be created.

 

SUMMARY OF PREVIOUS GUIDELINE

The prior version of the guidelines for the role of emerging and investigational therapy was written with one question: What evidence is available regarding emerging and investigational treatment options for MBTs?² This was then applied over a range of topics in order of consideration at that time, including high intensity focused ultrasound (HIFU), laser interstitial thermal therapy (LITT), radiosensitizers, interstitial modalities, immune modulators, and molecular targeted agents.

 

Insufficient evidence was available to make a recommendation regarding the use of HIFU, LITT, interstitial modalities, and immune modulators.

 

For radiation sensitizers, two level I recommendations were derived, both of which were negative. The first stating temozolomide as a radiation sensitizer is not recommended in the setting of WBRT for patients with breast cancer brain metastases. The second stated chloroquine as a radiation sensitizer is not recommended in the setting of WBRT for patients with brain metastases. There is insufficient evidence to make a recommendation regarding the routine use of motexafin-gadolinium, sodium nitrite, temozolomide, or chloroquine in patients with brain metastases.

 

For molecular targeted agents, one level I recommendation was derived, again negative, stating that the use of afatinib is not recommended in patients with brain metastasis due to breast cancer. Evidence did not support making a recommendation regarding the use of epidermal growth factor inhibitors in non–small cell lung carcinoma (NSCLC), BRAF inhibitors for melanoma, HER2 inhibitors in breast cancer, or VEGF inhibitors in parenchymal brain metastases.

To facilitate comparison of the new recommendations with those from the previous version, a table displaying them side by side has been created (Table 1). An additional table of the recommendations enumerated in this document by treatment modality and then divided by tumor type and subdivided by molecular subtypes is provided (Table 2). This will facilitate access to recommendations for readers most interested in recommendations by tumor type.

 

RESULTS

Targeted Therapy for Brain Metastases

Targeted Therapy of Parenchymal Brain Metastases

Question 1: In patients with parenchymal brain metastases, does the use of molecular targeted agents provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, immune modulators, SRS, WBRT, and surgical resection.

 

The literature search yielded 2634 abstracts. Task force members reviewed all titles and abstracts yielded from the literature search and identified the literature for full-text review and extraction, addressing the clinical questions, in accordance with the literature search protocol (Appendix I). Task force members identified the best research evidence available to answer the targeted clinical questions. When level I, II, and or III literature was available to answer specific questions, the task force did not review level IV studies.

 

The task force selected 263 full-text articles for full-text review. Of these, 216 were rejected for not meeting inclusion criteria or for being off topic. Forty-seven articles were selected for systematic review (Appendix III).

 

All 47 studies included in the qualitative analysis also met the criteria to be included in the quantitative analysis. Three studies were class I, 3 were class II, and 41 studies were class III. To ease the discussion of the targeted therapy of parenchymal brain metastases, the qualifying manuscripts are divided into those related to NSCLC, melanoma, and breast adenocarcinoma. The recommendations for the different tumor types are provided after the synthesis for each circumstance to ease understanding of where the recommendations apply.

 

NSCLC

Prognostic Studies

Gong et al¹ performed a cross-section study collecting retrospective data of patients with NSCLC and BM treated between 2007 and 2012. The objective of this study was to observe the therapeutic efficacy and prognostic factors that influence survival rates of patients with NSCLC with multiple brain metastases (BMs; >3 and <10). A total of 209 patients were included, all of whom received WBRT. Two hundred patients received combined chemotherapy during the treatment process, 99 received targeted drug therapy, and 9 received only symptomatic and supportive treatment. The median survival time for all patients with BMs was 12.1 months (95% confidence interval [CI], 9.37-14.83). The 6-month and 1- and 2-year cumulative survival rates were 80%, 50.2%, and 10.7%, respectively. Based on univariate and multivariate analysis, the authors concluded that active treatment of NSCLC with multiple BMs was beneficial, and the patients’ cultural background had a strong influence on survival prognoses. Three or more cycles of chemotherapy (P = .001) combined with targeted drug therapy (P = .01) could increase the patients’ median and OS rates. Also, cultural backgrounds of the patients had significant effects on the patients’ survival prognoses. Though targeted therapy is mentioned in this article, the focus of this study was not targeted therapy. It provides class III prognostic data; additional confirming class III or better data is necessary before using this information to formulate a recommendation.

 

Targeted Therapy for the Treatment of NSCLC Parenchymal Brain Metastases

Most of the qualifying articles provided class III evidence (30 studies), 3 provided class II evidence, and 3 provided class I evidence. Details of the qualifying and informative manuscript data are available in the evidence table (Table 3). For better comprehension, this discussion is initially subdivided into groups of manuscripts that analyze different genetic profiles of the NSCLC: EGRF mutation status (present or absent) and/or ALK mutation status. Secondarily, the studies are grouped according to relatively common treatment themes for each of the groups. Patients were excluded if they discontinued TKI after RT or ever received surgery for BM. The objective of this study was to compare OS and intracranial PFS between these 2 groups.

 

Targeted Therapy for the Treatment of EGFR Mutant NSCLC Parenchymal Brain Metastases

The presence of EGFR mutation can be treated with tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, afatinib, and osimertinib. Huang et al⁴ published a study that investigated the efficacy of 3 different EGFR TKIs (gefitinib, erlotinib, and afatinib) in association with bevacizumab as the first-line treatment in patients with advanced EGFR mutant lung adenocarcinoma.⁴ A total of 36 patients were included in the final analysis. Three patients received gefitinib, 17 received erlotinib, and 16 received afatinib combined with bevacizumab as the first-line treatment. Since only 3 patients received gefitinib, the comparison analysis involved only erlotinib and afatinib. Regarding the use of different EGFR TKIs, the median PFS was 17.1 months in the erlotinib group and 21.6 months in the afatinib group (P = .617). In patients with brain metastasis at baseline, the median PFS was 18.9 months in the erlotinib group and 16.4 months in the afatinib group (P = .747). Among patients harboring an exon 19 deletion, the median PFS was 16.2 months in the erlotinib group and not reached in the afatinib group (P = .141). In patients with L858R mutation, the median PFS was 18.9 months in the erlotinib group and 16.2 months in the afatinib group (P = .481). Based on these results, the authors concluded that not only either erlotinib or afatinib combined with bevacizumab, as first-line treatment, provides solid clinical efficacy in patients with advanced EGFR mutant lung adenocarcinoma.

 

Wu et al⁵ designed a clinical trial to evaluate patients with advanced EGFR mutant NSCLC who experience disease progression with previous EGFR TKI treatment. The study compared osimertinib CNS efficacy with platinum-pemetrexed. Patients with asymptomatic, stable CNS metastases were eligible for enrollment and were randomly assigned 2:1 to osimertinib 80 mg once daily or platinum-pemetrexed. The primary objective for this analysis was CNS objective response rate (ORR). Of 419 patients randomly assigned to treatment, 116 had measurable and/or nonmeasurable CNS lesions, including 46 patients with measurable CNS lesions. At data cutoff (April 15, 2016), CNS ORR in patients with ≥1 measurable CNS lesions was 70% (21/30 [95% CI 51%-85%]) with osimertinib and 31% (5/16 [95% CI 11%-59%]) with platinum-pemetrexed (odds ratio [OR] 5.13 [95% CI 1.44-20.64]; P = .015); the ORR was 40% (30/75 [95% CI 29%-52%) and 17% (7/41 [95% CI 7%-32%]), respectively, in patients with measurable and/or nonmeasurable CNS lesions (OR 3.24 [95% CI 1.33-8.81]; P = .014). Median CNS duration of response in patients with measurable and/or nonmeasurable CNS lesions was 8.9 months (95% CI 4.3 months to not calculable) for osimertinib and 5.7 months (95% CI 4.4-5.7 months) for platinum-pemetrexed; median CNS PFS was 11.7 months and 5.6 months, respectively (hazard ratio [HR] 0.32 [95% CI 0.15-0.69]; P = .004). The authors concluded that osimertinib demonstrated superior CNS efficacy compared with PP.

 

Chiou et al⁶ performed retrospectively reviewed consecutive cases of EGFR mutant NSCLC with BM treated between 2012 and 2020. The goal of this study was to compare outcomes between EGFR TKE therapy alone (group I) and combined EGFR TKI therapy + SRS (group II) in patients with NSCLC with BMs and EGFR mutations. Tumor control (<10% increase in tumor volume) and OS rates were compared. The study cohort included 280 patients (n = 90 in group I and n = 190 in group II). Cumulative tumor control rates were higher in group II than in group I (79.8% vs 31.2% at 36 months, P < .0001). Cumulative OS rates were comparable between groups I and II (43.8% vs 59.4% at 36 months, P = .3203). Independent predictors of tumor control were older age (P < .01, HR 1.03), fewer BMs (P < .01, HR 1.09), lack of extracranial metastasis (P < .02, HR 0.70), and combined SRS and TKI therapy (P < .01, HR 0.25). Independent predictors of OS were fewer BMs (P < .01, HR 1.04) and a higher Karnofsky performance status score (P < .01, HR 0.97). Although the OS rate did not differ between TKI therapy with and without SRS, the addition of SRS to TKI therapy resulted in improvement of intracranial tumor control. The lack of effect on survival rate with the addition of SRS may be attributable to extracranial disease progression.

 

He et al⁷ performed a historic cohort comparing the efficacy of concurrent EGFR-TKI and whole-brain radiation therapy (WBRT) with EGFR TKI alone as a first-line therapy for advanced EGFR mutated NSCLC with brain metastases. One hundred four patients were included, 56 in the concurrent EGFR TKI group and 48 in the EGFR TKI alone group. The median follow-up of the sample was 23 months. Concurrent EGFR TKI and WBRT significantly improved the median intracranial PFS (iPFS) compared with EGFR TKI alone (17.7 vs 11.0 months, P = .015). Subgroup analysis showed that concurrent EGFR TKI and WBRT improved median iPFS compared with EGFR TKI alone in patients with >3 brain metastases (P = .001); however, no significant difference was observed between the 2 regimens in patients with ≤3 brain metastases (P = .526). Of note, the OS analysis was biased because 20 patients in the EGFR TKI alone group migrated to the other group with salvage WBRT upon brain metastasis progression.

 

He et al⁸ conducted a historic cohort aiming to compare erlotinib with pemetrexed as second-/third-line treatment in patients with lung adenocarcinoma with asymptomatic brain metastases. From January 2012 to June 2014, all patients with lung adenocarcinoma with asymptomatic brain metastases who received treatment with erlotinib or pemetrexed as second-/third-line treatment were retrospectively reviewed. Even though the EGFR mutation status was assessed in this study, patients were divided into 2 groups according to the therapeutic regimen received, not EGFR status. A total of 99 patients were included, 68 in the erlotinib-treated group and 31 in the pemetrexed-treated group. Among the 99 patients, 44 (44.4%) had EGFR mutated. Median PFS was not different between the groups treated with erlotinib and pemetrexed (4.2 vs 3.4 months; 95% CIs 2.01-6.40 vs 2.80-5.00, respectively; P = .635). A subanalysis based on EGFR status was performed by the authors. In the erlotinib-treated group, median PFS in EGFR mutation–positive patients was 8.0 months, whereas it was 1.3 months in EGFR mutation–negative patients (95% CI 5.85-10.15 vs 0.26-2.35; P < .001(Table 3). The median PFS in EGFR mutation–positive patients was 8.0 months in the erlotinib-treated group but was 3.9 months in the pemetrexed-treated group (95% CI 5.85-10.15 vs 1.25-6.55; P = .032). In conclusion, erlotinib and pemetrexed may be used as second-/third-line treatment in patients with lung adenocarcinoma with asymptomatic brain metastases, and detection of EGFR mutation status is particularly important in these patients. EGFR mutation–positive lung adenocarcinoma patients with asymptomatic brain metastases showed longer PFS when treated with erlotinib as opposed to pemetrexed.

 

Liu et al⁹ selected patients with NSCLC with brain metastases who had good responses to EGFR TKI to examine the role of early brain RT on intracranial disease control and survival. The selection method was not clearly outlined and introduces the risk of substantial bias into this article. All the patients were treated with EGFR TKI monotherapy (gefitinib 250 mg 4 times daily or erlotinib 150 mg 4 times daily or icotinib 125 mg 3 times daily). One hundred thirteen patients were included, 49 (43%) treated with brain radiation therapy within 4 weeks after EGFR TKI initiation and 64 (57%) were treated with EGFR TKI alone. Among the 64 patients in the second group, 27 received salvage brain radiation therapy and only 27 were truly treated only with EGFR TKI. When the 3 groups were compared at baseline, patients with early brain RT were more likely to be symptomatic from their BMs (80% early RT vs 13% EGFR TKI alone vs 33% salvage RT, P < .001). Besides, there were more patients with a less favorable prognosis in early RT group (DS-GPA of 0-2.0: 86% early RT vs 51% EGFR TKI vs 78% deferred RT, P = .002). The median iPFS of patients with early RT was significantly longer than those without early RT (21.4 vs 15.0 months, P = .001). The effect of early brain RT on iPFS remained significant on multivariate analysis (HR 0.34 [95% CI 0.19-0.61]; P < .001). However, after salvage brain RT, the iPFS did not differ significantly between the salvage RT and early RT groups (23.6 vs 21.4 months, P = .253). No significant difference of the IC-PFS was found between the patients with salvage RT and those with EGFR TKI alone (23.6 vs 24.4 months, P = .277). The median OS for early brain RT, EGFR TKI alone, and salvage brain RT groups was 28.1 months (95% CI 17.9-38.3), 24.5 months (95% CI 20.6-28.4), and 24.6 months (95% CI 19.0-30.1), respectively (P = .604). No significant difference in OS was observed between patients with early RT and those with salvage RT (28.1 vs 24.6 months, P = .385).

 

Huang et al¹⁰ retrospectively analyzed patients with EGFR mutant NSCLC treated in a single institution between January 2018 and December 2020 in order to compare the efficacy of 2 different EGFR TKI (osimertinib and afatinib) as first-line treatment in these patients. One hundred twenty-eight patients were selected for this study. The osimertinib group included 47 patients, while 81 patients received afatinib. The median PFS was 18.8 months and 13.1 months in the osimertinib and afatinib groups, respectively (HR 0.75 [95% CI 0.48-1.18]). The median OS was not reached in the osimertinib group and was 41.7 months in the afatinib group (HR 0.79 [95% CI 0.36-1.72]). In patients with brain metastasis at baseline, the median PFS was 22.1 months in the osimertinib group, and 10.9 months in the afatinib group (adjusted HR 0.45 [95% CI 0.21-0.96]). Their research demonstrates that there was no compelling evidence showing that patients taking osimertinib as first-line treatment experienced longer median PFS and OS than patients treated with afatinib. However, there was a statistical significance revealing that osimertinib provided better median PFS than afatinib in patients with brain metastasis at baseline.

 

Chiu et al¹¹ designed a retrospective study to analyze patients with EGFR mutant NSCLC with brain metastasis who received first-line EGFR TKI (erlotinib or gefitinib) monotherapy or with bevacizumab. During the period of 2014 to 2019, 310 patients were identified and included in the study in which 267 (86.1%) patients received the treatment of single-agent EGFR TKI and 43 (13.9%) patients received the treatment of EGFR TKI plus bevacizumab. Patients receiving EGFR TKI and bevacizumab were significantly younger and had better performance status and with high incidence of brain metastasis (55.8%). In the propensity-score matched cohort, PFS (13.5 vs 13.7 months; log-rank P = .700) was similar between the 2 groups. The OS (61.3 vs 34.2 months; log-rank P = .010) and risk reduction of death (HR 0.42 [95% CI 0.20-0.85]; P = .017) were significantly improved in EGFR TKI plus bevacizumab group. Analysis of treatment by brain metastasis status demonstrated EGFR TKI plus bevacizumab in patients with brain metastasis was associated with significant OS benefit compared with other groups (log-rank P = .030) and these patients had lower early CNS and early systemic progressions.

 

Fan et al¹² conducted a retrospective study to compare upfront RT combined with icotinib to icotinib alone as first-line therapies for patients with EGFR-mutant NSCLC and BM. A total of 152 patients with metastatic EGFR-mutant adenocarcinoma with BM who were diagnosed and received icotinib therapy between October 2011 and October 2014 were identified. Of these, 55 patients were excluded and 97 included. A total of 56 of 97 patients received RT for treatment of brain metastases, while 41 patients received TKI therapy alone. Surgical resection preceded RT in 9 patients. RT was delivered with either localized SRS (Gamma Knife) or WBRT. There was no difference in OS between the RT followed by icotinib group and the icotinib alone group (31.9 vs 27.9 months, P = .237), and similar results were found in the SRS subgroup (35.5 vs 27.9 months, P = .12). Intracranial PFS was improved in the patients who received RT followed by icotinib compared with those receiving icotinib alone (22.4 vs 13.9 months, P = .043).

 

Wang et al¹³ retrospectively reviewed patients with EGFR mutant patients treated in a single institution from January 2010 to December 2016 to compare the role of upfront RT in association to EGFR TKI versus target therapy alone. in these patients.¹³ Among the 93 patients included, 53 patients received upfront RT and TKI and 40 patients received TKI only. The upfront RT group showed lower intracranial progression risk with adjusted SHR 0.38 (95% CI 0.19-0.75, P = .006) and longer median time to sPFS (15.6 vs 8.9 months, P = .009). After the salvage RT, upfront RT did not prolong the median time to SST (23.6 vs 18.9 months, P = .862) and OS (median time, 35.4 vs 35.8 months, P = .695) compared with TKI alone. The authors concluded that compared with upfront intracranial RT, the salvage RT to oligo-progressive disease allowed patients receiving TKI to have similar time on initial TKI and OS despite worse iPFS. The best timing of intracranial RT remains to be further verified.

 

Jiang et al¹⁴ aimed to evaluate if EGFR TKI plus WBRT provide a better survival benefit than EGFR TKIs alone in patients with NSCLC with EGFR mutation and brain metastases. Two hundred thirty patients were included, 116 patients received EGFR TKIs alone (as first-line therapy in 91 cases) and 51 patients received EGFR TKIs plus WBRT therapy (as first-line treatment in 30 cases). Compared with TKIs alone, EGFR TKIs plus WBRT did not have superior intracranial PFS (6.9 vs 7.4 months, P = .232) and systemic PFS (7.5 vs 7.9 months, P = .546) but was associated with worse OS (21.6 vs 26.4 months, P = .049) in NSCLC with EGFR mutation and BM. The authors concluded that the addition of WBRT to EGFR TKIs did not appear to have survival benefit superior to that of EGFR TKIs alone in with EGFR mutant NSCLC with BM. WBRT also did not bring additional benefit to chemotherapy in patients with BM and EGFR of wild-type or unknown status.

 

Yang et al¹⁵ led a multicentered (17 institutions), open-label, randomized clinical trial including patients with EGFR mutated NSCLC and multiple brain metastases (≥3 lesions), who were naïve to treatment with EGFR TKI or radiation therapy. The participants were randomly assigned in a 1:1 ratio to either chemotherapy plus icotinib 125 mg orally (3 times per day) or chemotherapy plus WBRT (30 Gy in 10 fractions of 3 Gy). Groups were stratified by EGFR gene mutation status, treatment line (first or second), brain metastases only versus both intracranial and extracranial metastases, and presence or absence of symptoms of intracranial hypertension. Between December 2012 and June 2015, 176 participants were assigned to treatment: 85 to icotinib and 91 to WBRT. Median intracranial PFS was 10.0 months (95% CI 5.6-14.4) with icotinib versus 4.8 months (2.4-7.2) with WBRT (equating to a 44% risk reduction with icotinib for an event of intracranial disease progression or death; HR 0.56 [95% CI 0.36-0.90]; P = .014). The authors concluded that in patients with EGFR-mutant NSCLC and multiple brain metastases, icotinib was associated with significantly longer intracranial PFS than WBI plus chemotherapy, indicating that icotinib might be a better first-line therapeutic option for this patient population.

 

Chen et al¹⁶ proposed a study to compare the outcomes of first‐line EGFR TKI alone with EGFR TKI plus WBRT for the treatment of BM in patients with EGFR‐mutated lung adenocarcinoma. A total of 1665 patients were screened from 2008 to 2014, and 132 were enrolled in our study.¹⁶ None of the patients had received previous systemic therapy. All patients included in this analysis received 250 mg gefitinib or 150 mg erlotinib orally once daily. Among the 132 patients, 97 (73.5%) showed multiple intracranial lesions, and 67 (50.8%) had asymptomatic BM. Seventy‐nine patients (59.8%) were treated with EGFR TKI alone, 53 with concomitant WBRT. The intracranial objective response rate was significantly higher in the EGFR TKI plus WBRT treatment group (67.9%) compared with the EGFR TKI alone group (39.2%, P = .001). The median intracranial time to progression was 24.7 months (95% CI 19.5-29.9) in patients who received WBRT, which was significantly longer than in those who received EGFR TKI alone, with the median intracranial time to progression of 18.2 months (95% CI 12.5-23.9, P = .004). There was no significant difference in OS between WBRT and EGFR TKI alone groups (median 48.0 vs 41.1 months; P = .740). OS is significantly prolonged in patients who had an intracranial time to progression exceeding 22 months compared with those who developed intracranial progression <22 months after treatment (median 58.0 vs 28.0 months; P = .001). The authors concluded that for patients with EGFR mutated lung adenocarcinoma with BM treatment with concomitant WBRT achieved a higher response rate of BM and significant improvement in intracranial PFS compared with EGFR TKI alone.

 

Magnuson et al¹⁷ conducted a multi-institutional (6 institutions) analysis to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not previously received EGFR-TKI. Patients were divided into 3 groups: SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT.¹⁷ Of the 351 patients, 131 (37%) received EGFR-TKI followed by SRS or WBRT at intracranial progression, 120 (34%) were treated with WBRT followed by EGFR-TKI, and 100 (29%) received SRS followed by EGFR-TKI. Baseline comparison among the 3 groups demonstrated that patients who received upfront EGFR-TKI were less likely to have symptomatic brain metastases (12% EGFR-TKI vs 51% WBRT and 49% SRS; P < .001) and were more likely to have brain metastases ≤1 cm (66% EGFR-TKI vs 35% WBRT and 44% SRS; P < .001). Patients who received upfront WBRT were more likely to have a less favorable prognosis (ds-GPA of 0-1.5; 75% WBRT vs 59% EGFR-TKI and 52% SRS; P = .001) and have >10 brain metastases (37% WBRT vs 15% EGFR-TKI and 7% SRS; P < .001). Patients treated with upfront EGFR-TKI and upfront WBRT were more likely to be stage IV at diagnosis (91% EGFR-TKI and 92% WBRT vs 80% SRS; P = .014). In terms of outcomes, the median OS for the upfront SRS, WBRT, and EGFR-TKI groups was 46 months (95% CI 37-57), 30 months (95% CI 27-38), and 25 months (95% CI 20-28), respectively (log-rank P < .001). OS at 2 years for the upfront SRS, WBRT, and EGFR-TKI groups was 78% (95% CI 66-85%), 62% (95% CI 52-70%), and 51% (95% CI 42-60%), respectively. After controlling for significant covariables in a multivariable model, upfront SRS was independently associated with improved OS relative to EGFR-TKI (adjusted HR 0.39 [95% CI 0.26-0.58]; P < .001). Upfront WBRT was also associated with improved OS relative to EGFR-TKI (adjusted HR 0.70 [95% CI 50-98%]; P = .039). They concluded that their analysis demonstrated that the use of upfront EGFR-TKI and deferral of radiation therapy is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.

 

Cheng et al¹⁸ aimed to define the ideal EGFR TKI treatment when combined to SRS for patients with BM from NSCLC EGFR mutated tumors. The authors conducted a retrospective study comparing 3 EGFR‐TKIs (gefitinib, erlotinib, or afatinib) as first‐line therapy between January 2012 and October 2019. A total of 150 patients were enrolled during the period determined: 37 were treated with gefitinib, 76 with erlotinib, and 37 with afatinib. Significantly longer PFS was noted among those patients who received afatinib as first‐line therapy (gefitinib vs erlotinib vs afatinib: 8.4 vs 10.6 vs 12.1 months, P = .042). Afatinib or erlotinib as first‐line treatment significantly reduced mortality compared with gefitinib (HR 0.521, P = .004). The addition of local therapy with SRS provided patients with better outcomes (HR 0.531, P = .014), and patients treated with EGFR‐TKI plus SRS had increased median OS than those without SRS (39.4 vs 24.8 months; P = .002). Patients were divided into 2 groups to identify potential differences in the benefits of additional treatment (Lung‐mol GPA ≥3 and Lung‐mol GPA <3). The Lung-mol GPA system consists of 5 factors: age, Karnofsky performance status (KPS), extracranial metastases (ECM), number of BM, and gene status. The median OS for patients with Lung‐mol GPA ≥3 who received EGFR‐TKI plus SRS was longer than for those treated with EGFR‐TKI without SRS (44.9 vs 26.7 months, P = .005). However, no significant difference in OS was observed between patients with Lung‐mol GPA <3 who received EGFR‐TKI plus SRS and those who received EGFR‐TKI without SRS (30.2 vs 22.2 months, P = .309). Patients who received antiangiogenetic agents appeared to have longer OS than those without antiangiogenetic treatment in the univariate analysis (HR 0.454, P = .044). However, no significant difference in OS was observed after multivariate analysis (HR 0.579, P = .169). The authors demonstrated that patients with EGFR‐mutant NSCLC with BMs could be precisely treated with SRS according to Lung‐mol GPA ≥3. Sequential osimertinib was associated with prolonged survival, regardless of T790M status.

 

Wang et al¹⁹ assessed the factors that impact the prognosis of patients with EGFR-mutated NSCLC and BMs. The authors retrospectively reviewed the charts of consecutive patients with EGFR-mutated NSCLC diagnosed between January 2011 and December 2014 at a single institution. From 560 patients with NSCLC who underwent radical resection and EGFR mutation testing, 113 (20.2%) with exon 19 deletion and exon 21 L858R missense mutation of EGFR and developed BMs as the first progression were included in this study. All cases were adenocarcinomas. The proportion of patients with a complete or partial response after BM was significantly different across the treatment groups (P < .05). The proportion of CR + PR was 63.0% (17/27) for radiation therapy, 26.7% (4/15) for chemotherapy, 50.0% (7/14) for targeted therapy, and 89.7% (35/39) for targeted therapy combined with radiation therapy. The median survival of the 4 treatments was 20, 9, 12, and 25 months after BMs, respectively (P = .001). Multivariable analysis showed that <3 BMs (OR = 3.34 [95% CI 1.89-5.91], P < .001) and treatment after BMs (OR = 0.68 [95% CI 0.54-0.85], P = .001) were independently associated with better prognosis.

 

Synthesis for Targeted Therapy for EGFR-Mutant NSCLC

One class I study provided data that icotinib plus radiation for newly diagnosed with ≥3 brain metastases from EGFR-mutant NSCLC provided superior control of those metastases compared with icotinib plus cytotoxic chemotherapy. Though of interest, icotinib is not available in the United States. Similar second-generation agents, e.g., afatinib and dacomitinib, have not been assessed in the exact same manner but when done in less well-designed studies have not provided class I data. A series of qualifying articles provide class III data suggesting the addition of ≥1 EGFR TKIs to radiation in the form of WBRT or SRS provided survival and intracranial disease control benefits. The study populations, agents used, and radiation treatment paradigms used varied enough from study to study that a strong recommendation of one or another TKI or type of radiation could not be formulated. Studies comparing one targeted agent to another were unable to demonstrate superiority of any single agent. Taken together, these data support a level I recommendation that states that in subjects with ≥3 untreated brain metastases from EGFR mutant NSCLC, the use of icotinib and WBRT is recommended to improve intracranial PFS. Additionally, a level III recommendation can be formulated stating that in subjects with brain metastases from EGFR mutant NSCLC the addition of EGFR tyrosine kinase inhibitors to radiation therapy in the form of WBRT or SRS is suggested to improve OS, PFS, and intracranial PFS.

 

Recommendations

 

Level I: In subjects with ≥3 untreated brain metastases from EGFR mutant NSCLC the use of icotinib and WBRT is recommended to improve intracranial PFS.

 

Level III: In subjects with brain metastases from EGFR mutant NSCLC the addition of EGFR TKIs to radiation therapy in the form of WBRT or SRS is suggested to improve OS, PFS, and intracranial PFS.

 

Targeted Therapy for the Treatment of ALK Mutation Positive NSCLC Parenchymal Brain Metastases

 

The FDA has approved 5 ALK inhibitors for the treatment of ALK mutation positive NSCLC parenchymal brain metastases (alectinib, lorlatinib, brigatinib, ceritinib and crizotinib). Chen et al²⁰ published a study to explore the relationship between ALK fusion status and metastasis sites. A total of 291 patients with advanced NSCLC (ALK⁺, n = 97; both ALK and EGFR^–, n = 194) were enrolled. The occurrence of brain metastasis in patients with ALK‐positive NSCLC was significantly higher than double‐negative ones both at baseline (26.5% vs 16.5%, P = .038) and during treatment (25.8% vs 11.9%, P = .003), but opposite for pleural effusion (6.2% vs 26.9%, P < .001 at baseline; 3.1% vs. 10.3%, P = .031 during treatment). Among the 97 patients with ALK‐positive NSCLC, 53.6% used crizotinib, whereas 37.1% only received chemotherapy and 9% received supportive care. Usage of crizotinib prolonged PFS compared with chemotherapy in patients with ALK‐positive NSCLC (median PFS 17.6 m vs. 4.8 m, P < .001).

 

Yin et al²¹ performed a retrospective study to compare the effectiveness of alectinib or crizotinib, together with intracranial therapies in patients with untreated ALK⁺ NSCLC. A total of 34 patients with ≤3 intracranial metastases were included. Of these patients, 13 received oral alectinib 600 mg twice daily, and 21 received oral crizotinib 250 mg twice daily, until progressive disease, unacceptable toxicity, or death. All intracranial metastases were treated with craniotomy, CyberKnife, or both. Median overall PFS was 32.8 months (95% CI 24.4-41.2 months) in patients treated with alectinib and 8.0 months (95% CI 7.3-8.7 months) in patients treated with crizotinib (HR 0.007 [95% CI 0.000-0.258], P < .001). Median PFS of brain lesions was not yet reached with alectinib (95% CI 30.1 months-not estimated) and was 8.5 months (95% CI 7.2-12.3 months) with crizotinib (HR 0.007 [95% CI 0.000-0.558], P < .001). Median OS was not yet reached with alectinib (95% CI 31.0 months-not estimated) and 30.3 months (95% CI 27.3-37.1 months) with crizotinib (HR 0.141 [95% CI 0.032-0.625], P = .003). Compared with crizotinib, alectinib showed superior efficacy and lower toxicity in the treatment of ALK⁺ NSCLC and symptomatic and synchronic brain metastases. The inclusion of intracranial therapies such as craniotomy or CyberKnife further improved the brain PFS and OS of these patients.

 

Gadgeel et al²² also compared alectinib to crizotinib in patients with untreated ALK⁺ NSCLC. However, the authors aimed to analyze the outcomes, specifically in the CNS.²² Patients ≥18 years of age underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points included PFS, CNS objective response rate (ORR), and time to CNS progression. In total, 122 patients were included (alectinib, n = 64; crizotinib, n = 58). Time to CNS progression was significantly longer with alectinib versus crizotinib (P < .0001) for patients with and without baseline CNS metastases. CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiation therapy and 78.6% versus 40.0%, respectively, in those who had not. The authors concluded that alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK⁺ NSCLC, irrespective of previous CNS disease or radiation therapy.

 

Thomas et al²³ led a multi-institutional retrospective analysis aimed in comparing outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases. The 2 treatment groups were compared for both EGFR- and ALK-positive cohorts. Outcome variables included time to progression, time to intracranial progression, and time to treatment failure, measured from the date of initiation of CNS-penetrant TKI therapy. A total of 147 patients were included (EGFR n = 94, ALK n = 52, both n = 1). There were no significant differences between TKI and CNS radiation therapy plus TKI groups for any of the study outcomes, including time to progression (8.5 vs 6.9 mo, P = .13 [EFGR] and 11.4 vs 13.4 mo, P = .98 [ALK]), time to intracranial progression (14.8 vs 20.5 mo, P = .51 [EGFR] and 18.1 vs 21.8 mo, P = .65 [ALK]), or time to treatment failure (13.8 vs 8.6 mo, P = .26 [EGFR] and 13.5 vs 23.2 mo, P = .95 [ALK]). The authors concluded their data provides preliminary evidence that intracranial activity of CNS-penetrant TKIs may enable local radiation to be deferred in appropriately selected patients without negatively affecting progression.

 

Shaw et al²⁴ conducted a multicentric (104 centers) randomized (in a 1:1 ratio) phase 3 trial comparing lorlatinib with crizotinib in patients with advanced ALK⁺ NSCLC who had received no previous systemic treatment for metastatic disease. Patients with asymptomatic treated or untreated CNS metastases were eligible. A total of 296 were randomized, 149 to the lorlatinib group and 147 to the crizotinib group. The percentage of patients who were alive without disease progression at 12 months was 78% (95% CI 70%-84%) in the lorlatinib group and 39% (95% CI 30%-48%) in the crizotinib group (HR for disease progression or death 0.28 [95% CI 0.19-0.41]; P < .001). An objective response occurred in 76% (95% CI 68%-83%) of the patients in the lorlatinib group and 58% (95% CI 49%-66%) of those in the crizotinib group; among those with measurable brain metastases, 82% (95% CI 57%-96%) and 23% (95% CI 5%-54%), respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response. In conclusion, for patients with previously untreated advanced ALK⁺ NSCLC, those who received lorlatinib had significantly longer PFS and a higher frequency of intracranial response than those who received crizotinib.

 

Synthesis for Targeted Therapy of ALK Mutation Positive NSCLC

Manuscripts providing class I and class II evidence support the use of alectinib in untreated brain metastases secondary to ALK mutation positive NSCLC. Additionally, there is class II evidence to support the use of lorlatinib in untreated brain metastases secondary to ALK mutation positive NSCLC. Qualifying manuscripts addressing other agents targeted to this mutation provide class III evidence their superiority over standard cytotoxic agents and suggest positive benefits in terms of systemic control but differences in study approach and data analysis do not clearly allow formulation of a recommendation. Based on this information, a level I recommendation stating that in patients with ALK mutation positive NSCLC with untreated brain metastases the use of alectinib be used to delay time to intracranial tumor progression. Also, a level II recommendation can be formulated stating that in patients with untreated brain metastases from ALK⁺ NSCLC lorlatinib can be used to prolong intracranial tumor control and improve overall PFS.

 

Recommendations

Level I: In patients with ALK mutation positive NSCLC with untreated brain metastases the use of alectinib is recommended to delay time to intracranial tumor progression.

 

Level II: In patients with untreated brain metastases from ALK mutation positive NSCLC lorlatinib is recommended to prolong intracranial tumor control and improve overall PFS.

 

Targeted Therapy for the Treatment of NSCLC Parenchymal Brain Metastases Not Assessed the EGFR and ALK Mutation Status

Yang et al²⁵ performed a retrospective analysis of 228 patients treated between 2008 to 2014 who had previously been allocated into 1 of the following 3 groups: bevacizumab + gefitinib + WBRT (group 1), gefitinib + WBRT (group 2), and WBRT (group 3). The number of patients included in each group was 76, 77, and 65; the number of patients who were EGFR mutation negative was 43, 40, and 38 in groups 1, 2, and 3, respectively. The 3 groups were compared on the rate of partial response (71.1% vs 62.3% vs 38.7%, P < .05), progressive disease rate (3.9% vs 11.7% vs 26.7%, P < .05), response rate (80.3% vs 70.1% vs 44%, P < .05), and disease control rate (96.1% vs 83.1% vs 60%, P < .05). However, there was no difference in terms of complete response (P = .657) or disease stability (P = .843).

 

Tian et al²⁶ performed a retrospective study including stage IV NSCLC with brain metastases that had been treated with pemetrexed-platinum (PP) alone or PP + bevacizumab as the first line of treatment. The EFGR status was evaluated, but no TKIs were prescribed as the first line of therapy.²⁶ The authors found 71 patients eligible for the study in the period of 2013 to 2017. Twenty-six patients were allocated to the PP + bevacizumab group and 45 were allocated to the PP group. Regarding EGFR status, there was no difference in the rate of positive EGFR mutation between groups (P = .527). Overall response rates (ORRs), disease control rates (DCRs) of the thoracic tumors, and intracranial metastases and OS were not significantly different between the 2 groups. However, PFS and intracranial PFS were significantly prolonged in the PP + bevacizumab group compared with the PP group. The median PFS was 9.2 and 8.2 months, and the 1-year PFS rates were 47.1% and 15.9%, respectively, in the 2 groups (P = .029). The median intracranial PFS were 24.3 and 10.9 months, and the 1-year intracranial PFS rates were 80.1% and 40.1%, respectively, in the 2 groups (P = .008). The authors concluded that the addition of bevacizumab to the first-line pemetrexed and platinum significantly improved clinical outcomes of patients with advanced adenocarcinoma NSCLC and brain metastases.

 

Li et al²⁷ performed a single-institution study to compare PP chemotherapy with or without bevacizumab as first-line treatment for patients with stages IIIB-IV NSCLC. The authors included patients with and without BM in the analysis. Data from 233 patients were revised and included in the analysis, with 136 patients in the PP group and 97 patients in the PP + bevacizumab group. The 2 groups had no difference in terms of sex, age, stage, performance status, and EGFR mutation status. However, they differed in the number and percentage of patients with brain metastases: n = 47 (34.46%) in the PP group and n = 15 (15.46%) in the PP + bevacizumab group. In the overall population, the median PFS was significantly longer in the PP + bevacizumab group than in the PP group (10.97 vs 6.67 months; P = .0002). Similarly, the ORR was improved in the PP + bevacizumab group (63.92% vs 20.74%; OR 7.63; P < .0001). Consistently, intracranial remission in patients with brain metastases was significantly improved in the PP + bevacizumab group, with a higher ORR (66.67% vs 22.22%; P = .0045). In the subgroup with brain metastases, the median PFS in the PP + bevacizumab group was 9.79 months compared with 6.21 months in the PP group (HR 0.569; P = .115). They concluded that their data further support the concept that PP + bevacizumab could be an effective and tolerable regimen in patients with advanced NS-NSCLC.

 

Li et al²⁸ performed a single-institution prospective study of patients with multiple brain metastases from NSCLC who were admitted from December 2016 to October 2018. All patients were routinely given corresponding chemotherapy. However, the patients were treated either with radiation therapy alone (control group) or radiation therapy associated with EGFR TKI (gefitinib) and anti-VEGF (endostar, approved for use in China), which was the study group. A total of 87 patients were included, of which 40 patients were in the control and 47 patients were in the study group. The objective remission rate and the disease control rate in the research group were 46.81% and 89.36% respectively, which were significantly higher than those in the control group (22.50% and 67.50%, P < .050). Comparing the surviving patients in the 2 groups, there was no difference in survival at 6 months of follow-up (P > .050), but there was a significant higher survival in the study group at 12 months of follow-up (P < .050).

 

Sun et al delineated a randomized clinical trial of patients with NSCLC and brain metastasis and compared the outcomes of patients receiving chemotherapy and radiation therapy (control group) and patients receiving target therapy (gefitinib) and WBRT (study group).²⁹ Fifty-eight patients were admitted between October 2016 and October 2017 were randomly divided into a control group and a study group, 29 cases in each group. The disease control rate of the study group was 68.97%, significantly higher than 41.38% of the control group (P < .05); the total incidence of adverse reactions in the study group was 6.90%, significantly lower than 24.14% of the control group (P < .05); the median survival time of the study group was (16.81 ± 5.32) months, significantly longer than that of the control group (9.76 ± 3.25 months). The 1- and 2-year survival rates in the study group were significantly higher than those in the control group (P < .05). They concluded that WBRT combined with targeted therapy is superior to concurrent radiation therapy and chemotherapy in the treatment of NSCLC with brain metastasis and has high safety. It can effectively prolong the life span of patients.

 

Cho et al³⁰ performed a study aiming to evaluate the OS and complication rate of patients with NSCLC with BM that had been treated with Gamma Knife Radiosurgery (GKRS) alone or in association to immunotherapy or targeted therapy. The authors did not assess the EGFR or ALK mutation status. A retrospective review of NSCLC treated with GKRS identified a total of 488 patients that were enrolled in the study. Ninety patients were included in the immunotherapy group, receiving 1 of the following medications: nivolumab, pembrozilumab, atezolizumab, or durvalumab. Seventy-two patients included in the targeted therapy group received 1 of the following medications: erlotinib, gefitinib, afatinib, alectinib, crizotinib, osimertinib, nintedanib, brigatinib, or ceritinib. Twenty-four patients received a nonspecified combination of immunotherapy and targeted therapy and 286 received GKRS alone. After the first GKRS, the estimated median survival was 9.9 months (95% CI 8.3-11.4 months). Patients with concurrent immunotherapy or targeted therapy presented a significantly longer survival than patients with GKRS alone (P < .001). These significant differences in the survival remained after adjustment for KPS, recursive partitioning analysis (RPA) class, sex, and multiple BMs. Of note, there were no statistically significant differences among groups in the occurrence of radiation reaction, radiation necrosis, or intralesional hemorrhage.

 

Yomo et al³¹ conducted a study aiming to investigate the influence of EGFR TKI in terms of efficacy and toxicity for patients with NSCLC with BM that had been treated with GK. The authors reassessed a database that collected data about GK in patients with NSCLC with BM, in order to filter the patients that had been treated with EGFR TKI concurrently or during the post-GK clinical course. Among the 1194 patients registered in the primary database, 608 patients were lung adenocarcinoma and 238 of them had received EGFR TKI. The authors performed a propensity score matching to determine the impact of this therapy in the outcome. After performing this matching, there were 200 patient pairs with/without post-SRS EGFR-TKI use. When both groups were compared, EGFR-TKI use was associated with longer OS (median 25.5 vs 11.0 months, HR 0.60 [95% CI 0.48-0.75], P < .001). Distant intracranial recurrence was more likely in patients receiving EGFR-TKI (HR 1.45 [95% CI 1.12-1.89], P = .005). Neurological death, local recurrence, and SRS-related adverse event rates did not differ significantly between the 2 groups.

 

Chabot et al³² led a global phase 2, randomized, double blinded, multicenter study to evaluate WBRT in combination with veliparib or placebo in patients with brain metastases from NSCLC. The EGFR and ALK mutation status were not assessed in these patients. The patients were randomly assigned to 1 of 3 groups: WBRT + placebo (group 1), WBRT + veliparib 50 mg twice daily (group 2) or WBRT + veliparib 200 mg twice daily (group 3). In total, 307 patients were enrolled, 102 assigned to group 1, 103 to group 2, and 102 to group 3. Baseline characteristics of the patients were generally well balanced among the treatment groups. The median OS was 185 days for patients treated with WBRT plus placebo, 209 days for WBRT plus 50 mg veliparib (P = .927 vs placebo), and 209 days for WBRT plus 200 mg veliparib (P = .905 versus placebo). There was no significant difference in OS between either of the WBRT plus veliparib (50 or 200 mg) arms and the WBRT plus placebo arm. Evaluation of secondary end points (tumor response rate, time to clinical brain metastases progression, and time to intracranial radiographic progression), also did not identify any significant differences between either of the veliparib (50 mg vs 200 mg) plus WBRT arms and the placebo plus WBRT arm.

 

Synthesis for Targeted Therapy for NSCLC Not Assessed for EGFR and ALK Mutation Status

Class I evidence supports the use of gefitinib with radiation therapy over the use of cytotoxic chemotherapy with radiation in providing better OS. In support of this, class III data from studies designed in various manners also support gefitinib contributing positively to OS. Three class III studies suggest that the addition of bevacizumab to either targeted therapy in the form of gefitinib or the combination of pemetrexed and platinum compounds improves CNS control and to a lesser extent PFS and OS. Well-done studies, be they positive or negative, are of value and it should be noted that class I data suggest that veliparib contribute no value to survival or local disease control when added to radiation therapy. These data warrant a level I recommendation about the use of gefitinib for patients with newly diagnosed brain metastases secondary to NSCLC to improve tumor control in the brain and in survival. In addition, a level III recommendation can be formulated stating that in select circumstances bevacizumab may have a role in improving local tumor control and survival.

 

Recommendations

Level I: It is recommended that for patients with newly diagnosed brain metastases secondary to NSCLC not assessed for EGFR and ALK mutations, and for whom WBRT is indicated, gefitinib be added to the treatment regimen to obtain improved local tumor control and improved OS.

 

Level III: For individuals with brain metastases secondary to NSCLC not assessed for EGFR and ALK mutations and for whom targeted therapy in the form of gefitinib or the combination of pemetrexed and platinum compounds are indicated, it is suggested that bevacizumab, when not contraindicated by other underlying medical conditions, be added to the treatment regimen to improve CNS control and to a lesser extent PFS and OS.  

 

Targeted Therapy for the Treatment of EGFR Mutation Negative, ALK Mutation Negative NSCLC Parenchymal Brain Metastases

 

He et al³³ performed a case control study of patients with NSCLC with brain metastasis and non-EGFR/ALK/ROS1-TKIs indication. The groups analyzed were anlotinib + cranial radiation therapy versus cranial radiation therapy alone.³³ During the period of 2016 to 2020, 73 patients were identified (45 patients received cranial radiation therapy alone, and 28 patients received cranial radiation therapy + anlotinib). There was no significant difference in clinical features between the 2 groups (P > .05). Compared with the cranial radiation therapy only group, the combined group had longer intracranial PFS (median 3.0 months vs 11.0 months, P = .048). However, there were no significant differences in OS, extracranial PFS, and systemic PFS. For clinical features, univariate and multivariate analysis showed that the anlotinib treatment was an independent advantage predictor of intracranial PFS (HR 0.51 [95% CI 0.27-0.95]; P = .04), and age ≥57 years (HR 1.04 [95% CI 1.01-1.08], P = .014) and KPS score ≤80 (HR 1.04 [95% CI 1.01-1.08], P = .014) were independent disadvantage predictors of OS (P < .05). The authors concluded that anlotinib can improve the intracranial lesion control and survival prognosis of NSCLC patients with cranial radiation therapy.

 

Ren et al³⁴ retrospectively reviewed 34 patients with symptomatic multiple brain metastases from NSCLC (>4, and at least 1 measurable brain metastasis lesion with cerebral edema) in order to evaluate the effects and safety of apatinib (125 mg or 250 mg oral dose once daily) combined with WBRT in comparison to WBRT alone. Thirteen cases received apatinib combined with WBRT and 21 cases received chemotherapy combined with WBRT. The apatinib combination group reduced the volume of intracranial tumors, peritumoral brain edema and total steroid dosage used. It was associated with a better intracranial objective response rate (84.6% vs 47.6%, P = .067) and longer median intracranial PFS (6.97 vs 4.77 months; P = .014). There was no significant difference in median OS (7.70 vs 6.67 months; P = .14) between the 2 groups. Apatinib plus WBRT is well tolerated and may be a potential choice for patients with relapsed or drug-resistant advanced NSCLC with symptomatic multiple brain metastases and peritumoral brain edema.

 

Synthesis of Targeted Therapy for EGFR Mutation Negative, ALK Mutation Negative NSCLC

Two class III studies suggest that the addition of TKI to radiation therapy (eg, SRS or WBRT) improves CNS control and to a lesser extent OS. These data warrant a level I recommendation about the use of TKI for patients with newly diagnosed brain metastases secondary to NSCLC to improve tumor control in the brain and in survival. In addition, a level III recommendation can be formulated stating that in selected circumstances, TKI may have a role in improving local tumor control and survival.

 

Recommendations

Level III: For individuals with brain metastases secondary to NSCLC that are EGFR and ALK mutation negative and for whom targeted therapy in the form of TKI are indicated, it is suggested that TKI, when not contraindicated by other underlying medical conditions, be added to the treatment regimen, including radiation therapy, to improve CNS control and to a lesser extent PFS and OS.

 

Targeted Therapy for the Treatment of Melanoma Parenchymal Brain Metastases

The 9 qualifying articles all provided class III evidence, primarily because they were retrospective collections of cases with concurrent or historical controls, or no comparisons provided. Details of the qualifying and informative article data are available in the Evidence Table (Table 2). In an attempt to provide some cohesiveness, this discussion is subdivided into groups of articles with relatively common treatment themes.

 

All studies aimed to analyze the impact of adding BRAF kinase inhibitor (BRAFi) to SRS in patients with metastatic melanoma to the brain, evaluating different outcomes such as local control, response to SRS, development of new lesions in the brain, PFS, and OS.

 

Mastorakos et al³⁵ published a multicentric retrospective study including 198 patients with brain metastatic melanoma, divided in 3 groups: group A patients had confirmed BRAFV600 mutation but did not receive BRAFi after diagnosis of BM.³⁵ Group B patients had confirmed BRAFV600 mutation and were treated with therapeutic doses of BRAFi. All patients who received dabrafenib received adjuvant MEK inhibitor. Group C patients were those with wild-type BRAF protein status. All patients in this study were treated with SRS. There was no statistically significant difference in extracranial disease burden between groups. These authors concluded a BRAF mutation is an independent predictor of better prognosis in patients with melanoma BM that underwent BRAFi associated to SRS. Importantly, the effect of BRAFi was significantly affected by the timing of administration and appears to have optimal effect when treatment is initiated at least 1 week after SRS. They also found that the use of BRAFi may increase the risk of ICH. Furthermore, they found that the effectiveness of PD-1 inhibitors in patients with melanoma BM who undergo SRS was more pronounced in BRAF wild-type (negative) patients.

 

Xu et al³⁶ performed a similar study, including 65 patients diagnosed with metastatic melanoma to the brain. All received SRS. Patients were divided into 3 groups: group A, those with mutant BRAF without BRAFi treatment (13 patients); group B, those with mutant BRAF with BRAFi treatment (17 patients); and group C, those with wild-type BRAF (35 patients).³⁶ The objective of this study was to examine the impact of BRAF mutation status and use of BRAFi in conjunction with SRS in terms of median survival and local control. Median survival times after the diagnosis of melanoma BM and after SRS were favorable in patients with a BRAF mutation and treated with SRS in conjunction with BRAFi (group B) compared with the patients with wild-type BRAF (group C, 23 vs 8 months and 13 vs 5 months, respectively; P < .01, log-rank test). SRS provided a local tumor control rate of 89.4% in the entire cohort of patients. Furthermore, the local control rate was improved in the patients treated with SRS in conjunction with BRAFi (group B) compared with patients with wild-type (group C) or with BRAF

mutation but no BRAFi (group A) as an adjunct treatment for BMs. According to this author’s findings, BRAF mutation status plays a significant role as a potent prognostic factor in patients harboring melanoma BM. BRAFi in conjunction with SRS benefits this group of patients.

 

Gorka et al³⁶ designed a case-controlled study, including 30 patients with BRAF mutated melanoma with brain metastasis diagnosed between 2014 to 2017 that were treated with BRAFi (dabrafenib) and compared with a control group of 204 patients treated with local radiation therapies (SRS or WBRT) and/or chemotherapy, between 2003 and 2015. The goal of this study was to compare OS and PFS between these 2 groups. Intracranial disease control rate (DCR) was 83% including 4 (13%) complete remissions (CRs), 9 (30%) partial remissions (PRs) and 12 (40%) stable diseases (SDs) in contrast to 5 (17%) progressive diseases (PDs). Median follow-up was 14 months, and median PFS and OS were 5.5 months and 8.8 months, respectively. If calculated from BM onset, the OS turned to be 11.8 months on the dabrafenib arm, while it was 6.0 months in the control arm (HR 0.45, P = .0014). The authors concluded that their analysis succeeded in confirming that dabrafenib had therapeutic effect on BM from melanoma in patients with BRAF mutation. Both PFS and OS improved with the use of dabrafenib, the significant OS improvement was demonstrated even by our comparative analysis versus local therapies and/or chemotherapy.

 

Wolf et al³⁷ performed a study to compare the PFS and OS in patients with BRAF mutant versus BRAF wild type. All 35 patients in the BRAF mutant group received BRAFi (dabrafenib, vemurafenib, or dabrafenib/trametinib combination therapy) either before or after SRS.³⁷ The 45 patients with BRAF-WT disease were treated most commonly with immunotherapies, other targeted therapies, or chemotherapy. The groups did not differ with respect to previous surgery or WBRT, RPA class, or extent of disease. As well, no significant differences were seen between groups for total number treated metastases, total number of SRS procedures, or total tumor volume. There was no significant difference in overall local control between BRAF-M on a BRAFi (94.6% ± 20.8%) and BRAF-WT (90.8% ± 25.2%) groups (P = .51). The time to progression/new metastasis was significantly longer for the patients with a BRAF-M treated with a BRAFi (median 3.9 months, range 0.8-16.6 months) compared with BRAF-WT patients (median 1.7 months, range 0.4-9.3 months) (P = .02). The median survival was 11.2 months (95% CI 5.3-17.0 months) for the BRAF-M group on an inhibitor and 4.5 months (95% CI 2.5-6.5 months) for the BRAF-WT group from the time of SRS (log-rank, P = .03). Thus, the authors concluded patients with BRAF-mutation treated with both SRS and BRAF inhibitors, at or after SRS, have increased OS from the time of SRS.

 

Forschner et al³⁸ reported the outcomes OS and brain control (BC) in patients with metastatic brain melanoma (MBM) in 108 patients treated from 2010 to 2015. The authors included patients that received immunotherapy (anti-PD1 inhibitor or anti-CTLA4), targeted agents of the mitogen activated protein kinase (MAPK) pathway (BRAFi and/or MEKi) within 6 weeks of SRS and compared the outcomes of these 2 groups with patients that did not receive systemic therapy. The median OS were anti-CTLA4 7.5 months (95% CI 4.4-15.6), anti-PD1 20.4 months (95% CI 8.8-not available) and BRAFi + MEKi 17.8 months (95% CI 11.8-not available). Median BC for anti-CTLA4 was 7.5 months (95% CI 4.0-15.6), for anti-PD1 was 12.7 months (95% CI 5.5-not available) and for BRAFi/ MEKi was 12.7 months (95% CI 8.3-18.5). No statistical difference was noted among patients based on the type of systemic therapy received (P = .33). The median OS for those who did not receive any systemic drug therapy was 10.8 months. The OS was similar in patients with BRAF mutant melanoma who received BRAFi and those who did not. When authors analyzed the likelihood to die after SRS, patients who had immunotherapy were 49% less likely to die (HR 0.51 [95% CI 0.25-1.05]), and those who received BRAFi-based therapy were 70% less likely to die (HR 0.30 [95% CI 0.14-0.64]) compared with those who did not receive any systemic therapy. The likelihood to die difference was statistically significant favoring the BRAFi + MEKi group in a multivariate analysis (P = .0072). The authors conclude that in the setting of cerebral metastasis, patients treated with targeted therapy showed a longer median OS than patients treated with ipilimumab.

 

Acharya et al³⁹ compared the local and distant intracranial failure rates of brain melanoma metastasis among patients who received SRS, SRS and target therapy, or SRS and immunotherapy. A total of 72 patients were included, with a median follow-up of 8.9 months. Among these 72 patients, 38 were in the SRS only groups, 18 were in the SRS and immunotherapy group, and 16 were in the SRS and target therapy group. These authors conclude that SRS with immunotherapy is associated with decreased distant and local intracranial failure compared with SRS alone.

 

Davies et al⁴⁰ led a multicenter, multicohort, open-label, phase 2 study to evaluate oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in 4 patient cohorts with MBMs: (A) BRAFV600E-positive, asymptomatic MBMs, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAFV600E-positive, asymptomatic MBMs, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAFV600D/K/R-positive, asymptomatic MBMs, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAFV600D/E/K/R-positive, symptomatic MBMs, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. Thirty-two institutions contributed to the study.⁴⁰ Between February 28, 2014, and August 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. Intracranial response was achieved in 44 (58% [95% CI 46-69]) of 76 patients in cohort A, 9 (56% [95% CI 30-80]) of 16 patients in cohort B, 7 (44% [95% CI 20-70]) of 16 patients in cohort C, and 10 (59% [95% CI 33-82]) of 17 patients in cohort D. They conclude that dabrafenib plus trametinib was active with a manageable safety profile in patients with BRAF V600–mutant MBMs, but that the median duration of response was relatively short.

 

Synthesis of Targeted Therapy for the Treatment of Melanoma Metastases

Class I evidence supports the use of dabrafenib plus trametinib providing better local control in brain metastases secondary to BRAFV600E-positive melanoma. In support of this, class III data from studies designed in various manners also support BRAFi (dabrafenib, vemurafenib, or dabrafenib/trametinib combination therapy) contributing positively to OS. Five class III studies suggest that the addition of SRS to BRAFi improves CNS control and to a lesser extent PFS and OS. Well-done studies, be they positive or negative, are of value, and it should be noted that class I data suggest that dabrafenib plus trametinib contributes no value to OS. These data warrant a level I recommendation about the use of dabrafenib plus trametinib for patients with newly diagnosed brain metastases secondary to BRAFV600E-altered melanoma to improve local control. In addition, a level III recommendation can be formulated stating that in selected circumstances, immunotherapy (eg, anti-PD-1) may have a role in improving local tumor control and survival with or without SRS.

 

Recommendations

Level I: It is recommended that for patients with newly diagnosed brain metastases secondary to BRAF V600E-positive melanoma dabrafenib plus trametinib be added to the treatment regimen to obtain improved local tumor control.

 

Level III: For individuals with brain metastases secondary to BRAF-altered melanoma for whom targeted therapy in the form of BRAF-inibitors  are indicated, it is suggested that immunotherapy, when not contraindicated by other underlying medical conditions, be added to the treatment regimen to improve CNS control and to a lesser extent PFS and OS.

 

Targeted Therapy for the Treatment of Breast Adenocarcinoma Parenchymal Brain Metastases

The 4 qualifying articles all provided class III evidence, primarily because they were retrospective collections of cases with concurrent or historical controls, or no comparisons provided. Details of the qualifying and informative manuscript data are available in the Evidence Table (Table 2). In an attempt to provide some cohesiveness, this discussion is subdivided into groups of manuscripts with relatively common treatment themes.

 

All 4 studies evaluated the impact of HER2-blocking agents as an adjuvant therapy to brain radiation (SRS or WBRT). Three studies analyzed a single HER2-blocking medication (lapatinib or trastuzumab) and 1 study analyzed the dual HER2 blockage of trastuzumab and pertuzumab.

 

Bergen et al⁴¹ performed a retrospective study, including 252 nonconsecutive patients divided into 3 groups: dual HER2-blocking agents (trastuzumab and pertuzumab), single HER2-targeted therapy, and no HER2-targeted therapy. All patients also received systemic therapy and radiation therapy to the brain lesions (either SRS or WBRT). When the 3 groups were compared, the group that received trastuzumab and pertuzumab had a longest median OS when compared with the other groups (44 months vs 17 vs 3 months, P < .001, log-rank test).⁴¹

 

Zhang et al⁴² described a retrospective study of 60 HER2-positive breast cancer patients with BM after WBRT in combination with systemic treatments. Among them, 42 patients received systemic treatments while 18 patients did not receive it after WBRT.⁴² PFS was significantly longer in patients receiving trastuzumab therapy than in the nontrastuzumab group (HR 2.213 [P = .003] and HR 3.056 [P < .001], respectively) and significantly shorter in patients with ≥2 extracranial metastases (HR 0.417 [P = .002] and HR 0.317 [P < .001], respectively). Furthermore, patients on trastuzumab treatment experienced longer OS than patients in the nontrastuzumab group (HR 2.844 [P < .001] and HR 4.017 [P < .001], respectively.

 

Kim et al⁴³ and Parsai et al⁴⁴ analyzed the impact of single HER2 target therapy (lapatinib) versus no targeted therapy on brain local control and brain metastases response among patients with HER2-positive breast cancer with brain metastasis. Kim et al⁴³ included 18 patients in the study group (apatinib and SRS) and 66 patients in the control group (SRS only) and concluded that the addition of concurrent lapatinib to SRS was associated with improved complete response rates among patients with HER2-positive brain metastases. Parsai et al⁴⁴ included 126 patients divided into 3 groups: 24 with concurrent lapatinib and SRS, 23 with nonconcurrent lapatinib and SRS, and 79 who received SRS alone. This author concluded that for patients with HER2-positive breast cancer brain metastases, the use of lapatinib concurrently with SRS improved local failure rate at 12 months compared with nonconcurrent use (5.7% vs 15.1%, P < .01), without an increased rate of radiation necrosis. Concurrent lapatinib best augments the efficacy of SRS for lesions ≤1.10 cm³ in volume. Any use of lapatinib with SRS after development of brain metastasis improved median survival compared with SRS without lapatinib (27.3 vs 19.5 months, P = .03).

 

Synthesis Targeted Therapy for the Treatment of Breast Adenocarcinoma

The qualifying articles provide experience with the use of HER2-targeted agents in the form of trastuzumab or lapatinib with and without radiation in different sequences, all in a retrospective manner. The findings included improved OS, median survival, and PFS when trastuzumab is added to a treatment regimen. It was also noted that the addition of lapatinib to SRS improved CNS control and implied timing of administration may be important. This class III information warrants the formation of a recommendation suggesting the use of trastuzumab and radiation to improve PFS, median survival, and OS. The information also supports the ability of lapatinib in combination with SRS to improve intracranial response rate and median survival.

 

Recommendations

Level III: In adult patients with brain metastases from breast adenocarcinoma that are HER2-positive and for whom radiation therapy is indicated, it is suggested that trastuzumab be added to the treatment regimen to improve PFS, median survival, and OS.

 

Level III: In adult patients with brain metastases from breast adenocarcinoma for whom SRS is indicated, it is suggested that lapatinib be added to that treatment to improve intracranial response rate and median survival.

 

Targeted Therapy of Leptomeningeal Metastases

Question 2: In patients with leptomeningeal brain metastases, does the use of molecular targeted agents provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, immune modulators, SRS, WBRT, and surgical resection.

 

The literature searches for targeted therapy and immunotherapy for parenchymal brain metastases resulted in some overlap in citations despite careful design of the search terminology. Therefore, the numerical results of the 2 searches are being combined to reflect that we reviewed and used citations from the results from both searches. The literature search yielded 3005 abstracts. Task force members reviewed all abstracts yielded from the literature searches and identified the literature for full-text review and extraction, addressing the clinical questions, in accordance with the Literature Search Protocol (Appendix I). Task force members identified the best research evidence available to answer the targeted clinical questions.

 

The task force selected 303 full-text articles for review. Of these, 292 were rejected for not meeting inclusion criteria or for being off-topic. Eleven were selected for systematic review. (Appendix III). In order to ease the discussion of the therapy of parenchymal brain metastases with leptomeningeal metastases, the qualifying articles are divided into those related to NSCLC or melanoma.

 

Targeted Therapy for the Therapy of NSCLC Leptomeningeal Metastases

Information on qualifying for this topic is presented in the Evidence Table (Table 4). Summaries of this information follow here. Zou et al,⁴⁵ in a multicenter retrospective study of 65 patients with ALK-positive NSCLC with BMs or leptomeningeal metastases (LMs), found significant benefit of the second-generation ALK-TKI alectinib. In the patients treated with alectinib, CNS time to progression (TTP) for patients with LM was 408 days and 100% (8/8 patients) experienced significant improvement in CNS-related symptoms.

 

Yi et al⁴⁶ retrospectively analyzed 27 patients with LMs with EGFR-mutant NSCLC receiving osimertinib with or without bevacizumab. The study showed improved survival of patients with LM patients in the osimertinib plus bevacizumab group, with a median OS of 18 months (n = 16) compared with 13.7 months with osimertinib alone (n = 11).

 

In a single-center retrospective series of 53 patients with EGFR-mutated NSCLC treated with EGFR-TK inhibitors, Li et al⁴⁷ found patients who received osimertinib after developing LM (n = 35) had a significantly higher rate of LM disease control (P = .008) and significantly longer OS (15.0 vs 6.0 months; HR 2.4292 [95% CI 1.234-4.779]; P = .045) than those who received previous generations of EGFR TKIs or other localized therapies.

 

Similarly, Zhang et al⁴⁸ in a retrospective study of 78 patients with EGFR-mutated NSCLC and

LM showed that osimertinib demonstrated significant efficacy against LM associated with NSCLC. Forty-four patients treated with osimertinib had an improved median OS of 13.15 months (95% CI [5.74-20.57]) and a median PFS of 9.50 months (95% CI [6.77-12.23]) when compared with patients treated with first- or second-generation EGFR-TKIs (median OS 3.00 months [95% CI 1.32-4.68] and median PFS 1.50 months [95% CI 0.00-3.14]).

 

Miyawaki et al⁴⁹ found that patients treated with the third-generation TKI osimertinib had significantly better OS and TTF than those treated with first-/second-generation TKIs such as erlotinib. In the multivariate analysis for OS, treatment with osimertinib after onset of LM (HR 0.09 [95% CI 0.01-0.48]; P = .005) was associated with better OS.

 

In another retrospective study of 351 patients with EGFR-mutated NSCLC and cytologically confirmed LM, Lee et al⁵⁰ showed that osimertinib was an effective treatment option for EGFR-mutated NSCLC with LM regardless of T790M mutational status. Patients treated with osimertinib had a superior OS of 17.0 months (95% CI 15.13-18.94) compared with those not treated with osimertinib who had a median OS of 5.5 months (95% CI 4.34-6.63) regardless of T790M mutational status (HR 0.36 [95% CI 0.28-0.47], P < .001).

 

Ahn et al⁵¹ found significant clinical benefit of osimertinib in 22 patients with LM with EGFR T790M-positive advanced NSCLC and progression after previous EGFR-TKI therapy. They found that of the 22 patients in the study, median LM PFS was 11.1 months (95% CI 4.6-NC) and median LM OS was 18.8 months (95% CI 6.3-NC).

 

Kwon et al retrospectively analyzed EGFR-mutant NSCLC with LM in 117 patients and found that therapeutic interventions including EGFR-TKIs, cytotoxic chemotherapy, or Ommaya reservoir, and good performance status were related to favorable survival outcomes.⁵² They found of the 62 patients treated with EGFR-TKIs, the 11 patients who received third-generation EGFR- TKIs had survival outcomes that were significantly longer than with other treatments, including first-generation EGFR-TKIs and cytotoxic chemotherapy.

 

Nosakiet al⁵³ in a single-center phase II trial evaluating the efficacy of erlotinib for patients with NSCLC with LMs found that median OS was significantly longer in patients with mutant EGFR (P = .0113 and P < .0054). The median OS was 3.4 months with median values of 4.0 months for patients with EGFR mutations and 1.2 months for patients with wild-type EGFR.

 

In a multicenter retrospective study of 92 patients with EGFR-mutated NSCLC and LMs, Flippot et al⁵⁴ found clinical benefit of patients rechallenged with TKI. Among 87 patients with TKI failure, patients rechallenged with TKI had a median LM OS of 7.6 months (95% CI 5.7-10.9) compared with 4.2 months (95% CI 1.6-6.7) in patients without further therapy. Of note, all 4 patients who received osimertinib after first- and second-generation TKIs experienced clinical benefit.

 

Wu et al⁵⁵ in a retrospective, single-institution study of 29 patients with advanced NSCLC and LMs receiving effective first-generation EGFR TKI treatment found no significant difference in OS in patients who continued first-generation EGFR TKI after LM compared with patients who stopped treatment. Of note, this study did not examine the third-generation TKI osimertinib. In their study, OS after LM did not differ between the patients who continued erlotinib treatment versus those who did not (5.3 months vs 4.0 months, respectively; P = .941).

 

Yan et al⁵⁶ reported after multivariate analysis that EGFR-TKIs (HR 0.507 [95% CI 0.283-0.908]; P = .022) after LM diagnosis was an independent favorable predictor of survival in a retrospective, single-institution study of 156 patients with pathology-proven NSCLC with either positive cerebrospinal fluid cytology or leptomeningeal enhancement by MRI. Of note, they found that the 30 patients who received WBRT plus EGFR TKIs achieved longer survival than those who only received WBRT (median 13.6 vs 8.8 months; P = .027), but did not add any survival benefit than those only received EGFR TKIs (median 13.6 vs 13.9 months; P = .352). This study did not list specific TKI treatments and grouped them together and, therefore, only provides a general observation in regard to TKIs in LM.

 

In a single-institution retrospective study, Choi et al⁵⁷ examined subjects with leptomeningeal disease secondary to EGFR-mutant NSCLC treated with or without pemetrexed. Survival after diagnosis with leptomeningeal disease was significantly longer with pemetrexed use (median 13.7 months) than without pemetrexed use (median 4.0 months; P = .008).

 

Li et al⁵⁸ Click or tap here to enter text.found that EGFR TKIs were the optimal treatment for LM, and active treatment with WBRT did not prolong OS for patients with EGFR-mutated disease. Among the 109 patients with common EGFR mutations, the 88 patients who received TKI therapy demonstrated longer OS than those who did not (10.0 months vs 3.3 months [P < .001]). This is another study that did not list specific TKI treatments and grouped them together and, therefore, only provides a general observation in regard to TKIs in LM.

 

Xu et al⁵⁹ demonstrated that of the 108 patients who had been diagnosed with LM from NSCLC, the 42 patients who were treated with EGFR-TKIs after being diagnosed with LM had prolonged survival (11.1 vs 4.4 months, P < .01). In addition, patients who received concomitant WBRT and EGFR-TKIs had the longest median survival time (12.3 months).

 

Synthesis

Fifteen retrospective studies provide class III evidence examining the role of TKIs in the treatment of patients with EGFR-mutant NSCLC with LM. The articles provide strong evidence for the use of the third-generation TKI osimertinib for patients with EGFR-mutant NSCLC, while the evidence for first- and second-generation TKIs is not as robust. In addition, for ALK-mutated NSCLC, there is evidence for the benefit of second-generation ALK-TKI alectinib for the treatment of LM in ALK-positive NSCLC. Given the studies only provided level III evidence, this warrants a level III recommendation stating that in individuals with leptomeningeal disease from NSCLC with EGFR mutations it is suggested that EGFR TKIs be used to increase median survival, specifically the third-generation TKI osimertinib for patients with EGFR-mutant NSCLC and the second-generation ALK-TKI alectinib for the treatment of LM in ALK-positive NSCLC.

 

Targeted Therapy for Breast Cancer LMs

 

One study by Figura et al,⁶⁰ as noted in the Evidence Table (Table 5), retrospectively studied 56 patients with LM in breast cancer, 18 of whom were treated with IT trastuzumab. They found that this therapy provided superior PFS and OS when compared with IT cytotoxic chemotherapy or WBRT and particularly improved survival for LM in Her2+ disease. As this is a retrospective study, it provides class III data.

 

Synthesis

The 1 study meeting inclusion criteria provided class III data suggesting IT trastuzumab is useful in LMs from breast cancer. It warrants a level III recommendation stating that in individuals with leptomeningeal disease from Her2+ breast cancer, it is suggested that IT trastuzumab be used to increase median survival. Of note, a recent phase I/II study published in 2023 specifically examined the role of IT trastuzumab for HER2-positive breast cancer with LD. The study could not be included in the evidence table since it did not make our initial search criteria (search interval for this update are January 1, 2016 through May 3, 2022). In this multicenter phase I/II study, Kumthekar et al⁶¹ found that IT trastuzumab was well-tolerated at an IT dose of ≤80 mg dosed twice weekly as initial therapy and the median OS was 10.5 months in patients with HER2-positive breast cancer at the phase II dose in this study which was favorable compared with the historical control median OS of approximately 3 to 4 months.

 

Recommendations

 

Level III: In individuals with leptomeningeal disease from NSCLC with EGFR mutations, it is suggested that EGFR TKIs be utilized to increase median survival, specifically third-generation TKI osimertinib for patients with EGFR-mutant NSCLC and second-generation ALK-TKI alectinib for the treatment of LMs in ALK-positive NSCLC.

 

Level III: In individuals with LM disease from Her2+ breast cancer, it is suggested that IT trastuzumab be utilized to increase median survival.

 

As there are fewer subcategories of tumor types for questions regarding immunotherapy, immune-modulating agents, interstitial modalities, radiosensitizers, LITT, and HIFU the recommendations fewer in number than with the targeted therapy section and are stated after each question.

 

Immunotherapy for Brain Metastases

Immunotherapy for Parenchymal Metastases

Question 3: In patients with parenchymal brain metastases, does the use of immune modulators provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, molecular targeted agents, SRS, WBRT, and surgical resection.

 

Recommendations

 

Level III: In individuals with brain metastases from NSCLC it is suggested that ICIs be utilized with radiation therapy to increase median survival, decrease incidence of local failure, increase intracranial PFS, and decrease distant intracranial failure.

 

Level III: In individuals with brain metastases from NSCLC that are clinically stable for at least 4 weeks and with PD-L1 TPS >50% it is suggested that ICIs be utilized without radiation to improve median OS.

 

Level I: In individuals with active, untreated, asymptomatic MBMs ipilimumab plus nivolumab is recommended to be utilized without radiation to improve median OS.

 

Level III: In individuals with brain metastases from breast cancer or colon carcinoma it is suggested that therapy with ICIs be considered alone or with radiation therapy to increase median survival and decrease incidence of local failure.

 

The literature searches for targeted therapy and immunotherapy for parenchymal brain metastases resulted in some overlap in citations despite careful design of the search terminology. Therefore, the numerical results of the 2 searches are being combined to reflect that we reviewed citations from the results from both searches. The literature search yielded 3005 abstracts. Task force members reviewed all abstracts yielded from the literature searches and identified the literature for full-text review and extraction, addressing the clinical questions, in accordance with the literature search protocol (Appendix I ). Task force members identified the best research evidence available to answer the targeted clinical questions.

 

The task force selected 303 full-text articles for review. Of these, 244 rejected for not meeting inclusion criteria or for being off-topic. Fifty-nine articles were selected for systematic review (Appendix III ). In order to improve the coherence the discussion of the immunotherapy of parenchymal brain metastases, the qualifying articles are divided into those related to NSCLC, melanoma, renal cell carcinoma, and finally those that combined histologies in their analysis.

 

Immune Modulators for the Therapy of NSCLC Parenchymal Brain Metastases

 

The qualifying articles all provided class III evidence, primarily because they were retrospective collections of cases with concurrent or historical controls or no comparisons provided. Details of the qualifying and informative manuscript data are available in the Evidence Table (Table 6). In an attempt to provide some cohesiveness, this discussion is subdivided into groups of articles with relatively common treatment themes.

 

Immunotherapy Combined With Radiation Therapy

Many studies investigated the impact of ICIs given with SRS and less frequently with WBRT.

 

SRS Plus Immunotherapy Versus SRS Alone or Combined With Targeted Therapy or Cytotoxic Chemotherapy

Abdulhaleem et al⁶² carried out a single-institution retrospective analysis of 80 consecutive subjects treated with concurrent ICI and SRS compared with 235 individuals treated with SRS alone or with other systemic therapies. Concurrent therapy was defined as ICI given ±30 days of SRS. The median OS time was improved in patients receiving upfront immunotherapy compared with the historical control group (40 months vs 8 months, P < .001). The cumulative incidence of local failure in the historical control group was 10% at 1 year compared to 1.1% at 1 year in the concurrent immunotherapy group (P = .025). In a smaller study, Lau et al⁶³ conducted a retrospective case review of subjects comprising 36 ICI- and 33 chemotherapy-treated patients with baseline CNS metastases, all of whom received radiation (SRS or WBRT) upon diagnosis. ICI therapy included PD-1 inhibitors or PD-L1 inhibitors in combination with CTLA-4 inhibitors. At the time of progression, CNS involvement was identified in 30% of ICI-treated patients compared with 64% of chemotherapy control subjects (P = .02). ICI-treated patients had superior iPFS (13.5 vs 8.4 months). Superior CNS outcomes in ICI-treated patients were driven by the PD-L1 high subgroup where the 12-month cumulative incidence rate of CNS progression was 19% in ICI-treated PD-L1 ≥50%, 50% in ICI-treated PD-L1 <50%, and 58% in chemotherapy-treated patients (P = .03).

 

Lauko et al⁶⁴ carried out a single-institution retrospective study of 800 subjects with brain metastases from NSCLC. The main focus was assessment of efficacy of immunotherapy with subjects divided into groups who received immunotherapy ≤90 days of brain metastases diagnosis, ≥90 days form diagnosis, or not at all. In summary, they found that the those that received immunotherapy had better median OS than those that did not (12.5 months vs 9.1 months, respectively, P < .001). Molecular analysis was carried out and those with tumors that contained a KRAS mutation and were treated with immunotherapy within 90 days of diagnosis had better survival than the other subgroups combined demonstrating 1-year survival of 60.4% versus 34.1%, respectively (P = .004). The subjects had a variety of other therapies including radiation and targeted therapies, limiting direct comparisons and recommendations that might be developed.

 

Scoccianti et al⁶⁵ reported a multicenter, retrospective analysis of immunotherapy (IT nivolumab, pembrolizumab, or atezolizumab) and stereotactic radiation therapy (SRT, 1-5 fractions) for NSCLC brain metastases comprising 150 cases. Patients receiving SRT + IT had a longer intracranial local PFS than with SRT alone (propensity score-adjusted P = .007). In terms of timing, IT administration after SRT was shown to be related to a better OS (P = .037). Time intervals between SRT and IT ≤7 days was shown to be related to a longer OS if compared with an SRT-IT interval >7 days.

 

In a retrospective, single-institution study of subjects with brain metastases from NSCLC, Singh et al⁶⁶ assessed the differences in cases treated with single fraction SRS and either immunotherapy, chemotherapy, or targeted therapy. Immunotherapy consisted of pembrolizumab, nivolumab, or ipilimumab. Concurrent systemic therapy was that provided within 30 days of SRS. One-year distant intracranial PFS (DI-PFS) was improved with any use of immunotherapy (58% vs 39%; P = .03) and concurrent immunotherapy was superior versus chemotherapy or targeted therapy (67% vs 37% vs 39%, respectively; P = .01). In the immunotherapy cohort, 1-year DI-PFS was improved for programmed death-ligand 1 expression >50% versus 1%-49% versus 0% (80% vs 49% vs 19%, respectively; P < .01).

 

SRS or WBRT Plus Immunotherapy Versus SRS or WBRT Alone

In the first of 2 small studies, Enright et al⁶⁷ found that the addition of ICI to SRS (n = 33 subjects) provided better OS (P = .03) and better 2-year local control rates (P = .046) compared with SRS alone (n = 44 subjects). In the second study, Liao et al⁶⁸ compared patients treated with WBRT alone (n = 41) or in combination with anti–PD-1 therapy (n = 29, within 30 days of the first dose of radiation). The median survival times for WBRT alone and WBRT plus anti–PD-1 therapy cohorts were 20 months (95% CI 11.6-28.3 months) and 27 months (95% CI 19.5-28.5 months), respectively (P = .035).

 

Wasilewski et al⁶⁹ carried out a single-center retrospective collection of subjects comparing effectiveness of ICI to chemotherapy in combination with radiation therapy from a group of 480 individuals having undergone craniotomy for the metastatic NSCLC. Radiation therapy of any form was included. Propensity matching of the selected cohorts was then carried out. The 2 cohorts of interest included 108 patients (31%) with radiation therapy and chemotherapy and 63 patients (16%) with radiation therapy and ICI following neurosurgical metastasis removal (before matching). After covariate equalization using propensity score matching (62 patients per group), patients receiving radiation therapy and chemotherapy after neurosurgery had significantly lower OS (11.8 months [95% CI 9.1-15.2]) compared with patients with radiation therapy and ICIs (23.0 months [95% CI 20.3-53.8], P < .001).

 

In a small retrospective, single-institution, matched cohort study of subjects with brain metastases from NSCLC treated with SRS with (n = 17) or without concurrent ICI (nivolumab, pembrolizumab, or atezolizumab, n = 34), Shepard et al⁷⁰ found that there was no statistically significant difference in OS (P = .99) or CNS PFS (P = .11) between the 2 groups. Concurrent ICI administration was defined as their administration within 3 months of SRS. This finding is generally contrary to other studies suggesting at least some improvement in outcomes with the addition of ICI to radiation therapy.

 

Immunotherapy Not Combined With Radiation Therapy

In a post hoc pooled analysis of the KEYNOTE-001, -010, -024, and -042 studies by Mansfield et al,⁷¹ 293 subjects had baseline NSCLC brain metastases that were clinically stable for ≥4 weeks. One hundred ninety-nine patients (67.9%) were assigned to pembrolizumab monotherapy and 94 (32.1%) to chemotherapy. Among patients with PD-L1 TPS >50% with brain metastases at baseline median OS was 19.7 (95% CI 12.1-31.4) for the pembrolizumab group and 9.7 (95% CI 7.2-19.4) months for the chemotherapy group. In another post hoc pooled analysis of the KEYNOTE-021, -189, and -407 studies, all studies permitted enrollment of patients with previously treated or untreated stable (≥2 weeks) brain metastases.⁷² Patients were assigned to carboplatin and pemetrexed with or without the addition of 35 cycles of pembrolizumab 200 mg every 3 weeks. Median OS was 18.8 months (95% CI 13.8-25.9) with pembrolizumab plus chemotherapy and 7.6 months (95% CI 5.4-10.9) with chemotherapy alone, and median PFS was 6.9 months and 4.1 months, respectively. This benefit even extended to subjects with TPS PD-L1 < 1%. The authors concluded the addition of pembrolizumab to platinum-based chemotherapy improves clinical outcomes.

 

In a propensity-matched analysis of data extracted from the National Cancer Database addressing a population of 42,512 patients with stage IV NSCLC of which 11,810 patients with BMs, Takamori et al⁷³ assessed the effect of ICI therapy at some time during their management. In a univariate analysis, patients with NSCLC with BMs treated with immunotherapy had a significantly longer OS than those without immunotherapy after propensity score matching (median OS 12.8 vs 10.1 months, HR 0.80 [95% CI 0.72-0.89], P < .0001).

 

Immune Modulators for the Therapy of Melanoma Parenchymal Brain Metastases

Except for 1 instance, the qualifying articles all provided class III evidence, primarily because they were retrospective collections of cases with concurrent or historical controls or no comparisons provided. One study met criteria for designation as class I data. Details of the qualifying and informative manuscripts are available in the Evidence Table (Table 7). In an attempt to provide some cohesiveness, this discussion is subdivided into groups of articles with relatively common treatment themes.

 

SRS With Immunotherapy Versus SRS Alone or Combined With Targeted Therapy, or Cytotoxic Chemotherapy

Pedersen et al⁷⁴ retrospectively reviewed a total of 527 patients with MBMs from across multiple Danish institutions assessing the benefit of surgical excision, SRS, WBRT, and a variety of systemic therapies. Patients receiving surgical excision as a first choice of treatment had the best median OS of 10.9 months, whereas patients receiving WBRT had the worst outcome (median OS 3.4 months). Postoperative SRS did not improve survival or local control after surgical excision of brain metastases. Of the 40 patients alive >3 years after diagnosis of MBMs, 80% received immunotherapy at some point after diagnosis suggesting this intervention may be beneficial in a small proportion of these subjects.

 

A collection of 380 subjects from 23 skin cancer centers treated with ipilimumab and nivolumab for their MBMs was assessed by Amaral et al.⁷⁵ They were treated with a variety of other therapies, including surgery, various forms of radiation, targeted therapy, and cytotoxic chemotherapy. In the subgroups of patients with BRAFV600-mutated melanoma and BRAFV600 wild-type tumors, they found no differences in terms of OS when receiving as first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (P = .085, and P = .996, respectively). Also, receiving combined immunotherapy as first-line treatment or at a later time point made no difference in terms of OS in this study population (P = .119). Surprisingly, in the face of those statistics, the authors still concluded that the combination of nivolumab and ipilimumab improves OS. These data are class III in nature, and contradict some other positive studies, but the widely variable therapies provided to these subjects beyond the immunotherapy limits its impact.

 

In a 2-institution study, Stera et al⁷⁶ looked at 48 patients with MBMs treated with single fraction SRS in combination with immunotherapy (nivolumab, ipilimumab, or pembrolizumab) or targeted therapy (dabrafenib, trametinib, vemurafenib, cobimetinib, and buparlisib). Immunotherapy and the application of systemic treatment directly before or concomitant to SRS were both associated with improved OS (P = .037 and .045, respectively). Immunotherapeutic medications showed only a trend for better results compared with kinase inhibitors (P = .112).

 

Vosoughi et al⁷⁷ retrospectively collected data from 2 institutional databases for 79 subjects with MBMs. A variety of combinations of therapies were noted, including craniotomy, WBRT, and SRS. These were used with or followed by systemic therapies including anti–CTLA-4 antibody, anti–PD-1 antibody, or BRAF inhibitors (with or without a MEK inhibitor) in 39 (49.4%), 28 (35.4%), and 24 (30.4%), respectively. To add to the complexity, 35 (44.3%) and 10 (12.7%) patients were treated with cytotoxic chemotherapy and interleukin 2 treatment, respectively. Following a diagnosis of melanoma brain metastasis, 39 (49.4%), 28 (35.4%), and 24 (30.4%) patients were treated with anti–CTLA-4 antibody, anti–PD-1 antibody, or BRAF inhibitors (with or without a MEK inhibitor), with a median OS of 19.2 months, 37. 9 months, and 12.7 months, respectively. By multivariate analysis, there was trend toward significance for improved overall treatment with anti–PD-1 antibody (P = .055).

 

Acharya et al³⁹ carried out a single-institution retrospective study of subjects with MBMs treated with SRS alone, SRS and targeted therapy (vemurafenib or dabrafenib/trametinib), or SRS and immunotherapy (pembrolizumab or nivolumab/ipilimumab). SRS with systemic therapy was considered “combination therapy” when the agents were delivered within 3 months of the SRS. On multivariate analysis, after adjusting for steroid use and number of MBMs, SRS plus immunotherapy was associated with a significant reduction in distant intracranial failure compared with SRS alone (P = .003) and compared with SRS + targeted therapy (P = .001). On multivariate analysis, after adjusting for dose, SRS plus immunotherapy was associated with a significant reduction in local failure compared with SRS alone (P = .04). The authors concluded the addition of immunotherapy to SRS provided improved local and distant tumor control compared with SRS alone.

 

In a single-institution retrospective study of individuals receiving SRS for MBMs, Choong et al⁷⁸ looked at the survival and brain control in those who received immunotherapy (anti–CTLA-4 or anti-PD1 therapy) or targeted therapy (BRAFi with or without MEK inhibitors or MEK inhibitors alone) within 6 weeks of the radiation treatment. The median duration of brain control, stratified according to types of systemic treatment received within 6 weeks of SRS, were as follows: anti–CTLA-4 = 7.5 months, BRAFi ± MEK inhibitor = 12.7 months and anti-PD1 = 12.7 months. The median duration of brain control for those that received SRS alone was 10.8 months. The addition of systemic agents did not significantly improve brain control in this series. Median OS according to type of systemic treatment received at time of SRS were as follows: anti–CTLA-4 = 7.5 months, anti-PD1 = 20.4 months, BRAFi ± MEK inhibitor = 17.8 months. The median OS for those who did not receive any systemic drug therapy was 10.8 months. The addition of systemic agents did not significantly improve OS in this series. The authors note likely benefit from the addition of immunotherapeutic or targeted agents but that additional clinical work and comparisons will be necessary to define their roles.

 

Gaudy-Marqueste et al⁷⁹ carried out a single-institution retrospective study of patients with melanoma with brain metastases treated with single fraction radiosurgery and then treated at any point in follow-up with either ipilimumab, anti–PD-1 agents, or BRAF ± MEK inhibitors. Among 179 consecutive patients treated with SRS, 109 received immunotherapy and/or targeted therapy after the first SRS. Median OS was 10.95 months for those that received either immunotherapy and/or targeted therapy and 2.29 months (P < .001) in those who did not receive the systemic therapy. Best OS was observed in BRAF wild-type patients receiving anti-PD1 or in BRAF-mutated patients receiving BRAFis and anti-PD1 therapy (12.26 and 14.82 months, respectively). The data do not allow clear determination of superiority of immunotherapy or targeted therapy in this series.

 

SRS or WBRT With Immunotherapy Versus SRS or WBRT Alone

In a retrospective, single-institution study of subjects with MBMs, Borzillo et al⁸⁰ reviewed subjects undergoing single fraction SRS/SRT and then divided them into those who had received radiation therapy and ipilimumab (RT+IPI) and those who had received radiation therapy alone (NO-IPI). The median OS was 10.6 months for all patients, 10.7 months for RT+IPI, and 3.3 months for NO-IPI (P = .96). One-year local control was 50% for all patients, 56% for RT+IPI, and 18% for NO-IPI (P = .08). The authors concluded that ipilimumab with SRS/SRT treatment could improve local control, but the improvement of survival outcome was not significant and only represented a trend.

 

A single-institution retrospective analysis of patients with MBMs treated with GKRS with or without immunotherapy or targeted therapy during or after the radiation dose was reported by Gatterbauer et al.⁸¹ Patients treated with anti–PD-1 or a combination of anti–CTLA-4/PD-1 showed a longer time to new MBM after radiation (P = .012) and a significantly longer survival (P < .001) after first GKRS compared with all other forms of treatment.

 

Moyers et al⁸² carried out a retrospective analysis based on a query of the National Cancer Database for patients with MBMs receiving cranial radiation (SRS or WBRT) alone, cranial radiation with immunotherapy (immunotherapy included nivolumab, ipilimumab, nivolumab and ipilimumab, or pembrolizumab) or immunotherapy alone. Concurrent therapy was defined as immunotherapy given within 28 days before or after radiation therapy; nonconcurrent defined as immunotherapy administered within 28 to 90 days of radiation therapy. Results were then propensity score adjusted with SRS + immunotherapy providing a median OS of 15.5 months, which was greater than SRS alone at 10.1 months (P = .010). WBRT + immunotherapy provided a median OS of 4.6 months which was greater than WBRT alone at 2.9 months (P < .001). SRS + immunotherapy survival at 24 months was 47% for concurrent therapy and was not significantly different that the 37% for nonconcurrent therapy (P = .40). Similarly, there was no difference in 24-month survival for the concurrent WBRT + immunotherapy group when compared with the nonconcurrent WBRT + immunotherapy group, 20% compared with 21%, respectively.

 

In a retrospective single-institution study, Diao et al⁸³ identified 91 patients with MBMs treated with SRS with or without ipilimumab. Twenty-three patients received ipilimumab concurrent (defined as within ±4 weeks of the SRS procedure) with SRS, 28 patients nonconcurrently, and 40 patients did not receive ipilimumab. Regardless of timing, patients who received ipilimumab had a median OS of 15.1 months compared with 7.8 months in patients who did not (P = .02).

 

Gabani et al⁸⁴ carried out a retrospective analysis of subjects with MBMs from the National Cancer Database looking at radiation and immunotherapy. A total of 1104 patients were identified: 912 received radiation therapy (WBRT or SRS) alone and 192 received radiation therapy plus immunotherapy (agent not specified). When dividing the cohort based on treatment groups, it was found that treatment group SRS + immunotherapy was associated with the highest median OS: 17.0 (10.7-23.2) months in SRS + immunotherapy versus 11.9 (9.8-14.0) months for SRS alone, 8.5 (6.5-10.5) months for WBRT + immunotherapy, and 4.4 (3.9-4.9) months in WBRT alone group (P < .001 for all 4 cohorts by log-rank statistic). Recognizing the limitation of a database review, the authors conclude that the addition of immunotherapy to radiation therapy is associated with improved OS in individuals with MBMs.

 

In a study looking at timing of immunotherapy administration, Schmidberger et al⁸⁴ compared individuals who received ipilimumab before hypofractionated WBRT, stereotactic radiation, or both to those who received ipilimumab after those forms of radiation. Forty-one patients were included, of whom 15 were treated with stereotactic radiation, 7 with a combination of stereotactic radiation and hypofractionated WBRT, and 19 with hypofractionated WBRT alone. All patients received ≥2 doses of ipilimumab. Patients treated with ipilimumab after radiation therapy had a censored median survival of 11 months, compared with 3 months for the patients who received ipilimumab before radiation therapy (P = .015).

 

Trommer-Nestler et al⁸⁶ carried out a single-institution retrospective analysis of 26 subjects with MBMs harboring 48 brain metastases receiving pembrolizumab or nivolumab and SRS or SRS alone. Thirteen subjects were in each of the 2 groups. Local control was obtained after 6 months with SRS and anti–PD-1 agents in 86% of cases and in 80% of cases receiving SRS alone, a nonsignificant difference. This is a conflicting study with others above showing SRS given along with immune modulators improves local control.

 

In a single-institution retrospective review, Patel et al⁸⁷ evaluated 54 subjects with brain metastases from melanoma treated with SRS alone or in combination with ipiluimumab administered within 4 months of the radiation. The addition of ipilimumab to the SRS did not result in significantly better 1-year local control, overall intracranial control, or OS.

 

Yusef et al⁸⁸ looked at a single-institution retrospective series of 51 patients with metastatic brain melanoma treated with SRS as first-line therapy. ICI therapy in the form of ipilimumab or prembrolizumab was administered within 4 weeks of radiation in 18 cases. Median OS for patients receiving SRS and ICI therapy was 7.4 months compared with 7.1 months for patients receiving SRS alone (P = .212). Though there was no survival benefit with the addition of ICI therapy, there was a trend suggesting this therapy decreased both local and distant intracranial failure. In a follow-up study this same group looked at additional subjects in greater detail pointing out the influence of dose-size relationships on local control using this combined therapy strategy.⁸⁹

 

Immunotherapy Alone Compared With Immunotherapy Plus Radiation

In a study of ICI therapy alone (n = 10) compared with SRS plus ICI therapy (n = 32) or SRS alone or with other systemic therapies (n = 20), Le Rhun et al⁹⁰ found that ICI therapy alone showed no objective responses and had worse outcome than patients treated with SRT without or with ICI therapy.

 

White et al⁹¹ carried out a retrospective analysis based on a query of the National Cancer Database for patients with MBMs receiving cranial radiation (SRS or WBRT) with immunotherapy (n = 528, type not specified) or immunotherapy alone (n = 142, type not specified). After propensity matching, the median OS for SRS + immunotherapy was 19.0 months and superior to immunotherapy alone at 11.5 months (P = .006). WBRT + immunotherapy had a median OS of 7.7 months and was inferior to immunotherapy alone at 11.5 months (P = .0255). The differential effect between types of radiation is notable and the authors suggested that for patients with MBMs that are otherwise candidates for WBRT, immunotherapy alone may be a reasonable consideration in patients who are asymptomatic.

 

Studies of Immunotherapy Modalities Compared With Other Immunotherapy Modalities, or Immunotherapy Combined With Cytotoxic Chemotherapy or Targeted Chemotherapy

Di Giacomo et al⁹² provide a prospective, multiinstitutional, randomized study of adult patients with active, untreated, asymptomatic brain metastases with fotemustine (n = 27), ipilimumab plus fotemustine (n = 36), or ipilimumab plus nivolumab (n = 26). Median OS was 8.5 months in the fotemustine arm, 8.2 months in the ipilimumab plus fotemustine arm (P = .78 vs fotemustine), and 29.2 months in the ipilimumab plus nivolumab arm (P = .017 vs fotemustine). The 4-year survival rate was significantly higher for ipilimumab plus nivolumab than fotemustine alone (41.0% vs 10.9%, P = .015). Four-year survival was 10.3% for ipilimumab plus fotemustine and similar to fotemustine alone, again significantly less than ipilimumab plus nivolumab. Compared with fotemustine, ipilimumab plus nivolumab significantly improved OS and long-term survival of patients with melanoma with asymptomatic brain metastases. The prospective, randomized, well -designed and completed nature of this study provides class I data.

 

In a 4-institution retrospective collection of 116 subjects with MBMs, Hilbers et al⁹³ compared subjects treated with combined ICI therapy in the form of ipilimumab/nivolumab (n = 53) or combined targeted therapy (dabrafenib/trametinib or vemurafenib/cobimetinib, n = 63) within 3 months after diagnosis of the MBMs. Of those that received ipilimumab/nivolumab, the disease control rate (complete response + partial response + stable disease) was 60.3%. The intracranial response rate was 43.8% at 3 months with durable responses at 6 (46.5%) and 12 months (53.1%). Median PFS was 9.6 months and median OS 44.8 months. Of those that received combination targeted therapy, the disease control rate was 60.4%. The intracranial response rate was 50% at 3 months, but dropped at 6 months (20.9%). Median PFS was 5.8 months and median OS was 14.2 months. ICI therapy resulted in greater intracranial response rates over longer periods of time and longer PFS and median OS, though these differences did not reach statistical significance. In cases with BRAFV600 mutations, 26.7% of patients received combined immunotherapy and 73.3% received combination targeted therapy with OS “median not reached,” and 14.2 months, respectively (P = .0053). For this same cohort, median PFS was 14.7 and 3.1 months, respectively (P = .03), favoring combined ICI therapy.

 

Wilson et al⁹⁴ collected 70 subjects treated with a broad range of therapies in a single-institution retrospective series. Sixty-nine patients received systemic treatment. Patients treated with first-line dual immunotherapy (nivolumab and ipilimumab) had the best median OS (26.7 months), compared with single agent anti–PD-1 therapy with either nivolumab or pembrolizumab (14.1 months) or with ipilimumab alone (14.3 months) and kinase inhibitors (inhibitors of BRAF alone or in combination with MEK inhibitors, 10.9 months). These differences were not statistically significant. Individuals able to have surgery, SRS, or both as first-line therapy had superior OS compared with those who had first-line systemic therapy (P < .001).

 

In a small multicenter randomized phase II study of asymptomatic MBMs, Long et al⁹⁵ compared nivolumab plus ipilimumab to nivolumab alone. With a median follow-up of 17 months, intracranial responses were achieved by 16 of 35 (46%) patients receiving nivolumab plus ipilimumab and 5 of 25 (20%) in those receiving nivolumab alone. No statistical inference was computed because the study was not designed for a formal comparison between cohorts.

 

Use of Immune Modulators in Studies of Parenchymal Brain Metastases Combining Histologies

 

The qualifying articles all provided class III evidence, primarily because they were retrospective collections of cases with concurrent or historical controls or no comparisons provided. Details of the qualifying and informative manuscripts are available in the Evidence Table (Table 8).

 

A retrospective TriNetX database analysis of subjects with brain metastases to assess the survival benefit of treatment with or without ICIs was carried out by Du et al.⁹⁶ Subjects with NSCLC, triple-negative breast cancer, melanoma, and renal cell carcinoma were the main cancers included. Subjects with driver mutations were excluded. Exposure to ICIs was defined as treatment with ≥1 dose of nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, or ipilimumab. For all these types of cancer, median OS durations for the ICI and non-ICI cohorts were 14.0 and 7.9 months, respectively. More specifically, OS was remarkably prolonged in patients with NSCLC (14.4 vs 8.2 months), triple-negative breast cancer (23.9 vs 11.6 months), and melanoma (27.6 vs 16.8 months) if patients had exposure to ICIs. In contrast, there was no significant difference in OS of patients with renal cell carcinoma treated with and without ICIs (16.7 vs 14.0 months). The authors point out a number of limitations of a retrospective database analysis including lack of knowledge of intracranial and extracranial tumor burden, other treatments or when they were used, steroid use, and tumor PD-1/PD-L1 expression.

 

Amin et al⁹⁷ carried out a retrospective study of cases from the National Cancer Database. This study included 3112 adult patients in the National Cancer Database from 2010 to 2016 with NSCLC, breast cancer, melanoma, colorectal cancer, or kidney cancer and brain metastases at the time of diagnosis and who received definitive surgery of the primary site. Treatment groups were stratified as follows: 1) any treatment with or without immunotherapy; 2) chemotherapy with or without immunotherapy; 3) radiation therapy (RT) with or without immunotherapy; and 4) chemoradiation with or without immunotherapy. In the multivariable analysis, patients who received immunotherapy had significantly improved OS compared with no immunotherapy (HR 0.62 [95% CI 0.51-0.76]; P < .001).Treatment with RT plus immunotherapy was associated with significantly improved OS compared with RT alone (HR 0.59 [95% CI 0.42-0.84]; P = .003). Other combinations of therapy with immunotherapy did not have an impact on OS.

 

Kowalski et al did a multiinstitution retrospective study of subjects with brain metastases with renal cell carcinoma, melanoma, squamous cell carcinoma and non–small-cell adenocarcinoma treated with single or multiple fraction stereotactic radiation looking at the effect of ICI therapy (ipilimumab, pembrolizumab, nivolumab, durvalumab, or atezolizumab) as additional interventions.⁹⁸   Timing was also investigated with ICI therapy being termed concurrent if it occurred ≤3 months of the radiation. Lesions treated with SRS and ICI therapy had significantly improved 1-year local control compared with SRS alone (98% and 89.5%, respectively [P = .0078]). On subset analysis of non–small-cell adenocarcinoma patients alone, addition of ICI therapy was also associated with improved 1-year local control (100% vs 90.1%; P = .018). On multivariate analysis, only tumor size ≤2 cm was significantly associated with local control (P = .02), as was concurrent ICI therapy with SRS (P = .08). For combined SRS and ICI therapy, 1-year distant brain failure (41% vs 53%; P = .21), OS (58% vs 56%; P = .79) and radiation necrosis incidence (7% vs 4%; P = .25) were similar to SRT alone for the population as a whole and for the subset of those patients with non–small-cell adenocarcinoma.

  

A single-institution retrospective study was conducted by Chen et al to evaluate subjects treated with brain metastases from NSCLC, melanoma, and renal cell carcinoma who were treated with single or multiple fraction radiosurgery and ipilimumab and nivolumab or pembrolizumab.⁹⁹ A large focus of the study was on timing of radiation and immunotherapy. Concurrent therapy was defined as ICI therapy within 2 weeks before or after SRT. The median OS for patients treated with SRT alone, SRT with nonconcurrent ICI, and SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRT with concurrent ICI was associated with improved OS compared with SRT alone (P = .002) and compared with nonconcurrent SRT and ICI (P = .006) on multivariate analysis. The OS benefit of concurrent SRT and ICI was significant in comparison with patients treated with SRT before ICI (P = .002) or after ICI (P = .021).

 

Immune Modulators for the Therapy of Parenchymal Brain Metastases of Primaries Other Than NSCLC or Melanoma

One study of immune therapy on a single histology other than NSCLC or melanoma met inclusion criteria and was included in the Evidence Table (Table 9). Uezono et al reported a single-institution retrospective analysis of subjects with renal cell carcinoma brain metastases treated with SRS alone or with immunotherapy (ipilimumab or nivolumab, combined ipilimumab and nivolumab, or cytokine agents [interleukin 2 and/or interferon alpha]). ¹⁰⁰ Median OS was 27.2 months for the immunotherapy group and 14.9 months for the nonimmunotherapy group (P = .014). Patients who received ICI at any time had a median OS of 33 months compared with 16.7 months in those who never received ICI (P = .03). Limitations in this study for the purposes of this guideline include a definition of immunotherapy in some portions of the analysis that includes interleukin 2 and interferon alpha lumped together with ICIs.

 

Synthesis

NSCLC

The literature regarding immunotherapy for parenchymal metastases from NSCLC provides 11 class III articles. These are largely related to the combined use of SRT and ICIs. The data primarily support the use of ICIs with SRS or SRT in a small number of fractions over radiation alone, or radiation plus cytotoxic chemotherapy, as it provides superior median survival, a smaller incidence of local failure, longer intracranial PFS, and decreased distant intracranial failure.^62,65–67 There is only 1 contradicting study finding no survival benefit or disease control benefit with to the addition of ICIs.⁷⁰ Intracranial progression is also lower in subjects treated with ICIs whose tumor cell population expression of PD-L1 receptor is >50% whether or not they receive concurrent radiation therapy. In terms of timing, immunotherapy administration before, during, or after SRT was studied by more than one set of authors but in an inconsistent manner, precluding the ability to conclusively say which time schedule was superior for disease control. The addition of anti–PD-1 therapy to WBRT was noted to improve median survival time.⁶⁸ In 1 study combining SRT and WBRT the authors still observed better OS with the addition of ICIs compared with cytotoxic chemotherapy. In selected cases when radiation is not part of the treatment, and especially when tumors are stable for ≥4 weeks and PD-L1 expression is >50%, median OS with pembrolizumab is superior to cytotoxic chemotherapy.^63,66,71 It should be recognized that this benefit may also extend to a broader population, namely subjects whose tumors have been stable for only 2 weeks and TPS PD-L1 expression is >1%.⁷² The superiority of PD-1 inhibitors alone versus their combination with CTLA-4 inhibitors or CTLA-4 inhibitors alone cannot be determined with this information because of variations in study design and comparisons across the qualifying studies. Based on this information, one level III recommendation can be created stating that in individuals with brain metastases from NSCLC it is suggested that ICIs be used with radiation therapy to increase median survival, decrease incidence of local failure, increase intracranial PFS, and decrease distant intracranial failure. In addition, a second level III recommendation can be formulated stating that in individuals with brain metastases from NSCLC that are clinically stable for ≥4 weeks and with PD-L1 TPS >50% it is suggested that ICIs be used without radiation to improve median OS.

 

Melanoma

One class I study regarding the use of ICI therapy for MBMs is available.⁹² It demonstrates that in subjects with active, untreated, asymptomatic lesions treatment with ipilimumab plus nivolumab provides superior median OS compared with other systemic therapies. The remainder of the qualifying articles provided class III data. One retrospective study and 1 underpowered prospective study support the class I study suggesting the superiority of combined ICI therapy to combination targeted therapy in terms of response rate and survival.⁹³ However, this is contradicted in another study where upfront immunotherapy without surgery or radiation produced inferior OS.⁹⁴ As with NSCLC brain metastases, many of these investigations looked at ICI therapy in some combination with radiation. SRS combined with immunotherapy provided superior local control, a reduction of distant intracranial failure, and longer survival when compared with SRS alone or SRS in combination with targeted agents.^80–83,91 As is common with class III data, some articles provided contradictory data and there were instances where the addition of immunotherapy did not improve local control or survival compared with SRS alone or SRS combined with targeted agents.^78,87,88,90 Interestingly, 6 qualifying articles suggest that immunotherapy added to some form of radiation is beneficial for disease control and survival and 6 reached the opposite conclusion. This precludes the ability to make a recommendation about the use of ICIs and stereotactic radiation in single or multiple fraction applications. Studies of the timing of administration of immunotherapy in relation to radiation therapy was investigated and concurrent administration could not be conclusively shown to be superior to nonconcurrent administration.^82,83,85 Also, the addition of immunotherapy to WBRT does not appear to improve median OS and in fact was inferior to immunotherapy alone.⁹¹ Qualifications were often needed to describe benefits, ie, better local control or survival was seen only in long-term survivors or providing only a trend toward improved survival when compared with targeted therapies or radiation. As with NSCLC, the variability in study design precluded the ability to specifically state which ICI or combination thereof was superior when added to radiation therapy. Based upon this information, a level I recommendation can be created stating that in individuals with active, untreated, asymptomatic MBMs ipilimumab plus nivolumab is recommended to increase median OS.

 

Other Primary Sites

Five qualifying articles evaluated brain metastases from multiple primary sites including melanoma and NSCLC or looked at primary sites other than melanoma and NSCLC. In 2 large database studies, even with minimal exposure to ICI therapy OS was prolonged in NSCLC, breast carcinoma, colon carcinoma, and melanoma.^96,97 As was seen in some studies of NSCLC and MBMs, the addition of immunotherapy to radiation of one form or another improved local control and OS for other histologies, especially when given ≤2 weeks of the radiation therapy.^98,99 Contradictory results were present for renal cell carcinoma.^96,97,100 Based on this information, a level III recommendation can be formulated stating that in individuals with brain metastases from breast cancer or colon carcinoma it is suggested that therapy with ICIs be considered alone or with radiation therapy to increase median survival and decrease the incidence of local failure.

 

Immunotherapy of Leptomeningeal Metastases

Question 4: In patients with leptomeningeal brain metastases, does the use of immune modulators provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, molecular targeted agents, SRS, WBRT, and surgical resection?

 

Recommendation

There is insufficient evidence to make a recommendation regarding the use of immune modulators for the therapy of leptomeningeal brain metastases.

 

The literature searches for targeted therapy and immunotherapy for leptomeningeal brain metastases resulted in some overlap in citations despite careful design of the search terminology. Therefore, the numerical results of the 2 searches were combined to reflect that we used citations from the results from both searches. The literature search yielded 3005 abstracts. Task force members reviewed all abstracts yielded from the literature searches and identified the literature for full-text review and extraction, addressing the clinical questions in accordance with the Literature Search Protocol (Appendix I). Task force members identified the best research evidence available to answer the targeted clinical questions.

 

The task force selected 40 full-text articles related to immunotherapy for leptomeningeal brain metastases for full-text review. Of these, 28 rejected for not meeting inclusion criteria or for being off topic. Twelve were selected for systematic review (Appendix III). In order to improve the coherence the discussion of the immunotherapy of leptomeningeal brain metastases, the qualifying articles are divided into those related to a mixed group of histologies and those that dealt with melanoma leptomeningeal brain metastases.

 

Immunotherapy for a Mixed Cohort of Leptomeningeal Metastases

 

One qualifying study was published with an analysis combining two different tumor types (Table 10). Minniti et al¹⁰¹ retrospectively analyzed a mixed cohort of patients with LMs, including NSCLC and melanoma, and found that immunotherapy combined with fractionated SRS was better than fractionated SRS alone in preventing leptomeningeal spread.¹⁰¹ Also, the median OS was 24.8 months in the combination treatment group and 14.7 months in the nonimmunotherapy group (P = .007). Given the mixed cohort, and the analysis combining histologies, it is difficult to draw individual conclusions for primary cancer subtypes without additional data.

 

Synthesis

One study suggests value in the addition of immunotherapy to fractionated SRS in relationship to NSCLC and melanoma. The data were analyzed by combining the histologies, precluding the ability to make reasonably focused recommendations.

 

Immune Modulators for the Therapy of Melanoma Leptomeningeal Metastases

 

Tétu et al¹⁰² retrospectively studied 41 melanoma patients with LM treated with targeted therapy, radiation therapy, immunotherapy, or some combination of them (Table 11).¹⁰² The median OS of the 10 patients in which treatment sequence after leptomeningeal tumor diagnosis included BRAF inhibitors was 6.4 months, while median OS was 5.1 months for the 22 patients in which treatment sequence after leptomeningeal tumor diagnosis included ICIs. Median OS was 7.1 months for the 9 patients receiving radiation therapy combined with some form of systemic therapy and 3.2 months for the 20 patients not receiving radiation therapy. Immunotherapy was not associated with significantly improved OS (P = .37). The mixed nature of the therapies limits the ability to make strong conclusions about one therapy versus another.

 

Synthesis

One retrospective study assessed the use of immunotherapy in melanoma after diagnosis with leptomeningeal tumor, finding no survival benefit to treatment. The mixed nature of the therapies in the single article limits the ability to make strong conclusions about one therapy versus another and precludes creation of a recommendation.

 

Interstitial Modalities in the Therapy of MBTs

Question 5: In patients with parenchymal brain metastases, does the use of interstitial modalities, in the form of interstitial chemotherapy or radiation (brachytherapy, intraoperative radiation therapy), provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, immune modulators and molecular targeted agents, SRS, WBRT, and surgical resection?

 

Recommendations

There is insufficient evidence to make a recommendation regarding the use of interstitial modalities in the form of interstitial chemotherapy or radiation.

 

The literature search yielded 552 abstracts. Task force members reviewed all abstracts yielded from the literature search and identified the literature for full-text review and extraction, addressing this clinical question, in accordance with the Literature Search Protocol (Appendix I). Task force members identified the best research evidence available to answer the targeted clinical questions.

 

The task force selected 74 full-text articles for full-text review. Of these, 62 were rejected for not meeting inclusion criteria or for being off topic. Twelve were selected for systematic review; however, 11 studies captured in the search more appropriately apply to other questions in this guideline. This is because of the overlapping nature of the topics in the questions in this guideline. Therefore the writers deemed these 11 articles were best discussed in the text for those questions because of better context and similar studies. Thus, 1 study was reviewed for this question (Appendix III).

 

This qualifying article provided class III evidence, primarily because it was retrospective collection of cases. Details of the qualifying and informative article are available in Table 12.

 

The study by Julie et al¹⁰³ was a prospective collection of consecutive patients treated with resection and brachytherapy at a single institution between 2002 and 2014 who were retrospectively selected for study inclusion (30 patients).¹⁰³ Inclusion criteria included an ECOG of 0 to 2 and minimum expected survival of 6 months. Exclusion criteria included tumor proximity to the chiasm or brainstem, small cell carcinoma pathology, and pregnancy or refusal to use birth control. For comparison, a group of 60 patients who received adjuvant SRS during the same period and who also met the aforementioned inclusion criteria were retrospectively selected. To create clinically comparable cohorts, patients were matched according to preoperative tumor maximum dimension, histology, RPA class, and ECOG performance status. Tumor size was matched within ±5 mm. After resection, 10-cm suture-stranded Cs-131 seeds with a median activity of 3.8 mCi (IQR 3.5-4.0 mCi) were permanently implanted within the tumor bed, with 0.5-cm interseed spacing. Strands were placed tangentially within the resection cavity, with interstrand separation of 7 to 10 mm, and secured with dural sealant. A median of 14.5 seeds (IQR 8.25-20 seeds) were placed per cavity.¹  A dose of 80 Gy was prescribed to a 5-mm depth from the cavity surface. SRS was performed using linear accelerator, prescribed to the 80% isodose line. Prescriptions ranged from 18 to 33 Gy (median 24 Gy) in 1 to 5 fractions, to a 2-mm margin surrounding the resection cavity. Patients treated with Cs-131 had a significantly lower LR rate; 3 (10%) compared with 17 (28.3%) in the SRS group (OR 0.281 [95% CI 0.082-0.949]; P = .049). RR occurred in 5 (16.7%) Cs-131 patients and 6 (10.0%) SRS patients, with no significant difference between the groups (OR 1.8 [95% CI 0.545-6.252]; P = .363). DR occurred in 14 (46.7%) Cs-131 and 40 (66.7%) SRS patients, and this was not significantly different between the groups (OR 0.438 [95% CI 0.185-1.113]; P = .068). There was no significant difference in OS between the groups on log-rank testing (P = .093). Despite the well-controlled matching of this study attempted, there remained large differences in groups ensuing in varying results based on the type of statistical analysis performed. In addition, with the retrospective nature of this study, this study provides class III data.

 

Synthesis

As discussed, the literature for the utilization of interstitial modalities in the management of brain metastases is limited. It would be premature to make any recommendations based on a single study conducted in a retrospective in nature. However, with the current study it does suggest that there is a trend for benefit when using Cs-131 brachytherapy in some circumstances.  Additional studies need to be conducted in manner that class III data can be analyzed in such a way that the study is not flawed with mixed pathologies and or size of lesion, which may be difficult to control and accrue. Thus, a recommendation is being reserved until additional data are available.

 

Radiosensitizers in the Therapy of MBTs

Question 6: In patients with parenchymal brain metastases, does the use of radiosensitizers provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, immune modulators and molecular targeted agents, SRS, WBRT, and surgical resection?

 

Recommendations

Level II: When WBRT is utilized for brain metastases from NSCLC, it is recommended that temozolomide be added to provide a smaller incidence of local failure, longer intracranial PFS, and longer OS.

 

Level III: For brain metastases from NSCLC with an EGFR mutation where WBRT or SRS is indicated, is it suggested that EFGR TKIs be added to that therapy to improved intracranial response rate and survival.

 

The literature search yielded 251 abstracts. Task force members reviewed all abstracts yielded from the literature search and identified the literature for full-text review and extraction, addressing this clinical question, in accordance with the Literature Search Protocol (Appendix I). Task force members identified the best research evidence available to answer the targeted clinical questions.

 

The task force selected 97 full-text articles for review. Of these, 81 were rejected for not meeting inclusion criteria or for being off topic. Sixteen were selected for systematic review (Appendix III).

 

Most of the qualifying articles all provided class III evidence, primarily because they were retrospective collections of cases with concurrent or historical controls, or no comparisons provided. The remaining were small randomized or not well-controlled prospective or randomized studies thus providing class II evidence. Details of the qualifying and informative manuscripts are available in Table 13.

 

Temozolomide With Radiation Therapy

Most of the qualifying studies (8/16) were to determine the extent of disease control using temozolomide with radiation therapy, primarily WBRT.

 

The first of these studies was Liu et al,¹⁰⁴ who in 2017 performed a randomized single-institution study of adult patients with pathologically diagnosed with ≥3 BMs with a KPS ≥60 and expected survival time was >3 months who underwent WBRT (36 pts, single radiotherapeutic dose was 2.0 Gy, once daily, 5 times every week, with a total dose of 40 Gy) or WBRT + TMZ (36 pts, during radiation therapy, 75 mg/m²/day, once daily, after radiation therapy, complementary TMZ administrated of 150-200 mg/m²/day, for continuously 5 days, with 28 days as a cycle, until the disease progression or drug withdrawal due to intolerable toxic responses).¹⁰⁴ The authors found ORR in among the WBRT+TMZ group (77.78%, 28/36) was higher than that of in WBRT only group (47.22%, 17/36), with significant difference (P = .0074). However, the disease control rate in the WBRT + TMZ group (94.44%, 34/36) was only slightly higher than that of WBRT alone group (86.11%, 31/36) (P = .4263).¹⁰⁴ Moreover, after WBRT+TMZ treatment, compared with WBRT alone group, additionally the WBRT+TZ group showed markedly better improvement in symptoms and signs, as well as QOL (P < .001), with significantly longer OS and PFS (P < .001). Due to small size and mixing of various BM pathologies this was considered class II evidence.

 

In a similar study, a single-institution retrospective study of 238 NSCLC patients with BM were reviewed and categorized into WBRT + TMZ arm and WBRT alone.¹⁰⁵ Deng et al¹⁰⁵ found that intracranial ORR and disease control rate (DCR) for WBRT +TMZ (129 pts, 30 Gy for 10 fractions + TMZ 75 mg/m²/day was administered daily during radiation treatment, after the completion of WBRT, TMZ 100 mg/m² was continued for 14 days and repeated every 28 days until unacceptable toxicity or disease progression for up to 6 cycles) and WBRT alone arm (109 pts, 30 Gy for 10 fractions) were 34.9% versus 20.2% (P = .01) and 98.4% versus 92.7% (P = .03), respectively. The median intracranial PFS and OS of NSCLC patients with BM were 5.2 and 7.3 months, respectively. The median PFS of WBRT+TMZ arm was significantly longer than that of WBRT alone arm (5.9 vs 4.9 months, P = .002).¹⁰⁵ The median OS of the WBRT+TMZ arm was also slightly longer than that of the WBRT alone arm (8.5 vs 5.9 months), but without statistical significance (P = .11). Due to the retrospective nature of this study this was considered class III evidence.

 

A smaller similar study by Zhu et al¹⁰⁶ was a single-institution retrospective study of 78 NSCLC patients with BM including 45 patients who received WBRT + TMZ (2 Gy × 5 days each week for 4 weeks, for a total dose of 40 Gy.¹⁰⁶  TMZ was administered at 75 mg/m²/day during WBRT and 150 mg/m²/day × 5 days every 28 days after WBRT to fasting patients for a maximum of 6 additional cycles; treatment was continued until disease progression or unacceptable toxicity) and 33 patients who received WBRT alone (2 Gy × 5 days each week for 4 weeks, for a total dose of 40 Gy). The TMZ + WBRT arm achieved significant improvement in ORR (P = .0108) compared with the WBRT arm.¹⁰⁶ PFS in the TMZ + WBRT arm was significantly longer than in the RT arm (6.0 vs 3.5 months, P = .038). However, OS was not significantly different between the 2 arms. Statistically significant differences in neurocognitive function and QOL were observed between the arms at one time point of 6 months. Due to retrospective analysis performed this was classified as class III evidence.

 

A larger prospective randomized single-institution study of adult patients with histologically diagnosed BM with a ECOG status of the subjects ranged between 0 and 3, and had no uncontrolled morbidities were enrolled and divided into 2 groups treated with either WBRT + TMZ (122 pts) or WBRT alone (117 pts).¹⁰⁷ All patients received 30 Gy WBT, with or without concomitant TMZ (75 mg/m²/day) during the irradiation period, and subsequently up to 6 cycles of TMZ (150 mg/m²/day). Zhan et al¹⁰⁷ found that the intracranial ORR for WBRT arm and WBRT+TMZ group arm were 32.48 and 56.56 %, respectively (P = .03). The median OS for WBTT alone group (6.53 months) was significantly shorter than that of the WBT + TMZ arm (9.57 months, P = .001). In addition, a statistically significant difference in QOL was observed between both arms at one time point of 6 months (P < .05).¹⁰⁷ Due to the size and prospective collection these data were categorized as class II evidence.

 

A similar designed study in design but focused on NSCLC was conducted with 77 patients with confirmed primary of NSCLC and BM treated with concurrent WBRT + TMZ (40 pts [75 mg/m² orally, once daily until the end of WBRT]) compared with WBRT alone (37 pts [total dose of 30 Gy/10 fractions, 3 Gy/day on days 1-5 weekly]).¹⁰⁸ The patients were required to meet the following criteria: 1) Ffirst-time patients with pathologically diagnosed NSCLC and with no other prior tumors, and with a KPS score ≥70; 2) BM confirmed by MRI with cranial lesions and no previously administered cranial RT; 3) 18 < age < 75 years; iv) no other serious medical conditions, an expected survival >3 months and adequate renal, hepatic and hematological function. Lv et al¹⁰⁸ found the use of TMZ + WBRT exhibited an advantage over the using WBRT alone in terms of objective response and OS (P < .5) without notable toxicity.¹⁰⁸ This small prospective study was deemed class II evidence.

 

A more recent but small study of 18 patients with confirmed primary of NSCLC and BM treated with concurrent WBRT + TMZ (75 mg/m²/day from the first day to the end of day 14) compared with WBRT alone (30 Gy in 10 daily fractions to clinical tumor volume [CTV, which they defined as whole brain] according to intensity‐modulated radiation therapy [IMRT], then an additional dose of 9 Gy in 3 fractions of IMRT was delivered to gross tumor volume [GTV]). Patients with histologically confirmed lung adenocarcinoma with no more than 4 (≥1 and ≤4) BMs by MRI and controlled extracranial disease were recruited. Patients were aged ≤75 years and had a World Health Organization Performance Status (PS) of ≤3. Eligible patients may have received previous radiation therapy to the primary tumor or systemic metastatic sites but no previous WBRT or RT for BMs. Li et al⁴⁷ showed an increase in CR (11.1%), PR (66.7%), and OR (77.8%) for the WBRT + TMZ versus CR was 0, PR rate was 44.4%, OR rate was 44.4% for WBRT alone group. The mean QoL score after 3 months was significantly improved, and there were significant differences (P ≤ .05). Due to the very small size of this study this was classified as class III evidence.

 

Similar to previous studies, Liu et al⁹ retrospectively analyzed 128 patients with BM originating from NSCLC.⁹  These patients received synchronous SRS with TMZ+WBRT (TMZ group TME was taken from 3 day before radiation therapy at a dose of 75 mg/m²/day once a day, 5 times a week, and 2 courses of TME chemotherapy (150-200 mg/m² once a day for 5 consecutive days, with 28 days as 1 course), and 64 underwent SRS+WBRT (SRT [complementary irradiation of lesions once every other day], 3 times a week, 80-90% isodose curves covered the planning target volume [PTV], the single dose was 6-8 Gy, 3 times a week, and the final intracranial lesion dose was 48-64 Gy, WBRT of 2 Gy/time, a total dose of 36-40 Gy, and a treatment course of about 4 weeks, radiation therapy group). Inclusion criteria were patients with extracranial lesions diagnosed by histopathology and intracranial metastases diagnosed via MRI examination, those with 1 to 5 brain metastasis/metastases <5 cm in diameter, those without dura/pia metastases, those with KPS ≥60 points, those with expected survival time >3 months, those without a history of craniocerebral radiation therapy, and those who never received TMZ.⁹ OS and PFS of patients in the TMZ group were more prolonged than those in the radiation therapy group (P = .041, P = .025). Univariate and multivariate regression analyses suggested that the absence of extracranial metastasis (P = .001), number of intracranial metastases <3 (P = .001), RPA class I (P = .001), and Mini Mental Status Examination score ≥27 points before radiation therapy (P = .001), and treatment with TMZ were statistically significant factors affecting the prognosis. Due to retrospective collection and various dosages of SRS and WBRT this study was classified as class III data.

 

Lastly and the most recent study via Zhang et al¹⁰⁹ was a prospective randomized study of 106 patients with MBTs into TMZ + WBRT (53 patients, TMZ dosing and scheduled not defined) or WBRT alone groups (53 patients, radiation dose of 4000 cGy being delivered in 20 fractions at 200 cGy per fraction, 5 days per week over 4 weeks).¹⁰⁹ Short-term remission after treatment was higher in the TMZ + WBRT group compared with WBRT alone (P < .05). During the 24-month follow-up, they found that patients in the TMZ + WBRT group had longer recurrence time and survival time than their counterparts in the WBRT alone group (P < .05).¹⁰⁹ After treatment, the scores of the QOL of patients in the TMZ+WBRT were better than those in the WBRT alone group (P < .05). Also, there was a lower rate of the incidence of the adverse reactions in the TMZ+WBRT (P < .05). This prospective study provides class III data based on the lack of methodology for randomization and unclear dosing of TMZ.

 

Radiation-Enhancing Agents With Radiation Therapy

Various agents are being used as radiation-enhancing agents or radiosensitizers both in the treatment of primary solid tumors outside the CNS but more recently with in the treatment of BMs. Zeng et al¹¹⁰ performed a single-institution blinded randomized study of 64 patients with multiple brain metastases from NSCLC into the 2 groups of WBRT + sodium glycididazole (32 pts, 700 mg/m² intravenously 30 min before radiation therapy, 3 times a week) versus WBRT (32 pts, of 30 Gy in 10 fractions [from Monday to Friday, in equal doses of 3 Gy daily] were delivered over 3 weeks).¹¹⁰ Eligibility criteria included newly radiographically diagnosed brain metastasis from NSCLC, without previous craniotomy or SRS, age ≥18 years, ECOG performance status ≥3, and evidence of normal hematologic and hepatic function during the 30 days before starting the protocol treatment.¹¹⁰ Patients with solitary brain metastasis suitable for SRS or surgical resection, or with miliary brain metastases, were excluded. They found that CNS disease control rate was better (90.6% vs 65.6%, P = .016) in the WBRT + sodium glycididazole group than in the WBRT alone group at 3 months of follow-up. The median CNS PFS time was longer in the WBRT + sodium glycididazole group than in the WBRT alone control group (7.0 months vs 4.0 months, P = .038).¹¹⁰ However, there was no significant difference of the median OS time between the WBRT + sodium glycididazole group and the WBRT alone group (11.0 months vs 9.0 months, P = .418).¹¹⁰ Lastly, treatment-related toxicity showed no statistically significant difference between these 2 groups (P > .05). This prospective randomized study was concluded to provide class II evidence.

 

Another agent traditionally not thought as radiosensitizer, simvastatin, was investigated by El-Hamamsy et al¹¹¹ in a prospective randomized, controlled, open-label pilot study of 50 patients with BM who were randomly assigned to receive 30 Gy WBRT (control group 25 patients) or 30 Gy WBRT+ simvastatin 80 mg/day for the WBRT period (simvastatin group 25 patients).¹¹¹  Response rates were 60% and 78.6% (P = .427), 1-year PFS rates were 5.2% and 17.7% (P = .392), and 1-year OS rates were 12% and 8% (P = .880) for the control and simvastatin groups, respectively. Nonsignificant differences were found between the 2 arms regarding health-related QOL scales. The addition of simvastatin at the dose tested did not improve the clinical outcomes of patients with BM receiving WBRT. This randomized study provided class II evidence.

 

Lastly, sorafenib has demonstrated both antitumor efficacy and radiosensitizing activity preclinically. Morikawa et al¹¹² conducted a phase I trial of WBRT + sorafenib using a 3+3 (NCT01724606) design with safety-expansion cohort. Sorafenib was given daily at the start of WBRT for 21 days.¹¹² The study included patients with histologically confirmed breast cancer and new or progressive BMs (≥10 mm in longest dimension) by MRI of the brain. Patients were required to have planned WBRT based on number or size as assessed by the treating investigator. The protocol specified WBRT (1 fraction /day × 10 fractions) to be administered. Patients with leptomeningeal metastases were allowed if confined to the WBRT field only (additional MRI spine was required to demonstrate no other area of involvement within 4 weeks of enrollment). Other key eligibility criteria included KPS≥70, a nonescalating dose of steroid (<16 mg daily of oral dexamethasone) for ≥5 days, and no previous exposure to an anti-VEGF agent except bevacizumab. Patients must have had adequate organ function. The study planned for 3 dose levels of sorafenib dosed once daily at 200 mg, 400 mg, and 600 mg. The authors found that concurrent WBRT and sorafenib appear safe at the 200 mg daily dose with clinical activity. CNS response was favorable compared with historical control subjects. A small phase I clinical trial provides class III data.

 

Targeted Therapy With Radiation Therapy

Targeted therapy is increasingly being employed concurrently as an adjuvant in the treatment of metastatic disease with radiation therapy. One such agent, vandetanib, an inhibitor of vascular endothelial growth factor receptor, EGFR, and rearranged during transfection tyrosine kinases, was recently investigated in a double-blind, multicenter, phase 2 trial of patients with melanoma BM in which they were randomized to receive WBRT (30 Gy in 10 fractions) plus 3 weeks of concurrent vandetanib 100 mg once daily or placebo.¹¹³ Gupta et al¹¹³ recruited 24 patients, 6 to the safety phase and 18 to the randomized phase. They found that the combination of WBRT plus vandetanib was well tolerated. However, compared with WBRT alone, there was no significant improvement in PFS brain or OS, the authors were unable to provide a definitive result secondary due to poor accrual. Due to failure of power and accrual this study provides class III evidence.

 

Newer-generation TKIs can improve outcomes in patients with EGFR-mutant NSCLC-BM.¹¹⁴ Lee et al¹¹⁴ conducted a retrospective review of consecutive cases of NSCLC BM who underwent SRS. Inclusion criteria were as follows: 1) patients for whom a diagnosis of NSCLC had been confirmed by lung biopsy or open surgery and for whom EGFR mutation status was checked; 2) patients who had diagnoses of 1 or several BMs confirmed by MRI; 3) patients who had been treated with SRS; and 4) patients who underwent clinical and neuroimaging follow-up at least once. EGFR-TKI agents included gefitinib (Iressa), erlotinib (Tarceva), afatinib (Gilotrif), and osimertinib (Tagrisso). Patients who did not undergo SRS and cases that were not proven to be NSCLC were excluded. During the 2-year follow-up period of 264 patients (1069 BMs) after SRS, the intracranial response rate in the EGFR-mutant group was approximately 3-fold higher than that in the wild-type group (P < .001).¹¹⁴ Cox regression multivariate analysis identified EGFR mutation status, extracranial metastasis, primary tumor control, and prescribed margin dose as predictors of tumor control (P = .004, P < .001, P = .004, and P = .026, respectively). Treatment with a combination of SRS and TKIs was the most important predictor of OS (P < .001). This retrospective review due to use of various TKI data lends itself to class III evidence for the utilization of TKIs in NSCLC and thus a suggestion of their use in the management in NSCLC BMs.

 

A similar study was conducted by Yomo et al³¹ in which they retrospectively reviewed NSCLC BM patients that the authors divided into 2 groups based on the use of EGFR-TKI.³¹ The definition of EGFR-TKI use includes concurrent use at the time of the first GKS and/or post-SRS use for ≥3 weeks. Cases with early withdrawal due to side effects were not included in the EGFR-TKI use group. Six hundred eight eligible patients with lung adenocarcinoma were identified. Of these, 238 patients (39%) had received EGFR-TKI concurrently or in the post-SRS clinical course and 370 had not. During the case registration period (2009-2012), only first-generation EGFR-TKIs gefitinib and erlotinib were available. The median OS was 25.5 months (95% CI 20.1-29.4) in the patients receiving EGFR-TKI versus 11.0 months (95% CI 8.8-13.0) in those not receiving EGFR-TKI (HR 0.60 [95% CI 0.48-0.75], P < .001). The cumulative incidences of distant intracranial recurrence were higher in patients receiving EGFR-TKI than in those not receiving EGFR-TKI after adjustment for competing events (HR 1.45 [95% CI 1.12-1.89], P = .005). The risk of leptomeningeal dissemination did not, however, differ significantly between the 2 groups (HR 1.32 [95% CI 0.87-2.00], P = .19). There was no statistically significant difference in the cumulative incidences of local tumor progression between the 2 groups (HR 0.87 [95% CI 0.49-1.54], P = .63). The major limitation of this study was a lack of genetic information on the presence or absence of EGFR mutations. This retrospective review due to use of various TKI and the EGFR status of those receiving EGFR-TKI lends itself to class III evidence for the utilization of TKIs in NSCLC BMs.

 

Sun et al²⁹ performed a randomized single-institution study of 58 patients with NSCLC with BMs into 2 groups: control group (29 pts, WBRT + chemotherapy) versus observation group (29 pts, WBRT + targeted therapy).²⁹ The control group received concurrent WBRT (8 mV X-ray for 5 times per week, 3 Gy per time, totaling 30 Gy) and paclitaxel and pemetrexed were intravenously infused at the dose of 175 mg/m2 and 500 mg/m2 respectively; cisplatin was infused intravenously at the dose of 25 mg/m² from the first day to the third day. There was an interval of 3 weeks or 4 weeks between every course, totaling 3 courses. The observation group received concurrent WBRT (8 mV X-ray, 2 Gy/time, 5 w/time, 40 Gy for 4 weeks) and gefitinib for targeted therapy for those diagnosed with adenocarcinoma, 250 mg per day; for patients diagnosed as squamous cell cancer, erlotinib 150 mg per day. Targeted therapy stopped 2 months after the completion of radiation therapy.²⁹ The disease control rate of the observation group was 68.97%, significantly higher than 41.38% of the control group (P < .05); the total incidence of adverse reactions in the observation group was 6.90% significantly lower than 24.14% of the control group (P < .05); the median survival time of the observation group was (16.81 ± 5.32) months, significantly longer than that of the control group (9.76 ± 3.25 months). The 1- and 2-year survival rates in the observation group were significantly higher than those in the control group (P < .05). This yields class III evidence as mixed targeted therapy was based on pathology and there was inconsistent WBRT treatment between groups. This precludes formulation of specifically worded recommendations regarding use of specific targeted therapy as a radiosensitizer based on this article.

 

Pyrotinib is an irreversible pan-ErbB receptor TKI that simultaneously targets HER1, HER2, and HER4 and thus it has been used as targeted therapy against HER2-positive breast cancer.¹¹⁵ Tian et al¹¹⁵ conducted a single-institution randomized study of 20 patients with HER2+ BM breast cancer that were separated into pyrotinib (400 mg/daily days 1-21) plus capecitabine and capecitabine-only (1000 mg 2 times daily, days 1-14) groups, all of which were treated with WBRT (30 Gy delivered in 10 fractions over the course of 2 weeks). Only patients who have only received ≤2 prior lines of chemotherapy for metastasis were included. Other exclusion criteria include any anticancer treatment received <4 weeks before enrollment, any previous treatment with HER2-targeted TKIs, including pyrotinib, lapatinib, and neratinib, and prior presence of any breast cancer–unrelated brain tumors. In terms of intracranial disease extent, all included patients were diagnosed with 1 or 2 brain metastasis sites. Patients with brain metastases to the cerebrospinal fluid—that is, leptomeningeal disease—were not included. Only patients with diameters of intracranial metastases <3 cm were included in the study. Drug treatment was maintained until one of the following criteria was reached: unacceptable toxicity, withdrawal of patient consent, and doctor’s recommendation of termination. A significant difference was observed in the ORR between the 2 groups (P < .0001). In addition, median PFS, TTP, and DoR were all significantly improved for patients in the pyrotinib + capecitabine + WBRT group compared with capecitabine + WBRT (all P < .0001). This randomized study was classified as class III evidence due to the randomization process, small size, and poorly defined treatment regimens.

 

Immunotherapy With Radiation Therapy

Most recently immunotherapy, specifically immune checkpoint blockade, has been under investigation with radiation therapy as it is often used for systemic management of the primary tumor. Schmidberger et al¹¹⁶ performed a retrospective review of patients with BM from melanoma treated at their institution that received ipilimumab (IPI) with WBRT or SRS (41 patients) compared with those that received WBRT as a historical controls (27 patients). They found that patients treated patients who received IPI after irradiation had the best OS compared not only with the historical controls (3.0 months, P = .000001) but also with the patients who had received IPI before irradiation (3.0 months, P = .015). The difference between the 2 previously mentioned groups (IPI before radiation therapy vs historical controls) was only marginally significant (P = .045). Regarding PFS, patients who had received IPI after radiation therapy again had a significantly more favorable outcome than those who had been treated with IPI before radiation therapy (6.0 vs 2.0 months, P = .019), thus suggesting that the sequence of RT and ICI inhibition with IPI may be crucial for the success of combined modality treatment of MBMs. This is retrospective study qualified for inclusion in this guideline and provides class III evidence, but because the immunotherapy was not concurrent with the radiation, this article does not really address a radiation sensitizer and cannot be used for the purposes of a recommendation.

 

Synthesis

No qualifying manuscripts were found to address intraoperative radiation therapy and thus no recommendations were developed regarding that topic.

 

Temozolomide With Radiation Therapy

The literature regarding temozolomide with radiation therapy for parenchymal metastases from primarily NSCLC but also other primary tumors provides 5 class III articles and 3 class II articles. These are largely related to the combined use of WBRT and temozolomide. The data primarily support the use of temozolomide with radiation therapy, as it provides a smaller incidence of local failure, longer intracranial PFS, and longer OS. There were no contradicting studies of the benefit of local control with the addition of temozolomide to standard radiation therapy regimens for brain metastases. Overall, the use of TMZ with radiation therapy appears to result in a survival benefit in patients with 4 or fewer BMs for those with controlled systemic disease; however, toxicity or neurocognition data are limited to short time periods of 6 months and additional studies will be needed for long periods and in conjunction with stereotactic radiation. Based on this information, a level II recommendation can be formulated stating that when WBRT is used for BMs from NSCLC it is recommended that temozolomide be added to provide a smaller incidence of local failure, longer intracranial PFS, and longer OS.

 

Radiation-Enhancing Agents With Radiation Therapy

The literature regarding radiation-enhancing agents with radiation therapy for parenchymal metastases included provides 1 class III articles and 2 class II articles. These agents are reviewed are heterogenous as each paper discussed different radiation-enhancing agents. Thus, comparisons and recommendations should be tempered as conclusions per agent rest on a single qualifying study for each agent reviewed. Overall, there are agents that seem to have a beneficial radiation-enhancing effects when used with WBRT; however, these studies need to be expanded and replicated in additional pathologies and newer targeted radiation technologies which may also validate any abscopal effects if these agents. At this point, creation of a recommendations regarding any single agent noted in this guideline will require more published data focusing on each agent.

 

Targeted Therapy With Radiation Therapy

The literature regarding targeted therapy with radiation therapy for parenchymal metastases included 5 class III articles. The agents and study designs reviewed are heterogenous as each paper discusses different targeted therapies, tumor types, and tumor characteristics being evaluated. The study of pyrotinib for brain metastases from HER2 positive breast carcinoma supported its use with radiation therapy, keeping in mind that this was a class III study. Given its small size, the use of the single study for creation of a recommendation is not warranted at this time. The positive effect of newer-generation EGFR TKI inhibiting agents for NSCLC is present when given with SRS and WBRT. This warrants a level III recommendation stating that for brain metastases from NSCLC with EGFR mutation status where WBRT or SRS is indicated, is it suggested that EFGR TKIs be added to that therapy to improved intracranial response rate and survival.

 

LITT in the Management of MBTs

 

Question 7. In patients with parenchymal brain metastases, does the use of LITT provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, immune modulators and molecular targeted agents, SRS, WBRT, and surgical resection?

 

Recommendation

Level III: For adults who have undergone SRS for brain metastases with subsequent imaging progression due to tumor progression, it is suggested that LITT be considered as equivalent to craniotomy in terms of PFS and OS and the choice of management should be individualized based on the unique characteristics of the tumor location and the subject’s clinical status.

 

Level III: For adults who have undergone SRS for brain metastases with subsequent imaging progression due to radiation necrosis, it is suggested that LITT be considered as equivalent to medical management for radiation necrosis and the choice of management should be individualized based on the unique characteristics of the tumor location and the subject’s clinical status.

 

The literature search yielded 76 abstracts. Task force members reviewed all abstracts yielded from the literature search and identified the literature for full-text review and extraction, addressing this clinical question, in accordance with the Literature Search Protocol (Appendix I). Task force members identified the best research evidence available to answer the targeted clinical question.

 

The task force selected 28 full-text articles for review. Of these, 26 were rejected for not meeting inclusion criteria or for being off topic. Two were selected for systematic review (Appendix III).

 

All of the qualifying articles provided class III evidence, primarily because they were retrospective collections of cases with concurrent or historical controls, or no comparisons provided. Details of the qualifying and informative articles are available in Table 14.

 

LITT for MBTs

The first of these studies was Hong et al,¹¹⁷ in which their group performed a single-institution retrospective review of the clinical information for all patients who underwent craniotomies or LITT procedures for brain metastases after failing SRS between 2007 and 2016. Lesional regrowth was defined as an increase in 20% in any single dimension of the lesion as defined by RECIST criteria. Lesions considered to be radiation necrosis demonstrated no viable tumor cells after histologic analysis. Samples comprised of a mixture of necrosis and viable tumor cells were classified as recurrent tumor in this study. The decision to pursue craniotomy versus LITT was based upon surgeon judgment and patient preference on a case-by-case basis. Follow-up MRI scans and clinical outpatient visits typically occurred at 1, 3, and 6 months postsurgery.¹¹⁷ Failure of the surgical procedure was defined as regrowth of the ablated or resected lesion on T1-weighted post-contrast MRI with associated increased surrounding fluid-attenuated inversion- recovery, regardless of whether there was symptom recurrence. Among the 75 patients, 41 underwent craniotomy and 34 underwent LITT. Of the 41 treated with craniotomy, 15 patients had radiation necrosis and 26 had recurrent tumors. Among the 34 treated with LITT, 18 patients had radiation necrosis and 16 had recurrent tumors. The most common primary pathology was lung cancer (33/75, 44%) followed by melanoma (27/75, 36%) and breast cancer (7/75, 9.3%).

 

 The most common primary pathology was lung cancer (33/75, 44%) followed by melanoma (27/75, 36%) and breast cancer (7/75, 9.3%). Among patients treated for radiation necrosis, PFS was similar between those undergoing craniotomy (86.7% at 6, 12, 18, and 24 months) and those who had LITT (87.8% at 6, 12, and 18 and 73.2% at 24 months) (P = .68). Likewise, in patients who had recurrent tumor, PFS for craniotomy (61.0% at 6, 44.4% at 12, 18, and 24 months) was similar to LITT (62.5% at 6, 54.7% at 12, 43.8% at 18 and 24 months) (P = .99). In the craniotomy group, OS rates were 92.7% at 6 months, 69.3% at 12 months, 52.4% at 18 months, and 49.5% at 24 months, which was not significantly different from the LITT group with OS rates of 79.4% at 6 months, 69.0% at 12 months, 65.3% at 18 months, and 56.6% at 24 months (P = .904).¹¹⁷ Improvement (complete or partial) in symptoms was seen in 87% (20/23) of LITT patients and 90% (26/29) craniotomy patients. Complete resolution of preoperative symptoms, however, was reported in 21 of 29 (72.4%) of those treated with craniotomy compared with 6 of 23 (26.1%) treated with LITT (P < .01). Due to the study’s retrospective nature, various pathologies included, and rationale over treatment strategy, this was considered class III evidence.

 

In the second study, Sankey et al¹¹⁸ performed a multi-institutional, retrospective cohort review on 57 consecutive patients who underwent LITT versus 15 patients who received MM alone consisting of steroids for biopsy-proven RN after SRS for BM between 2009 and 2018. MM patients received biopsy independently from and without intent of LITT administration. No patients received additional therapies such as bevacizumab, vitamin E, or hyperbaric oxygen during the study period. Clinical and radiographic data were analyzed for disease progression or treatment response by a modified response assessment in neurooncology criteria. Local progression was defined as significant radiographic growth, >20% of the target contrast-enhancing lesion volume, with associated worsening symptomatology that necessitated an escalation in therapy (bevacizumab and/or craniotomy). Of note, transient changes in steroid dosing were not used as criteria for tumor progression because of a wide variation in dosing regimens and treatment course across patients.¹¹⁸ A total of 81 patients who presented with biopsy-proven RN after SRS for BM. Fifty-seven of these patients underwent LITT, and 24 did not.¹¹⁸ Of those 24, 2 were excluded for undergoing a subsequent craniotomy for RN resection and 7 did not receive any treatment.¹¹⁸ The LITT cohort was significantly faster to wean off steroids with a median duration after treatment of 37 days compared with 245 days (after biopsy-confirmed diagnosis) for those medically managed (ratio of 0.151 [95% CI 0.071-0.319], P < .001).¹¹⁸ The nonprogressing LITT cohort identified significant reduction from the baseline contrast-enhancing lesion volume at the 10 to 12 months posttreatment time point (P = .003) and from the first postoperative scan at 7 to 9 months (P = .005).¹¹⁸ By contrast, there were no statistically significant declines in contrast-enhancing lesion volume for the MM cohort.¹¹⁸ PFS and OS were not statistically different, P = .44 and P = .60, respectively. Again, due to its retrospective nature, various pathologies included, and rationale over treatment strategy, this study was considered class III evidence.

 

Synthesis

As discussed above, the qualifying literature for the use of LITT in the management of BMs is limited. Based on the 2 qualifying studies noted, there may be a benefit for employing LITT in some circumstances. Both demonstrate relative equality of LITT and craniotomy for tumor management and LITT and medical management for radiation necrosis based on similar PFS and OS in both settings. Both studies emphasize their limitations and that physicians need to carefully consider all clinical factors and individualize interventions. Having said that, these retrospective studies are well done and warrant serious consideration. Additional studies need to be designed in manner that they provide class II or better data that is not flawed with mixed pathologies, lesion sizes, and strategy limiting accrual.

 

Focused Ultrasound in the Management of MBTs

 

Question 8. In patients with parenchymal brain metastases, does the use of HIFU provide benefit in terms of local control, OS, PFS, performance status, or reduction in CNS side effects compared to standard management with chemotherapy, immune modulators and molecular targeted agents, SRS, WBRT, and surgical resection?

 

The literature searches for focused ultrasound for parenchymal and leptomeningeal brain metastases resulted in yielded 21 abstracts in accordance with the Literature Search Protocol (Appendix I). Task force members reviewed all abstracts and identified 1 item that addressed the clinical question for full-text review. Upon further review, this article was rejected for the small number of subjects studied, only including 4 cases (Appendix III).

 

Synthesis

As there was no qualifying literature, a recommendation cannot be formulated for the use of focused ultrasound in the management of parenchymal and leptomeningeal brain metastases.

 

Discussion

Updates are an integral part of guidelines in all portions of medicine. In relatively circumscribed topics, this can be straightforward and accomplished with literature searches finding a few dozen new pertinent articles to accomplish the update. The topic of emerging therapies for MBTs, or any other medical topic, is the opposite of that in the sense it is purposely more open ended. Thus, there are various limitations in updates such as this one. The searches result in a considerably greater amount of literature to be considered over what can be quite different treatment modalities. The updates are also limited by the authors’ knowledge of the field and imagination in creating searches encompassing what they consider those topics to be pertinent in the field. The dissemination of updates on emerging therapies also presents a conundrum in that it does take time to accomplish the steps of the update using a defined end date in the search parameters; by the time publication occurs, the information may no longer be “emerging therapy.”

 

An additional limitation is that much of the literature for targeted therapy and immunotherapy for metastatic tumors has been collected in a post hoc manner from trials designed to mainly assess systemic disease. This limits power and often results in uneven numbers of subjects between comparison groups, yielding class III data. Ideally, future studies would be directed toward cases with brain metastases as the group of primary interest, facilitating class II or even class I data and provide the ability to make stronger recommendations.

 

Having recognized those limitations, it is important to note that since the last version of this guideline, considerable progress has been made in the understanding of the use of targeted agents for brain metastases. This is important progress and is worth reiterating here as it rises to a level that allows formulation of concrete recommendations as noted in the beginning of this document. Impactful instances of this progress include ALK mutation positive NSCLC, where these agents provide improved local control and survival when used alone. In other cases, such as EGFR mutant NSCLC, newly diagnosed brain metastases secondary to NSCLC not assessed for EGFR and ALK mutations, EGFR and ALK mutation negative NSCLC, and HER2 mutation positive breast adenocarcinoma, the value of targeted therapy is best seen when combined with some form of radiation therapy. Melanoma metastases that are from tumors that are BRAF V600E positive have been shown to respond to dabrafenib plus trametinib with better local tumor control. Fewer data are available for leptomeningeal carcinoma, but there appears to be some limited survival value to the use of targeted agents in EGFR mutation positive NSCLC, ALK mutation positive NSCLC, and HER2 mutation positive breast carcinoma.

 

When considering immune modulating agents for parenchymal metastases, the clearest benefit appears to be in active, untreated, asymptomatic MBMs where ipilimumab plus nivolumab has been shown to increase median OS. Class III evidence supports the use of ICIs for brain metastases from NSCLC, breast cancer, and colon carcinoma. Though there are some data in regard to the use of immunotherapy for leptomeningeal carcinoma, they do not allow confident formulation of a guideline statement.

 

The previous version of these guidelines provided negative recommendations regarding radiosensitizers. This includes the lack of value of temozolomide in breast cancer brain metastases and the use of chloroquine for any type of brain metastases. New data now allow for positive recommendations that temozolomide, and to a lesser extent EGFR TKIs, serve as radiation sensitizers when given concurrently with radiation therapy for NSCLC.

 

With refinement of thermal imaging, targeting systems, laser sources, and delivery fibers the use of LITT has seen wider use. Despite this, well-done prospective comparative studies of this technology are wanting. However, enough data are now available to state that LITT is equivalent to craniotomy in the management of brain metastases progressing after radiosurgery. LITT is also noted to be equivalent to medical management of radiation necrosis after radiosurgery. These are low level recommendations, and the next version of this guideline will conduct a careful search to assess whether there are data to upgrade or add to them.

 

Looking through the qualifying publications on interstitial modalities such as implantable radiation therapy, implantable chemotherapy, and intraoperative radiation therapy, we find that further experience has been gained, but not to the extent that meaningful recommendations can be created. HIFU is a promising technology and publications about it were identified within the search strategies used, but none met inclusion criteria and thus no gradable data were available to pursue for recommendation formulation. The next version of this guideline will carry out a careful search on these 4 topics in an effort to find data that might eventually support meaningful recommendations.

 

Overall, and as is reflected in the comparative information in Table 1, a greater body of information on the emerging therapies for brain metastases has developed since the 2019 version of this guideline. This has allowed for concrete recommendations to be made on various levels to assist medical and surgical practitioners to manage this population of patients.

 

Since the completion of the search for this update, the proliferation of reported clinical research for targeted therapy and immune modulating agents for brain metastases has been the most notable. This includes newly reported prospective comparative studies on EGFR mutant NSCLC and low expression HER-2 breast cancer where incremental advances in knowledge have been made.¹¹⁹ Similarly, prospective, comparative analysis of PD-1 inhibition combined with cytotoxic chemotherapy for NSCLC has proved informative in regard to combining therapies with different antineoplastic mechanisms.¹²⁰ These and other such studies will likely be considered in the next version of this guideline.

 

Key Issues for Future Investigation

Ideally, future studies of all the modalities noted in this document would be directed toward cases with brain metastases as the group of primary interest, facilitating class II or even class I data and providing the ability to make stronger recommendations. Application of targeted therapy and immunotherapy is often applied in an adjuvant setting after surgery. Now, more often than in the past, these options are being explored as the initial therapy and such steps, even if investigational, are encouraged. Success on this front may preclude the need for surgery or radiation or at least delay need for those interventions or provide smaller and safer surgical or radiation targets. Truly prospective and comparative studies of LITT, beyond simple registries, looking at its value in relation to localized forms of radiation and medical/targeted therapies will clarify its value in the management of brain metastases. Until that is accomplished, increasing volumes of class III data are unlikely to increase acceptance and use of the technology. Similarly, HIFU is an exciting technology whose value is yet to be determined. As with LITT , it will require prospective, comparative studies to truly delineate its place on the menu of options for management of brain metastases.

 

Conclusions

Advancement of nonsurgical and surgical therapies for MBTs is occurring at a rapid rate as confirmed in this document. The most coherent approaches will be developed with cooperative study development across the specialties of radiation oncology, medical oncology, and neurosurgery.  Enrollment of subjects in trials of these interventions, be they sponsored by industry, academic institutions, or cooperative groups, is encouraged as this will assist in crystalizing our understanding of their role in MBTs.

 

Conflicts of Interest

All Guideline Task Force members were required to disclose all potential conflicts of interest (COIs) prior to beginning work on the guideline, using the COI disclosure form of the AANS/CNS Joint Guidelines Review Committee. The CNS Guidelines Committee and Guideline Task Force Chair reviewed the disclosures and either approved or disapproved the nomination and participation on the task force. The CNS Guidelines Committee and Guideline Task Force Chair may approve nominations of task force members with possible conflicts and restrict the writing, reviewing, and/or voting privileges of that person to topics that are unrelated to the possible COIs. See Appendix V for a complete list of disclosures.

 

Disclosure of Funding

These evidence-based clinical practice guidelines were funded exclusively by the Congress of Neurological Surgeons, which received no funding from outside commercial sources to support the development of this document.

 

Disclaimer of Liability

This clinical systematic review and evidence-based guideline was developed by a physician volunteer task force as an educational tool that reflects the current state of knowledge at the time of completion. Each chapter is designed to provide an accurate review of the subject matter covered. This guideline is disseminated with the understanding that the recommendations by the authors and consultants who have collaborated in their development are not meant to replace the individualized care and treatment advice from a patient's physician(s). If medical advice or assistance is required, the services of a competent physician should be sought. The proposals contained in these guidelines may not be suitable for use in all circumstances. The choice to implement any particular recommendation contained in these guidelines must be made by a managing physician in light of the situation in each particular patient and on the basis of existing resources.

 

Acknowledgments

The guidelines task force would like to acknowledge the CNS Guidelines Committee for their contributions throughout the development of the guideline, the AANS/CNS Joint Guidelines Review Committee, as well as the contributions Trish Rehring, MPH, Director for Evidence-Based Practice Initiatives for the CNS, and Janet Waters, MLS, BSN, RN, for assistance with the literature searches. The guidelines task force would also like to acknowledge the following CNS Guidelines Fellows: Michael Brendan Cloney, MD, MPH, University of Michigan,  George W. Koutsouras, D.O., M.P.H., Upstate University Hospital, Syracuse, NY. Throughout the review process, the reviewers and authors were blinded from one another. At this time the guidelines task force would like to acknowledge the following individual peer reviewers for their contributions: Ketan Bulsara, MD, Marshall Holland, MD,  Emanuella Binello, MD.

 

 

Table 1:  Side by Side Comparison of Recommendations from the 2019 and 2024 Guidelines

Topic	2019 Recommendations	2024 Recommendations
Molecular and targeted agents	Level 1: The use of afatinib is not recommended in patients with brain metastasis due to breast cancer.   There is insufficient evidence to make recommendations regarding:   1. The use of EGFR inhibitors erlotinib and gefitinib in patients with brain metastasis due to NSCLC; 2. The use of BRAF inhibitors dabrafenib and vemurafenib in the treatment of patients with brain metastases due to metastatic melanoma; 3. The use of HER2 agents trastuzumab and lapatinib to treat patients with brain metastases due to metastatic breast cancer; 4. The use of VEGF agents bevacizumab, sunitinib, and sorafenib in the treatment of patients with solid tumor brain metastases.	Unchanged Recommendation Level 1: The use of afatinib is not recommended in patients with brain metastasis due to breast cancer.   New Recommendations Parenchymal Brain Metastases EGFR-Mutant NSCLC Level I: In subjects with ≥3 untreated brain metastases from EGFR-mutant NSCLC, the use of icotinib and WBRT is recommended to improve intracranial PFS. Level III: In subjects with brain metastases from EGFR-mutant NSCLC, the addition of EGFR TKIs to radiation therapy in the form of WBRT or SRS is suggested to improve OS, PFS, and intracranial PFS.   ALK-Mutant NSCLC Level I: In patients with ALK mutation positive NSCLC with untreated brain metastases, the use of alectinib is recommended to delay time to intracranial tumor progression. Level II: In patients with untreated brain metastases from ALK mutation positive NSCLC, lorlatinib is recommended to prolong intracranial tumor control and improve overall PFS.   NSCLC With Unknown EGFR and ALK Mutation Status Level I: It is recommended that for patients with newly diagnosed brain metastases secondary to NSCLC, and for whom WBRT is indicated, gefitinib be added to the treatment regimen to obtain improved local tumor control and improved OS. Level III: For individuals with brain metastases secondary to NSCLC and for whom targeted therapy in the form of gefitinib or the combination of pemetrexed and platinum compounds are indicated, it is suggested that bevacizumab, when not contraindicated by other underlying medical conditions, be added to the treatment regimen to improve CNS control and to a lesser extent PFS and OS.   NSCLC Without EGFR or ALK Mutation Level III: For individuals with brain metastases secondary to NSCLC that are EGFR negative, ALK negative, and for whom targeted therapy in the form of TKIs are indicated, it is suggested that TKIs, when not contraindicated by other underlying medical conditions, be added to the treatment regimen, including radiation therapy, to improve CNS control and to a lesser extent PFS and OS.   Melanoma Brain Metastases Level I: It is recommended that for patients with newly diagnosed brain metastases secondary to melanoma with BRAFV600E positive, dabrafenib plus trametinib be added to the treatment regimen to obtain improved local tumor control. Level III: For individuals with brain metastases secondary to BRAF-altered melanoma for whom targeted therapy in the form of BRAFi are indicated, it is suggested that immunotherapy, when not contraindicated by other underlying medical conditions, be added to the treatment regimen to improve CNS control and to a lesser extent PFS and OS.   Breast Adenocarcinoma Level III: In adult patients with brain metastases from breast adenocarcinoma for whom radiation therapy is indicated, it is suggested that trastuzumab be added to the treatment regimen to improve PFS, median OS, and OS. Level III: In adult patients with brain metastases from breast adenocarcinoma for whom SRS is indicated, it is suggested that lapatinib be added to that treatment to improve intracranial response rate and median survival.   Leptomeningeal Brain Metastases Level III: In individuals with leptomeningeal disease from NSCLC with EGFR mutations, it is suggested that EGFR TKIs be utilized to increase median survival, specifically the third-generation TKI osimertinib for patients with EGFR-mutant NSCLC and the second-generation ALK-TKI alectinib for the treatment of LMs in ALK-positive NSCLC.
Immune modulators	There is insufficient evidence to make a recommendation regarding the use of immune therapy for brain metastases.	New Recommendations Parenchymal Brain Metastases Level I: In individuals with active, untreated, asymptomatic parenchymal melanoma brain metastases, ipilimumab plus nivolumab is recommended to increase median OS.be utilized without radiation to improve median OS. Level III: In individuals with parenchymal brain metastases from NSCLC, it is suggested that ICIs be utilized with radiation therapy to increase median survival, decrease incidence of local failure, increase intracranial PFS, and decrease distant intracranial failure. Level III: In individuals with parenchymal brain metastases from NSCLC that are clinically stable for at least 4 weeks and with PD-L1 TPS >50%, it is suggested that ICIs be utilized without radiation to improve median OS. Level III: In individuals with parenchymal brain metastases from breast cancer or colon carcinoma it is suggested that therapy with ICIs be considered alone or with radiation therapy to increase median survival and decrease incidence of local failure.   Unchanged Recommendation Leptomeningeal Brain Metastases There is insufficient evidence to make a recommendation regarding the use of immune modulators in leptomeningeal brain metastases.
Interstitial modalities	There is insufficient evidence to make a recommendation regarding the routine use of existing local therapies, such as interstitial chemotherapy, brachytherapy, or other local modalities, aside from their use in approved clinical trials.	There is insufficient evidence to make a recommendation regarding the use of interstitial modalities in the form of interstitial chemotherapy or radiation.
Radiosensitizers	Level 1: The use of temozolomide as a radiation sensitizer is not recommended in the setting of WBRT for patients with breast cancer brain metastases.   Level 1: The use of chloroquine as radiation sensitizer is not recommended in the setting of WBRT for patients with brain metastases.   There is insufficient evidence to make a recommendation regarding the routine use of radiation sensitizers, such as motexafin-gadolinium, sodium nitrite, temozolomide, or chloroquine, in other clinical settings for patients with brain metastases.	Unchanged Recommendations Level 1: The use of temozolomide as a radiation sensitizer is not recommended in the setting of WBRT for patients with breast cancer brain metastases.   Level 1: The use of chloroquine as radiation sensitizer is not recommended in the setting of WBRT for patients with brain metastases.   New Recommendations Level II: When WBRT is utilized for brain metastases from NSCLC, it is recommended that temozolomide be added to provide a smaller incidence of local failure, longer intracranial PFS, and longer OS. Level III: For brain metastases from NSCLC with EGFR mutation status where WBRT or SRS is indicated, is it suggested that EFGR TKIs be added to that therapy to improved intracranial response rate and survival.
LITT	There is insufficient evidence to make a recommendation regarding the routine use of LITT aside from use as part of approved clinical trials.	New Recommendations Level III: For adults who have undergone SRS for brain metastases with subsequent imaging progression due to tumor progression, it is suggested that LITT be considered as equivalent to craniotomy in terms of PFS and OS and the choice of management should be individualized based on the unique characteristics of the tumor location and the subject’s clinical status. Level III: For adults who have undergone SRS for brain metastases with subsequent imaging progression due to radiation necrosis, it is suggested that LITT be considered as equivalent to medical management for radiation necrosis and the choice of management should be individualized based on the unique characteristics of the tumor location and the subject’s clinical status.
Magnetic resonance–guided focused ultrasound	There is insufficient evidence to make a recommendation regarding the use of HIFU for the treatment of patients with brain metastases.	Unchanged Recommendation There is insufficient evidence to make a recommendation regarding the use of magnetic resonance–guided focused ultrasound for parenchymal and leptomeningeal brain metastases.

 

ALK = anaplastic lymphoma kinase; BRAFi = BRAF inhibitor; CNS = central nervous system; EGFR = epidermal growth factor receptor; HIFU = high-intensity focused ultrasound; ICI = immune checkpoint inhibitor; LITT = laser interstitial thermal therapy; LM = leptomeningeal metastasis; NSCLC = non–small-cell lung cancer; OS = overall survival; PFS = progression-free survival; SRS = stereotactic radiosurgery; TKI = tyrosine kinase inhibitor; TPS = tumor proportion score; VEGF = vascular endothelial growth factor; WBRT = whole-brain radiation therapy.

 

Table 2. Recommendations by Treatment, Tumor Histology, and Molecular Classification

Intervention	Tumor Type	Molecular Classification	Recommendations
Molecular and targeted therapy	NSCLC of the lung	EGFR mutation positive	Level I: In subjects with ≥3 untreated brain metastases from EGFR-mutant NSCLC, the use of icotinib and WBRT is recommended to improve intracranial PFS. Level III: In subjects with brain metastases from EGFR-mutant NSCLC, the addition of EGFR TKIs to radiation therapy in the form of whole-brain radiation therapy or SRS is suggested to improve OS, PFS, and intracranial PFS. Level III: In individuals with leptomeningeal disease from NSCLC with EGFR mutations, it is suggested that EGFR TKIs be utilized to increase median survival, specifically the third-generation TKI osimertinib for patients with EGFR-mutant NSCLC.
		ALK-mutation positive	Level I: In patients with ALK mutation-positive NSCLC with untreated brain metastases, the use of alectinib is recommended to delay time to intracranial tumor progression. Level II: In patients with untreated brain metastases from ALK mutation-positive NSCLC, lorlatinib is recommended to prolong intracranial tumor control and improve overall PFS. Level III: In individuals with leptomeningeal disease from NSCLC with ALK mutations, it is suggested that the second-generation ALK-TKI alectinib be utilized.
		EGFR and ALK mutation not assessed	Level I: It is recommended that for patients with newly diagnosed brain metastases secondary to NSCLC not assessed the EGFR and ALK mutation status, and for whom WBRT is indicated, gefitinib be added to the treatment regimen to improve local tumor control and OS. Level III: For individuals with brain metastases secondary to NSCLC not assessed the EGFR and ALK mutation status and for whom targeted therapy in the form of gefitinib or the combination of pemetrexed and platinum compounds are otherwise indicated, it is suggested that bevacizumab, when not contraindicated by other underlying medical conditions, be added to the treatment regimen to improve CNS control and to a lesser extent PFS and OS.
		EGFR and ALK mutation negative	Level III: For individuals with brain metastases secondary to NSCLC that are EGFR and ALK mutation negative and for whom targeted therapy in the form of TKI are indicated, it is suggested that TKI, when not contraindicated by other underlying medical conditions, be added to the treatment regimen, including radiation therapy, to improve CNS control and to a lesser extent PFS and OS.
	Melanoma	BRAF V600E mutation positive	Level I: It is recommended that for patients with newly diagnosed brain metastases secondary to melanoma that is BRAFV600E positive, dabrafenib plus trametinib be added to the treatment regimen to obtain improved local tumor control. Level III: For individuals with brain metastases secondary to BRAF-altered melanoma for whom targeted therapy in the form of BRAF inhibitors are indicated, it is suggested that immunotherapy, when not contraindicated by other underlying medical conditions, be added to the treatment regimen to improve CNS control and to a lesser extent PFS and OS.
	Breast carcinoma	HER2 mutation positive	Level III: In adult patients with brain metastases from breast adenocarcinoma that are HER2 positive for whom radiation therapy is indicated, it is suggested that trastuzumab be added to the treatment regimen to improve PFS, median OS, and OS. Level III: In adult patients with brain metastases from breast adenocarcinoma for whom SRS is indicated, it is suggested that lapatinib be added to that treatment to improve intracranial response rate and median survival. Level III: In individuals with leptomeningeal disease from Her2+ breast cancer, it is suggested that IT trastuzumab be utilized to increase median survival.
		Mutation status nonspecific	Level I: The use of afatinib is not recommended in patients with brain metastasis due to breast cancer.
Immune modulators	NSCLC of the lung	Mutation status nonspecific	Level III: In individuals with parenchymal brain metastases from NSCLC, it is suggested that ICIs be utilized with radiation therapy to increase median survival, decrease incidence of local failure, increase intracranial PFS, and decrease distant intracranial failure. Level III: In individuals with parenchymal brain metastases from NSCLC that are clinically stable for at least 4 weeks and with PD-L1 TPS >50% it is suggested that ICIs be utilized without radiation to improve median OS.
	Melanoma	Mutation status nonspecific	Level I: In individuals with active, untreated, asymptomatic parenchymal melanoma brain metastases, ipilimumab plus nivolumab is recommended to increase median OS.be utilized without radiation to improve median OS.
	Breast	Mutation status nonspecific	Level III: In individuals with parenchymal brain metastases from breast cancer, it is suggested that therapy with ICIs be considered alone or with radiation therapy to increase median survival and decrease incidence of local failure.
	Colon	Mutation status nonspecific	Level III: In individuals with parenchymal brain metastases from colon carcinoma, it is suggested that therapy with ICIs be considered alone or with radiation therapy to increase median survival and decrease incidence of local failure.
Interstitial modalities	All histologies	Mutation status nonspecific	There is insufficient evidence to make a recommendation regarding the use of interstitial modalities in the form of interstitial chemotherapy or radiation.
Radiosensitizers	NSCLC	EGFR mutation positive	Level III: for brain metastases from NSCLC with EGFR mutation-positive status where WBRT or SRS is indicated, it is suggested that EFGR TKIs be added to that therapy to improved intracranial response rate and survival.
		Mutation status nonspecific	Level II: When WBRT is utilized for brain metastases from NSCLC, it is recommended that temozolomide be added to provide a smaller incidence of local failure, longer intracranial PFS, and longer OS.
	Breast carcinoma	Mutation status nonspecific	Level 1: The use of temozolomide as a radiation sensitizer is not recommended in the setting of WBRT for patients with breast cancer brain metastases.
	All histologies	Mutation status nonspecific	Level 1: The use of chloroquine as a radiation sensitizer is not recommended in the setting of WBRT for patients with brain metastases.
LITT	All histologies	Mutation status nonspecific	Level III: For adults who have undergone SRS for brain metastases with subsequent imaging progression due to tumor progression, it is suggested that LITT be considered as equivalent to craniotomy in terms of PFS and OS and the choice of management should be individualized based on the unique characteristics of the tumor location and the subject’s clinical status. Level III: For adults who have undergone SRS for brain metastases with subsequent imaging progression due to radiation necrosis, it is suggested that LITT be considered as equivalent to medical management for radiation necrosis and the choice of management should be individualized based on the unique characteristics of the tumor location and the subject’s clinical status.
Magnetic resonance–guided focused ultrasound	All histologies	Mutation status nonspecific	There is insufficient evidence to make a recommendation regarding the use of magnetic resonance–guided focused ultrasound for parenchymal and leptomeningeal brain metastases.

 

ALK = anaplastic lymphoma kinase; BRAFi = BRAF inhibitor; EGFR = epidermal growth factor receptor; IT = intrathecal; LITT = laser interstitial thermal therapyNSCLC = non–small-cell lung cancer; OS = overall survival; PFS = progression-free survival; TKI = tyrosine kinase inhibitor; TPS = tumor proportion score; WBRT = whole-brain radiation therapy.

 

Appendix I. Literature Searches

Search Strategies

OVID MEDLINE

 

PICO 1 – BRAIN METS ET UPDATE PARENCHYMAL – MOLECULAR TARGETED AGENTS

 

1.	Vemurafenib/
2.	(207smy3fqt or plx 4032 or plx4032 or r05185426 or rg 7204 or rg-7204 or rg7204 or vemurafenib or zelboraf).ti,ab,kw.
3.	(encorafenib or Braftovi).mp.
4.	(dabrafenib or Tafinlar).mp.
5.	braf.ti,ab,kw.
6.	Proto-Oncogene Proteins B-raf/
7.	(b raf kinase* or b-raf kinase* or braf kinase* or proto oncogene protein b raf or proto oncogene proteins b raf or proto-oncogene protein b-raf or proto-oncogene proteins b-raf).ti,ab,kw.
8.	(plx 4032 or plx4032 or r 7204 or r7204 or rg 7204 or rg7204 or ro 5185426 or ro5185426 or lgx 818 or lgx818 or nvp lgx 818 or nvp lgx 818 nxa or nvp lgx818 or nvp lgx818 nxa or ono 7702 or ono7702 or "pf 07263896" or pf 7263896 or pf07263896 or pf7263896 or "w 0090" or w0090).ti,ab,kw.
9.	MEK.ti,ab,kw.
10.	"BRAF/MEK".ti,ab,kw.
11.	Mitogen-Activated Protein Kinases/
12.	(mitogen activated protein kinase* or Mitogen-activated protein kinase*).ti,ab,kw.
13.	benimetinib.mp.
14.	binimetinib.mp.
15.	(arry 162 or arry 438162 or arry162 or arry438162 or balimek or mek 162 or mek162 or mektovi or ono 7703 or ono7703 or "pf 06811462" or pf 6811462 or pf06811462 or pf6811462).ti,ab,kw.
16.	cobimetanib.mp.
17.	cobimetinib.mp.
18.	(cobimetinib fumarate or cobimetinib hemifumarate or cotellic or "gdc 0973" or gdc0973 or rg 7420 or rg7420 or ro 5514041  or ro5514041 or xl 518 or xl518).ti,ab,kw.
19.	trametinib.mp.
20.	(gsk 1120212 or gsk 1120212b or gsk1120212 or gsk1120212b or jtp 74057 or jtp74057 or mekinist or snr 1611 or snr1611 or tmt 212 or tmt212).ti,ab,kw.
21.	exp trastuzumab/ or exp ado-trastuzumab emtansine/
22.	(180288-69-1 or herceptin or p188anx8ck or trastuzumab or trastuzumab beta or trastuzumab qyyp or trastuzumab-qyyp or trazimera).ti,ab,kw.
23.	Lapatinib/
24.	(0vua21238f or g873gx646r or gw 282974x or gw 572016 or gw-282974x or gw-572016 or gw282974x or gw572016 or lapatinib or lapatinib ditosylate or tykerb).ti,ab,kw.
25.	(abp 980 or abp980 or amt 901 or amt901 or aryotrust or "bcd 022" or bcd022 or bx 2318 or bx2318 or ct p06 or ct p6 or ctp06 or ctp6 or da 3111 or da3111 or dmb 3111 or dmb3111 or eg 12014 or eg12014 or hd 201 or hd201 or herceptin or herclon or hermyl 1401o or hermyl1401o or herticad or hertraz or hervelous or herzuma or "hlx 02" or hlx02 or kanjinti or myl 1401o or myl1401o or ogivri or ons 1050 or ons1050 or ontruzant or "pf 05280014" or pf 5280014 or pf05280014 or pf5280014 or r 597 or r597 or rg 597 or rg597 or samfenet or sb 3 or sb3 or trasturel or trastuzumab anns or trastuzumab beta or trastuzumab dkst or trastuzumab dttb or trastuzumab pkrb or trastuzumab qyyp or trastuzumab-anns or trastuzumab-dkst or trastuzumab-dttb or trastuzumab-pkrb or trastuzumab-qyyp or trazimera or "tx 05" or tx05 or ub 921 or ub921 or vivitra or zedora or zercepac or zrc 3256 or zrc3256).ti,ab,kw.
26.	(gw 2016 or gw 572016 or gw 572016f or gw2016 or gw572016 or gw572016f or lapatinib ditosylate or lapatinib ditosylate monohydrate or lapatinib tosylate).ti,ab,kw.
27.	Pertuzumab.mp.
28.	(2C4 or hs 627 or hs627 or monoclonal antibody 2C4 or omnitarg or perjeta or ql 1209 or ql1209 or r 1273 or r1273 or rg 1273 or rg1273 or rhumab 2C4 or ro 4368451 or ro4368451).ti,ab,kw.
29.	Tucatinib.mp.
30.	(arry 380 or arry380 or irbinitinib or mk 7119 or mk7119 or ont 380 or ont380 or tukysa).ti,ab,kw.
31.	Capecitabine/
32.	(154361-50-9 or 6804dj8z9u or capecitabine).ti,ab,kw.
33.	(apecitab or atubri or cacit or capcel or capebina or capecite or capegard or capezam or capicet or capiibine or capnat or capoda or capostat or capsy or capxcel or caxeta or citabin or ecansya or naprocap or r 340 or r340 or "ro 09 1978" or ro 09-1978 or "ro 091978" or ro09 1978 or ro09-1978 or ro091978 or xabine or xecap or xelocel or xeloda or zocitab).ti,ab,kw.
34.	Neratinib.mp.
35.	("can 030" or can030 or hki 272 or hki272 or neratinib maleate or nerlynx or pb 272 or pb272 or way 177820 or way177820).ti,ab,kw.
36.	Receptor, ErbB-2/
37.	(cd340 antigen* or erb b2 receptor tyrosine kinases* or erb-b2 receptor tyrosine kinases* or erbb-2 receptor* or her 2 proto oncogene protein* or her-2 proto-oncogene protein* or metastatic lymph node gene 19 protein* or neu receptor* or oncogene protein her 2 or oncogene protein her-2 or proto oncogene protein her 2 or proto oncogene proteins c erbb 2 or proto-oncogene proteins c-erbb-2 or proto-oncogene protein neu or tyrosine kinase type cell surface receptor her2 or tyrosine kinase-type cell surface receptor her2 or c erbb 2 protein* or c-erbb-2 protein* or erbb 2 proto oncogene protein* or erbb 2 receptor protein tyrosine kinase* or erbb-2 proto-oncogene protein* or erbb-2 receptor protein-tyrosine kinase* or erbb-2 receptors or neu proto oncogene protein* or neu proto-oncogene protein* or p185erbb2 protein).ti,ab,kw.
38.	epidermal growth factor receptor 2.ti,ab,kw.
39.	(c ErbB2 protein or ErbB 2 kinase or ErbB 2 receptor or ErbB receptor 2 or ErbB2 protein or ErbB2 receptor or HER 2 protein or HER 2 receptor or HER2 protein or neu differentiation factor receptor or neu protein or neu receptor or neuregulin receptor or oncoprotein HER 2 or oncoprotein HER2 or oncoprotein neu or protein c ErbB 2 or protein c ErbB2 or protein Erb B 2 or protein ErbB 2 or protein ErbB2 or protein HER 2 or protein HER 2 neu or protein HER2 or protein HER2 neu or protein neu or protein tyrosine kinase ErbB2 or protein tyrosine kinase receptor ErbB2 or proto-oncogene proteins c-erbb-2 or receptor neu or tyrosine kinase HER2).ti,ab,kw.
40.	(HER KINASE* or Her-2-Neu or HER2-NEU).ti,ab,kw.
41.	Alectanib.mp.
42.	ALECTINIB.mp.
43.	(af 802 or af802 or alecensa or alecensaro or alectinib hydrochloride or ch 5424802 or ch5424802 or rg 7853 or rg7853 or ro 5424802 or ro5424802).ti,ab,kw.
44.	Anaplastic Lymphoma Kinase/
45.	(alk kinase or alk tyrosine kinase receptor or anaplastic lymphoma kinase or anaplastic lymphoma receptor tyrosine kinase or cd246 antigen or npm-alk or nucleophosmin anaplastic lymphoma kinase or nucleophosmin-anaplastic lymphoma kinase).ti,ab,kw.
46.	Ceritinib.mp.
47.	(jikadia or ldk 378 or ldk378 or nvp ldk 378 or nvp ldk 378 nx or nvp ldk378 or nvp ldk378 nx or zykadia).ti,ab,kw.
48.	Crizotinib/
49.	(53ah36668s or crizotinib or "pf 02341066" or pf 2341066 or pf-02341066 or pf-2341066 or pf02341066 or pf2341066 or xalkori).ti,ab,kw.
50.	("pf 02341066" or pf 1066 or pf 2341066 or pf02341066 or pf1066 or pf2341066 or xalkori).ti,ab,kw.
51.	Brigatinib.mp.
52.	(Alunbrig or ap 26113 or ap26113).ti,ab,kw.
53.	Erlotinib Hydrochloride/
54.	(11c erlotinib or 11c-erlotinib or 183319-69-9 or cp 358774 or da87705x9k or erlotinib or erlotinib hcl or erlotinib hydrochloride or j4t82ndh7e or osi 774 or osi-774 or osi774 or tarceva).ti,ab,kw.
55.	(cp 358774 or cp 35877401 or cp358774 or "cp358774 01" or cp35877401 or erlotinib hydrochloride or nsc 718781 or nsc718781 or osi 774 or osi774 or r 1415 or r1415 or rg 1415 or rg1415 or ro 50 8231 or ro 508231 or ro508231 or sgt 210 or sgt210 or tarceva).ti,ab,kw.
56.	Icotinib.mp.
57.	(bpi 2009 or bpi 2009h or bpi2009 or bpi2009h or conmana or icotinib hydrochloride).ti,ab,kw.
58.	Gefitinib/
59.	(gefitinib or iressa or s65743jhbs or zd 1839 or zd1839).ti,ab,kw.
60.	(gefitinib hydrochloride or geftinat or iressa or zd 1839 or zd1839).ti,ab,kw.
61.	Afatinib/
62.	(41ud74l59m or 850140-72-6 or afatinib or afatinib dimaleate or afatinib maleate or bibw 2992 or bibw 2992 ma2 or bibw 2992ma2 or bibw-2992 or bibw-2992-ma2 or bibw-2992ma2 or bibw2992 or bibw2992 ma2 or gilotrif or v1t5k7rz0b).ti,ab,kw.
63.	(afatinib dimaleate or bibw 2992 or bibw2992 or gilotrif or giotrif or tovok).ti,ab,kw.
64.	Osimertinib.mp.
65.	(azd 9291 or azd9291 or mereletinib or osimertinib mesilate or osimertinib mesylate or tagrisso).ti,ab,kw.
66.	EGFR.ti,ab,kw.
67.	Epidermal Growth Factor/
68.	(62229-50-9 or egf or epidermal growth factor or epidermal growth factor-urogastrone or human urinary gastric inhibitor or urogastrone or beta urogastrone or beta-urogastrone).ti,ab,kw.
69.	(EGF receptor inhibitor or epidermal growth factor receptor inhibitor or epidermal growth factor receptor protein tyrosine kinase inhibitor or epidermal growth factor receptor tyrosine kinase inhibitor).ti,ab,kw.
70.	entrectinib.mp.
71.	(nms e 628 or nms e628 or rg 6268 or rg6268 or rozlytrek or rxdx 101 or rxdx101).ti,ab,kw.
72.	Receptor, trkB/
73.	(bdnf receptor or brain derived neurotrophic factor receptor or ntrk2 receptor or neurotrophic tyrosine kinase receptor type 2 or trkb receptor).ti,ab,kw.
74.	ntrk.ti,ab,kw.
75.	Larotrectinib.mp.
76.	(arry 470 or arry470 or larotrectinib sulfate or loxo 101 or loxo101 or vitrakvi).ti,ab,kw.
77.	Sotorasib.mp.
78.	(amg 510 or amg510 or lumakras or lumykras or sotorasib hydrochloride).ti,ab,kw.
79.	Adagrasib.mp.
80.	(mrtx 849 or mrtx849).ti,ab,kw.
81.	KRAS G12C.mp.
82.	KRAS.ti,ab,kw.
83.	Erdafitinib.mp.
84.	(balversa or jnj 42756493 or jnj42756493).ti,ab,kw.
85.	exp Receptors, Fibroblast Growth Factor/
86.	FGFR.ti,ab,kw.
87.	Laparib.mp.
88.	olaparib.mp.
89.	(azd 2281 or azd2281 or "ku 0059436" or ku 59436 or ku0059436 or ku59436 or lynparza or mk 7339 or mk7339).ti,ab,kw.
90.	Niraparib.mp.
91.	(gsk 3985771 or gsk3985771 or jnj 64091742 or jnj64091742 or mk 4827 or mk4827 or niraparib 4 methylbenzenesulfonate or niraparib hydrochloride or niraparib tosilate or niraparib tosylate or zejula or zl 2306 or zl2306).ti,ab,kw.
92.	Rucaparib.mp.
93.	("ag 014699" or ag 14447 or ag 14699 or ag014699 or ag14447 or ag14699 or co 338 or co338 or "pf 01367338" or pf 1367338 or pf 1367338 bw or pf01367338 or pf1367338 or pf1367338bw or rubraca or rucaparib camphorsulfonate or rucaparib camsilate or rucaparib camsylate or rucaparib phosphate).ti,ab,kw.
94.	Protein-Tyrosine Kinases/
95.	(protein tyrosine kinase* or tyrosine kinase* or tyrosine protein kinase* or tyrosine specific protein kinase* or tyrosylprotein kinase*).ti,ab,kw.
96.	PARP.ti,ab,kw.
97.	"Poly(ADP-ribose) Polymerase Inhibitors".mp.
98.	Sorafenib/
99.	(5t62q3b36j or 5xyk65kigd or 9zoq3tzi87 or bay 43 9006 or bay 43-9006 or bay 439006 or bay 545 9085 or bay 545-9085 or bay 5459085 or bay 673472 or bay-545-9085 or bay-673472 or bay5459085 or nexavar or sorafenib or sorafenib n oxide or sorafenib n-oxide or sorafenib tosylate).ti,ab,kw.
100.	Sunitinib/
101.	(lvx8n1ut73 or "su 011248" or su 11248 or su-011248 or su-11248 or su011248 or su11248 or sunitinib or sunitinib malate or sutent or v99t50803m).ti,ab,kw.
102.	Bevacizumab/
103.	(2s9zzm9q9v or avastin or bevacizumab or bevacizumab awwb or bevacizumab-awwb or mvasi).ti,ab,kw.
104.	(bay 43-9006 or bay 439006 or bay43 9006 or bay43-9006 or bay439006 or nexavar).ti,ab,kw.
105.	(molecular adj2 targeted adj2 (therap* or treatment* or agent* or drug*)).mp
106.	or/1-105
107.	exp Brain Neoplasms/
108.	(brain* or brain stem* or BRAINSTEM* or cerebral* or intracranial* or INTRA-CRANIAL or cerebellum* or cerebellar* or frontal lobe* or temporal lobe* or occipital lobe* or parietal lobe* or cerebrum*).mp.
109.	exp FRONTAL LOBE/ or exp TEMPORAL LOBE/ or exp OCCIPITAL LOBE/ or exp PARIETAL LOBE/
110.	exp Neoplasm Metastasis/
111.	(metastas* or metastat*).mp.
112.	110 or 111
113.	(107 or 108 or 109) and 112
114.	exp Brain Neoplasms/sc [Secondary]
115.	113 or 114
116.	limit 115 to english language
117.	Animals/
118.	Humans/
119.	117 not (117 and 118)
120.	116 not 119
121.	adolescent/ or child/ or infant/
122.	Adult/
123.	121 not (121 and 122)
124.	120 not 123
125.	comment/ or editorial/ or letter/ or in vitro techniques/ or culture techniques/ or review/ or systematic review/
126.	exp case-control studies/
127.	case reports/
128.	127 not 126
129.	124 not 125
130.	129 not 128
131.	limit 130 to yr="2016-2022"
132.	Drug Evaluation, Preclinical/ or Disease Models, Animal/ or Xenograft Model Antitumor Assays/
133.	131 not 132
134.	106 and 133

 

PICO 2 – BRAIN METS ET UPDATE LEPTOMENINGEAL – MOLECULAR TARGETED AGENTS

 

1.	Vemurafenib/
2.	(207smy3fqt or plx 4032 or plx4032 or r05185426 or rg 7204 or rg-7204 or rg7204 or vemurafenib or zelboraf).ti,ab,kw.
3.	(encorafenib or Braftovi).mp.
4.	(dabrafenib or Tafinlar).mp.
5.	braf.ti,ab,kw.
6.	Proto-Oncogene Proteins B-raf/
7.	(b raf kinase* or b-raf kinase* or braf kinase* or proto oncogene protein b raf or proto oncogene proteins b raf or proto-oncogene protein b-raf or proto-oncogene proteins b-raf).ti,ab,kw.
8.	(plx 4032 or plx4032 or r 7204 or r7204 or rg 7204 or rg7204 or ro 5185426 or ro5185426 or lgx 818 or lgx818 or nvp lgx 818 or nvp lgx 818 nxa or nvp lgx818 or nvp lgx818 nxa or ono 7702 or ono7702 or "pf 07263896" or pf 7263896 or pf07263896 or pf7263896 or "w 0090" or w0090).ti,ab,kw.
9.	MEK.ti,ab,kw.
10.	"BRAF/MEK".ti,ab,kw.
11.	Mitogen-Activated Protein Kinases/
12.	(mitogen activated protein kinase* or Mitogen-activated protein kinase*).ti,ab,kw.
13.	benimetinib.mp.
14.	binimetinib.mp.
15.	(arry 162 or arry 438162 or arry162 or arry438162 or balimek or mek 162 or mek162 or mektovi or ono 7703 or ono7703 or "pf 06811462" or pf 6811462 or pf06811462 or pf6811462).ti,ab,kw.
16.	cobimetanib.mp.
17.	cobimetinib.mp.
18.	(cobimetinib fumarate or cobimetinib hemifumarate or cotellic or "gdc 0973" or gdc0973 or rg 7420 or rg7420 or ro 5514041 or ro5514041 or xl 518 or xl518).ti,ab,kw.
19.	trametinib.mp.
20.	(gsk 1120212 or gsk 1120212b or gsk1120212 or gsk1120212b or jtp 74057 or jtp74057 or mekinist or snr 1611 or snr1611 or tmt 212 or tmt212).ti,ab,kw.
21.	exp trastuzumab/ or exp ado-trastuzumab emtansine/
22.	(180288-69-1 or herceptin or p188anx8ck or trastuzumab or trastuzumab beta or trastuzumab qyyp or trastuzumab-qyyp or trazimera).ti,ab,kw.
23.	Lapatinib/
24.	(0vua21238f or g873gx646r or gw 282974x or gw 572016 or gw-282974x or gw-572016 or gw282974x or gw572016 or lapatinib or lapatinib ditosylate or tykerb).ti,ab,kw.
25.	(abp 980 or abp980 or amt 901 or amt901 or aryotrust or "bcd 022" or bcd022 or bx 2318 or bx2318 or ct p06 or ct p6 or ctp06 or ctp6 or da 3111 or da3111 or dmb 3111 or dmb3111 or eg 12014 or eg12014 or hd 201 or hd201 or herceptin or herclon or hermyl 1401o or hermyl1401o or herticad or hertraz or hervelous or herzuma or "hlx 02" or hlx02 or kanjinti or myl 1401o or myl1401o or ogivri or ons 1050 or ons1050 or ontruzant or "pf 05280014" or pf 5280014 or pf05280014 or pf5280014 or r 597 or r597 or rg 597 or rg597 or samfenet or sb 3 or sb3 or trasturel or trastuzumab anns or trastuzumab beta or trastuzumab dkst or trastuzumab dttb or trastuzumab pkrb or trastuzumab qyyp or trastuzumab-anns or trastuzumab-dkst or trastuzumab-dttb or trastuzumab-pkrb or trastuzumab-qyyp or trazimera or "tx 05" or tx05 or ub 921 or ub921 or vivitra or zedora or zercepac or zrc 3256 or zrc3256).ti,ab,kw.
26.	(gw 2016 or gw 572016 or gw 572016f or gw2016 or gw572016 or gw572016f or lapatinib ditosylate or lapatinib ditosylate monohydrate or lapatinib tosylate).ti,ab,kw.
27.	Pertuzumab.mp.
28.	(2C4 or hs 627 or hs627 or monoclonal antibody 2C4 or omnitarg or perjeta or ql 1209 or ql1209 or r 1273 or r1273 or rg 1273 or rg1273 or rhumab 2C4 or ro 4368451 or ro4368451).ti,ab,kw.
29.	Tucatinib.mp.
30.	(arry 380 or arry380 or irbinitinib or mk 7119 or mk7119 or ont 380 or ont380 or tukysa).ti,ab,kw.
31.	Capecitabine/
32.	(154361-50-9 or 6804dj8z9u or capecitabine).ti,ab,kw.
33.	(apecitab or atubri or cacit or capcel or capebina or capecite or capegard or capezam or capicet or capiibine or capnat or capoda or capostat or capsy or capxcel or caxeta or citabin or ecansya or naprocap or r 340 or r340 or "ro 09 1978" or ro 09-1978 or "ro 091978" or ro09 1978 or ro09-1978 or ro091978 or xabine or xecap or xelocel or xeloda or zocitab).ti,ab,kw.
34.	Neratinib.mp.
35.	("can 030" or can030 or hki 272 or hki272 or neratinib maleate or nerlynx or pb 272 or pb272 or way 177820 or way177820).ti,ab,kw.
36.	Receptor, ErbB-2/
37.	(cd340 antigen* or erb b2 receptor tyrosine kinases* or erb-b2 receptor tyrosine kinases* or erbb-2 receptor* or her 2 proto oncogene protein* or her-2 proto-oncogene protein* or metastatic lymph node gene 19 protein* or neu receptor* or oncogene protein her 2 or oncogene protein her-2 or proto oncogene protein her 2 or proto oncogene proteins c erbb 2 or proto-oncogene proteins c-erbb-2 or proto-oncogene protein neu or tyrosine kinase type cell surface receptor her2 or tyrosine kinase-type cell surface receptor her2 or c erbb 2 protein* or c-erbb-2 protein* or erbb 2 proto oncogene protein* or erbb 2 receptor protein tyrosine kinase* or erbb-2 proto-oncogene protein* or erbb-2 receptor protein-tyrosine kinase* or erbb-2 receptors or neu proto oncogene protein* or neu proto-oncogene protein* or p185erbb2 protein).ti,ab,kw.
38.	epidermal growth factor receptor 2.ti,ab,kw.
39.	(c ErbB2 protein or ErbB 2 kinase or ErbB 2 receptor or ErbB receptor 2 or ErbB2 protein or ErbB2 receptor or HER 2 protein or HER 2 receptor or HER2 protein or neu differentiation factor receptor or neu protein or neu receptor or neuregulin receptor or oncoprotein HER 2 or oncoprotein HER2 or oncoprotein neu  or protein c ErbB 2 or protein c ErbB2 or protein Erb B 2 or protein ErbB 2 or protein ErbB2 or protein HER 2 or protein HER 2 neu or protein HER2 or protein HER2 neu or protein neu or protein tyrosine kinase ErbB2 or protein tyrosine kinase receptor ErbB2 or proto-oncogene proteins c-erbb-2 or receptor neu or tyrosine kinase HER2).ti,ab,kw.
40.	(HER KINASE* or Her-2-Neu or HER2-NEU).ti,ab,kw.
41.	Alectanib.mp.
42.	ALECTINIB.mp.
43.	(af 802 or af802 or alecensa or alecensaro or alectinib hydrochloride or ch 5424802 or ch5424802 or rg 7853 or rg7853 or ro 5424802 or ro5424802).ti,ab,kw.
44.	Anaplastic Lymphoma Kinase/
45.	(alk kinase or alk tyrosine kinase receptor or anaplastic lymphoma kinase or anaplastic lymphoma receptor tyrosine kinase or cd246 antigen or npm-alk or nucleophosmin anaplastic lymphoma kinase or nucleophosmin-anaplastic lymphoma kinase).ti,ab,kw.
46.	Ceritinib.mp.
47.	(jikadia or ldk 378 or ldk378 or nvp ldk 378 or nvp ldk 378 nx or nvp ldk378 or nvp ldk378 nx or zykadia).ti,ab,kw.
48.	Crizotinib/
49.	(53ah36668s or crizotinib or "pf 02341066" or pf 2341066 or pf-02341066 or pf-2341066 or pf02341066 or pf2341066 or xalkori).ti,ab,kw.
50.	("pf 02341066" or pf 1066 or pf 2341066 or pf02341066 or pf1066 or pf2341066 or xalkori).ti,ab,kw.
51.	Brigatinib.mp.
52.	(Alunbrig or ap 26113 or ap26113).ti,ab,kw.
53.	Erlotinib Hydrochloride/
54.	(11c erlotinib or 11c-erlotinib or 183319-69-9 or cp 358774 or da87705x9k or erlotinib or erlotinib hcl or erlotinib hydrochloride or j4t82ndh7e or osi 774 or osi-774 or osi774 or tarceva).ti,ab,kw.
55.	(cp 358774 or cp 35877401 or cp358774 or "cp358774 01" or cp35877401 or erlotinib hydrochloride or nsc 718781 or nsc718781 or osi 774 or osi774 or r 1415 or r1415 or rg 1415 or rg1415 or ro 50 8231 or ro 508231 or ro508231 or sgt 210 or sgt210 or tarceva).ti,ab,kw.
56.	Icotinib.mp.
57.	(bpi 2009 or bpi 2009h or bpi2009 or bpi2009h or conmana or icotinib hydrochloride).ti,ab,kw.
58.	Gefitinib/
59.	(gefitinib or iressa or s65743jhbs or zd 1839 or zd1839).ti,ab,kw.
60.	(gefitinib hydrochloride or geftinat or iressa or zd 1839 or zd1839).ti,ab,kw.
61.	Afatinib/
62.	(41ud74l59m or 850140-72-6 or afatinib or afatinib dimaleate or afatinib maleate or bibw 2992 or bibw 2992 ma2 or bibw 2992ma2 or bibw-2992 or bibw-2992-ma2 or bibw-2992ma2 or bibw2992 or bibw2992 ma2 or gilotrif or v1t5k7rz0b).ti,ab,kw.
63.	(afatinib dimaleate or bibw 2992 or bibw2992 or gilotrif or giotrif or tovok).ti,ab,kw.
64.	Osimertinib.mp.
65.	(azd 9291 or azd9291 or mereletinib or osimertinib mesilate or osimertinib mesylate or tagrisso).ti,ab,kw.
66.	EGFR.ti,ab,kw.
67.	Epidermal Growth Factor/
68.	(62229-50-9 or egf or epidermal growth factor or epidermal growth factor-urogastrone or human urinary gastric inhibitor or urogastrone or beta urogastrone or beta-urogastrone).ti,ab,kw.
69.	(EGF receptor inhibitor or epidermal growth factor receptor inhibitor or epidermal growth factor receptor protein tyrosine kinase inhibitor or epidermal growth factor receptor tyrosine kinase inhibitor).ti,ab,kw.
70.	entrectinib.mp.
71.	(nms e 628 or nms e628 or rg 6268 or rg6268 or rozlytrek or rxdx 101 or rxdx101).ti,ab,kw.
72.	Receptor, trkB/
73.	(bdnf receptor or brain derived neurotrophic factor receptor or ntrk2 receptor or neurotrophic tyrosine kinase receptor type 2 or trkb receptor).ti,ab,kw.
74.	ntrk.ti,ab,kw.
75.	Larotrectinib.mp.
76.	(arry 470 or arry470 or larotrectinib sulfate or loxo 101 or loxo101 or vitrakvi).ti,ab,kw.
77.	Sotorasib.mp.
78.	(amg 510 or amg510 or lumakras or lumykras or sotorasib hydrochloride).ti,ab,kw.
79.	Adagrasib.mp.
80.	(mrtx 849 or mrtx849).ti,ab,kw.
81.	KRAS G12C.mp.
82.	KRAS.ti,ab,kw.
83.	Erdafitinib.mp.
84.	(balversa or jnj 42756493 or jnj42756493).ti,ab,kw.
85.	exp Receptors, Fibroblast Growth Factor/
86.	FGFR.ti,ab,kw.
87.	Laparib.mp.
88.	olaparib.mp.
89.	(azd 2281 or azd2281 or "ku 0059436" or ku 59436 or ku0059436 or ku59436 or lynparza or mk 7339 or mk7339).ti,ab,kw.
90.	Niraparib.mp.
91.	(gsk 3985771 or gsk3985771 or jnj 64091742 or jnj64091742 or mk 4827 or mk4827 or niraparib 4 methylbenzenesulfonate or niraparib hydrochloride or niraparib tosilate or niraparib tosylate or zejula or zl 2306 or zl2306).ti,ab,kw.
92.	Rucaparib.mp.
93.	("ag 014699" or ag 14447 or ag 14699 or ag014699 or ag14447 or ag14699 or co 338 or co338 or "pf 01367338" or pf 1367338 or pf 1367338 bw or pf01367338 or pf1367338 or pf1367338bw or rubraca or rucaparib camphorsulfonate or rucaparib camsilate or rucaparib camsylate or rucaparib phosphate).ti,ab,kw.
94.	Protein-Tyrosine Kinases/
95.	(protein tyrosine kinase* or tyrosine kinase* or tyrosine protein kinase* or tyrosine specific protein kinase* or tyrosylprotein kinase*).ti,ab,kw.
96.	PARP.ti,ab,kw.
97.	"Poly(ADP-ribose) Polymerase Inhibitors".mp.
98.	Sorafenib/
99.	(5t62q3b36j or 5xyk65kigd or 9zoq3tzi87 or bay 43 9006 or bay 43-9006 or bay 439006 or bay 545 9085 or bay 545-9085 or bay 5459085 or bay 673472 or bay-545-9085 or bay-673472 or bay5459085 or nexavar or sorafenib or sorafenib n oxide or sorafenib n-oxide or sorafenib tosylate).ti,ab,kw.
100.	Sunitinib/
101.	(lvx8n1ut73 or "su 011248" or su 11248 or su-011248 or su-11248 or su011248 or su11248 or sunitinib or sunitinib malate or sutent or v99t50803m).ti,ab,kw.
102.	Bevacizumab/
103.	(2s9zzm9q9v or avastin or bevacizumab or bevacizumab awwb or bevacizumab-awwb or mvasi).ti,ab,kw.
104.	(bay 43-9006 or bay 439006 or bay43 9006 or bay43-9006 or bay439006 or nexavar).ti,ab,kw.
105.	(molecular adj2 targeted adj2 (therap* or treatment* or agent* or drug*)).mp.
106.	or/1-105
107.	exp Neoplasm Metastasis/
108.	(metastas* or metastat*).mp.
109.	107 or 108
110.	exp Brain Neoplasms/sc [Secondary]
111.	Animals/
112.	Humans/
113.	111 not (111 and 112)
114.	adolescent/ or child/ or infant/
115.	Adult/
116.	114 not (114 and 115)
117.	comment/ or editorial/ or letter/ or in vitro techniques/ or culture techniques/ or review/ or systematic review/
118.	exp case-control studies/
119.	case reports/
120.	119 not 118
121.	exp Meningeal Neoplasms/ and (INTRACRANIAL* or CEREBRAL* or INTRA-CRANIAL or BRAIN* or LEPTOMEN*).mp.
122.	(intracranial meningeal neoplasm* or intra-cranial meningeal neoplasm* or leptomening* or intracranial meningeal cancer* or intra-cranial meningeal cancer*).ti,ab,kw.
123.	121 or 122
124.	(109 or 110) and 123
125.	(LEPTOMENING* adj4 METAST*).mp.
126.	124 or 125
127.	limit 126 to english language
128.	127 not 113
129.	128 not 116
130.	129 not 117
131.	130 not 120
132.	Drug Evaluation, Preclinical/
133.	Xenograft Model Antitumor Assays/
134.	Disease Models, Animal/
135.	132 or 133 or 134
136.	131 not 135
137.	106 and 136

 

PICO 3 - BRAIN METS ET UPDATE – PARENCHYMAL – IMMUNE MODULATORS

 

1.	exp Immunomodulation/
2.	immunomodulat*.ti,ab,kw.
3.	Immunotherapy/
4.	immunotherap*.ti,ab,kw.
5.	(biologic response modifi* or BRM therap*).ti,ab,kw.
6.	(Immun* adj2 (therap* or modulat* or drug* or agent* or medic* or therap* or treatment*)).mp
7.	(biomodulator* or immune factor* or immunologic factor* or immunological factor*).ti,ab,kw.
8.	Adjuvants, Immunologic/
9.	(Immunoactivator* or Immunoadjuvant* or immunologic adjuvant* or immunological adjuvant* or immunopotentiator* or immunostimulant*).ti,ab,kw.
10.	(ICI) s/
11.	(immun* adj2 checkpoint adj2 inhibitor*).mp.
12.	Immunomodulating Agents/
13.	(ctla 4 inhibitor* or ctla-4 inhibitor* or cytotoxic t lymphocyte associated protein 4 inhibitor* or cytotoxic t-lymphocyte-associated protein 4 inhibitor* or immune checkpoint blockade* or immune checkpoint blocker* or immune checkpoint inhibition* or pd 1 inhibitor* or pd 1 pd l1 blockade* or pd l1 inhibitor* or pd-1 inhibitor* or pd-1-pd-l1 blockade* or pd-l1 inhibitor* or programmed cell death protein 1 inhibitor* or programmed death ligand 1 inhibitor* or programmed death-ligand 1 inhibitor*).ti,ab,kw.
14.	checkpoint inhibitor*.ti,ab,kw.
15.	Ipililimumab.mp.
16.	Ipilimumab/
17.	(bms 734016 or bms734016 or cs 1002 or cs1002 or ibi 310 or ibi310 or mdx 101 or mdx010 or mdx101 or strentarga or yervoy or 6t8c155666 or anti ctla 4 mab or ipilimumab or anti-ctla-4 mab or "mdx 010" or mdx ctla 4 or mdx-010 or mdx-ctla-4 or mdx010).ti,ab,kw.
18.	(CTLA 4 or CTLA-4 or 'cytotoxic T lymphocyte antigen 4').mp.
19.	Cemiplimab.mp.
20.	(cemiplimab rwlc or cemiplimab-rwlc or libtayo or regn 2810 or regn2810 or sar 439684 or sar439684).ti,ab,kw.
21.	Programmed Cell Death 1 Receptor/ai
22.	gilvetmab.mp.
23.	(PD 1 or PD-1 or PD1).ti,ab,kw.
24.	Pembrolizumab.mp.
25.	(keytruda or lambrolizumab or mk 3475 or mk3475 or sch 900475 or sch900475).ti,ab,kw.
26.	Nivolumab/
27.	(31yo63lbsn or bms 936558 or bms-936558 or bms936558 or mdx 1106 or mdx-1106 or mdx1106 or nivolumab or ono 4538 or ono-4538 or ono4538 or opdivo).ti,ab,kw.
28.	(cmab 819 or cmab819).ti,ab,kw.
29.	Atezolizumab.mp.
30.	(monoclonal antibody mpdl 3280a or monoclonal antibody mpdl3280a or mpdl 3280a or mpdl3280a or rg 7446 or rg7446 or ro 5541267 or ro5541267 or tecentriq or tecntriq).ti,ab,kw.
31.	Avelumab.mp.
32.	(bavencio or "msb 0010682" or msb 0010718c or msb 10682 or msb 10718c or msb0010682 or msb0010718c or msb10682 or msb10718c or "pf 06834635" or pf 6834635 or pf06834635 or pf6834635).ti,ab,kw.
33.	Durvalumab.mp.
34.	(imfinzi or medi 4736 or medi4736).ti,ab,kw.
35.	PD-L1.mp.
36.	Immunotherapy, Active/
37.	(active immunotherap* or immune rna manipulation* or vaccine therap*).ti,ab,kw.
38.	Cancer Vaccines/
39.	(cancer vaccine* or neoplasm vaccine* or tumor vaccine* or tumour vaccine*).ti,ab,kw.
40.	dcvax.ti,ab,kw.
41.	(dendritic cell adj2 vaccine*).mp.
42.	Allogeneic Vaccine*.ti,ab,kw.
43.	(allogeneic adj5 vaccine*).mp.
44.	(immunotherapy adj2 vaccine*).mp.
45.	(Autologous adj2 Vaccine*).mp.
46.	(CAR engineered T-cell* or CAR engineered T-lymphocyte* or CAR modified T-cell* or CAR modified T-lymphocyte* or CAR T-cell* or CAR T-lymphocyte* or chimeric antigen receptor T-lymphocyte*).ti,ab,kw. and (THERAP* or TREATMENT*).mp.
47.	Bevacizumab/
48.	(2s9zzm9q9v or avastin or bevacizumab or bevacizumab awwb or bevacizumab-awwb or mvasi).ti,ab,kw.
49.	LARGE NEUTRAL AMINO ACID-TRANSPORTER 1.mp.
50.	(e16 membrane protein* or lat1* or slc7a5).ti,ab,kw.
51.	(EFFLUX adj2 (TRANSPORT* or INHIBITOR*)).mp.
52.	(TRANSPORTER* adj3 DRUG* adj3 DELIVER*).mp.
53.	(TRANSPORTER* adj2 MEDIAT* adj3 DRUG*).mp.
54.	((ABCB1 or ABCB2) adj2 (ANTAGONIST* or INHIBITOR*)).mp.
55.	Prodrugs/
56.	PROTAC.ti,ab,kw.
57.	(proteolysis adj2 target* adj2 (chimaer* or chimer*)).mp.
58.	(CHIM* adj2 ANTIGEN* adj2 RECEPTOR*).mp.
59.	or/1-58
60.	exp Brain Neoplasms/
61.	(brain* or brain stem* or BRAINSTEM* or cerebral* or intracranial* or INTRA-CRANIAL or cerebellum* or cerebellar* or frontal lobe* or temporal lobe* or occipital lobe* or parietal lobe* or cerebrum*).mp.
62.	exp FRONTAL LOBE/ or exp TEMPORAL LOBE/ or exp OCCIPITAL LOBE/ or exp PARIETAL LOBE/
63.	exp Neoplasm Metastasis/
64.	(metastas* or metastat*).mp.
65.	63 or 64
66.	(60 or 61 or 62) and 65
67.	exp Brain Neoplasms/sc [Secondary]
68.	66 or 67
69.	limit 68 to english language
70.	Animals/
71.	Humans/
72.	70 not (70 and 71)
73.	69 not 72
74.	adolescent/ or child/ or infant/
75.	Adult/
76.	74 not (74 and 75)
77.	73 not 76
78.	comment/ or editorial/ or letter/ or in vitro techniques/ or culture techniques/ or review/ or systematic review/
79.	exp case-control studies/
80.	case reports/
81.	80 not 79
82.	77 not 78
83.	82 not 81
84.	limit 83 to yr="2016-2022"
85.	Drug Evaluation, Preclinical/ or Disease Models, Animal/ or Xenograft Model Antitumor Assays/
86.	84 not 85
87.	59 and 86

 

PICO 4 - BRAIN METS ET UPDATE – LEPTOMENINGEAL – IMMUNE MODULATORS

 

1.	exp Immunomodulation/
2.	immunomodulat*.ti,ab,kw.
3.	Immunotherapy/
4.	immunotherap*.ti,ab,kw.
5.	(biologic response modifi* or BRM therap*).ti,ab,kw.
6.	(Immun* adj2 (therap* or modulat* or drug* or agent* or medic* or therap* or treatment*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
7.	(biomodulator* or immune factor* or immunologic factor* or immunological factor*).ti,ab,kw.
8.	Adjuvants, Immunologic/
9.	(Immunoactivator* or Immunoadjuvant* or immunologic adjuvant* or immunological adjuvant* or immunopotentiator* or immunostimulant*).ti,ab,kw.
10.	Immune Checkpoint Inhibitors/
11.	(immun* adj2 checkpoint adj2 inhibitor*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
12.	Immunomodulating Agents/
13.	(ctla 4 inhibitor* or ctla-4 inhibitor* or cytotoxic t lymphocyte associated protein 4 inhibitor* or cytotoxic t-lymphocyte-associated protein 4 inhibitor* or immune checkpoint blockade* or immune checkpoint blocker* or immune checkpoint inhibition* or pd 1 inhibitor* or pd 1 pd l1 blockade* or pd l1 inhibitor* or pd-1 inhibitor* or pd-1-pd-l1 blockade* or pd-l1 inhibitor* or programmed cell death protein 1 inhibitor* or programmed death ligand 1 inhibitor* or programmed death-ligand 1 inhibitor*).ti,ab,kw.
14.	checkpoint inhibitor*.ti,ab,kw.
15.	Ipililimumab.mp.
16.	Ipilimumab/
17.	(bms 734016 or bms734016 or cs 1002 or cs1002 or ibi 310 or ibi310 or mdx 101 or mdx010 or mdx101 or strentarga or yervoy or 6t8c155666 or anti ctla 4 mab or ipilimumab or anti-ctla-4 mab or "mdx 010" or mdx ctla 4 or mdx-010 or mdx-ctla-4 or mdx010).ti,ab,kw.
18.	(CTLA 4 or CTLA-4 or 'cytotoxic T lymphocyte antigen 4').mp.
19.	Cemiplimab.mp.
20.	(cemiplimab rwlc or cemiplimab-rwlc or libtayo or regn 2810 or regn2810 or sar 439684 or sar439684).ti,ab,kw.
21.	Programmed Cell Death 1 Receptor/ai
22.	gilvetmab.mp.
23.	(PD 1 or PD-1 or PD1).ti,ab,kw.
24.	Pembrolizumab.mp.
25.	(keytruda or lambrolizumab or mk 3475 or mk3475 or sch 900475 or sch900475).ti,ab,kw.
26.	Nivolumab/
27.	(31yo63lbsn or bms 936558 or bms-936558 or bms936558 or mdx 1106 or mdx-1106 or mdx1106 or nivolumab or ono 4538 or ono-4538 or ono4538 or opdivo).ti,ab,kw.
28.	(cmab 819 or cmab819).ti,ab,kw.
29.	Atezolizumab.mp.
30.	(monoclonal antibody mpdl 3280a or monoclonal antibody mpdl3280a or mpdl 3280a or mpdl3280a or rg 7446 or rg7446 or ro 5541267 or ro5541267 or tecentriq or tecntriq).ti,ab,kw.
31.	Avelumab.mp.
32.	(bavencio or "msb 0010682" or msb 0010718c or msb 10682 or msb 10718c or msb0010682 or msb0010718c or msb10682 or msb10718c or "pf 06834635" or pf 6834635 or pf06834635 or pf6834635).ti,ab,kw.
33.	Durvalumab.mp.
34.	(imfinzi or medi 4736 or medi4736).ti,ab,kw.
35.	PD-L1.mp.
36.	Immunotherapy, Active/
37.	(active immunotherap* or immune rna manipulation* or vaccine therap*).ti,ab,kw.
38.	Cancer Vaccines/
39.	(cancer vaccine* or neoplasm vaccine* or tumor vaccine* or tumour vaccine*).ti,ab,kw.
40.	dcvax.ti,ab,kw.
41.	(dendritic cell adj2 vaccine*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
42.	Allogeneic Vaccine*.ti,ab,kw.
43.	(allogeneic adj5 vaccine*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
44.	(immunotherapy adj2 vaccine*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
45.	(Autologous adj2 Vaccine*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
46.	(CAR engineered T-cell* or CAR engineered T-lymphocyte* or CAR modified T-cell* or CAR modified T-lymphocyte* or CAR T-cell* or CAR T-lymphocyte* or chimeric antigen receptor T-lymphocyte*).ti,ab,kw. and (THERAP* or TREATMENT*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
47.	Bevacizumab/
48.	(2s9zzm9q9v or avastin or bevacizumab or bevacizumab awwb or bevacizumab-awwb or mvasi).ti,ab,kw.
49.	LARGE NEUTRAL AMINO ACID-TRANSPORTER 1.mp.
50.	(e16 membrane protein* or lat1* or slc7a5).ti,ab,kw.
51.	(EFFLUX adj2 (TRANSPORT* or INHIBITOR*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
52.	(TRANSPORTER* adj3 DRUG* adj3 DELIVER*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
53.	(TRANSPORTER* adj2 MEDIAT* adj3 DRUG*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
54.	((ABCB1 or ABCB2) adj2 (ANTAGONIST* or INHIBITOR*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
55.	Prodrugs/
56.	PROTAC.ti,ab,kw.
57.	(proteolysis adj2 target* adj2 (chimaer* or chimer*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
58.	(CHIM* adj2 ANTIGEN* adj2 RECEPTOR*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
59.	or/1-58
60.	exp Neoplasm Metastasis/
61.	(metastas* or metastat*).mp.
62.	60 or 61
63.	exp Brain Neoplasms/sc [Secondary]
64.	Animals/
65.	Humans/
66.	64 not (64 and 65)
67.	adolescent/ or child/ or infant/
68.	Adult/
69.	67 not (67 and 68)
70.	comment/ or editorial/ or letter/ or in vitro techniques/ or culture techniques/ or review/ or systematic review/
71.	exp case-control studies/
72.	case reports/
73.	72 not 71
74.	exp Meningeal Neoplasms/ and (INTRACRANIAL* or CEREBRAL* or INTRA-CRANIAL or BRAIN* or LEPTOMEN*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
75.	(intracranial meningeal neoplasm* or intra-cranial meningeal neoplasm* or leptomening* or intracranial meningeal cancer* or intra-cranial meningeal cancer*).ti,ab,kw.
76.	74 or 75
77.	(62 or 63) and 76
78.	(LEPTOMENING* adj4 METAST*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
79.	77 or 78
80.	limit 79 to english language
81.	80 not 66
82.	81 not 69
83.	82 not 70
84.	83 not 73
85.	Drug Evaluation, Preclinical/
86.	Xenograft Model Antitumor Assays/
87.	Disease Models, Animal/
88.	85 or 86 or 87
89.	84 not 88
90.	59 and 89

 

PICO – BRAIN METS – ET UPDATE – INTERSTITIAL MODALITIES

 

1.	Brachytherapy/
2.	brachytherap*.ti,ab,kw.
3.	(LOCAL adj2 THERAP*).ti,ab,kw.
4.	(LOCAL adj2 (RADIATION or IRRADIAT* or RADIOTHERAP*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
5.	(LOCAL adj2 CHEMOTHERAP*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
6.	((INTRAOPERATIV* or INTRA-OPERATIV*) adj2 (RADIOTHERAP* or IRRADIAT* or RADIATION*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
7.	CAVITY BOOST*.ti,ab,kw.
8.	IORT.ti,ab,kw.
9.	(I-125 seed* or 125I SEED*).ti,ab,kw.
10.	(IODINE-125 adj2 SEED*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
11.	Iodine Radioisotopes/tu [Therapeutic Use]
12.	(CESIUM 131 or CS 131).mp.
13.	Gliadel.ti,ab,kw.
14.	BCNU.ti,ab,kw.
15.	Carmustine/ or carmustine.mp.
16.	(INTERSTITIAL adj2 (MODALIT* or CHEMO* or DRUG* or AGENT* or ANTINEOPLASTIC* or ANTI-NEOPLASTIC* or RADIAT* or RADIO* or THERAP* or TREATMENT* or IRRADIAT*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
17.	or/1-16
18.	exp Brain Neoplasms/
19.	(brain* or brain stem* or BRAINSTEM* or cerebral* or intracranial* or INTRA-CRANIAL or cerebellum* or cerebellar* or frontal lobe* or temporal lobe* or occipital lobe* or parietal lobe* or cerebrum*).mp.
20.	exp FRONTAL LOBE/ or exp TEMPORAL LOBE/ or exp OCCIPITAL LOBE/ or exp PARIETAL LOBE/
21.	exp Neoplasm Metastasis/
22.	(metastas* or metastat*).mp.
23.	21 or 22
24.	(18 or 19 or 20) and 23
25.	exp Brain Neoplasms/sc [Secondary]
26.	24 or 25
27.	limit 26 to english language
28.	Animals/
29.	Humans/
30.	28 not (28 and 29)
31.	27 not 30
32.	adolescent/ or child/ or infant/
33.	Adult/
34.	32 not (32 and 33)
35.	31 not 34
36.	comment/ or editorial/ or letter/ or in vitro techniques/ or culture techniques/ or review/ or systematic review/
37.	exp case-control studies/
38.	case reports/
39.	38 not 37
40.	35 not 36
41.	40 not 39
42.	limit 41 to yr="2016-2022"
43.	Drug Evaluation, Preclinical/ or Disease Models, Animal/ or Xenograft Model Antitumor Assays/
44.	42 not 43
45.	17 and 44

 

PICO 6 – BRAIN METS ET UPDATE – RADIOSENSITIZERS

 

1.	(RADIATION SENSITI* or "radiosensit*" or "radio sensit*").ti,ab,kw.
2.	Radiation-Sensitizing Agents/
3.	motexafin gadolinium.mp.
4.	("gadolinium texaphyrin" or "motexafin gadolinium" or "pci 0120" or "xcytrin").ti,ab,kw.
5.	Temozolomide/
6.	(Methazolastone or Temodal or Temodar or Temozolomide Hexyl Ester or TMZA-HE or CCRG 81045 or CCRG-81045 or CCRG81045 or TMZ-Bioshuttle or TMZ Bioshuttle or NSC 362856 or NSC-362856 or NSC362856).ti,ab,kw.
7.	exp Chloroquine/
8.	(chloroquine* or chingamin or nivaquine or chloroquine sulphate or aralen or arechine).ti,ab,kw.
9.	Sodium Nitrite/
10.	SODIUM NITRITE*.ti,ab,kw.
11.	(7632-00-0 or m0kg633d4f).ti,ab,kw.
12.	epothilone B.mp.
13.	(patupilone or epo906).ti,ab,kw.
14.	Vorinostat/
15.	(18f suberoylanilide hydroxamic acid or 18f-saha or 18f-suberoylanilide hydroxamic acid or 58ifb293ji or m344 or "mk 0683" or mk-0683 or mk0683 or n1 hydroxy n8 phenyloctanediamide or n1-hydroxy-n8-phenyloctanediamide or nhnpoda or suberanilohydroxamic acid or suberoyl anilide hydroxamic acid or suberoylanilide hydroxamic acid or vorinostat or zolinza).ti,ab,kw.
16.	AK 2123.mp.
17.	(sanazole or senazole or technetium 99m cyclam ak 2123).ti,ab,kw.
18.	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17
19.	exp Brain Neoplasms/
20.	(brain* or brain stem* or BRAINSTEM* or cerebral* or intracranial* or INTRA-CRANIAL or cerebellum* or cerebellar* or frontal lobe* or temporal lobe* or occipital lobe* or parietal lobe* or cerebrum*).mp.
21.	exp FRONTAL LOBE/ or exp TEMPORAL LOBE/ or exp OCCIPITAL LOBE/ or exp PARIETAL LOBE/
22.	exp Neoplasm Metastasis/
23.	(metastas* or metastat*).mp.
24.	22 or 23
25.	(19 or 20 or 21) and 24
26.	exp Brain Neoplasms/sc [Secondary]
27.	25 or 26
28.	limit 27 to english language
29.	Animals/
30.	Humans/
31.	29 not (29 and 30)
32.	28 not 31
33.	adolescent/ or child/ or infant/
34.	Adult/
35.	33 not (33 and 34)
36.	32 not 35
37.	comment/ or editorial/ or letter/ or in vitro techniques/ or culture techniques/ or review/ or systematic review/
38.	exp case-control studies/
39.	case reports/
40.	39 not 38
41.	36 not 37
42.	41 not 40
43.	limit 42 to yr="2016-2022"
44.	Drug Evaluation, Preclinical/ or Disease Models, Animal/ or Xenograft Model Antitumor Assays/
45.	43 not 44
46.	18 and 45

 

PICO 7 – BRAIN METS ET UPDATE – LASER INTERSTITIAL THERMAL THERAPY (LITTS)

 

1.	Laser Therapy/
2.	(LASER* adj3 (THERAP* or ABLAT* or THERM* or INTERSTITIAL*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
3.	LITT.ti,ab.
4.	1 or 2 or 3
5.	exp Brain Neoplasms/
6.	(brain* or brain stem* or BRAINSTEM* or cerebral* or intracranial* or INTRA-CRANIAL or cerebellum* or cerebellar* or frontal lobe* or temporal lobe* or occipital lobe* or parietal lobe* or cerebrum*).mp.
7.	exp FRONTAL LOBE/ or exp TEMPORAL LOBE/ or exp OCCIPITAL LOBE/ or exp PARIETAL LOBE/
8.	exp Neoplasm Metastasis/
9.	(metastas* or metastat*).mp.
10.	8 or 9
11.	(5 or 6 or 7) and 10
12.	exp Brain Neoplasms/sc [Secondary]
13.	11 or 12
14.	limit 13 to english language
15.	Animals/
16.	Humans/
17.	15 not (15 and 16)
18.	14 not 17
19.	adolescent/ or child/ or infant/
20.	Adult/
21.	19 not (19 and 20)
22.	18 not 21
23.	comment/ or editorial/ or letter/ or in vitro techniques/ or culture techniques/ or review/ or systematic review/
24.	exp case-control studies/
25.	case reports/
26.	25 not 24
27.	22 not 23
28.	27 not 26
29.	limit 28 to yr="2016-2022"
30.	Drug Evaluation, Preclinical/ or Disease Models, Animal/ or Xenograft Model Antitumor Assays/
31.	29 not 30
32.	4 and 31

 

PICO 8 – BRAIN METS ET UPDATE – MR-GUIDED FOCUSED ULTRASOUND

 

1.	High-Intensity Focused Ultrasound Ablation/
2.	hifu.ti,ab,kw.
3.	((Ultrasound* or ultrasonic*) adj3 (intens* or ablat* or therap* or focus*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
4.	(MRgFUS* or Exablate* or MRIgFUS*).ti,ab,kw.
5.	((MR or MRI or MAGNETIC RESONANCE*) adj4 (GUID* or FOCUS*) adj5 (ULTRASOUND or ULTRASONO* or ULTRASONIC*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
6.	(SonoCloud* or SONOFIRST or SC-9 or SC9).ti,ab,kw.
7.	or/1-6
8.	exp Brain Neoplasms/
9.	(brain* or brain stem* or BRAINSTEM* or cerebral* or intracranial* or INTRA-CRANIAL or cerebellum* or cerebellar* or frontal lobe* or temporal lobe* or occipital lobe* or parietal lobe* or cerebrum*).mp.
10.	exp FRONTAL LOBE/ or exp TEMPORAL LOBE/ or exp OCCIPITAL LOBE/ or exp PARIETAL LOBE/
11.	exp Neoplasm Metastasis/
12.	(metastas* or metastat*).mp.
13.	11 or 12
14.	(8 or 9 or 10) and 13
15.	exp Brain Neoplasms/sc [Secondary]
16.	14 or 15
17.	limit 16 to english language
18.	Animals/
19.	Humans/
20.	18 not (18 and 19)
21.	17 not 20
22.	adolescent/ or child/ or infant/
23.	Adult/
24.	22 not (22 and 23)
25.	21 not 24
26.	comment/ or editorial/ or letter/ or in vitro techniques/ or culture techniques/ or review/ or systematic review/
27.	exp case-control studies/
28.	case reports/
29.	28 not 27
30.	25 not 26
31.	30 not 29
32.	limit 31 to yr="2016-2022"
33.	Drug Evaluation, Preclinical/ or Disease Models, Animal/ or Xenograft Model Antitumor Assays/
34.	32 not 33
35.	7 and 34

 

EMBASE.COM

 

PICO 1 - BRAIN METS ET UPDATE – PARENCHYMAL – MOLECULAR TARGETED THERAPY

 

('vemurafenib'/exp OR 'vemurafenib':ti,ab,kw OR ((((plx4032:ti,ab,kw OR r:ti,ab,kw) AND 7204:ti,ab,kw OR r7204:ti,ab,kw OR rg:ti,ab,kw) AND 7204:ti,ab,kw OR rg7204:ti,ab,kw OR ro:ti,ab,kw) AND 5185426:ti,ab,kw) OR zelboraf:ti,ab,kw OR 'encorafenib'/exp OR 'encorafenib':ti,ab,kw OR ((((((((((braftovi:ti,ab,kw OR lgx:ti,ab,kw) AND 818:ti,ab,kw OR lgx818:ti,ab,kw OR nvp:ti,ab,kw) AND lgx:ti,ab,kw AND 818:ti,ab,kw OR nvp:ti,ab,kw) AND lgx:ti,ab,kw AND 818:ti,ab,kw AND nxa:ti,ab,kw OR nvp:ti,ab,kw) AND lgx818:ti,ab,kw OR nvp:ti,ab,kw) AND lgx818:ti,ab,kw AND nxa:ti,ab,kw OR ono:ti,ab,kw) AND 7702:ti,ab,kw OR ono7702:ti,ab,kw OR pf:ti,ab,kw) AND 07263896:ti,ab,kw OR pf:ti,ab,kw) AND 7263896:ti,ab,kw OR pf07263896:ti,ab,kw OR pf7263896:ti,ab,kw OR w:ti,ab,kw) AND 0090:ti,ab,kw) OR 'dabrafenib'/exp OR 'dabrafenib':ti,ab,kw OR ((((((dabrafenib:ti,ab,kw AND mesilate:ti,ab,kw OR dabrafenib:ti,ab,kw) AND mesylate:ti,ab,kw OR drb:ti,ab,kw) AND 436:ti,ab,kw OR drb436:ti,ab,kw OR gsk:ti,ab,kw) AND 2118436:ti,ab,kw OR gsk:ti,ab,kw) AND 2118436a:ti,ab,kw OR gsk:ti,ab,kw) AND 2118436b:ti,ab,kw) OR gsk2118436:ti,ab,kw OR gsk2118436a:ti,ab,kw OR gsk2118436b:ti,ab,kw OR tafinlar:ti,ab,kw OR 'b raf kinase':ti,ab,kw OR 'b-raf kinase':ti,ab,kw OR 'braf kinase':ti,ab,kw OR 'proto oncogene protein b raf':ti,ab,kw OR 'proto oncogene proteins b raf':ti,ab,kw OR 'proto-oncogene protein b-raf':ti,ab,kw OR 'proto-oncogene proteins b-raf':ti,ab,kw OR braf:ti,ab,kw OR 'plx 4032':ti,ab,kw OR plx4032:ti,ab,kw OR 'r 7204':ti,ab,kw OR r7204:ti,ab,kw OR 'rg 7204':ti,ab,kw OR rg7204:ti,ab,kw OR 'ro 5185426':ti,ab,kw OR ro5185426:ti,ab,kw OR 'lgx 818':ti,ab,kw OR 'lgx818':ti,ab,kw OR 'nvp lgx 818':ti,ab,kw OR 'nvp lgx 818 nxa':ti,ab,kw OR 'nvp lgx818':ti,ab,kw OR 'nvp lgx818 nxa':ti,ab,kw OR 'ono 7702':ti,ab,kw OR ono7702:ti,ab,kw OR 'pf 07263896':ti,ab,kw OR 'pf 7263896':ti,ab,kw OR pf07263896:ti,ab,kw OR pf7263896:ti,ab,kw OR 'w 0090':ti,ab,kw OR w0090:ti,ab,kw OR mek:ti,ab,kw OR 'braf/mek':ti,ab,kw OR 'mitogen activated protein kinase'/exp OR 'mitogen activated protein kinase':ti,ab,kw OR 'binimetinib'/exp OR 'binimetinib':ti,ab,kw OR 'arry 162':ti,ab,kw OR 'arry 438162':ti,ab,kw OR arry162:ti,ab,kw OR arry438162:ti,ab,kw OR balimek:ti,ab,kw OR 'mek 162':ti,ab,kw OR mek162:ti,ab,kw OR mektovi:ti,ab,kw OR 'ono 7703':ti,ab,kw OR 'ono7703':ti,ab,kw OR 'pf 06811462':ti,ab,kw OR 'pf 6811462':ti,ab,kw OR pf06811462:ti,ab,kw OR pf6811462:ti,ab,kw OR 'cobimetinib'/exp OR 'cobimetinib':ti,ab,kw OR 'cobimetinib butyrate':ti,ab,kw OR 'cobimetinib fumarate':ti,ab,kw OR 'cobimetinib hemifumarate':ti,ab,kw OR cotellic:ti,ab,kw OR 'gdc 0973':ti,ab,kw OR gdc0973:ti,ab,kw OR 'rg 7420':ti,ab,kw OR rg7420:ti,ab,kw OR 'ro 5514041':ti,ab,kw OR ro5514041:ti,ab,kw OR 'xl 518':ti,ab,kw OR xl518:ti,ab,kw OR 'trametinib'/exp OR 'trametinib':ti,ab,kw OR 'gsk 1120212':ti,ab,kw OR 'gsk 1120212b':ti,ab,kw OR gsk1120212:ti,ab,kw OR gsk1120212b:ti,ab,kw OR 'jtp 74057':ti,ab,kw OR jtp74057:ti,ab,kw OR mekinist:ti,ab,kw OR 'snr 1611':ti,ab,kw OR snr1611:ti,ab,kw OR 'tmt 212':ti,ab,kw OR tmt212:ti,ab,kw OR 'trametinib dimethyl sulfoxide':ti,ab,kw OR 'trastuzumab'/exp OR 'trastuzumab':ti,ab,kw OR 'abp 980':ti,ab,kw OR abp980:ti,ab,kw OR 'amt 901':ti,ab,kw OR amt901:ti,ab,kw OR aryotrust:ti,ab,kw OR 'bcd 022':ti,ab,kw OR bcd022:ti,ab,kw OR 'bx 2318':ti,ab,kw OR bx2318:ti,ab,kw OR 'ct p06':ti,ab,kw OR 'ct p6':ti,ab,kw OR ctp06:ti,ab,kw OR ctp6:ti,ab,kw OR 'da 3111':ti,ab,kw OR da3111:ti,ab,kw OR 'dmb 3111':ti,ab,kw OR dmb3111:ti,ab,kw OR 'eg 12014':ti,ab,kw OR eg12014:ti,ab,kw OR 'hd 201':ti,ab,kw OR hd201:ti,ab,kw OR herceptin:ti,ab,kw OR herclon:ti,ab,kw OR 'hermyl 1401o':ti,ab,kw OR 'hermyl1401o':ti,ab,kw OR herticad:ti,ab,kw OR hertraz:ti,ab,kw OR hervelous:ti,ab,kw OR herzuma:ti,ab,kw OR 'hlx 02':ti,ab,kw OR hlx02:ti,ab,kw OR kanjinti:ti,ab,kw OR 'myl 1401o':ti,ab,kw OR 'myl1401o':ti,ab,kw OR ogivri:ti,ab,kw OR 'ons 1050':ti,ab,kw OR ons1050:ti,ab,kw OR ontruzant:ti,ab,kw OR 'pf 05280014':ti,ab,kw OR 'pf 5280014':ti,ab,kw OR pf05280014:ti,ab,kw OR pf5280014:ti,ab,kw OR 'r 597':ti,ab,kw OR r597:ti,ab,kw OR 'rg 597':ti,ab,kw OR rg597:ti,ab,kw OR samfenet:ti,ab,kw OR 'sb 3':ti,ab,kw OR sb3:ti,ab,kw OR trasturel:ti,ab,kw OR 'trastuzumab anns':ti,ab,kw OR 'trastuzumab beta':ti,ab,kw OR 'trastuzumab dkst':ti,ab,kw OR 'trastuzumab dttb':ti,ab,kw OR 'trastuzumab pkrb':ti,ab,kw OR 'trastuzumab qyyp':ti,ab,kw OR 'trastuzumab-anns':ti,ab,kw OR 'trastuzumab-dkst':ti,ab,kw OR 'trastuzumab-dttb':ti,ab,kw OR 'trastuzumab-pkrb':ti,ab,kw OR 'trastuzumab-qyyp':ti,ab,kw OR trazimera:ti,ab,kw OR 'tx 05':ti,ab,kw OR tx05:ti,ab,kw OR 'ub 921':ti,ab,kw OR ub921:ti,ab,kw OR vivitra:ti,ab,kw OR zedora:ti,ab,kw OR zercepac:ti,ab,kw OR 'zrc 3256':ti,ab,kw OR zrc3256:ti,ab,kw OR 'lapatinib'/exp OR 'lapatinib':ti,ab,kw OR 'gw 2016':ti,ab,kw OR 'gw 572016':ti,ab,kw OR 'gw 572016f':ti,ab,kw OR gw2016:ti,ab,kw OR gw572016:ti,ab,kw OR gw572016f:ti,ab,kw OR 'lapatinib ditosylate':ti,ab,kw OR 'lapatinib ditosylate monohydrate':ti,ab,kw OR 'lapatinib tosylate':ti,ab,kw OR tykerb:ti,ab,kw OR tyverb:ti,ab,kw OR 'pertuzumab'/exp OR 'pertuzumab':ti,ab,kw OR 2c4:ti,ab,kw OR 'hs 627':ti,ab,kw OR hs627:ti,ab,kw OR 'monoclonal antibody 2c4':ti,ab,kw OR omnitarg:ti,ab,kw OR perjeta:ti,ab,kw OR 'ql 1209':ti,ab,kw OR ql1209:ti,ab,kw OR 'r 1273':ti,ab,kw OR r1273:ti,ab,kw OR 'rg 1273':ti,ab,kw OR rg1273:ti,ab,kw OR 'rhumab 2c4':ti,ab,kw OR 'ro 4368451':ti,ab,kw OR ro4368451:ti,ab,kw OR 'tucatinib'/exp OR 'tucatinib':ti,ab,kw OR 'arry 380':ti,ab,kw OR arry380:ti,ab,kw OR irbinitinib:ti,ab,kw OR 'mk 7119':ti,ab,kw OR mk7119:ti,ab,kw OR 'ont 380':ti,ab,kw OR ont380:ti,ab,kw OR tukysa:ti,ab,kw OR 'capecitabine'/exp OR 'capecitabine':ti,ab,kw OR apecitab:ti,ab,kw OR atubri:ti,ab,kw OR capcel:ti,ab,kw OR capebina:ti,ab,kw OR capecite:ti,ab,kw OR capegard:ti,ab,kw OR capezam:ti,ab,kw OR capicet:ti,ab,kw OR capiibine:ti,ab,kw OR capnat:ti,ab,kw OR capoda:ti,ab,kw OR capostat:ti,ab,kw OR capsy:ti,ab,kw OR capxcel:ti,ab,kw OR caxeta:ti,ab,kw OR citabin:ti,ab,kw OR ecansya:ti,ab,kw OR 'r 340':ti,ab,kw OR r340:ti,ab,kw OR 'ro 09 1978':ti,ab,kw OR 'ro 09-1978':ti,ab,kw OR 'ro 091978':ti,ab,kw OR 'ro09 1978':ti,ab,kw OR 'ro09-1978':ti,ab,kw OR ro091978:ti,ab,kw OR xabine:ti,ab,kw OR xecap:ti,ab,kw OR xelocel:ti,ab,kw OR xeloda:ti,ab,kw OR zocitab:ti,ab,kw OR 'neratinib'/exp OR 'neratinib':ti,ab,kw OR 'can 030':ti,ab,kw OR can030:ti,ab,kw OR 'hki 272':ti,ab,kw OR hki272:ti,ab,kw OR 'neratinib maleate':ti,ab,kw OR nerlynx:ti,ab,kw OR 'pb 272':ti,ab,kw OR pb272:ti,ab,kw OR 'way 177820':ti,ab,kw OR way177820:ti,ab,kw OR 'epidermal growth factor receptor 2'/exp OR 'c erbb2 protein':ti,ab,kw,de OR 'erbb 2 kinase':ti,ab,kw,de OR 'erbb 2 receptor':ti,ab,kw,de OR 'erbb receptor 2':ti,ab,kw,de OR 'erbb2 protein':ti,ab,kw,de OR 'erbb2 receptor':ti,ab,kw,de OR 'her 2 protein':ti,ab,kw,de OR 'her 2 receptor':ti,ab,kw,de OR 'her2 protein':ti,ab,kw,de OR 'neu differentiation factor receptor':ti,ab,kw,de OR 'neu protein':ti,ab,kw,de OR 'neu receptor':ti,ab,kw,de OR 'neuregulin receptor':ti,ab,kw,de OR 'oncoprotein her 2':ti,ab,kw,de OR 'oncoprotein her2':ti,ab,kw,de OR 'oncoprotein neu':ti,ab,kw,de OR 'protein c erbb 2':ti,ab,kw,de OR 'protein c erbb2':ti,ab,kw,de OR 'protein erb b 2':ti,ab,kw,de OR 'protein erbb 2':ti,ab,kw,de OR 'protein erbb2':ti,ab,kw,de OR 'protein her 2':ti,ab,kw,de OR 'protein her 2 neu':ti,ab,kw,de OR 'protein her2':ti,ab,kw,de OR 'protein her2 neu':ti,ab,kw,de OR 'protein neu':ti,ab,kw,de OR 'protein tyrosine kinase erbb2':ti,ab,kw,de OR 'protein tyrosine kinase receptor erbb2':ti,ab,kw,de OR 'proto-oncogene proteins c-erbb-2':ti,ab,kw,de OR 'receptor neu':ti,ab,kw,de OR 'tyrosine kinase her2':ti,ab,kw,de OR 'epidermal growth factor receptor 2':ti,ab,kw OR 'her kinase':ti,ab,kw,de OR 'her-2-neu':ti,ab,kw,de OR 'her2-neu':ti,ab,kw,de OR 'alectinib'/exp OR 'alectinib':ti,ab,kw OR 'af 802':ti,ab,kw OR af802:ti,ab,kw OR alecensa:ti,ab,kw OR alecensaro:ti,ab,kw OR 'alectinib hydrochloride':ti,ab,kw OR 'ch 5424802':ti,ab,kw OR ch5424802:ti,ab,kw OR 'rg 7853':ti,ab,kw OR rg7853:ti,ab,kw OR 'ro 5424802':ti,ab,kw OR ro5424802:ti,ab,kw OR 'anaplastic lymphoma kinase'/exp OR 'anaplastic lymphoma kinase':ti,ab,kw OR 'alk kinase':ti,ab,kw OR 'alk tyrosine kinase receptor':ti,ab,kw OR 'anaplastic lymphoma receptor tyrosine kinase':ti,ab,kw OR 'cd246 antigen':ti,ab,kw OR 'npm-alk':ti,ab,kw OR 'nucleophosmin anaplastic lymphoma kinase':ti,ab,kw OR 'nucleophosmin-anaplastic lymphoma kinase':ti,ab,kw OR 'ceritinib'/exp OR 'ceritinib':ti,ab,kw OR jikadia:ti,ab,kw OR 'ldk 378':ti,ab,kw OR ldk378:ti,ab,kw OR 'nvp ldk 378':ti,ab,kw OR 'nvp ldk 378 nx':ti,ab,kw OR 'nvp ldk378':ti,ab,kw OR 'nvp ldk378 nx':ti,ab,kw OR zykadia:ti,ab,kw OR 'crizotinib'/exp OR 'crizotinib':ti,ab,kw OR 'pf 02341066':ti,ab,kw OR 'pf 1066':ti,ab,kw OR 'pf 2341066':ti,ab,kw OR pf02341066:ti,ab,kw OR pf1066:ti,ab,kw OR pf2341066:ti,ab,kw OR xalkori:ti,ab,kw OR 'brigatinib'/exp OR 'brigatinib':ti,ab,kw OR alunbrig:ti,ab,kw OR 'ap 26113':ti,ab,kw OR ap26113:ti,ab,kw OR 'erlotinib'/exp OR 'erlotinib':ti,ab,kw OR 'nsc 718781':ti,ab,kw OR nsc718781:ti,ab,kw OR 'osi 774':ti,ab,kw OR osi774:ti,ab,kw OR 'r 1415':ti,ab,kw OR r1415:ti,ab,kw OR 'rg 1415':ti,ab,kw OR rg1415:ti,ab,kw OR 'ro 50 8231':ti,ab,kw OR 'ro 508231':ti,ab,kw OR ro508231:ti,ab,kw OR 'sgt 210':ti,ab,kw OR sgt210:ti,ab,kw OR tarceva:ti,ab,kw OR 'icotinib'/exp OR 'icotinib':ti,ab,kw OR 'bpi 2009':ti,ab,kw OR 'bpi 2009h':ti,ab,kw OR bpi2009:ti,ab,kw OR bpi2009h:ti,ab,kw OR conmana:ti,ab,kw OR 'icotinib hydrochloride':ti,ab,kw OR 'gefitinib'/exp OR 'gefitinib':ti,ab,kw OR 'gefitinib hydrochloride':ti,ab,kw OR geftinat:ti,ab,kw OR iressa:ti,ab,kw OR 'zd 1839':ti,ab,kw OR zd1839:ti,ab,kw OR 'afatinib'/exp OR 'afatinib':ti,ab,kw OR 'afatinib dimaleate':ti,ab,kw OR 'bibw 2992':ti,ab,kw OR bibw2992:ti,ab,kw OR gilotrif:ti,ab,kw OR giotrif:ti,ab,kw OR tovok:ti,ab,kw OR 'osimertinib'/exp OR 'osimertinib':ti,ab,kw OR 'azd 9291':ti,ab,kw OR azd9291:ti,ab,kw OR mereletinib:ti,ab,kw OR 'osimertinib mesilate':ti,ab,kw OR 'osimertinib mesylate':ti,ab,kw OR tagrisso:ti,ab,kw OR 'egfr'/exp OR 'egfr':ti,ab,kw OR 'epidermal growth factor'/exp OR 'epidermal growth factor':ti,ab,kw OR 'beta urogastrone':ti,ab,kw OR 'epidermal growth factor urogastrone':ti,ab,kw OR 'epidermal growth factor-urogastrone':ti,ab,kw OR 'epidermis growth factor':ti,ab,kw OR 'epidermis growth factor urogastrone':ti,ab,kw OR 'entrectinib'/exp OR 'entrectinib':ti,ab,kw OR 'nms e 628':ti,ab,kw OR 'nms e628':ti,ab,kw OR 'rg 6268':ti,ab,kw OR rg6268:ti,ab,kw OR rozlytrek:ti,ab,kw OR 'rxdx 101':ti,ab,kw OR rxdx101:ti,ab,kw OR 'brain derived neurotrophic factor receptor'/exp OR 'bdnf receptor':ti,ab,kw OR 'brain derived neurotrophic factor receptor':ti,ab,kw OR 'ntrk2 receptor':ti,ab,kw OR 'neurotrophic tyrosine kinase receptor type 2':ti,ab,kw OR 'trkb receptor':ti,ab,kw OR ntrk:ti,ab,kw OR 'larotrectinib'/exp OR 'larotrectinib':ti,ab,kw OR 'arry 470':ti,ab,kw OR arry470:ti,ab,kw OR 'larotrectinib sulfate':ti,ab,kw OR 'loxo 101':ti,ab,kw OR loxo101:ti,ab,kw OR 'hydroxypyrrolidine 1 carboxamide sulfate':ti,ab,kw OR vitrakvi:ti,ab,kw OR 'sotorasib'/exp OR 'sotorasib':ti,ab,kw OR 'amg 510':ti,ab,kw OR amg510:ti,ab,kw OR lumakras:ti,ab,kw OR lumykras:ti,ab,kw OR 'sotorasib hydrochloride':ti,ab,kw OR 'adagrasib'/exp OR 'adagrasib':ti,ab,kw OR 'mrtx 849':ti,ab,kw OR mrtx849:ti,ab,kw OR kras:ti,ab,kw OR 'erdafitinib'/exp OR balversa:ti,ab,kw OR 'jnj 42756493':ti,ab,kw OR jnj42756493:ti,ab,kw OR 'fibroblast growth factor':ti,ab,kw,de OR 'fibroblast growth factors':ti,ab,kw,de OR fgfr:ti,ab,kw,de OR 'olaparib'/exp OR 'olaparib':ti,ab,kw OR 'azd 2281':ti,ab,kw OR azd2281:ti,ab,kw OR 'ku 0059436':ti,ab,kw OR 'ku 59436':ti,ab,kw OR ku0059436:ti,ab,kw OR ku59436:ti,ab,kw OR lynparza:ti,ab,kw OR 'mk 7339':ti,ab,kw OR mk7339:ti,ab,kw OR 'niraparib'/exp OR 'niraparib':ti,ab,kw OR 'gsk 3985771':ti,ab,kw OR gsk3985771:ti,ab,kw OR 'jnj 64091742':ti,ab,kw OR jnj64091742:ti,ab,kw OR 'mk 4827':ti,ab,kw OR mk4827:ti,ab,kw OR 'niraparib 4 methylbenzenesulfonate':ti,ab,kw OR 'niraparib hydrochloride':ti,ab,kw OR 'niraparib tosilate':ti,ab,kw OR 'niraparib tosylate':ti,ab,kw OR zejula:ti,ab,kw OR 'zl 2306':ti,ab,kw OR zl2306:ti,ab,kw OR 'rucaparib'/exp OR 'rucaparib':ti,ab,kw OR 'ag 014699':ti,ab,kw OR 'ag 14447':ti,ab,kw OR 'ag 14699':ti,ab,kw OR ag014699:ti,ab,kw OR ag14447:ti,ab,kw OR ag14699:ti,ab,kw OR 'co 338':ti,ab,kw OR co338:ti,ab,kw OR 'pf 01367338':ti,ab,kw OR 'pf 1367338':ti,ab,kw OR 'pf 1367338 bw':ti,ab,kw OR pf01367338:ti,ab,kw OR pf1367338:ti,ab,kw OR pf1367338bw:ti,ab,kw OR rubraca:ti,ab,kw OR 'rucaparib camphorsulfonate':ti,ab,kw OR 'rucaparib camsilate':ti,ab,kw OR 'rucaparib camsylate':ti,ab,kw OR 'rucaparib phosphate':ti,ab,kw OR 'protein tyrosine kinase'/exp OR 'protein tyrosine kinase':ti,ab,kw OR 'tyrosine kinase':ti,ab,kw OR 'tyrosine protein kinase':ti,ab,kw OR 'tyrosine specific protein kinase':ti,ab,kw OR 'tyrosylprotein kinase':ti,ab,kw OR parp:ti,ab,kw OR 'poly(adp-ribose) polymerase inhibitors':ti,ab,kw OR 'sorafenib'/exp OR 'sorafenib':ti,ab,kw OR (('bay 43-9006':ti,ab,kw OR 'bay 439006':ti,ab,kw OR bay43:ti,ab,kw) AND 9006:ti,ab,kw) OR 'bay43-9006':ti,ab,kw OR bay439006:ti,ab,kw OR nexavar:ti,ab,kw OR 'sorafenib tosylate':ti,ab,kw OR 'sunitinib'/exp OR 'sunitinib':ti,ab,kw OR 'pha 2909040ad':ti,ab,kw OR 'pha 290940ad':ti,ab,kw OR pha2909040ad:ti,ab,kw OR pha290940ad:ti,ab,kw OR 'pno 290940':ti,ab,kw OR pnu290940:ti,ab,kw OR 'su 010398':ti,ab,kw OR 'su 011248':ti,ab,kw OR 'su 10398':ti,ab,kw OR 'su 11248':ti,ab,kw OR su010398:ti,ab,kw OR su011248:ti,ab,kw OR su10398:ti,ab,kw OR su11248:ti,ab,kw OR 'sunitinib cyclamate':ti,ab,kw OR 'sunitinib malate':ti,ab,kw OR 'suo 11248':ti,ab,kw OR suo11248:ti,ab,kw OR sutent:ti,ab,kw OR 'bevacizumab'/exp OR 'bevacizumab':ti,ab,kw OR abevmy:ti,ab,kw OR 'abp 215':ti,ab,kw OR abp215:ti,ab,kw OR ainex:ti,ab,kw OR altuzan:ti,ab,kw OR alymsys:ti,ab,kw OR ankeda:ti,ab,kw OR 'ask b1202':ti,ab,kw OR askb1202:ti,ab,kw OR avastin:ti,ab,kw OR aybintio:ti,ab,kw OR 'bat 1706':ti,ab,kw OR bat1706:ti,ab,kw OR 'bcd 021':ti,ab,kw OR bcd021:ti,ab,kw OR 'bevacizumab awwb':ti,ab,kw OR 'bevacizumab beta':ti,ab,kw OR 'bevacizumab bvzr':ti,ab,kw OR 'bevacizumab-awwb':ti,ab,kw OR 'bevacizumab-bvzr':ti,ab,kw OR bevax:ti,ab,kw OR 'bevz 92':ti,ab,kw OR bevz92:ti,ab,kw OR 'bi 695502':ti,ab,kw OR bi695502:ti,ab,kw OR boyounuo:ti,ab,kw OR bryxta:ti,ab,kw OR byvasda:ti,ab,kw OR 'cbt 124':ti,ab,kw OR cbt124:ti,ab,kw OR 'chs 5217':ti,ab,kw OR chs5217:ti,ab,kw OR cizumab:ti,ab,kw OR 'ct p16':ti,ab,kw OR ctp16:ti,ab,kw OR equidacent:ti,ab,kw OR 'fkb 238':ti,ab,kw OR fkb238:ti,ab,kw OR 'gb 222':ti,ab,kw OR gb222:ti,ab,kw OR 'hd 204':ti,ab,kw OR hd204:ti,ab,kw OR 'hlx 04':ti,ab,kw OR hlx04:ti,ab,kw OR 'ibi 305':ti,ab,kw OR ibi305:ti,ab,kw OR 'jy 028':ti,ab,kw OR jy028:ti,ab,kw OR krabeva:ti,ab,kw OR kyomarc:ti,ab,kw OR lextemy:ti,ab,kw OR 'ly 01008':ti,ab,kw OR ly01008:ti,ab,kw OR 'mb 02':ti,ab,kw OR mb02:ti,ab,kw OR 'mil 60':ti,ab,kw OR mil60:ti,ab,kw OR mvasi:ti,ab,kw OR 'myl 14020':ti,ab,kw OR 'myl 1402o':ti,ab,kw OR myl14020:ti,ab,kw OR myl1402o:ti,ab,kw OR 'nsc 704865':ti,ab,kw OR nsc704865:ti,ab,kw OR onbevzi:ti,ab,kw OR 'ons 1045':ti,ab,kw OR 'ons 5010':ti,ab,kw OR ons1045:ti,ab,kw OR ons5010:ti,ab,kw OR oyavas:ti,ab,kw OR 'pf 06439535':ti,ab,kw OR 'pf 6439535':ti,ab,kw OR pf06439535:ti,ab,kw OR pf6439535:ti,ab,kw OR pusintin:ti,ab,kw OR 'ql 1101':ti,ab,kw OR ql1101:ti,ab,kw OR 'r 435':ti,ab,kw OR r435:ti,ab,kw OR 'rg 435':ti,ab,kw OR rg435:ti,ab,kw OR 'rhumab-vegf':ti,ab,kw OR 'ro 4876646':ti,ab,kw OR ro4876646:ti,ab,kw OR 'rph 001':ti,ab,kw OR rph001:ti,ab,kw OR 'sb 8':ti,ab,kw OR sb8:ti,ab,kw OR 'sct 510':ti,ab,kw OR sct510:ti,ab,kw OR 'stc 103':ti,ab,kw OR stc103:ti,ab,kw OR 'tab 008':ti,ab,kw OR tab008:ti,ab,kw OR 'tot 102':ti,ab,kw OR tot102:ti,ab,kw OR 'trs 003':ti,ab,kw OR trs003:ti,ab,kw OR 'tx 16':ti,ab,kw OR tx16:ti,ab,kw OR versavo:ti,ab,kw OR zirabev:ti,ab,kw OR 'zrc 113':ti,ab,kw OR zrc113:ti,ab,kw OR (molecular NEAR/2 target* NEAR/2 (therap* OR treatment* OR agent* OR drug*))) AND ('brain tumor'/exp OR brain*:ti,ab,kw OR 'brain stem':ti,ab,kw OR brainstem*:ti,ab,kw OR cerebral*:ti,ab,kw OR intracranial*:ti,ab,kw OR 'intra-cranial':ti,ab,kw OR cerebellum:ti,ab,kw OR cerebellar*:ti,ab,kw OR 'frontal lobe':ti,ab,kw OR 'frontal lobes':ti,ab,kw OR 'temporal lobe':ti,ab,kw OR 'temporal lobes':ti,ab,kw OR 'parietal lobe':ti,ab,kw OR 'parietal lobes':ti,ab,kw OR 'occipital lobe':ti,ab,kw OR 'occipital lobes':ti,ab,kw OR cerebrum*:ti,ab,kw OR 'frontal lobe'/exp OR 'temporal lobe'/exp OR 'occipital lobe'/exp) AND (metastas*:ti,ab,kw OR metastat*:ti,ab,kw OR 'metastasis'/exp) AND [english]/lim AND [2016-2022]/py NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('juvenile'/exp NOT ('juvenile' AND 'adult')) NOT ('editorial'/exp OR 'conference paper'/exp OR 'letter'/exp OR 'review'/exp OR 'systematic review'/exp) NOT ('case report'/exp NOT 'case control study'/exp) NOT ('in vitro study'/exp OR 'cell culture technique'/exp OR 'animal experiment'/exp OR 'animal model'/exp) NOT (('brain tumor'/exp OR brain*:ti,ab,kw OR 'brain stem':ti,ab,kw OR brainstem*:ti,ab,kw OR cerebral*:ti,ab,kw OR intracranial*:ti,ab,kw OR 'intra-cranial':ti,ab,kw OR cerebellum:ti,ab,kw OR cerebellar*:ti,ab,kw OR 'frontal lobe':ti,ab,kw OR 'frontal lobes':ti,ab,kw OR 'temporal lobe':ti,ab,kw OR 'temporal lobes':ti,ab,kw OR 'parietal lobe':ti,ab,kw OR 'parietal lobes':ti,ab,kw OR 'occipital lobe':ti,ab,kw OR 'occipital lobes':ti,ab,kw OR cerebrum*:ti,ab,kw OR 'frontal lobe'/exp OR 'temporal lobe'/exp OR 'occipital lobe'/exp) AND (metastas*:ti,ab,kw OR metastat*:ti,ab,kw OR 'metastasis'/exp) AND [english]/lim AND [2016-2022]/py NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('juvenile'/exp NOT ('juvenile' AND 'adult')) NOT ('editorial'/exp OR 'conference paper'/exp OR 'letter'/exp OR 'review'/exp OR 'systematic review'/exp) NOT ('case report'/exp NOT 'case control study'/exp) NOT ('in vitro study'/exp OR 'cell culture technique'/exp OR 'animal experiment'/exp OR 'animal model'/exp) AND 'conference abstract'/it)

 

PICO 2 - BRAIN METS ET UPDATE – LEPTOMENINGEAL – MOLECULAR TARGETED THERAPY

 

('vemurafenib'/exp OR 'vemurafenib':ti,ab,kw OR ((((plx4032:ti,ab,kw OR r:ti,ab,kw) AND 7204:ti,ab,kw OR r7204:ti,ab,kw OR rg:ti,ab,kw) AND 7204:ti,ab,kw OR rg7204:ti,ab,kw OR ro:ti,ab,kw) AND 5185426:ti,ab,kw) OR zelboraf:ti,ab,kw OR 'encorafenib'/exp OR 'encorafenib':ti,ab,kw OR ((((((((((braftovi:ti,ab,kw OR lgx:ti,ab,kw) AND 818:ti,ab,kw OR lgx818:ti,ab,kw OR nvp:ti,ab,kw) AND lgx:ti,ab,kw AND 818:ti,ab,kw OR nvp:ti,ab,kw) AND lgx:ti,ab,kw AND 818:ti,ab,kw AND nxa:ti,ab,kw OR nvp:ti,ab,kw) AND lgx818:ti,ab,kw OR nvp:ti,ab,kw) AND lgx818:ti,ab,kw AND nxa:ti,ab,kw OR ono:ti,ab,kw) AND 7702:ti,ab,kw OR ono7702:ti,ab,kw OR pf:ti,ab,kw) AND 07263896:ti,ab,kw OR pf:ti,ab,kw) AND 7263896:ti,ab,kw OR pf07263896:ti,ab,kw OR pf7263896:ti,ab,kw OR w:ti,ab,kw) AND 0090:ti,ab,kw) OR 'dabrafenib'/exp OR 'dabrafenib':ti,ab,kw OR ((((((dabrafenib:ti,ab,kw AND mesilate:ti,ab,kw OR dabrafenib:ti,ab,kw) AND mesylate:ti,ab,kw OR drb:ti,ab,kw) AND 436:ti,ab,kw OR drb436:ti,ab,kw OR gsk:ti,ab,kw) AND 2118436:ti,ab,kw OR gsk:ti,ab,kw) AND 2118436a:ti,ab,kw OR gsk:ti,ab,kw) AND 2118436b:ti,ab,kw) OR gsk2118436:ti,ab,kw OR gsk2118436a:ti,ab,kw OR gsk2118436b:ti,ab,kw OR tafinlar:ti,ab,kw OR 'b raf kinase':ti,ab,kw OR 'b-raf kinase':ti,ab,kw OR 'braf kinase':ti,ab,kw OR 'proto oncogene protein b raf':ti,ab,kw OR 'proto oncogene proteins b raf':ti,ab,kw OR 'proto-oncogene protein b-raf':ti,ab,kw OR 'proto-oncogene proteins b-raf':ti,ab,kw OR braf:ti,ab,kw OR 'plx 4032':ti,ab,kw OR plx4032:ti,ab,kw OR 'r 7204':ti,ab,kw OR r7204:ti,ab,kw OR 'rg 7204':ti,ab,kw OR rg7204:ti,ab,kw OR 'ro 5185426':ti,ab,kw OR ro5185426:ti,ab,kw OR 'lgx 818':ti,ab,kw OR 'lgx818':ti,ab,kw OR 'nvp lgx 818':ti,ab,kw OR 'nvp lgx 818 nxa':ti,ab,kw OR 'nvp lgx818':ti,ab,kw OR 'nvp lgx818 nxa':ti,ab,kw OR 'ono 7702':ti,ab,kw OR ono7702:ti,ab,kw OR 'pf 07263896':ti,ab,kw OR 'pf 7263896':ti,ab,kw OR pf07263896:ti,ab,kw OR pf7263896:ti,ab,kw OR 'w 0090':ti,ab,kw OR w0090:ti,ab,kw OR mek:ti,ab,kw OR 'braf/mek':ti,ab,kw OR 'mitogen activated protein kinase'/exp OR 'mitogen activated protein kinase':ti,ab,kw OR 'binimetinib'/exp OR 'binimetinib':ti,ab,kw OR 'arry 162':ti,ab,kw OR 'arry 438162':ti,ab,kw OR arry162:ti,ab,kw OR arry438162:ti,ab,kw OR balimek:ti,ab,kw OR 'mek 162':ti,ab,kw OR mek162:ti,ab,kw OR mektovi:ti,ab,kw OR 'ono 7703':ti,ab,kw OR 'ono7703':ti,ab,kw OR 'pf 06811462':ti,ab,kw OR 'pf 6811462':ti,ab,kw OR pf06811462:ti,ab,kw OR pf6811462:ti,ab,kw OR 'cobimetinib'/exp OR 'cobimetinib':ti,ab,kw OR 'cobimetinib butyrate':ti,ab,kw OR 'cobimetinib fumarate':ti,ab,kw OR 'cobimetinib hemifumarate':ti,ab,kw OR cotellic:ti,ab,kw OR 'gdc 0973':ti,ab,kw OR gdc0973:ti,ab,kw OR 'rg 7420':ti,ab,kw OR rg7420:ti,ab,kw OR 'ro 5514041':ti,ab,kw OR ro5514041:ti,ab,kw OR 'xl 518':ti,ab,kw OR xl518:ti,ab,kw OR 'trametinib'/exp OR 'trametinib':ti,ab,kw OR 'gsk 1120212':ti,ab,kw OR 'gsk 1120212b':ti,ab,kw OR gsk1120212:ti,ab,kw OR gsk1120212b:ti,ab,kw OR 'jtp 74057':ti,ab,kw OR jtp74057:ti,ab,kw OR mekinist:ti,ab,kw OR 'snr 1611':ti,ab,kw OR snr1611:ti,ab,kw OR 'tmt 212':ti,ab,kw OR tmt212:ti,ab,kw OR 'trametinib dimethyl sulfoxide':ti,ab,kw OR 'trastuzumab'/exp OR 'trastuzumab':ti,ab,kw OR 'abp 980':ti,ab,kw OR abp980:ti,ab,kw OR 'amt 901':ti,ab,kw OR amt901:ti,ab,kw OR aryotrust:ti,ab,kw OR 'bcd 022':ti,ab,kw OR bcd022:ti,ab,kw OR 'bx 2318':ti,ab,kw OR bx2318:ti,ab,kw OR 'ct p06':ti,ab,kw OR 'ct p6':ti,ab,kw OR ctp06:ti,ab,kw OR ctp6:ti,ab,kw OR 'da 3111':ti,ab,kw OR da3111:ti,ab,kw OR 'dmb 3111':ti,ab,kw OR dmb3111:ti,ab,kw OR 'eg 12014':ti,ab,kw OR eg12014:ti,ab,kw OR 'hd 201':ti,ab,kw OR hd201:ti,ab,kw OR herceptin:ti,ab,kw OR herclon:ti,ab,kw OR 'hermyl 1401o':ti,ab,kw OR 'hermyl1401o':ti,ab,kw OR herticad:ti,ab,kw OR hertraz:ti,ab,kw OR hervelous:ti,ab,kw OR herzuma:ti,ab,kw OR 'hlx 02':ti,ab,kw OR hlx02:ti,ab,kw OR kanjinti:ti,ab,kw OR 'myl 1401o':ti,ab,kw OR 'myl1401o':ti,ab,kw OR ogivri:ti,ab,kw OR 'ons 1050':ti,ab,kw OR ons1050:ti,ab,kw OR ontruzant:ti,ab,kw OR 'pf 05280014':ti,ab,kw OR 'pf 5280014':ti,ab,kw OR pf05280014:ti,ab,kw OR pf5280014:ti,ab,kw OR 'r 597':ti,ab,kw OR r597:ti,ab,kw OR 'rg 597':ti,ab,kw OR rg597:ti,ab,kw OR samfenet:ti,ab,kw OR 'sb 3':ti,ab,kw OR sb3:ti,ab,kw OR trasturel:ti,ab,kw OR 'trastuzumab anns':ti,ab,kw OR 'trastuzumab beta':ti,ab,kw OR 'trastuzumab dkst':ti,ab,kw OR 'trastuzumab dttb':ti,ab,kw OR 'trastuzumab pkrb':ti,ab,kw OR 'trastuzumab qyyp':ti,ab,kw OR 'trastuzumab-anns':ti,ab,kw OR 'trastuzumab-dkst':ti,ab,kw OR 'trastuzumab-dttb':ti,ab,kw OR 'trastuzumab-pkrb':ti,ab,kw OR 'trastuzumab-qyyp':ti,ab,kw OR trazimera:ti,ab,kw OR 'tx 05':ti,ab,kw OR tx05:ti,ab,kw OR 'ub 921':ti,ab,kw OR ub921:ti,ab,kw OR vivitra:ti,ab,kw OR zedora:ti,ab,kw OR zercepac:ti,ab,kw OR 'zrc 3256':ti,ab,kw OR zrc3256:ti,ab,kw OR 'lapatinib'/exp OR 'lapatinib':ti,ab,kw OR 'gw 2016':ti,ab,kw OR 'gw 572016':ti,ab,kw OR 'gw 572016f':ti,ab,kw OR gw2016:ti,ab,kw OR gw572016:ti,ab,kw OR gw572016f:ti,ab,kw OR 'lapatinib ditosylate':ti,ab,kw OR 'lapatinib ditosylate monohydrate':ti,ab,kw OR 'lapatinib tosylate':ti,ab,kw OR tykerb:ti,ab,kw OR tyverb:ti,ab,kw OR 'pertuzumab'/exp OR 'pertuzumab':ti,ab,kw OR 2c4:ti,ab,kw OR 'hs 627':ti,ab,kw OR hs627:ti,ab,kw OR 'monoclonal antibody 2c4':ti,ab,kw OR omnitarg:ti,ab,kw OR perjeta:ti,ab,kw OR 'ql 1209':ti,ab,kw OR ql1209:ti,ab,kw OR 'r 1273':ti,ab,kw OR r1273:ti,ab,kw OR 'rg 1273':ti,ab,kw OR rg1273:ti,ab,kw OR 'rhumab 2c4':ti,ab,kw OR 'ro 4368451':ti,ab,kw OR ro4368451:ti,ab,kw OR 'tucatinib'/exp OR 'tucatinib':ti,ab,kw OR 'arry 380':ti,ab,kw OR arry380:ti,ab,kw OR irbinitinib:ti,ab,kw OR 'mk 7119':ti,ab,kw OR mk7119:ti,ab,kw OR 'ont 380':ti,ab,kw OR ont380:ti,ab,kw OR tukysa:ti,ab,kw OR 'capecitabine'/exp OR 'capecitabine':ti,ab,kw OR apecitab:ti,ab,kw OR atubri:ti,ab,kw OR capcel:ti,ab,kw OR capebina:ti,ab,kw OR capecite:ti,ab,kw OR capegard:ti,ab,kw OR capezam:ti,ab,kw OR capicet:ti,ab,kw OR capiibine:ti,ab,kw OR capnat:ti,ab,kw OR capoda:ti,ab,kw OR capostat:ti,ab,kw OR capsy:ti,ab,kw OR capxcel:ti,ab,kw OR caxeta:ti,ab,kw OR citabin:ti,ab,kw OR ecansya:ti,ab,kw OR 'r 340':ti,ab,kw OR r340:ti,ab,kw OR 'ro 09 1978':ti,ab,kw OR 'ro 09-1978':ti,ab,kw OR 'ro 091978':ti,ab,kw OR 'ro09 1978':ti,ab,kw OR 'ro09-1978':ti,ab,kw OR ro091978:ti,ab,kw OR xabine:ti,ab,kw OR xecap:ti,ab,kw OR xelocel:ti,ab,kw OR xeloda:ti,ab,kw OR zocitab:ti,ab,kw OR 'neratinib'/exp OR 'neratinib':ti,ab,kw OR 'can 030':ti,ab,kw OR can030:ti,ab,kw OR 'hki 272':ti,ab,kw OR hki272:ti,ab,kw OR 'neratinib maleate':ti,ab,kw OR nerlynx:ti,ab,kw OR 'pb 272':ti,ab,kw OR pb272:ti,ab,kw OR 'way 177820':ti,ab,kw OR way177820:ti,ab,kw OR 'epidermal growth factor receptor 2'/exp OR 'c erbb2 protein':ti,ab,kw,de OR 'erbb 2 kinase':ti,ab,kw,de OR 'erbb 2 receptor':ti,ab,kw,de OR 'erbb receptor 2':ti,ab,kw,de OR 'erbb2 protein':ti,ab,kw,de OR 'erbb2 receptor':ti,ab,kw,de OR 'her 2 protein':ti,ab,kw,de OR 'her 2 receptor':ti,ab,kw,de OR 'her2 protein':ti,ab,kw,de OR 'neu differentiation factor receptor':ti,ab,kw,de OR 'neu protein':ti,ab,kw,de OR 'neu receptor':ti,ab,kw,de OR 'neuregulin receptor':ti,ab,kw,de OR 'oncoprotein her 2':ti,ab,kw,de OR 'oncoprotein her2':ti,ab,kw,de OR 'oncoprotein neu':ti,ab,kw,de OR 'protein c erbb 2':ti,ab,kw,de OR 'protein c erbb2':ti,ab,kw,de OR 'protein erb b 2':ti,ab,kw,de OR 'protein erbb 2':ti,ab,kw,de OR 'protein erbb2':ti,ab,kw,de OR 'protein her 2':ti,ab,kw,de OR 'protein her 2 neu':ti,ab,kw,de OR 'protein her2':ti,ab,kw,de OR 'protein her2 neu':ti,ab,kw,de OR 'protein neu':ti,ab,kw,de OR 'protein tyrosine kinase erbb2':ti,ab,kw,de OR 'protein tyrosine kinase receptor erbb2':ti,ab,kw,de OR 'proto-oncogene proteins c-erbb-2':ti,ab,kw,de OR 'receptor neu':ti,ab,kw,de OR 'tyrosine kinase her2':ti,ab,kw,de OR 'epidermal growth factor receptor 2':ti,ab,kw OR 'her kinase':ti,ab,kw,de OR 'her-2-neu':ti,ab,kw,de OR 'her2-neu':ti,ab,kw,de OR 'alectinib'/exp OR 'alectinib':ti,ab,kw OR 'af 802':ti,ab,kw OR af802:ti,ab,kw OR alecensa:ti,ab,kw OR alecensaro:ti,ab,kw OR 'alectinib hydrochloride':ti,ab,kw OR 'ch 5424802':ti,ab,kw OR ch5424802:ti,ab,kw OR 'rg 7853':ti,ab,kw OR rg7853:ti,ab,kw OR 'ro 5424802':ti,ab,kw OR ro5424802:ti,ab,kw OR 'anaplastic lymphoma kinase'/exp OR 'anaplastic lymphoma kinase':ti,ab,kw OR 'alk kinase':ti,ab,kw OR 'alk tyrosine kinase receptor':ti,ab,kw OR 'anaplastic lymphoma receptor tyrosine kinase':ti,ab,kw OR 'cd246 antigen':ti,ab,kw OR 'npm-alk':ti,ab,kw OR 'nucleophosmin anaplastic lymphoma kinase':ti,ab,kw OR 'nucleophosmin-anaplastic lymphoma kinase':ti,ab,kw OR 'ceritinib'/exp OR 'ceritinib':ti,ab,kw OR jikadia:ti,ab,kw OR 'ldk 378':ti,ab,kw OR ldk378:ti,ab,kw OR 'nvp ldk 378':ti,ab,kw OR 'nvp ldk 378 nx':ti,ab,kw OR 'nvp ldk378':ti,ab,kw OR 'nvp ldk378 nx':ti,ab,kw OR zykadia:ti,ab,kw OR 'crizotinib'/exp OR 'crizotinib':ti,ab,kw OR 'pf 02341066':ti,ab,kw OR 'pf 1066':ti,ab,kw OR 'pf 2341066':ti,ab,kw OR pf02341066:ti,ab,kw OR pf1066:ti,ab,kw OR pf2341066:ti,ab,kw OR xalkori:ti,ab,kw OR 'brigatinib'/exp OR 'brigatinib':ti,ab,kw OR alunbrig:ti,ab,kw OR 'ap 26113':ti,ab,kw OR ap26113:ti,ab,kw OR 'erlotinib'/exp OR 'erlotinib':ti,ab,kw OR 'nsc 718781':ti,ab,kw OR nsc718781:ti,ab,kw OR 'osi 774':ti,ab,kw OR osi774:ti,ab,kw OR 'r 1415':ti,ab,kw OR r1415:ti,ab,kw OR 'rg 1415':ti,ab,kw OR rg1415:ti,ab,kw OR 'ro 50 8231':ti,ab,kw OR 'ro 508231':ti,ab,kw OR ro508231:ti,ab,kw OR 'sgt 210':ti,ab,kw OR sgt210:ti,ab,kw OR tarceva:ti,ab,kw OR 'icotinib'/exp OR 'icotinib':ti,ab,kw OR 'bpi 2009':ti,ab,kw OR 'bpi 2009h':ti,ab,kw OR bpi2009:ti,ab,kw OR bpi2009h:ti,ab,kw OR conmana:ti,ab,kw OR 'icotinib hydrochloride':ti,ab,kw OR 'gefitinib'/exp OR 'gefitinib':ti,ab,kw OR 'gefitinib hydrochloride':ti,ab,kw OR geftinat:ti,ab,kw OR iressa:ti,ab,kw OR 'zd 1839':ti,ab,kw OR zd1839:ti,ab,kw OR 'afatinib'/exp OR 'afatinib':ti,ab,kw OR 'afatinib dimaleate':ti,ab,kw OR 'bibw 2992':ti,ab,kw OR bibw2992:ti,ab,kw OR gilotrif:ti,ab,kw OR giotrif:ti,ab,kw OR tovok:ti,ab,kw OR 'osimertinib'/exp OR 'osimertinib':ti,ab,kw OR 'azd 9291':ti,ab,kw OR azd9291:ti,ab,kw OR mereletinib:ti,ab,kw OR 'osimertinib mesilate':ti,ab,kw OR 'osimertinib mesylate':ti,ab,kw OR tagrisso:ti,ab,kw OR 'egfr'/exp OR 'egfr':ti,ab,kw OR 'epidermal growth factor'/exp OR 'epidermal growth factor':ti,ab,kw OR 'beta urogastrone':ti,ab,kw OR 'epidermal growth factor urogastrone':ti,ab,kw OR 'epidermal growth factor-urogastrone':ti,ab,kw OR 'epidermis growth factor':ti,ab,kw OR 'epidermis growth factor urogastrone':ti,ab,kw OR 'entrectinib'/exp OR 'entrectinib':ti,ab,kw OR 'nms e 628':ti,ab,kw OR 'nms e628':ti,ab,kw OR 'rg 6268':ti,ab,kw OR rg6268:ti,ab,kw OR rozlytrek:ti,ab,kw OR 'rxdx 101':ti,ab,kw OR rxdx101:ti,ab,kw OR 'brain derived neurotrophic factor receptor'/exp OR 'bdnf receptor':ti,ab,kw OR 'brain derived neurotrophic factor receptor':ti,ab,kw OR 'ntrk2 receptor':ti,ab,kw OR 'neurotrophic tyrosine kinase receptor type 2':ti,ab,kw OR 'trkb receptor':ti,ab,kw OR ntrk:ti,ab,kw OR 'larotrectinib'/exp OR 'larotrectinib':ti,ab,kw OR 'arry 470':ti,ab,kw OR arry470:ti,ab,kw OR 'larotrectinib sulfate':ti,ab,kw OR 'loxo 101':ti,ab,kw OR loxo101:ti,ab,kw OR 'hydroxypyrrolidine 1 carboxamide sulfate':ti,ab,kw OR vitrakvi:ti,ab,kw OR 'sotorasib'/exp OR 'sotorasib':ti,ab,kw OR 'amg 510':ti,ab,kw OR amg510:ti,ab,kw OR lumakras:ti,ab,kw OR lumykras:ti,ab,kw OR 'sotorasib hydrochloride':ti,ab,kw OR 'adagrasib'/exp OR 'adagrasib':ti,ab,kw OR 'mrtx 849':ti,ab,kw OR mrtx849:ti,ab,kw OR kras:ti,ab,kw OR 'erdafitinib'/exp OR balversa:ti,ab,kw OR 'jnj 42756493':ti,ab,kw OR jnj42756493:ti,ab,kw OR 'fibroblast growth factor':ti,ab,kw,de OR 'fibroblast growth factors':ti,ab,kw,de OR fgfr:ti,ab,kw,de OR 'olaparib'/exp OR 'olaparib':ti,ab,kw OR 'azd 2281':ti,ab,kw OR azd2281:ti,ab,kw OR 'ku 0059436':ti,ab,kw OR 'ku 59436':ti,ab,kw OR ku0059436:ti,ab,kw OR ku59436:ti,ab,kw OR lynparza:ti,ab,kw OR 'mk 7339':ti,ab,kw OR mk7339:ti,ab,kw OR 'niraparib'/exp OR 'niraparib':ti,ab,kw OR 'gsk 3985771':ti,ab,kw OR gsk3985771:ti,ab,kw OR 'jnj 64091742':ti,ab,kw OR jnj64091742:ti,ab,kw OR 'mk 4827':ti,ab,kw OR mk4827:ti,ab,kw OR 'niraparib 4 methylbenzenesulfonate':ti,ab,kw OR 'niraparib hydrochloride':ti,ab,kw OR 'niraparib tosilate':ti,ab,kw OR 'niraparib tosylate':ti,ab,kw OR zejula:ti,ab,kw OR 'zl 2306':ti,ab,kw OR zl2306:ti,ab,kw OR 'rucaparib'/exp OR 'rucaparib':ti,ab,kw OR 'ag 014699':ti,ab,kw OR 'ag 14447':ti,ab,kw OR 'ag 14699':ti,ab,kw OR ag014699:ti,ab,kw OR ag14447:ti,ab,kw OR ag14699:ti,ab,kw OR 'co 338':ti,ab,kw OR co338:ti,ab,kw OR 'pf 01367338':ti,ab,kw OR 'pf 1367338':ti,ab,kw OR 'pf 1367338 bw':ti,ab,kw OR pf01367338:ti,ab,kw OR pf1367338:ti,ab,kw OR pf1367338bw:ti,ab,kw OR rubraca:ti,ab,kw OR 'rucaparib camphorsulfonate':ti,ab,kw OR 'rucaparib camsilate':ti,ab,kw OR 'rucaparib camsylate':ti,ab,kw OR 'rucaparib phosphate':ti,ab,kw OR 'protein tyrosine kinase'/exp OR 'protein tyrosine kinase':ti,ab,kw OR 'tyrosine kinase':ti,ab,kw OR 'tyrosine protein kinase':ti,ab,kw OR 'tyrosine specific protein kinase':ti,ab,kw OR 'tyrosylprotein kinase':ti,ab,kw OR parp:ti,ab,kw OR 'poly(adp-ribose) polymerase inhibitors':ti,ab,kw OR 'sorafenib'/exp OR 'sorafenib':ti,ab,kw OR (('bay 43-9006':ti,ab,kw OR 'bay 439006':ti,ab,kw OR bay43:ti,ab,kw) AND 9006:ti,ab,kw) OR 'bay43-9006':ti,ab,kw OR bay439006:ti,ab,kw OR nexavar:ti,ab,kw OR 'sorafenib tosylate':ti,ab,kw OR 'sunitinib'/exp OR 'sunitinib':ti,ab,kw OR 'pha 2909040ad':ti,ab,kw OR 'pha 290940ad':ti,ab,kw OR pha2909040ad:ti,ab,kw OR pha290940ad:ti,ab,kw OR 'pno 290940':ti,ab,kw OR pnu290940:ti,ab,kw OR 'su 010398':ti,ab,kw OR 'su 011248':ti,ab,kw OR 'su 10398':ti,ab,kw OR 'su 11248':ti,ab,kw OR su010398:ti,ab,kw OR su011248:ti,ab,kw OR su10398:ti,ab,kw OR su11248:ti,ab,kw OR 'sunitinib cyclamate':ti,ab,kw OR 'sunitinib malate':ti,ab,kw OR 'suo 11248':ti,ab,kw OR suo11248:ti,ab,kw OR sutent:ti,ab,kw OR 'bevacizumab'/exp OR 'bevacizumab':ti,ab,kw OR abevmy:ti,ab,kw OR 'abp 215':ti,ab,kw OR abp215:ti,ab,kw OR ainex:ti,ab,kw OR altuzan:ti,ab,kw OR alymsys:ti,ab,kw OR ankeda:ti,ab,kw OR 'ask b1202':ti,ab,kw OR askb1202:ti,ab,kw OR avastin:ti,ab,kw OR aybintio:ti,ab,kw OR 'bat 1706':ti,ab,kw OR bat1706:ti,ab,kw OR 'bcd 021':ti,ab,kw OR bcd021:ti,ab,kw OR 'bevacizumab awwb':ti,ab,kw OR 'bevacizumab beta':ti,ab,kw OR 'bevacizumab bvzr':ti,ab,kw OR 'bevacizumab-awwb':ti,ab,kw OR 'bevacizumab-bvzr':ti,ab,kw OR bevax:ti,ab,kw OR 'bevz 92':ti,ab,kw OR bevz92:ti,ab,kw OR 'bi 695502':ti,ab,kw OR bi695502:ti,ab,kw OR boyounuo:ti,ab,kw OR bryxta:ti,ab,kw OR byvasda:ti,ab,kw OR 'cbt 124':ti,ab,kw OR cbt124:ti,ab,kw OR 'chs 5217':ti,ab,kw OR chs5217:ti,ab,kw OR cizumab:ti,ab,kw OR 'ct p16':ti,ab,kw OR ctp16:ti,ab,kw OR equidacent:ti,ab,kw OR 'fkb 238':ti,ab,kw OR fkb238:ti,ab,kw OR 'gb 222':ti,ab,kw OR gb222:ti,ab,kw OR 'hd 204':ti,ab,kw OR hd204:ti,ab,kw OR 'hlx 04':ti,ab,kw OR hlx04:ti,ab,kw OR 'ibi 305':ti,ab,kw OR ibi305:ti,ab,kw OR 'jy 028':ti,ab,kw OR jy028:ti,ab,kw OR krabeva:ti,ab,kw OR kyomarc:ti,ab,kw OR lextemy:ti,ab,kw OR 'ly 01008':ti,ab,kw OR ly01008:ti,ab,kw OR 'mb 02':ti,ab,kw OR mb02:ti,ab,kw OR 'mil 60':ti,ab,kw OR mil60:ti,ab,kw OR mvasi:ti,ab,kw OR 'myl 14020':ti,ab,kw OR 'myl 1402o':ti,ab,kw OR myl14020:ti,ab,kw OR myl1402o:ti,ab,kw OR 'nsc 704865':ti,ab,kw OR nsc704865:ti,ab,kw OR onbevzi:ti,ab,kw OR 'ons 1045':ti,ab,kw OR 'ons 5010':ti,ab,kw OR ons1045:ti,ab,kw OR ons5010:ti,ab,kw OR oyavas:ti,ab,kw OR 'pf 06439535':ti,ab,kw OR 'pf 6439535':ti,ab,kw OR pf06439535:ti,ab,kw OR pf6439535:ti,ab,kw OR pusintin:ti,ab,kw OR 'ql 1101':ti,ab,kw OR ql1101:ti,ab,kw OR 'r 435':ti,ab,kw OR r435:ti,ab,kw OR 'rg 435':ti,ab,kw OR rg435:ti,ab,kw OR 'rhumab-vegf':ti,ab,kw OR 'ro 4876646':ti,ab,kw OR ro4876646:ti,ab,kw OR 'rph 001':ti,ab,kw OR rph001:ti,ab,kw OR 'sb 8':ti,ab,kw OR sb8:ti,ab,kw OR 'sct 510':ti,ab,kw OR sct510:ti,ab,kw OR 'stc 103':ti,ab,kw OR stc103:ti,ab,kw OR 'tab 008':ti,ab,kw OR tab008:ti,ab,kw OR 'tot 102':ti,ab,kw OR tot102:ti,ab,kw OR 'trs 003':ti,ab,kw OR trs003:ti,ab,kw OR 'tx 16':ti,ab,kw OR tx16:ti,ab,kw OR versavo:ti,ab,kw OR zirabev:ti,ab,kw OR 'zrc 113':ti,ab,kw OR zrc113:ti,ab,kw OR (molecular NEAR/2 target* NEAR/2 (therap* OR treatment* OR agent* OR drug*))) AND ((leptomening* NEAR/4 metast*) OR (('meningioma'/exp OR meninge*) AND (intracranial* OR 'intra cranial*' OR cerebral* OR brain* OR leptomen*) AND (metastas*:ti,ab,kw,de OR metastat*:ti,ab,kw,de OR 'metastasis'/exp))) NOT ('editorial'/exp OR 'letter'/exp OR 'review'/exp OR 'conference paper'/exp OR ('case report'/exp NOT 'case control study'/exp) OR 'in vitro study'/exp OR 'animal model'/exp OR 'animal experiment'/exp OR 'cell culture technique'/exp) AND [english]/lim NOT (((leptomening* NEAR/4 metast*) OR (('meningioma'/exp OR meninge*) AND (intracranial* OR 'intra cranial*' OR cerebral* OR brain* OR leptomen*) AND (metastas*:ti,ab,kw,de OR metastat*:ti,ab,kw,de OR 'metastasis'/exp))) NOT ('editorial'/exp OR 'letter'/exp OR 'review'/exp OR 'conference paper'/exp OR ('case report'/exp NOT 'case control study'/exp) OR 'in vitro study'/exp OR 'animal model'/exp OR 'animal experiment'/exp OR 'cell culture technique'/exp) AND 'conference abstract'/it)

 

PICO 3 – BRAIN METS ET UPDATE – PARENCHYMAL – IMMUNE MODULATORS

 

('immunomodulating agent'/exp OR immunomodulat*:ti,ab,kw OR 'immunotherapy'/exp OR immunotherap*:ti,ab,kw OR 'biologic response modifier':ti,ab,kw OR 'biological response modifier':ti,ab,kw OR 'brm therapy':ti,ab,kw OR 'immune therapy':ti,ab,kw OR 'immunogenic therapy':ti,ab,kw OR 'immunoglobulin therapy':ti,ab,kw OR 'immunological therapy':ti,ab,kw OR 'immunological treatment':ti,ab,kw OR 'immunomodulant therapy':ti,ab,kw OR 'immunomodulary therapy':ti,ab,kw OR 'immunomodulating therapy':ti,ab,kw OR 'immunomodulation therapy':ti,ab,kw OR 'immunomodulative therapy':ti,ab,kw OR 'immunomodulator therapy':ti,ab,kw OR 'immunomodulatory intervention':ti,ab,kw OR 'immunomodulatory therapy':ti,ab,kw OR 'immunomoduling therapy':ti,ab,kw OR 'immunomodurating therapy':ti,ab,kw OR (immun* NEAR/2 (therap* OR modulat* OR drug* OR agent* OR medic* OR treatment)) OR biomodulat*:ti,ab,kw OR 'immunologic factor'/exp OR 'immunologic factor':ti,ab,kw OR (((immunoactivator*:ti,ab,kw OR immunoadjuvant*:ti,ab,kw OR immunologic:ti,ab,kw) AND adjuvant*:ti,ab,kw OR immunological:ti,ab,kw) AND adjuvant*:ti,ab,kw) OR immunopotentiator*:ti,ab,kw OR immunostimula*:ti,ab,kw OR 'immune checkpoint inhibitor'/exp OR 'immune checkpoint inhibitor':ti,ab,kw OR 'immune checkpoint blocker':ti,ab,kw OR (immun* NEAR/2 checkpoint NEAR/2 inhibitor*) OR 'ctla 4 inhibitor':ti,ab,kw OR 'ctla-4 inhibitor':ti,ab,kw OR 'cytotoxic t lymphocyte associated protein 4 inhibitor':ti,ab,kw OR 'cytotoxic t-lymphocyte-associated protein 4 inhibitor':ti,ab,kw OR 'immune checkpoint blockade':ti,ab,kw OR 'immune checkpoint inhibition':ti,ab,kw OR 'pd 1 inhibitor':ti,ab,kw OR 'pd 1 pd l1 blockade':ti,ab,kw OR 'pd l1 inhibitor':ti,ab,kw OR 'pd-1 inhibitor':ti,ab,kw OR 'pd-1-pd-l1 blockade':ti,ab,kw OR 'pd-l1 inhibitor':ti,ab,kw OR 'programmed cell death protein 1 inhibitor':ti,ab,kw OR 'programmed death ligand 1 inhibitor':ti,ab,kw OR 'programmed death-ligand 1 inhibitor':ti,ab,kw OR 'checkpoint inhibitor'/exp OR 'checkpoint inhibitor':ti,ab,kw OR 'ipilimumab'/exp OR 'ipilimumab':ti,ab,kw OR 'bms 734016':ti,ab,kw OR bms734016:ti,ab,kw OR 'cs 1002':ti,ab,kw OR cs1002:ti,ab,kw OR 'ibi 310':ti,ab,kw OR ibi310:ti,ab,kw OR 'mdx 010':ti,ab,kw OR 'mdx 101':ti,ab,kw OR mdx010:ti,ab,kw OR mdx101:ti,ab,kw OR strentarga:ti,ab,kw OR yervoy:ti,ab,kw OR 'ctla 4':ti,ab,kw OR 'ctla-4':ti,ab,kw OR ctla4:ti,ab,kw OR 'cytotoxic t lymphocyte antigen 4'/exp OR 'cytotoxic t lymphocyte antigen 4':ti,ab,kw OR 'antigen cd152':ti,ab,kw OR 'cd152 antigen':ti,ab,kw OR 'cytotoxic t lymphocyte associated antigen 4':ti,ab,kw OR 'cemiplimab'/exp OR 'cemiplimab rwlc':ti,ab,kw OR 'cemiplimab-rwlc':ti,ab,kw OR libtayo:ti,ab,kw OR 'regn 2810':ti,ab,kw OR regn2810:ti,ab,kw OR 'sar 439684':ti,ab,kw OR sar439684:ti,ab,kw OR cemiplimab:ti,ab,kw OR ('programmed cell death':ti,ab,kw AND receptor*:ti,ab,kw) OR 'gilvetmab'/exp OR 'gilvetmab':ti,ab,kw OR 'pd 1':ti,ab,kw OR 'pd-1':ti,ab,kw OR pd1:ti,ab,kw OR 'pembrolizumab'/exp OR 'pembrolizumab':ti,ab,kw OR keytruda:ti,ab,kw OR lambrolizumab:ti,ab,kw OR 'mk 3475':ti,ab,kw OR mk3475:ti,ab,kw OR 'sch 900475':ti,ab,kw OR sch900475:ti,ab,kw OR 'nivolumab'/exp OR 'nivolumab':ti,ab,kw OR 'bms 936558':ti,ab,kw OR bms936558:ti,ab,kw OR 'cmab 819':ti,ab,kw OR cmab819:ti,ab,kw OR 'mdx 1106':ti,ab,kw OR mdx1106:ti,ab,kw OR 'ono 4538':ti,ab,kw OR ono4538:ti,ab,kw OR opdivo:ti,ab,kw OR 'atezolizumab'/exp OR 'monoclonal antibody mpdl 3280a':ti,ab,kw OR 'monoclonal antibody mpdl3280a':ti,ab,kw OR 'mpdl 3280a':ti,ab,kw OR mpdl3280a:ti,ab,kw OR 'rg 7446':ti,ab,kw OR rg7446:ti,ab,kw OR 'ro 5541267':ti,ab,kw OR ro5541267:ti,ab,kw OR tecentriq:ti,ab,kw OR tecntriq:ti,ab,kw OR 'avelumab'/exp OR 'avelumab':ti,ab,kw OR bavencio:ti,ab,kw OR 'msb 0010682':ti,ab,kw OR 'msb 0010718c':ti,ab,kw OR 'msb 10682':ti,ab,kw OR 'msb 10718c':ti,ab,kw OR msb0010682:ti,ab,kw OR msb0010718c:ti,ab,kw OR msb10682:ti,ab,kw OR msb10718c:ti,ab,kw OR 'pf 06834635':ti,ab,kw OR 'pf 6834635':ti,ab,kw OR pf06834635:ti,ab,kw OR pf6834635:ti,ab,kw OR 'durvalumab'/exp OR 'durvalumab':ti,ab,kw OR imfinzi:ti,ab,kw OR 'medi 4736':ti,ab,kw OR medi4736:ti,ab,kw OR 'pd-l1':ti,ab,kw OR 'pd l1':ti,ab,kw OR pdl1:ti,ab,kw OR 'active immunotherapy'/exp OR 'active immunotherapy':ti,ab,kw OR (immun* NEAR/2 rna NEAR/2 manipulat*) OR 'cancer vaccine'/exp OR 'cancer vaccine':ti,ab,kw OR 'cancer vaccines':ti,ab,kw OR cancervax:ti,ab,kw OR myvax:ti,ab,kw OR 'neoplasm vaccine':ti,ab,kw OR 'neoplasm vaccines':ti,ab,kw OR 'tumor vaccine':ti,ab,kw OR 'tumour vaccine':ti,ab,kw OR 'tumor vaccines':ti,ab,kw OR 'tumour vaccines':ti,ab,kw OR 'dcvax'/exp OR 'dcvax':ti,ab,kw OR 'dendritic cell vaccine'/exp OR 'dendritic cell vaccine':ti,ab,kw OR 'dendritic cell-based vaccine':ti,ab,kw OR 'dendritic cell-based vaccines':ti,ab,kw OR (allogeneic NEAR/3 vaccine*) OR (immunotherap* NEAR/2 vaccine*) OR (autologous NEAR/2 vaccine*) OR 'chimeric antigen receptor t-cell'/exp OR 'chimeric antigen receptor t-cell':ti,ab,kw OR 'car engineered t-cell':ti,ab,kw OR 'car engineered t-lymphocyte':ti,ab,kw OR 'car modified t-cell':ti,ab,kw OR 'car modified t-lymphocyte':ti,ab,kw OR 'car t-cell':ti,ab,kw OR 'car t-lymphocyte':ti,ab,kw OR 'chimeric antigen receptor t-lymphocyte':ti,ab,kw OR 'bevacizumab'/exp OR 'bevacizumab':ti,ab,kw OR (((abevmy:ti,ab,kw OR 'abp 215':ti,ab,kw OR abp215:ti,ab,kw OR ainex:ti,ab,kw OR altuzan:ti,ab,kw OR alymsys:ti,ab,kw OR ankeda:ti,ab,kw OR 'ask b1202':ti,ab,kw OR askb1202:ti,ab,kw OR avastin:ti,ab,kw OR aybintio:ti,ab,kw OR 'bat 1706':ti,ab,kw OR bat1706:ti,ab,kw OR 'bcd 021':ti,ab,kw OR bcd021:ti,ab,kw OR 'bevacizumab awwb':ti,ab,kw OR 'bevacizumab beta':ti,ab,kw OR 'bevacizumab bvzr':ti,ab,kw OR 'bevacizumab-awwb':ti,ab,kw OR 'bevacizumab-bvzr':ti,ab,kw OR bevax:ti,ab,kw OR 'bevz 92':ti,ab,kw OR bevz92:ti,ab,kw OR 'bi 695502':ti,ab,kw OR bi695502:ti,ab,kw OR boyounuo:ti,ab,kw OR bryxta:ti,ab,kw OR byvasda:ti,ab,kw OR 'cbt 124':ti,ab,kw OR cbt124:ti,ab,kw OR 'chs 5217':ti,ab,kw OR chs5217:ti,ab,kw OR cizumab:ti,ab,kw OR 'ct p16':ti,ab,kw OR ctp16:ti,ab,kw OR equidacent:ti,ab,kw OR 'fkb 238':ti,ab,kw OR fkb238:ti,ab,kw OR 'gb 222':ti,ab,kw OR gb222:ti,ab,kw OR 'hd 204':ti,ab,kw OR hd204:ti,ab,kw OR 'hlx 04':ti,ab,kw OR hlx04:ti,ab,kw OR 'ibi 305':ti,ab,kw OR ibi305:ti,ab,kw OR 'jy 028':ti,ab,kw OR jy028:ti,ab,kw OR krabeva:ti,ab,kw OR kyomarc:ti,ab,kw OR lextemy:ti,ab,kw OR 'ly 01008':ti,ab,kw OR ly01008:ti,ab,kw OR 'mb 02':ti,ab,kw OR mb02:ti,ab,kw OR 'mil 60':ti,ab,kw OR mil60:ti,ab,kw OR mvasi:ti,ab,kw OR 'myl 14020':ti,ab,kw OR myl:ti,ab,kw) AND 1402o:ti,ab,kw OR myl14020:ti,ab,kw OR myl1402o:ti,ab,kw OR 'nsc 704865':ti,ab,kw OR nsc704865:ti,ab,kw OR onbevzi:ti,ab,kw OR 'ons 1045':ti,ab,kw OR ons:ti,ab,kw) AND 5010:ti,ab,kw) OR ons1045:ti,ab,kw OR ons5010:ti,ab,kw OR oyavas:ti,ab,kw OR 'pf 06439535':ti,ab,kw OR 'pf 6439535':ti,ab,kw OR pf06439535:ti,ab,kw OR pf6439535:ti,ab,kw OR pusintin:ti,ab,kw OR 'ql 1101':ti,ab,kw OR ql1101:ti,ab,kw OR 'r 435':ti,ab,kw OR r435:ti,ab,kw OR 'rg 435':ti,ab,kw OR rg435:ti,ab,kw OR 'rhumab-vegf':ti,ab,kw OR 'ro 4876646':ti,ab,kw OR ro4876646:ti,ab,kw OR 'rph 001':ti,ab,kw OR rph001:ti,ab,kw OR 'sb 8':ti,ab,kw OR sb8:ti,ab,kw OR 'sct 510':ti,ab,kw OR sct510:ti,ab,kw OR 'stc 103':ti,ab,kw OR stc103:ti,ab,kw OR 'tab 008':ti,ab,kw OR tab008:ti,ab,kw OR 'tot 102':ti,ab,kw OR tot102:ti,ab,kw OR 'trs 003':ti,ab,kw OR trs003:ti,ab,kw OR 'tx 16':ti,ab,kw OR tx16:ti,ab,kw OR versavo:ti,ab,kw OR zirabev:ti,ab,kw OR 'zrc 113':ti,ab,kw OR zrc113:ti,ab,kw OR 'amino acid transporter'/exp OR 'amino acid transporter':ti,ab,kw OR 'amino acid transport system':ti,ab,kw OR 'amino acid transport system a':ti,ab,kw OR 'amino acid transport system asc':ti,ab,kw OR 'amino acid transport system l':ti,ab,kw OR 'amino acid transport system n':ti,ab,kw OR 'amino acid transport system y+':ti,ab,kw OR 'amino acid transport system y+l':ti,ab,kw OR 'amino acid transport systems':ti,ab,kw OR 'aminoacid transporter':ti,ab,kw OR 'cationic amino acid transporter 1':ti,ab,kw OR 'cationic amino acid transporter 2':ti,ab,kw OR 'large neutral amino acid transporter 1':ti,ab,kw OR 'large neutral amino acid-transporter 1':ti,ab,kw OR 'lat1 protein'/exp OR 'lat1 protein':ti,ab,kw OR 'slc7a5 protein'/exp OR 'slc7a5':ti,ab,kw OR 'efflux transporter'/exp OR 'efflux transporter':ti,ab,kw OR (efflux NEAR/2 (transport* OR inhibitor*)) OR (transporter* NEAR/3 drug* NEAR/3 deliver*) OR (transporter* NEAR/3 mediat* NEAR/3 drug*) OR ((abcb1 OR abcb2) NEAR/2 (antagonist* OR inhibitor*)) OR 'prodrug'/exp OR prodrug*:ti,ab,kw OR 'protac'/exp OR 'protac':ti,ab,kw OR (proteolysis NEAR/3 target NEAR/3 (chimaer* OR chimer*)) OR (chim* NEAR/2 antigen* NEAR/2 receptor*)) AND ('brain tumor'/exp OR brain*:ti,ab,kw OR 'brain stem':ti,ab,kw OR brainstem*:ti,ab,kw OR cerebral*:ti,ab,kw OR intracranial*:ti,ab,kw OR 'intra-cranial':ti,ab,kw OR cerebellum:ti,ab,kw OR cerebellar*:ti,ab,kw OR 'frontal lobe':ti,ab,kw OR 'frontal lobes':ti,ab,kw OR 'temporal lobe':ti,ab,kw OR 'temporal lobes':ti,ab,kw OR 'parietal lobe':ti,ab,kw OR 'parietal lobes':ti,ab,kw OR 'occipital lobe':ti,ab,kw OR 'occipital lobes':ti,ab,kw OR cerebrum*:ti,ab,kw OR 'frontal lobe'/exp OR 'temporal lobe'/exp OR 'occipital lobe'/exp) AND (metastas*:ti,ab,kw OR metastat*:ti,ab,kw OR 'metastasis'/exp) AND [english]/lim AND [2016-2022]/py NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('juvenile'/exp NOT ('juvenile' AND 'adult')) NOT ('editorial'/exp OR 'conference paper'/exp OR 'letter'/exp OR 'review'/exp OR 'systematic review'/exp) NOT ('case report'/exp NOT 'case control study'/exp) NOT ('in vitro study'/exp OR 'cell culture technique'/exp OR 'animal experiment'/exp OR 'animal model'/exp) NOT (('brain tumor'/exp OR brain*:ti,ab,kw OR 'brain stem':ti,ab,kw OR brainstem*:ti,ab,kw OR cerebral*:ti,ab,kw OR intracranial*:ti,ab,kw OR 'intra-cranial':ti,ab,kw OR cerebellum:ti,ab,kw OR cerebellar*:ti,ab,kw OR 'frontal lobe':ti,ab,kw OR 'frontal lobes':ti,ab,kw OR 'temporal lobe':ti,ab,kw OR 'temporal lobes':ti,ab,kw OR 'parietal lobe':ti,ab,kw OR 'parietal lobes':ti,ab,kw OR 'occipital lobe':ti,ab,kw OR 'occipital lobes':ti,ab,kw OR cerebrum*:ti,ab,kw OR 'frontal lobe'/exp OR 'temporal lobe'/exp OR 'occipital lobe'/exp) AND (metastas*:ti,ab,kw OR metastat*:ti,ab,kw OR 'metastasis'/exp) AND [english]/lim AND [2016-2022]/py NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('juvenile'/exp NOT ('juvenile' AND 'adult')) NOT ('editorial'/exp OR 'conference paper'/exp OR 'letter'/exp OR 'review'/exp OR 'systematic review'/exp) NOT ('case report'/exp NOT 'case control study'/exp) NOT ('in vitro study'/exp OR 'cell culture technique'/exp OR 'animal experiment'/exp OR 'animal model'/exp) AND 'conference abstract'/it)

 

PICO 4 – BRAIN METS ET UPDATE – LEPTOMENINGEAL – IMMUNE MODULATORS

 

('immunomodulating agent'/exp OR immunomodulat*:ti,ab,kw OR 'immunotherapy'/exp OR immunotherap*:ti,ab,kw OR 'biologic response modifier':ti,ab,kw OR 'biological response modifier':ti,ab,kw OR 'brm therapy':ti,ab,kw OR 'immune therapy':ti,ab,kw OR 'immunogenic therapy':ti,ab,kw OR 'immunoglobulin therapy':ti,ab,kw OR 'immunological therapy':ti,ab,kw OR 'immunological treatment':ti,ab,kw OR 'immunomodulant therapy':ti,ab,kw OR 'immunomodulary therapy':ti,ab,kw OR 'immunomodulating therapy':ti,ab,kw OR 'immunomodulation therapy':ti,ab,kw OR 'immunomodulative therapy':ti,ab,kw OR 'immunomodulator therapy':ti,ab,kw OR 'immunomodulatory intervention':ti,ab,kw OR 'immunomodulatory therapy':ti,ab,kw OR 'immunomoduling therapy':ti,ab,kw OR 'immunomodurating therapy':ti,ab,kw OR (immun* NEAR/2 (therap* OR modulat* OR drug* OR agent* OR medic* OR treatment)) OR biomodulat*:ti,ab,kw OR 'immunologic factor'/exp OR 'immunologic factor':ti,ab,kw OR (((immunoactivator*:ti,ab,kw OR immunoadjuvant*:ti,ab,kw OR immunologic:ti,ab,kw) AND adjuvant*:ti,ab,kw OR immunological:ti,ab,kw) AND adjuvant*:ti,ab,kw) OR immunopotentiator*:ti,ab,kw OR immunostimula*:ti,ab,kw OR 'immune checkpoint inhibitor'/exp OR 'immune checkpoint inhibitor':ti,ab,kw OR 'immune checkpoint blocker':ti,ab,kw OR (immun* NEAR/2 checkpoint NEAR/2 inhibitor*) OR 'ctla 4 inhibitor':ti,ab,kw OR 'ctla-4 inhibitor':ti,ab,kw OR 'cytotoxic t lymphocyte associated protein 4 inhibitor':ti,ab,kw OR 'cytotoxic t-lymphocyte-associated protein 4 inhibitor':ti,ab,kw OR 'immune checkpoint blockade':ti,ab,kw OR 'immune checkpoint inhibition':ti,ab,kw OR 'pd 1 inhibitor':ti,ab,kw OR 'pd 1 pd l1 blockade':ti,ab,kw OR 'pd l1 inhibitor':ti,ab,kw OR 'pd-1 inhibitor':ti,ab,kw OR 'pd-1-pd-l1 blockade':ti,ab,kw OR 'pd-l1 inhibitor':ti,ab,kw OR 'programmed cell death protein 1 inhibitor':ti,ab,kw OR 'programmed death ligand 1 inhibitor':ti,ab,kw OR 'programmed death-ligand 1 inhibitor':ti,ab,kw OR 'checkpoint inhibitor'/exp OR 'checkpoint inhibitor':ti,ab,kw OR 'ipilimumab'/exp OR 'ipilimumab':ti,ab,kw OR 'bms 734016':ti,ab,kw OR bms734016:ti,ab,kw OR 'cs 1002':ti,ab,kw OR cs1002:ti,ab,kw OR 'ibi 310':ti,ab,kw OR ibi310:ti,ab,kw OR 'mdx 010':ti,ab,kw OR 'mdx 101':ti,ab,kw OR mdx010:ti,ab,kw OR mdx101:ti,ab,kw OR strentarga:ti,ab,kw OR yervoy:ti,ab,kw OR 'ctla 4':ti,ab,kw OR 'ctla-4':ti,ab,kw OR ctla4:ti,ab,kw OR 'cytotoxic t lymphocyte antigen 4'/exp OR 'cytotoxic t lymphocyte antigen 4':ti,ab,kw OR 'antigen cd152':ti,ab,kw OR 'cd152 antigen':ti,ab,kw OR 'cytotoxic t lymphocyte associated antigen 4':ti,ab,kw OR 'cemiplimab'/exp OR 'cemiplimab rwlc':ti,ab,kw OR 'cemiplimab-rwlc':ti,ab,kw OR libtayo:ti,ab,kw OR 'regn 2810':ti,ab,kw OR regn2810:ti,ab,kw OR 'sar 439684':ti,ab,kw OR sar439684:ti,ab,kw OR cemiplimab:ti,ab,kw OR ('programmed cell death':ti,ab,kw AND receptor*:ti,ab,kw) OR 'gilvetmab'/exp OR 'gilvetmab':ti,ab,kw OR 'pd 1':ti,ab,kw OR 'pd-1':ti,ab,kw OR pd1:ti,ab,kw OR 'pembrolizumab'/exp OR 'pembrolizumab':ti,ab,kw OR keytruda:ti,ab,kw OR lambrolizumab:ti,ab,kw OR 'mk 3475':ti,ab,kw OR mk3475:ti,ab,kw OR 'sch 900475':ti,ab,kw OR sch900475:ti,ab,kw OR 'nivolumab'/exp OR 'nivolumab':ti,ab,kw OR 'bms 936558':ti,ab,kw OR bms936558:ti,ab,kw OR 'cmab 819':ti,ab,kw OR cmab819:ti,ab,kw OR 'mdx 1106':ti,ab,kw OR mdx1106:ti,ab,kw OR 'ono 4538':ti,ab,kw OR ono4538:ti,ab,kw OR opdivo:ti,ab,kw OR 'atezolizumab'/exp OR 'monoclonal antibody mpdl 3280a':ti,ab,kw OR 'monoclonal antibody mpdl3280a':ti,ab,kw OR 'mpdl 3280a':ti,ab,kw OR mpdl3280a:ti,ab,kw OR 'rg 7446':ti,ab,kw OR rg7446:ti,ab,kw OR 'ro 5541267':ti,ab,kw OR ro5541267:ti,ab,kw OR tecentriq:ti,ab,kw OR tecntriq:ti,ab,kw OR 'avelumab'/exp OR 'avelumab':ti,ab,kw OR bavencio:ti,ab,kw OR 'msb 0010682':ti,ab,kw OR 'msb 0010718c':ti,ab,kw OR 'msb 10682':ti,ab,kw OR 'msb 10718c':ti,ab,kw OR msb0010682:ti,ab,kw OR msb0010718c:ti,ab,kw OR msb10682:ti,ab,kw OR msb10718c:ti,ab,kw OR 'pf 06834635':ti,ab,kw OR 'pf 6834635':ti,ab,kw OR pf06834635:ti,ab,kw OR pf6834635:ti,ab,kw OR 'durvalumab'/exp OR 'durvalumab':ti,ab,kw OR imfinzi:ti,ab,kw OR 'medi 4736':ti,ab,kw OR medi4736:ti,ab,kw OR 'pd-l1':ti,ab,kw OR 'pd l1':ti,ab,kw OR pdl1:ti,ab,kw OR 'active immunotherapy'/exp OR 'active immunotherapy':ti,ab,kw OR (immun* NEAR/2 rna NEAR/2 manipulat*) OR 'cancer vaccine'/exp OR 'cancer vaccine':ti,ab,kw OR 'cancer vaccines':ti,ab,kw OR cancervax:ti,ab,kw OR myvax:ti,ab,kw OR 'neoplasm vaccine':ti,ab,kw OR 'neoplasm vaccines':ti,ab,kw OR 'tumor vaccine':ti,ab,kw OR 'tumour vaccine':ti,ab,kw OR 'tumor vaccines':ti,ab,kw OR 'tumour vaccines':ti,ab,kw OR 'dcvax'/exp OR 'dcvax':ti,ab,kw OR 'dendritic cell vaccine'/exp OR 'dendritic cell vaccine':ti,ab,kw OR 'dendritic cell-based vaccine':ti,ab,kw OR 'dendritic cell-based vaccines':ti,ab,kw OR (allogeneic NEAR/3 vaccine*) OR (immunotherap* NEAR/2 vaccine*) OR (autologous NEAR/2 vaccine*) OR 'chimeric antigen receptor t-cell'/exp OR 'chimeric antigen receptor t-cell':ti,ab,kw OR 'car engineered t-cell':ti,ab,kw OR 'car engineered t-lymphocyte':ti,ab,kw OR 'car modified t-cell':ti,ab,kw OR 'car modified t-lymphocyte':ti,ab,kw OR 'car t-cell':ti,ab,kw OR 'car t-lymphocyte':ti,ab,kw OR 'chimeric antigen receptor t-lymphocyte':ti,ab,kw OR 'bevacizumab'/exp OR 'bevacizumab':ti,ab,kw OR (((abevmy:ti,ab,kw OR 'abp 215':ti,ab,kw OR abp215:ti,ab,kw OR ainex:ti,ab,kw OR altuzan:ti,ab,kw OR alymsys:ti,ab,kw OR ankeda:ti,ab,kw OR 'ask b1202':ti,ab,kw OR askb1202:ti,ab,kw OR avastin:ti,ab,kw OR aybintio:ti,ab,kw OR 'bat 1706':ti,ab,kw OR bat1706:ti,ab,kw OR 'bcd 021':ti,ab,kw OR bcd021:ti,ab,kw OR 'bevacizumab awwb':ti,ab,kw OR 'bevacizumab beta':ti,ab,kw OR 'bevacizumab bvzr':ti,ab,kw OR 'bevacizumab-awwb':ti,ab,kw OR 'bevacizumab-bvzr':ti,ab,kw OR bevax:ti,ab,kw OR 'bevz 92':ti,ab,kw OR bevz92:ti,ab,kw OR 'bi 695502':ti,ab,kw OR bi695502:ti,ab,kw OR boyounuo:ti,ab,kw OR bryxta:ti,ab,kw OR byvasda:ti,ab,kw OR 'cbt 124':ti,ab,kw OR cbt124:ti,ab,kw OR 'chs 5217':ti,ab,kw OR chs5217:ti,ab,kw OR cizumab:ti,ab,kw OR 'ct p16':ti,ab,kw OR ctp16:ti,ab,kw OR equidacent:ti,ab,kw OR 'fkb 238':ti,ab,kw OR fkb238:ti,ab,kw OR 'gb 222':ti,ab,kw OR gb222:ti,ab,kw OR 'hd 204':ti,ab,kw OR hd204:ti,ab,kw OR 'hlx 04':ti,ab,kw OR hlx04:ti,ab,kw OR 'ibi 305':ti,ab,kw OR ibi305:ti,ab,kw OR 'jy 028':ti,ab,kw OR jy028:ti,ab,kw OR krabeva:ti,ab,kw OR kyomarc:ti,ab,kw OR lextemy:ti,ab,kw OR 'ly 01008':ti,ab,kw OR ly01008:ti,ab,kw OR 'mb 02':ti,ab,kw OR mb02:ti,ab,kw OR 'mil 60':ti,ab,kw OR mil60:ti,ab,kw OR mvasi:ti,ab,kw OR 'myl 14020':ti,ab,kw OR myl:ti,ab,kw) AND 1402o:ti,ab,kw OR myl14020:ti,ab,kw OR myl1402o:ti,ab,kw OR 'nsc 704865':ti,ab,kw OR nsc704865:ti,ab,kw OR onbevzi:ti,ab,kw OR 'ons 1045':ti,ab,kw OR ons:ti,ab,kw) AND 5010:ti,ab,kw) OR ons1045:ti,ab,kw OR ons5010:ti,ab,kw OR oyavas:ti,ab,kw OR 'pf 06439535':ti,ab,kw OR 'pf 6439535':ti,ab,kw OR pf06439535:ti,ab,kw OR pf6439535:ti,ab,kw OR pusintin:ti,ab,kw OR 'ql 1101':ti,ab,kw OR ql1101:ti,ab,kw OR 'r 435':ti,ab,kw OR r435:ti,ab,kw OR 'rg 435':ti,ab,kw OR rg435:ti,ab,kw OR 'rhumab-vegf':ti,ab,kw OR 'ro 4876646':ti,ab,kw OR ro4876646:ti,ab,kw OR 'rph 001':ti,ab,kw OR rph001:ti,ab,kw OR 'sb 8':ti,ab,kw OR sb8:ti,ab,kw OR 'sct 510':ti,ab,kw OR sct510:ti,ab,kw OR 'stc 103':ti,ab,kw OR stc103:ti,ab,kw OR 'tab 008':ti,ab,kw OR tab008:ti,ab,kw OR 'tot 102':ti,ab,kw OR tot102:ti,ab,kw OR 'trs 003':ti,ab,kw OR trs003:ti,ab,kw OR 'tx 16':ti,ab,kw OR tx16:ti,ab,kw OR versavo:ti,ab,kw OR zirabev:ti,ab,kw OR 'zrc 113':ti,ab,kw OR zrc113:ti,ab,kw OR 'amino acid transporter'/exp OR 'amino acid transporter':ti,ab,kw OR 'amino acid transport system':ti,ab,kw OR 'amino acid transport system a':ti,ab,kw OR 'amino acid transport system asc':ti,ab,kw OR 'amino acid transport system l':ti,ab,kw OR 'amino acid transport system n':ti,ab,kw OR 'amino acid transport system y+':ti,ab,kw OR 'amino acid transport system y+l':ti,ab,kw OR 'amino acid transport systems':ti,ab,kw OR 'aminoacid transporter':ti,ab,kw OR 'cationic amino acid transporter 1':ti,ab,kw OR 'cationic amino acid transporter 2':ti,ab,kw OR 'large neutral amino acid transporter 1':ti,ab,kw OR 'large neutral amino acid-transporter 1':ti,ab,kw OR 'lat1 protein'/exp OR 'lat1 protein':ti,ab,kw OR 'slc7a5 protein'/exp OR 'slc7a5':ti,ab,kw OR 'efflux transporter'/exp OR 'efflux transporter':ti,ab,kw OR (efflux NEAR/2 (transport* OR inhibitor*)) OR (transporter* NEAR/3 drug* NEAR/3 deliver*) OR (transporter* NEAR/3 mediat* NEAR/3 drug*) OR ((abcb1 OR abcb2) NEAR/2 (antagonist* OR inhibitor*)) OR 'prodrug'/exp OR prodrug*:ti,ab,kw OR 'protac'/exp OR 'protac':ti,ab,kw OR (proteolysis NEAR/3 target NEAR/3 (chimaer* OR chimer*)) OR (chim* NEAR/2 antigen* NEAR/2 receptor*)) AND ((leptomening* NEAR/4 metast*) OR (('meningioma'/exp OR meninge*) AND (intracranial* OR 'intra cranial*' OR cerebral* OR brain* OR leptomen*) AND (metastas*:ti,ab,kw,de OR metastat*:ti,ab,kw,de OR 'metastasis'/exp))) NOT ('editorial'/exp OR 'letter'/exp OR 'review'/exp OR 'conference paper'/exp OR ('case report'/exp NOT 'case control study'/exp) OR 'in vitro study'/exp OR 'animal model'/exp OR 'animal experiment'/exp OR 'cell culture technique'/exp) AND [english]/lim NOT (((leptomening* NEAR/4 metast*) OR (('meningioma'/exp OR meninge*) AND (intracranial* OR 'intra cranial*' OR cerebral* OR brain* OR leptomen*) AND (metastas*:ti,ab,kw,de OR metastat*:ti,ab,kw,de OR 'metastasis'/exp))) NOT ('editorial'/exp OR 'letter'/exp OR 'review'/exp OR 'conference paper'/exp OR ('case report'/exp NOT 'case control study'/exp) OR 'in vitro study'/exp OR 'animal model'/exp OR 'animal experiment'/exp OR 'cell culture technique'/exp) AND 'conference abstract'/it)

 

PICO 5 – BRAIN METS ET UPDATE – INTERSTITIAL MODALITIES

 

('brachytherapy'/exp OR brachytherap*:ti,ab,kw OR (local* NEAR/2 (therap* OR treatment*)) OR (local* NEAR/2 (radiation OR irradiat* OR radiotherap*)) OR (local* NEAR/2 chemotherap*) OR ((intraoperativ* OR 'intra-operative') NEAR/2 (radiotherap* OR irradiat* OR radiation*)) OR 'intraoperative radiotherapy'/exp OR ('cavity' NEAR/2 boost*) OR iort:ti,ab,kw OR (('iodine 125'/exp OR 'iodine 125':ti,ab,kw) AND (seed:ti,ab,kw OR seeds:ti,ab,kw)) OR (('125 i':ti,ab,kw OR 125i:ti,ab,kw OR 'i 125':ti,ab,kw OR i125:ti,ab,kw OR 'iodide 125':ti,ab,kw OR 'iodide i 125':ti,ab,kw OR 'iodide i125':ti,ab,kw OR 'iodine 125 source':ti,ab,kw OR 'iodine i 125':ti,ab,kw OR 'iodium 125':ti,ab,kw OR 'radio iodine i 125':ti,ab,kw OR 'radioactive iodine 125':ti,ab,kw OR 'radiodine i 125':ti,ab,kw OR 'radioiodine 125':ti,ab,kw OR 'radioiodine i 125':ti,ab,kw) AND (seed:ti,ab,kw OR seeds:ti,ab,kw)) OR 'radioactive iodine'/exp OR 'cesium 131'/exp OR 'cesium 131':ti,ab,kw OR 'caesium 131':ti,ab,kw OR 'cs 131':ti,ab,kw OR 'gliadel wafer'/exp OR 'gliadel wafer':ti,ab,kw OR bcnu:ti,ab,kw OR 'carmustine'/exp OR 'carmustine':ti,ab,kw OR (interstitial* NEAR/2 (modalit* OR chemo* OR drug* OR agent* OR antineoplastic* OR 'anti-neoplastic' OR radiat* OR radio* OR therap* OR treatment* OR irradiat*))) AND ('brain tumor'/exp OR brain*:ti,ab,kw OR 'brain stem':ti,ab,kw OR brainstem*:ti,ab,kw OR cerebral*:ti,ab,kw OR intracranial*:ti,ab,kw OR 'intra-cranial':ti,ab,kw OR cerebellum:ti,ab,kw OR cerebellar*:ti,ab,kw OR 'frontal lobe':ti,ab,kw OR 'frontal lobes':ti,ab,kw OR 'temporal lobe':ti,ab,kw OR 'temporal lobes':ti,ab,kw OR 'parietal lobe':ti,ab,kw OR 'parietal lobes':ti,ab,kw OR 'occipital lobe':ti,ab,kw OR 'occipital lobes':ti,ab,kw OR cerebrum*:ti,ab,kw OR 'frontal lobe'/exp OR 'temporal lobe'/exp OR 'occipital lobe'/exp) AND (metastas*:ti,ab,kw OR metastat*:ti,ab,kw OR 'metastasis'/exp) AND [english]/lim AND [2016-2022]/py NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('juvenile'/exp NOT ('juvenile' AND 'adult')) NOT ('editorial'/exp OR 'conference paper'/exp OR 'letter'/exp OR 'review'/exp OR 'systematic review'/exp) NOT ('case report'/exp NOT 'case control study'/exp) NOT ('in vitro study'/exp OR 'cell culture technique'/exp OR 'animal experiment'/exp OR 'animal model'/exp) NOT (('brain tumor'/exp OR brain*:ti,ab,kw OR 'brain stem':ti,ab,kw OR brainstem*:ti,ab,kw OR cerebral*:ti,ab,kw OR intracranial*:ti,ab,kw OR 'intra-cranial':ti,ab,kw OR cerebellum:ti,ab,kw OR cerebellar*:ti,ab,kw OR 'frontal lobe':ti,ab,kw OR 'frontal lobes':ti,ab,kw OR 'temporal lobe':ti,ab,kw OR 'temporal lobes':ti,ab,kw OR 'parietal lobe':ti,ab,kw OR 'parietal lobes':ti,ab,kw OR 'occipital lobe':ti,ab,kw OR 'occipital lobes':ti,ab,kw OR cerebrum*:ti,ab,kw OR 'frontal lobe'/exp OR 'temporal lobe'/exp OR 'occipital lobe'/exp) AND (metastas*:ti,ab,kw OR metastat*:ti,ab,kw OR 'metastasis'/exp) AND [english]/lim AND [2016-2022]/py NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('juvenile'/exp NOT ('juvenile' AND 'adult')) NOT ('editorial'/exp OR 'conference paper'/exp OR 'letter'/exp OR 'review'/exp OR 'systematic review'/exp) NOT ('case report'/exp NOT 'case control study'/exp) NOT ('in vitro study'/exp OR 'cell culture technique'/exp OR 'animal experiment'/exp OR 'animal model'/exp) AND 'conference abstract'/it)

 

PICO 6 – BRAIN METS ET UPDATE – RADIOSENSITIZERS

 

('radiosensitizing agent'/exp OR 'radiosensitizing agent':ti,ab,kw OR 'radiation sensitizer':ti,ab,kw OR 'radiation sensitizing agent':ti,ab,kw OR 'radiation sensitizing agents':ti,ab,kw OR 'radiation-sensitizing agents':ti,ab,kw OR 'radio sensitizing agent':ti,ab,kw OR 'radiosensitivity infusion':ti,ab,kw OR radiosensitizer*:ti,ab,kw OR 'gadolinium texaphyrin'/exp OR 'gadolinium texaphyrin':ti,ab,kw OR 'gadolinium motexafin':ti,ab,kw OR 'motexafin gadolinium':ti,ab,kw OR 'pci 0120':ti,ab,kw OR xcytrin:ti,ab,kw OR 'temozolomide'/exp OR 'temozolomide':ti,ab,kw OR 'ccrg 81045':ti,ab,kw OR ccrg81045:ti,ab,kw OR kimozo:ti,ab,kw OR 'm and b 39831':ti,ab,kw OR 'm b 39831':ti,ab,kw OR 'mb 39831':ti,ab,kw OR mb39831:ti,ab,kw OR methazolastone:ti,ab,kw OR 'mk 7365':ti,ab,kw OR mk7365:ti,ab,kw OR 'nsc 362856':ti,ab,kw OR nsc362856:ti,ab,kw OR 'orp 005':ti,ab,kw OR orp005:ti,ab,kw OR 'rp 46161':ti,ab,kw OR rp46161:ti,ab,kw OR 'sch 052365':ti,ab,kw OR 'sch 52365':ti,ab,kw OR sch052365:ti,ab,kw OR sch52365:ti,ab,kw OR 'si 053':ti,ab,kw OR si053:ti,ab,kw OR temcad:ti,ab,kw OR temodal:ti,ab,kw OR temodar:ti,ab,kw OR temodex:ti,ab,kw OR temodol:ti,ab,kw OR temomedac:ti,ab,kw OR temoxol:ti,ab,kw OR 'chloroquine'/exp OR 'chloroquine':ti,ab,kw OR 'a-cq':ti,ab,kw OR amokin:ti,ab,kw OR amokine:ti,ab,kw OR anoclor:ti,ab,kw OR aralan:ti,ab,kw OR aralen:ti,ab,kw OR 'aralen hydrochloride':ti,ab,kw OR 'aralen phosphate':ti,ab,kw OR aralene:ti,ab,kw OR arechin:ti,ab,kw OR arechine:ti,ab,kw OR arequine:ti,ab,kw OR arthrochin:ti,ab,kw OR arthrochine:ti,ab,kw OR arthroquine:ti,ab,kw OR artrichin:ti,ab,kw OR artrichine:ti,ab,kw OR artriquine:ti,ab,kw OR avloclor:ti,ab,kw OR avoclor:ti,ab,kw OR bemaphata:ti,ab,kw OR bemaphate:ti,ab,kw OR bemasulph:ti,ab,kw OR bipiquin:ti,ab,kw OR cadiquin:ti,ab,kw OR chemochin:ti,ab,kw OR chemochine:ti,ab,kw OR chingamine:ti,ab,kw OR chingaminum:ti,ab,kw OR chloraquine:ti,ab,kw OR chlorochin:ti,ab,kw OR chlorochine:ti,ab,kw OR chlorofoz:ti,ab,kw OR chloroquin:ti,ab,kw OR 'chloroquin phosphate':ti,ab,kw OR 'chloroquine diphosphate':ti,ab,kw OR 'chloroquine disulfate':ti,ab,kw OR 'chloroquine disulphate':ti,ab,kw OR 'chloroquine hydrochloride':ti,ab,kw OR 'chloroquine phosphate':ti,ab,kw OR 'chloroquine streuli':ti,ab,kw OR 'chloroquine sulfate':ti,ab,kw OR 'chloroquine sulphate':ti,ab,kw OR chloroquinesulphate:ti,ab,kw OR 'chloroquini diphosphas':ti,ab,kw OR 'chloroquinum diphosphoricum':ti,ab,kw OR chlorquin:ti,ab,kw OR chlorquine:ti,ab,kw OR choloquine:ti,ab,kw OR 'choroquine sulfate':ti,ab,kw OR 'choroquine sulphate':ti,ab,kw OR cidanchin:ti,ab,kw OR 'clo-kit junior':ti,ab,kw OR clorichina:ti,ab,kw OR clorichine:ti,ab,kw OR cloriquine:ti,ab,kw OR clorochina:ti,ab,kw OR delagil:ti,ab,kw OR delagyl:ti,ab,kw OR dichinalex:ti,ab,kw OR diclokin:ti,ab,kw OR diquinalex:ti,ab,kw OR diroquine:ti,ab,kw OR emquin:ti,ab,kw OR genocin:ti,ab,kw OR gontochin:ti,ab,kw OR gontochine:ti,ab,kw OR gontoquine:ti,ab,kw OR heliopar:ti,ab,kw OR imagon:ti,ab,kw OR iroquine:ti,ab,kw OR klorokin:ti,ab,kw OR klorokine:ti,ab,kw OR klorokinfosfat:ti,ab,kw OR lagaquin:ti,ab,kw OR malaquin:ti,ab,kw OR malarex:ti,ab,kw OR malarivon:ti,ab,kw OR malaviron:ti,ab,kw OR maliaquine:ti,ab,kw OR maquine:ti,ab,kw OR mesylith:ti,ab,kw OR mexaquin:ti,ab,kw OR mirquin:ti,ab,kw OR nivachine:ti,ab,kw OR nivaquin:ti,ab,kw OR nivaquine*:ti,ab,kw OR 'p roquine':ti,ab,kw OR quinachlor:ti,ab,kw OR quingamine:ti,ab,kw OR repal:ti,ab,kw OR resochen:ti,ab,kw OR resochene:ti,ab,kw OR resochin:ti,ab,kw OR 'resochin junior':ti,ab,kw OR resochina:ti,ab,kw OR resochine:ti,ab,kw OR resochinon:ti,ab,kw OR resoquina:ti,ab,kw OR resoquine:ti,ab,kw OR reumachlor:ti,ab,kw OR roquine:ti,ab,kw OR 'rp 3377':ti,ab,kw OR rp3377:ti,ab,kw OR sanoquin:ti,ab,kw OR sanoquine:ti,ab,kw OR silbesan:ti,ab,kw OR siragan:ti,ab,kw OR sirajan:ti,ab,kw OR 'sn 7618':ti,ab,kw OR sn7618:ti,ab,kw OR solprina:ti,ab,kw OR solprine:ti,ab,kw OR tresochin:ti,ab,kw OR tresochine:ti,ab,kw OR tresoquine:ti,ab,kw OR trochin:ti,ab,kw OR trochine:ti,ab,kw OR troquine:ti,ab,kw OR 'w 7618':ti,ab,kw OR w7618:ti,ab,kw OR 'win 244':ti,ab,kw OR win244:ti,ab,kw OR 'sodium nitrite'/exp OR 'sodium nitrite':ti,ab,kw OR 'air 001':ti,ab,kw OR air001:ti,ab,kw OR aironite:ti,ab,kw OR erinitrit:ti,ab,kw OR 'jan 101':ti,ab,kw OR jan101:ti,ab,kw OR 'nitrite sodium':ti,ab,kw OR 'tv 1001':ti,ab,kw OR tv1001:ti,ab,kw OR 'epothilone b'/exp OR 'epothilone b':ti,ab,kw OR 'epo 906':ti,ab,kw OR epo906:ti,ab,kw OR patupilone:ti,ab,kw OR 'vorinostat'/exp OR 'vorinostat':ti,ab,kw OR 'mk 0683':ti,ab,kw OR mk0683:ti,ab,kw OR saha:ti,ab,kw OR 'suberoylanilide hydroxamic acid':ti,ab,kw OR 'vorinostat msd':ti,ab,kw OR zolinza:ti,ab,kw OR 'senazole'/exp OR 'senazole':ti,ab,kw OR 'ak2123':ti,ab,kw OR 'ak 2123':ti,ab,kw) AND ('brain tumor'/exp OR brain*:ti,ab,kw OR 'brain stem':ti,ab,kw OR brainstem*:ti,ab,kw OR cerebral*:ti,ab,kw OR intracranial*:ti,ab,kw OR 'intra-cranial':ti,ab,kw OR cerebellum:ti,ab,kw OR cerebellar*:ti,ab,kw OR 'frontal lobe':ti,ab,kw OR 'frontal lobes':ti,ab,kw OR 'temporal lobe':ti,ab,kw OR 'temporal lobes':ti,ab,kw OR 'parietal lobe':ti,ab,kw OR 'parietal lobes':ti,ab,kw OR 'occipital lobe':ti,ab,kw OR 'occipital lobes':ti,ab,kw OR cerebrum*:ti,ab,kw OR 'frontal lobe'/exp OR 'temporal lobe'/exp OR 'occipital lobe'/exp) AND (metastas*:ti,ab,kw OR metastat*:ti,ab,kw OR 'metastasis'/exp) AND [english]/lim AND [2016-2022]/py NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('juvenile'/exp NOT ('juvenile' AND 'adult')) NOT ('editorial'/exp OR 'conference paper'/exp OR 'letter'/exp OR 'review'/exp OR 'systematic review'/exp) NOT ('case report'/exp NOT 'case control study'/exp) NOT ('in vitro study'/exp OR 'cell culture technique'/exp OR 'animal experiment'/exp OR 'animal model'/exp) NOT (('brain tumor'/exp OR brain*:ti,ab,kw OR 'brain stem':ti,ab,kw OR brainstem*:ti,ab,kw OR cerebral*:ti,ab,kw OR intracranial*:ti,ab,kw OR 'intra-cranial':ti,ab,kw OR cerebellum:ti,ab,kw OR cerebellar*:ti,ab,kw OR 'frontal lobe':ti,ab,kw OR 'frontal lobes':ti,ab,kw OR 'temporal lobe':ti,ab,kw OR 'temporal lobes':ti,ab,kw OR 'parietal lobe':ti,ab,kw OR 'parietal lobes':ti,ab,kw OR 'occipital lobe':ti,ab,kw OR 'occipital lobes':ti,ab,kw OR cerebrum*:ti,ab,kw OR 'frontal lobe'/exp OR 'temporal lobe'/exp OR 'occipital lobe'/exp) AND (metastas*:ti,ab,kw OR metastat*:ti,ab,kw OR 'metastasis'/exp) AND [english]/lim AND [2016-2022]/py NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('juvenile'/exp NOT ('juvenile' AND 'adult')) NOT ('editorial'/exp OR 'conference paper'/exp OR 'letter'/exp OR 'review'/exp OR 'systematic review'/exp) NOT ('case report'/exp NOT 'case control study'/exp) NOT ('in vitro study'/exp OR 'cell culture technique'/exp OR 'animal experiment'/exp OR 'animal model'/exp) AND 'conference abstract'/it)

 

PICO 7 – BRAIN METS ET UPDATE – LASER INTERSTITIAL THERMAL THERAPY (LITT)

 

('brain tumor'/exp OR brain*:ti,ab,kw OR 'brain stem':ti,ab,kw OR brainstem*:ti,ab,kw OR cerebral*:ti,ab,kw OR intracranial*:ti,ab,kw OR 'intra-cranial':ti,ab,kw OR cerebellum:ti,ab,kw OR cerebellar*:ti,ab,kw OR 'frontal lobe':ti,ab,kw OR 'frontal lobes':ti,ab,kw OR 'temporal lobe':ti,ab,kw OR 'temporal lobes':ti,ab,kw OR 'parietal lobe':ti,ab,kw OR 'parietal lobes':ti,ab,kw OR 'occipital lobe':ti,ab,kw OR 'occipital lobes':ti,ab,kw OR cerebrum*:ti,ab,kw OR 'frontal lobe'/exp OR 'temporal lobe'/exp OR 'occipital lobe'/exp) AND (metastas*:ti,ab,kw OR metastat*:ti,ab,kw OR 'metastasis'/exp) AND [english]/lim AND [2016-2022]/py NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('juvenile'/exp NOT ('juvenile' AND 'adult')) NOT ('editorial'/exp OR 'conference paper'/exp OR 'letter'/exp OR 'review'/exp OR 'systematic review'/exp) NOT ('case report'/exp NOT 'case control study'/exp) NOT ('in vitro study'/exp OR 'cell culture technique'/exp OR 'animal experiment'/exp OR 'animal model'/exp) NOT (('brain tumor'/exp OR brain*:ti,ab,kw OR 'brain stem':ti,ab,kw OR brainstem*:ti,ab,kw OR cerebral*:ti,ab,kw OR intracranial*:ti,ab,kw OR 'intra-cranial':ti,ab,kw OR cerebellum:ti,ab,kw OR cerebellar*:ti,ab,kw OR 'frontal lobe':ti,ab,kw OR 'frontal lobes':ti,ab,kw OR 'temporal lobe':ti,ab,kw OR 'temporal lobes':ti,ab,kw OR 'parietal lobe':ti,ab,kw OR 'parietal lobes':ti,ab,kw OR 'occipital lobe':ti,ab,kw OR 'occipital lobes':ti,ab,kw OR cerebrum*:ti,ab,kw OR 'frontal lobe'/exp OR 'temporal lobe'/exp OR 'occipital lobe'/exp) AND (metastas*:ti,ab,kw OR metastat*:ti,ab,kw OR 'metastasis'/exp) AND [english]/lim AND [2016-2022]/py NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('juvenile'/exp NOT ('juvenile' AND 'adult')) NOT ('editorial'/exp OR 'conference paper'/exp OR 'letter'/exp OR 'review'/exp OR 'systematic review'/exp) NOT ('case report'/exp NOT 'case control study'/exp) NOT ('in vitro study'/exp OR 'cell culture technique'/exp OR 'animal experiment'/exp OR 'animal model'/exp) AND 'conference abstract'/it) AND ('laser therapy'/exp OR 'laser therapy':ti,ab,kw OR (laser NEAR/3 (therap* OR ablat* OR therm* OR interstitial*)) OR litt:ti,ab,kw)

 

PICO 8 – BRAIN METS ET UPDATE – MR-GUIDED FOCUSED ULTRASOUND

 

('high intensity focused ultrasound'/exp OR 'high intensity focused ultrasound':ti,ab,kw OR hifu:ti,ab,kw OR 'magnetic resonance guided high intensity focused ultrasound'/exp OR 'magnetic resonance guided high intensity focused ultrasound':ti,ab,kw OR ((ultrasound* OR ultrsonic*) NEAR/3 (intens* OR ablat* OR therap* OR focus*)) OR 'mr-guided focused ultrasound'/exp OR 'mr-guided focused ultrasound':ti,ab,kw OR 'ultrasound ablation device'/exp OR 'ultrasound ablation device':ti,ab,kw OR exablate:ti,ab,kw OR sonatherm:ti,ab,kw OR 'sonatherm 600':ti,ab,kw OR 'sonatherm 600i':ti,ab,kw OR tivus:ti,ab,kw OR ultracinch:ti,ab,kw OR 'ultracinch lp':ti,ab,kw OR 'ultrasound ablation system':ti,ab,kw OR mrgfus*:ti,ab,kw OR mrigfus*:ti,ab,kw OR ((mr OR mri OR 'magnetic resonance') NEAR/4 guid* NEAR/4 focus* NEAR/4 (ultrasound* OR ultrasonic*)) OR 'sonocloud'/exp OR 'sonocloud':ti,ab,kw OR 'sc-9':ti,ab,kw OR sc9:ti,ab,kw) AND ('brain tumor'/exp OR brain*:ti,ab,kw OR 'brain stem':ti,ab,kw OR brainstem*:ti,ab,kw OR cerebral*:ti,ab,kw OR intracranial*:ti,ab,kw OR 'intra-cranial':ti,ab,kw OR cerebellum:ti,ab,kw OR cerebellar*:ti,ab,kw OR 'frontal lobe':ti,ab,kw OR 'frontal lobes':ti,ab,kw OR 'temporal lobe':ti,ab,kw OR 'temporal lobes':ti,ab,kw OR 'parietal lobe':ti,ab,kw OR 'parietal lobes':ti,ab,kw OR 'occipital lobe':ti,ab,kw OR 'occipital lobes':ti,ab,kw OR cerebrum*:ti,ab,kw OR 'frontal lobe'/exp OR 'temporal lobe'/exp OR 'occipital lobe'/exp) AND (metastas*:ti,ab,kw OR metastat*:ti,ab,kw OR 'metastasis'/exp) AND [english]/lim AND [2016-2022]/py NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('juvenile'/exp NOT ('juvenile' AND 'adult')) NOT ('editorial'/exp OR 'conference paper'/exp OR 'letter'/exp OR 'review'/exp OR 'systematic review'/exp) NOT ('case report'/exp NOT 'case control study'/exp) NOT ('in vitro study'/exp OR 'cell culture technique'/exp OR 'animal experiment'/exp OR 'animal model'/exp) NOT (('brain tumor'/exp OR brain*:ti,ab,kw OR 'brain stem':ti,ab,kw OR brainstem*:ti,ab,kw OR cerebral*:ti,ab,kw OR intracranial*:ti,ab,kw OR 'intra-cranial':ti,ab,kw OR cerebellum:ti,ab,kw OR cerebellar*:ti,ab,kw OR 'frontal lobe':ti,ab,kw OR 'frontal lobes':ti,ab,kw OR 'temporal lobe':ti,ab,kw OR 'temporal lobes':ti,ab,kw OR 'parietal lobe':ti,ab,kw OR 'parietal lobes':ti,ab,kw OR 'occipital lobe':ti,ab,kw OR 'occipital lobes':ti,ab,kw OR cerebrum*:ti,ab,kw OR 'frontal lobe'/exp OR 'temporal lobe'/exp OR 'occipital lobe'/exp) AND (metastas*:ti,ab,kw OR metastat*:ti,ab,kw OR 'metastasis'/exp) AND [english]/lim AND [2016-2022]/py NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) NOT ('juvenile'/exp NOT ('juvenile' AND 'adult')) NOT ('editorial'/exp OR 'conference paper'/exp OR 'letter'/exp OR 'review'/exp OR 'systematic review'/exp) NOT ('case report'/exp NOT 'case control study'/exp) NOT ('in vitro study'/exp OR 'cell culture technique'/exp OR 'animal experiment'/exp OR 'animal model'/exp) AND 'conference abstract'/it)

 

Appendix II: Rating Evidence Quality

Classification of Evidence on Therapeutic Effectiveness and Levels of Recommendation

Class I Evidence Level I (or A) Recommendation	Evidence from one or more well-designed, randomized controlled clinical trial, including overviews of such trials.
Class II Evidence Level II (or B) Recommendation	Evidence from one or more well-designed comparative clinical studies, such as non-randomized cohort studies, case-control studies, and other comparable studies, including less well-designed randomized controlled trials.
Class III Evidence Level III (or C) Recommendation	Evidence from case series, comparative studies with historical controls, case reports, and expert opinion, as well as significantly flawed randomized controlled trials.

Classification of Evidence on Prognosis and Levels of Recommendation

Class I Evidence Level I (or A) Recommendation	All 5 technical criteria above are satisfied.
Class II Evidence Level II (or B) Recommendation	Four of five technical criteria are satisfied.
Class III Evidence Level III (or C) Recommendation	Everything else.

 

Classification of Evidence on Diagnosis and Levels of Recommendation

Class I Evidence Level I (or A) Recommendation	Evidence provided by one or more well-designed clinical studies of a diverse population using a “gold standard” reference test in a blinded evaluation appropriate for the diagnostic applications and enabling the assessment of sensitivity, specificity, positive and negative predictive values, and, where applicable, likelihood ratios.
Class II Evidence Level II (or B) Recommendation	Evidence provided by one or more well-designed clinical studies of a restricted population using a “gold standard” reference test in a blinded evaluation appropriate for the diagnostic applications and enabling the assessment of sensitivity, specificity, positive and negative predictive values, and, where applicable, likelihood ratios.
Class III Evidence Level III (or C) Recommendation	Evidence provided by expert opinion or studies that do not meet the criteria for the delineation of sensitivity, specificity, positive and negative predictive values, and, where applicable, likelihood ratios.

 

Classification of Evidence on Clinical Assessment and Levels of Recommendation

Class I Evidence Level I (or A) Recommendation	Evidence provided by one or more well-designed clinical studies in which interobserver and/or intraobserver reliability is represented by a Kappa statistic > 0.60.
Class II Evidence Level II (or B) Recommendation	Evidence provided by one or more well-designed clinical studies in which interobserver and/or intraobserver reliability is represented by a Kappa statistic > 0.40.
Class III Evidence Level III (or C) Recommendation	Evidence provided by one or more well-designed clinical studies in which interobserver and/or intraobserver reliability is represented by a Kappa statistic < 0.40.

 

Appendix III. PRISMA Flowcharts

 

PRISMA Flowchart for Targeted Therapy of Parenchymal Brain Metastases

 

 

PRISMA Flowchart for Targeted Therapy of Leptomeningeal Brain Metastases

 

 

PRISMA Flowchart for Immune Modulators of Parenchymal Brain Metastases

 

 

PRISMA Flowchart for Immune Modulators of Leptomeningeal Brain Metastases

Full-text articles excluded N = 28 Exclude (N = 28)

Records after duplicates removed N = 371

Records excluded N = 331

Records screened N = 371

 

PRISMA Flowchart for the use of Interstitial Modalities for Brain Metastases

 

 

PRISMA Flowchart for the use of Radiosensitizers for Brain Metastases

 

 

PRISMA Flowchart for the use of Lase Interstitial Thermal Therapy for Brain Metastases

 

 

PRISMA Flowchart for the use of Magnetic Resonance-Guided Focused Ultrasound for Brain Metastases

 

 

Appendix IV.  Evidence Tables

Targeted Therapy

Table 3. Targeted Therapy for Parenchymal Metastases

 

PICO  Question	Author, Year	Type of Evidence	Study Type	Level of Evidence	Reviewer’s Conclusions
1	Cheng et al, 202218	Therapy	Retrospective comparative	III	Patients with the GPA for lung cancer using molecular markers (Lung-mol GPA) ≥3 (HR 0.538), who received afatinib or erlotinib as first-line treatment (HR 0.521), underwent SRS therapy (HR 0.531), or were sequentially treated with osimertinib (HR 0.400) were associated with improved OS. Furthermore, SRS plus EGFR-TKI provided more OS benefits in patients with Lung-mol GPA ≥3 compared with EGFR-TKI alone in our patient cohort (44.9 vs 26.7 months, P = .005). The OS in patients who received sequential osimertinib therapy was significantly longer than those without osimertinib treatment (43.5 vs 24.3 months, P < .001), regardless of T790 mutation status (positive vs negative vs unknown: 40.4 vs 54.6 vs 43.4 months, P = .227). Authors’ conclusions: That patients with EGFR-mutant NSCLC with BMs could be precisely treated with SRS according to Lung-mol GPA ≥3. Sequential osimertinib was associated with prolonged survival, regardless of T790M status. Conclusion: The retrospective nature of this study provides class III evidence.
1	Chiu et al, 202211	Therapy	Retrospective comparative, patients who received a first-generation EGFR-TKI (gefitinib or erlotinib) monotherapy or with bevacizumab as the first-line treatment of advanced NSCLC with common EGFR mutation	III	The OS (61.3 vs 34.2 months; log-rank P = .010) and risk reduction of death (P = .017) were significantly improved in EGFR-TKI plus bevacizumab group. Analysis of treatment by brain metastasis status demonstrated EGFR-TKI plus bevacizumab in patients with brain metastasis was associated with significant OS benefit compared with other groups (log-rank P = .030) and these patients had lower early-CNS and early systemic progressions. Authors’ conclusions: First-generation EGFR-TKI with bevacizumab improved treatment efficacy in real-world patients of NSCLC with EGFR mutation. Patients with brain metastasis received additional OS benefit from this treatment. Conclusion: The retrospective nature of this study provides class III evidence
1	Chow et al, 2022	Therapy	Randomized clinical trial, phase II ASCEND-7 (NCT02336451), efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with ALK+ NSCLC metastatic to the brain and/or leptomeninges. Arm 1: prior radiation therapy/ALKi-pretreated; arm 2: no radiation therapy/ALKi-pretreated; arm 3: prior radiation therapy/ALKi-naïve; arm 4: no radiation therapy/ALKi-naïve). Arm 5 included patients with leptomeningeal carcinomatosis	II	Intracranial ORRs (95% CI): 39.3% (21.5-59.4), 27.6% (12.7-47.2), 28.6% (3.7-71.0), and 51.5% (33.5-69.2), in arms 1, 2, 3, and 4, respectively. In arm 5 (n = 18), whole-body ORR was 16.7% (95% CI 3.6-41.4) and DCR was 66.7% (95% CI 41.0-86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood–brain barrier. Authors’ conclusions: Ceritinib showed antitumor activity in patients with ALK+ NSCLC with active brain metastases and/or leptomeningeal disease and could be considered in the management of intracranial disease. Conclusions: This RCT provides class I data.
1	Huang et al, 202210	Therapy	Retrospective comparative, single-institution, patients with advanced and recurrent NSCLC who harbored an EGFR mutation and were treated either osimertinib or afatinib as first-line treatment	III	In patients without brain metastasis, the median PFS was 17.9 months and 17.2 months in the osimertinib and afatinib groups, respectively (HR 1.02 [95% CI 0.56-1.85]). In patients with brain metastasis at baseline, the median PFS was 22.1 months in the osimertinib group, and 10.9 months in the afatinib group (adjusted HR 0.45 [95% CI 0.21-0.96]). Authors’ conclusions: There was no strong evidence showing that patients taking osimertinib as first-line treatment experienced longer median PFS and OS than patients treated with afatinib. However, there was a statistical significance revealing that osimertinib provided better median PFS than afatinib in patients with brain metastasis at baseline. Conclusion: The retrospective nature of this study provides class III evidence.
1	Huang et al, 20224	Therapy	Retrospective study of 36 subjects with advanced EGFR mutant NSCLC treated with first line EGFR-TKI (either erlotinib or afatinib) plus bevacizumab, 22 of which also had brain metastases	III	In patients with brain metastasis at baseline, the median PFS was 18.9 months in the erlotinib group and 16.4 months in the afatinib group (P = .747). The use of this regimen resulted in patients with brain metastases having survival statistically the same as patients without brain metastases. Authors’ conclusions: Not only erlotinib combined with bevacizumab, but also afatinib plus bevacizumab as first-line treatment, provides solid clinical efficacy in advanced EGFR-mutant lung adenocarcinoma patients. Conclusion: The retrospective nature of this data provides class III data.
1	Thomas et al, 202223	Therapy	Retrospective comparative, multicenter study comparing outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial	III	There were no significant differences between TKI and CNS radiation therapy plus TKI groups for any of the study outcomes, including time to progression (P = .13 [EFGR] and 11.4 vs 13.4 mo, P = .98 [ALK]), time to intracranial progression (P = .51 [EGFR] and P = .65 [ALK]), or time to treatment failure (P = .26 [EGFR] and P = .95 [ALK]). Authors’ conclusions: These results provide preliminary evidence that intracranial activity of CNS-penetrant TKIs may enable local radiation to be deferred in appropriately selected patients without negatively affecting progression. Conclusion: The retrospective nature of this study provides class III evidence.
1	Bergen et al, 202141	Therapy	Retrospective comparative, single-institution of 252 HER2-positive breast cancer brain metastasis patients treated with trastuzumab and pertuzumab, “other-HER2-targeted therapy” or no-HER2-targeted therapy as a first line systemic therapy after first diagnosis of the brain metastases	III	Patients treated with trastuzumab and pertuzumab as systemic first-line therapy after diagnosis of BM had a significantly longer OS compared with treatment with other-HER2-targeted therapy and no-HER2-targeted therapy (P < .001). Among radiologically reassessed patients treated with TP as systemic first-line therapy after diagnosis of BM, 5/14 patients (35.7%) had complete intracranial remission, 8/14 patients (57.1%) and 0/14 patients (0.0%) progressive intracranial disease as best response resulting in an intracranial objective response rate of 92.9% and an intracranial clinical benefit rate of 100.0%. Authors’ conclusions: First-line therapy with dual HER2-inhibition of pertuzumab after BM diagnosis was associated with the longest median OS times in patients with breast cancer BMs. Conclusion: The retrospective nature of this study provides class III evidence.
1	Chiou et al, 20216	Therapy	Retrospective comparative NSCLC patients with EGFR mutations and BMs treated with TKIs were in this study. Patients were categorized into two groups based on SRS: TKI therapy alone (group I) and combined SRS and TKI therapy (group II).	III	Cumulative tumor control rates were higher in group II than in group I (79.8% vs 31.2% at 36 months, P < .0001). Cumulative OS rates were comparable between groups I and II (43.8% vs 59.4% at 36 months, P = .3203). Authors’ conclusions: Although the OS rate did not differ between TKI therapy with and without SRS, the addition of SRS to TKI therapy resulted in improvement of intracranial tumor control. The lack of effect on survival rate with the addition of SRS may be attributable to extracranial disease progression. The addition of SRS to TKI therapy is recommended for intracranial disease control in NSCLC patients with BMs and EGFR mutations. Conclusion: The retrospective nature of this study provides class III evidence
1	He et al, 202133	Therapy	Retrospective comparative, single-institution, anlotinib + RT vs RT alone in NSCLC patients with BM and non-EGFR/ALK/ROS1 mt from 2016- 2020	III	Compared with the RT group, the combined group had longer intracranial PFS (P = .048). However, there were no significant differences in OS, extracranial PFS, and systemic PFS. Authors’ conclusions: Anlotinib can improve the intracranial lesion control and survival prognosis of NSCLC patients with RT. Conclusion: The retrospective nature of this study provides class III evidence.
.1	Li et al, 202128	Therapy	Prospective comparative, single-institution, nonrandomized, NSCLC patients with multiple brain metastases, treated with whole brain radiation therapy, or received gefitinib plus endostar (approved for use in China) in addition to whole brain radiation therapy	III	When comparing radiation therapy alone vs radiation therapy plus gefitinib plus endostar, it was found no difference in survival at 6 months’ follow-up, but there was a significant higher survival in the gefitinib plus endostar group at 12 months’ follow-up (P = .012). Authors’ conclusions: Gefitinib plus endostar has significant curative effects and better prognosis in NSCLC patients with multiple brain metastases undergoing WBRT. Conclusion: The retrospective nature of this study provides class III evidence.
1	Ren et al, 202134	Therapy	Retrospective comparative, 34 patients with symptomatic multiple brain metastases from NSCLC (number >4, and at least 1 measurable brain metastasis)	III	Apatinib combination group can better reduce the volume of intracranial tumors and peritumoral brain edema and total steroid dosage used. It was associated with a better IORR (P = .067), longer mIPFS (P = .014). There was no significant difference in median OS (P = .14) between the 2 groups. Authors’ conclusions: Apatinib plus WBRT is well tolerated and may be a potential choice for relapsed or drug-resistant advanced NSCLC patients with symptomatic multiple brain metastases and peritumoral brain edema. Conclusion: The retrospective nature of this study provides class III evidence
1	Yin et al, 202121	Therapy	Retrospective comparative, single-institution, untreated ALK-positive NSCLC patients with ≤3 intracranial metastases, comparing alectinib and crizotinib	III	Median PFS of brain lesions was not yet reached with alectinib (95% CI 30.1 months–not estimated) and was 8.5 months (95% CI 7.2-12.3 months) with crizotinib.  Authors’ conclusions: Compared with crizotinib, alectinib showed superior efficacy and lower toxicity in the treatment of ALK-positive patients with NSCLC and symptomatic and synchronic brain metastases. The inclusion of intracranial therapies such as craniotomy or CyberKnife further improved the brain PFS and OS of these patients. Conclusion: The retrospective nature of this study provides class III evidence.
1	Cho et al, 202030	Therapy	Retrospective comparative, 496 NSCLC patients with BMs, who were treated with GKRS, comparing IT or TT on the outcome after GKRS	III	Patients with concurrent IT or TT presented with a significantly longer survival after GKRS1 than patients without IT or TT (P < .001). Authors’ conclusions: In NSCLC-BM patients, the concomitant use of GKRS and IT or TT showed an increase in OS without increased complications related to GKRS. Conclusion: The retrospective nature of this study provides class III evidence
1	Shaw et al, 202024	Therapy	Interim analysis of a randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK+ NSCLC who had received no previous systemic treatment for metastatic disease, NCT03052608	II	Among those with measurable brain metastases, 82% and 23%, lorlatinib and crizotinib groups respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response. Authors’ conclusions: In an interim analysis of results among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer PFS and a higher frequency of intracranial response than those who received crizotinib. Conclusions: This RCT provides class II data as it is an interim analysis and still underpowered for the analysis planned.
1	Sun et al, 202029	Therapy	Prospective comparative, single-institution, NSCLC with	III	The DCR, median OS, 1-year, and 2-year survival rates in the patients treated with gefinitib plus WBRT were significantly higher than those treated with chemotherapy plus WBRT (P < .05). Authors’ conclusions: WBRT combined with targeted therapy is superior to concurrent radiation therapy and chemotherapy in the treatment of NSCLC with brain metastasis and has high safety. Conclusion: The prospective nature of this study provides class III evidence, due to a lack of data and statistical analysis.
1	Wang et al, 202019	Therapy	Retrospective cohort, single-institution, patients with EGFR-mutated (exon 19 or 21) NSCLC diagnosed with BM from 2011-2014 treated with chemotherapy, targeted therapy and/or radiation	III	The proportion of CR + PR was 63.0% (17/27) for radiation therapy, 26.7% (4/ 15) for chemotherapy, 50.0% (7/14) for targeted therapy, and 89.7% (35/39) for targeted therapy combined with radiation therapy. The median survival of the four treatments was 20, 9, 12, and 25 months after BMs, respectively (P = .001). Authors’ conclusions: The prognosis of patients with NSCLC and EGFR mutation in exon 19 or 21 after BM is associated with the number of brain metastasis and the treatment method. Targeted treatment combined with radiation therapy may have some advantages over other treatments. Conclusions: This retrospective study provides class III data.
1	He et al, 20197	Therapy	Retrospective comparative, single-institution study of 104 treatment-naïve, advanced EGFR-mutant	III	Concurrent EGFR-TKI and WBRT significantly improved the median intracranial PFS compared with EGFR TKI alone (P = .015); however, no significant difference was seen in median OS between the 2 cohorts (P = .756). In addition, the median iPFS was found to significantly vary in the number of brain metastases (<3 vs >3 metastases: P = .044). Subgroup analysis showed that concurrent EGFR TKI and WBRT improved median iPFS compared with EGFR-TKI alone in patients with >3 brain metastases (P = .001); however, no significant difference was observed between the 2 regimens in patients with ≤3  brain metastases (P = .526). Authors’ conclusions: Concurrent EGFR-TKI and WBRT achieves longer iPFS than EGFR-TKI alone in advanced EGFR-mutant NSCLC with brain metastases. In advanced EGFR-mutant NSCLC with ≤3 brain metastases, EGFR-TKI alone may be an option as a first-line therapy. Conclusion: The retrospective nature of this study provides class III evidence
1	Kim et al, 201943	Therapy	Retrospective cohort study, single-institution, patients with newly diagnosed HER2-amplified breast cancer brain metastasis	III	Compared with patients treated with SRS alone, patients treated with concurrent lapatinib had higher rates of complete response (P = .008). On a per-lesion basis, best objective response was superior in the concurrent lapatinib group (P < .001). Concurrent lapatinib was not associated with an increased risk of grade 2+ radiation necrosis (P = .27). Authors’ conclusions: The addition of concurrent lapatinib to SRS was associated with improved complete response rates among patients with HER2-positive brain metastases Conclusion: The retrospective nature of this study provides class III evidence
1	Li et al, 201927	Therapy	Retrospective comparative, single-institution, nonsquamous NSCLC who received PP with (136 patients) or without (97 patients) bevacizumab (Bev) from 2012-2017	III	Compared with the PP regimen, the PP + Bev regimen was associated with a significantly longer median PFS and a higher ORR in the overall population (P = .0002). An improvement in ORR was observed in PP + Bev treated patients with brain metastasis (P = .0045). Authors’ conclusions: These results from clinical practice further support the concept that pemetrexed-platinum plus bevacizumab could be an effective and tolerable regimen in patients with advanced nonsquamous NSCLC. Conclusion: The retrospective nature of this study provides class III evidence.
1	Mastorakos et al, 201935	Therapy	Retrospective comparative,	III	In multivariate analysis, the BRAF mutation was an independent, positive prognostic factor with a HR of 0.59. BRAF-mutated patients who received BRAFi following SRS had improved survival compared with patients who received it before (P < .001) or concurrently (P = .007). PD-1 inhibitors improved survival, with more pronounced effect in patients not carrying the BRAF mutation. Among the patients who were treated with BRAFi, 10.4% developed intracerebral hematoma, in comparison to 3% of patients who were not treated with BRAFi (P = .03). Authors’ conclusions: The presence of a BRAF mutation is an independent predictor of better prognosis in patients with melanoma BM that underwent SRS. The effect of BRAFi is optimal when treatment is initiated at least 1 wk following SRS. BRAFi may increase the frequency of asymptomatic intracerebral hematoma. Conclusion: The retrospective nature of this study provides class III evidence
1	Parsai et al, 201944	Therapy	Retrospective cohort, single-institution, patients with HER2+ breast cancer brain metastases who underwent SRS from 1997-2015	III	Concurrent lapatinib was associated with reduction in local failure at 12 months (P < .01). For lesions in the ≤75th percentile by volume, concurrent lapatinib significantly decreased local failure. However, for lesions in the >75th percentile (>1.10 cm3), concurrent lapatinib did not significantly improve local failure. Any use of lapatinib after development of brain metastasis improved median survival compared with SRS without lapatinib (P = .03). The 12-month risk of radiation necrosis was consistently lower in the lapatinib cohort compared with the SRS-alone cohort (P < .01), despite extended survival. Authors’ conclusions: For patients with HER2+ breast cancer brain metastases, the use of lapatinib concurrently with SRS improved local control of brain metastases, without an increased rate of radiation necrosis. Concurrent lapatinib best augments the efficacy of SRS for lesions ≤1.10 cm3 in volume. In patients who underwent SRS for HER2+ breast cancer brain metastases, the use of lapatinib at any time point in the therapy course was associated with a survival benefit. Conclusion: The retrospective nature of this study provides class III evidence
1	Tian et al, 201926	Therapy	Retrospective comparative, at 2 sites for patients with adenocarcinoma NSCLC and symptomatic or asymptomatic brain metastases that underwent chemotherapy regimen	III	PFS and intracranial PFS were significantly longer in the bevacizumab + PP group than the PP group (P = .008). Authors’ conclusions: PFS and intracranial PFS were significantly prolonged in the bevacizumab + PP group compared with the PP group alone. Conclusion: The retrospective nature of this study provides class III evidence.
1	Wang et al, 201913	Therapy	Single-institution retrospective study of 93 subjects with brain metastases from NSCLCs having EGFR mutations comparing the impact of administration of TKIs alone to radiation therapy plus TKIs as first-line therapy on disease control and survival.	III	Among the 93 patients included, 53 patients received upfront RT and TKI, and 40 patients received TKI only. The median intracranial PFS for the RT plus TKI group and the TKI group were 27.6 months and 16.1 months, respectively (log-rank P = .053). With regression analysis and matching, the upfront RT group showed a significantly lower probability of intracranial progression (P = .006). The upfront RT plus TKI group showed longer median systemic PFS (15.6 vs 8.9 months, P = .009). Nine subjects in the RT + TKI group and 16 in the TKI alone group progressed and received salvage RT. After the salvage RT, upfront RT did not prolong the median time to second-line systemic therapy (23.6 vs 18.9 months, P = .862) or OS (median time, 35.4 vs 35.8 months, P = .695) compared with TKI alone. Authors conclusions: Compared with upfront intracranial RT, the use of salvage RT for oligo-progressive disease allowed patients getting up front TKI to have similar time on initial TKI and OS despite worse iPFS. Conclusions: This retrospective study provides class III data.
1	Yomo et al, 201931	Therapy	Retrospective comparative, multicenter, patients that had RS for BM from lung adenocarcinoma patients were divided into 2 groups based on the use	III	EGFR-TKI use was associated with longer OS (median 25.5 vs 11.0 months, HR 0.60 [95% CI 0.48-0.75], P < .001), although the long-term OS curves eventually crossed. Distant intracranial recurrence was more likely in patients receiving EGFR-TKI (HR 1.45 [95% CI 1.12-1.89], P = .005). Authors’ conclusions: Although patients receiving EGFR-TKI concurrently or after SRS had significantly longer OS, the local treatment efficacy and toxicity of SRS did not differ between patients with/without EGFR-TKI use Conclusion: The retrospective nature of this study provides class III evidence
1	Gadgeel et al, 201822	Therapy	Prospective randomized, controlled, phase III study was conducted on 303 patients with asymptomatic treatment-naïve ALK+ NSCLC underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg, NCT02075840	I	Time to CNS progression was significantly longer with alectinib vs crizotinib and comparable between patients with and without baseline CNS metastases (P < .0001). CNS ORR was 85.7% with alectinib vs 71.4% with crizotinib in patients who received prior radiation therapy and 78.6% vs 40.0%, respectively, in those who had not. Authors’ conclusions: Alectinib demonstrated superior CNS activity and significantly delayed CNS progression vs crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiation therapy. Conclusions: This RCT provides class I data.
1	Gorka et al, 2018126	Therapy	Retrospective comparative, single-institution, melanoma patients with asymptomatic BM, verified BRAF mutation, and ECOG 0-2 who received dabrafenib therapy between 2014 and 2017	III	Intracranial DCR was 83% including 4 (13%) CRs, 9 (30%) PRs, and 12 (40%) SDs in contrast to 5 (17%) PD. Median follow-up of 14 months, median PFS and OS were 5.5 months, and 8.8 months, respectively. If calculated from BM onset, the OS turned to be 11.8 months on the dabrafenib arm, while it was 6.0 months in the control arm (HR = 0.45, P = .0014). Authors’ conclusions: The current analysis succeeded to confirm that dabrafenib had therapeutic effect on BM from melanoma in patients with BRAF mutation. Both PFS and OS improved with the use of dabrafenib, the significant OS improvement was demonstrated even by our comparative analysis versus local therapies and/or chemotherapy. Conclusion: The retrospective nature of this study provides class III evidence.
1	Wu et al, 20185	Therapy	CNS efficacy of osimertinib in AURA3, a phase III, open-label, randomized study to assess the efficacy and safety of osimertinib (80 mg orally, once daily) vs platinum-pemetrexed (pemetrexed 500 mg/m2 plus either cisplatin 75 mg/m2 or carboplatin target area under the curve 5, every 3 weeks for up to 6 cycles) in patients with centrally confirmed advanced EGFR T790M mutation–positive NSCLC and disease progression after prior EGFR-TKI treatment, NCT02151981	II	At data cutoff, CNS ORR in patients with ≥1 measurable CNS lesion(s) was 70% with osimertinib and 31% with platinum-pemetrexed (P = .015); the ORR was 40% and 17%, respectively, in patients with measurable and/or nonmeasurable CNS lesions (P = .014). Median CNS duration of response in patients with measurable and/or on measurable CNS lesions was 8.9 months for osimertinib and 5.7 months for platinum-pemetrexed; median CNS PFS was 11.7 months and 5.6 months, respectively (P = .004). Authors’ conclusions: Osimertinib demonstrated superior CNS efficacy versus platinum-pemetrexed in T790M-positive advanced NSCLC. Conclusions: This RCT provides class I data.
1	Acharya et al, 201739	Therapy	Retrospective case series, single-institution chart review of patients in melanoma BM treated with SRS in combination with IMT or targeted therapy	III	One-year distant intracranial control rates for SRS, SRS + IMT, and SRS + targeted therapy was 11.5%, 60%, and 10%, respectively (P < .001). SRS + IMT remained associated with a significant reduction in distant intracranial failure compared with SRS (P = .003) and compared with SRS + targeted therapy (P = .001). One-year local control for SRS, SRS + IMT, and SRS + targeted therapy was 66%, 85%, and 72%, respectively (P = .044). On multivariate analysis, after adjusting for dose, SRS + IMT remained associated with a significant reduction in local failure compared with SRS alone (P = .04). Authors’ conclusions: SRS with immunotherapy is associated with decreased distant and local intracranial failure compared with SRS alone. However, prospective studies are required to validate this result. Conclusion: The retrospective nature of this study provides class III evidence
1	Chabot et al, 201732	Therapy	Randomized, double-blind, global phase 2, randomized, multicenter, WBRT in combination with veliparib	I	Median OS was 185 days for patients treated with WBRT plus placebo and 209 days for WBRT plus veliparib (50 or 200 mg). Authors’ conclusions: There was no significant difference in OS between either of the WBRT plus veliparib (50 or 200 mg) arms and the WBRT plus placebo arm Conclusions: This RCT provides class I data.
1	Chen et al, 201720	Therapy	Retrospective comparative, single-institution, ALK-positive NSCLC patients with BM, response to crizotinib vs chemotherapy	III	Usage of crizotinib prolonged PFS compared with chemotherapy in ALK-positive patients (median PFS 17.6 m vs 4.8 m, P < .001). ALK-positive NSCLC had more brain metastasis and less pleural effusion than double-negative ones. Authors conclusion: Crizotinib showed better PFS than chemotherapy in advanced ALK-positive NSCLC patients Conclusions: This retrospective study provides class III data.
1	Davies et al, 201740	Therapy	Randomized open-label, multicohort, phase 2 trial evaluated the activity and safety of dabrafenib plus trametinib in 4 patient cohorts: 1) BRAF V600E–mutant, asymptomatic melanoma brain metastases, without prior local brain-directed therapy, ECOG ≤1; 2) BRAF V600E–mutant, asymptomatic melanoma brain metastases, with prior local therapy, ECOG ≤1; 3) BRAF V600D/K/R–mutant, asymptomatic melanoma brain metastases, with or without prior local therapy, ECOG ≤1; and 4) BRAF V600D/E/K/R–mutant, symptomatic melanoma brain metastases, with or without prior local therapy ECOG ≤2, COMBI-MB trial (NCT02039947)	I	At the data cutoff investigator-assessed intracranial response rate was 58% (n = 44/76) in cohort 1. Intracranial response by investigator assessment was also achieved in 56% in cohort 2, 44% in cohort 3, and 59% in cohort 4. Safety results were consistent with prior dabrafenib plus trametinib studies, 48% patients across cohorts experiencing grade 3/4 adverse events. Authors’ conclusions: Dabrafenib plus trametinib was active with a manageable safety profile in patients with BRAF V600–mutant MBMs, but the median duration of response was relatively short Conclusions: This RCT provides class I data.
1	Fan et al, 201712	Therapy	Retrospective comparative, with metastatic EGFR-mutant adenocarcinoma with BM	III	There was no difference in OS between the RT followed by icotinib group and the icotinib alone group (31.9 vs 27.9 months, P = .237), and similar results were found in the SRS subgroup (35.5 vs 27.9 months, P = .12). Intracranial PFS was improved in the patients who received RT followed by icotinib compared with those receiving icotinib alone (22.4 vs 13.9 months, P = .043). Authors’ conclusions: Patients with EGFR-mutant adenocarcinoma and BM treated with icotinib exhibited prolonged survival. A longer duration of intracranial control was observed with brain RT. Conclusion: The retrospective nature of this study provides class III evidence
1	Forschner et al, 201738	Therapy	Retrospective cohort, single-institution, patients diagnosed with metastatic melanoma between 2011 and 2014	III	In the case of cerebral metastasis, they detected a clear improvement of median OS for targeted treated patients (14 months) vs patients treated by immunotherapy (7 months) or chemotherapy (9 months). Authors’ conclusions: Patients with BM treated with targeted therapy showed a longer median OS than patients treated with ipilimumab Conclusion: The retrospective nature of this study provides class III evidence.
1	Liu et al, 20179	Therapy	Retrospective comparative, single-institution, EGFR-mutant NSCLC patients with newly diagnosed BMs received brain RT within 4 weeks after EGFR-TKI initiation and or were treated with EGFR-TKI alone as an initial therapy	III	The patients with early brain RT had superior IC-PFS than those without early brain RT (P = .001), which remained significant in multivariate analysis (HR 0.30, P < .001). For patients with DS-GPA scores of 0 to 2, early brain RT was the independent factor for improved OS (HR 0.33, P = .025). Authors’ conclusions: Concurrent early brain RT with EGFR-TKI may improve intracranial disease control in EGFR-mutant NSCLC with BM and have survival benefit in patients with low DS-GPA scores. Salvage brain RT upon BM progression may be acceptable in some patients. Conclusion: The retrospective nature of this study provides class III evidence.
1	Magnuson et al, 201717	Therapy	Retrospective comparative	III	The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively (P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis (P = .001). Authors’ conclusions: This multiinstitutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiation therapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. Conclusion: The retrospective nature of this study provides class III evidence.
1	Xu et al, 201736	Therapy	Retrospective comparative, single-institution, melanoma brain metastasis divided into 3 groups. Group A, those with mutant BRAF without BRAFi treatment (13 patients); group B, those with mutant BRAF with BRAFi treatment (17 patients); and group C, those with WT BRAF (35 patients).	III	Median survival times after the diagnosis of melanoma BM and after SRS were favorable in patients with a BRAF mutation and treated with SRS in conjunction with BRAFi (group B) compared with the patients with WT BRAF (group C, 23 vs 8 months and 13 vs 5 months, respectively; P < .01, log-rank test). SRS provided a local tumor control rate of 89.4% in the entire cohort of patients. Furthermore, the local control rate was improved in the patients treated with SRS in conjunction with BRAFi (group B) compared with patients with WT (group C) or with BRAF mutation but no BRAFi (group A) as an adjunct treatment for BMs. Authors’ conclusions: BRAF mutation status appears to play a key role as a potent prognostic factor in patients harboring melanoma BM. BRAFi in conjunction with SRS may benefit this group of patients in terms of BM survival and SRS with an acceptable safety profile. Conclusion: The retrospective nature of this study provides class III evidence.
1	Yang et al, 201725	Therapy	Retrospective study, single-institution of NSCLC BM patients treated with either of the 3 combination treatments of bevacizumab + gefitinib + WBRT	III	Compared with the standard WBRT, bevacizumab and gefitinib could significantly enhance RR and DCR of WBRT (P = .001). At the same time, RR and DCR of patients who received bevacizumab-gefitinib-WBRT were higher than those who received gefitinib-WBRT. The OS and PFS rates also differed significantly among the bevacizumab-gefitinib-WBRT, gefitinib-WBRT, and WBRT (groups (P = .05). Authors’ conclusions: Although bevacizumab + gefitinib + WBRT was slightly more toxic than gefitinib-WBRT, the toxicity was tolerable. As suggested by prolonged PFS and OS status, bevacizumab substantially improved the overall efficacy of WBRT in the management of patients with NSCLC. Conclusion: The retrospective nature of this study provides class III evidence.
1	Yang et al, 201715	Therapy	Randomized control trial (BRAIN), multicenter (17 sites), open-label, NSCLC with EGFR mutations, who were naive to treatment with EGFR-TKIs or radiation therapy and had at least three metastatic brain lesions. We randomly assigned participants (1:1) to either icotinib 125 mg orally (3 times per day) or WBI (30 Gy in 10 fractions of 3 Gy) plus concurrent or sequential chemotherapy for 4-6 cycles, until unacceptable adverse events or intracranial disease progression occurred, NCT01724801	I	Median intracranial PFS was 10.0 months (95% CI 5.6-14.4) with icotinib versus 4.8 months (2.4-7.2) with WBRT (equating to a 44% risk reduction with icotinib for an event of intracranial disease progression or death; HR 0.56 [95% CI 0.36-0.90]; P = .014). Authors conclusions: Icotinib was associated with significantly longer intracranial PFS than WBRT plus chemotherapy, indicating that icotinib might be a better first-line therapeutic option for this patient population. Conclusions: This RCT provides class I data.
1	Chen et al, 201616	Therapy	Retrospective comparative, single-institution, EGFR-mutant NSCLC with BM, comparing TKI with and without WBRT	III	The intracranial ORR was significantly higher in the EGFR-TKI plus WBRT treatment group compared with the EGFR-TKI alone group (P = .001). The median intracranial TTP was 24.7 months in patients who received WBRT, which was significantly longer than in those who received EGFR-TKI alone, with the median intracranial TTP of 18.2 months (P = .004). There was no significant difference in OS between WBRT and EGFR-TKI alone groups, (P = .740). Authors’ conclusions: For EGFR-mutated lung adenocarcinoma patients with BM, treatment with concomitant WBRT achieved a higher response rate of BM and significant improvement in intracranial PFS compared with EGFR-TKI alone. Conclusions: This retrospective study provides class III data.
1	Gong et al, 2016121	Therapy	Retrospective comparative, single-institution, prognostic factors that influence survival rates in NSCLC patients with multiple BMs	III	Three or more cycles of chemotherapy combined with targeted drug therapy could increase the patients’ median and OS rates (P < .05). Authors’ conclusions: Chemotherapy combined with targeted drug therapy could increase the patients’ median and OS rates. The number of chemotherapy cycles undergone, and the administration of combined targeted drug therapy had significant effects on the patients’ survival prognoses. Conclusion: This study meets 2 and possibly 3 of the 5 quality criteria for prognostic studies and thus provides class III evidence.
1	He et al, 20168	Therapy	Retrospective comparative, single-institution, 99 patients were enrolled into the study. Eligible patients were confirmed with stage IV lung adenocarcinoma of which 44 were positive for activating mutation of EGFR (exon 19 deletion or an exon 21 L858R mutation), who received treatment with erlotinib or pemetrexed as second-/third-line treatment	III	Median PFS in months was not significantly different between the erlotinib- and pemetrexed-treated groups (4.2 vs 3.4 months, respectively; P = .635). Median PFS was found to be significantly longer in EGFR mutation–positive patients in the erlotinib-treated group (8.0 months [95% CI 5.85-10.15]) compared with the pemetrexed group (3.9 months [95% CI 1.25-6.55]; P = .032). Authors’ conclusions: Erlotinib and pemetrexed may be used as second-/third-line treatment in lung adenocarcinoma patients with asymptomatic brain metastases, and detection of EGFR mutation status is especially important in these patients. EGFR mutation–positive lung adenocarcinoma patients with asymptomatic brain metastases showed longer PFS when treated with erlotinib as opposed to pemetrexed. Conclusion: The retrospective nature of this study provides class III evidence
1	Jiang et al, 201614	Therapy	Retrospective comparative, single-institution, NSCLC patients with BM and EGFR, compared patients received EGFR TKIs alone vs patients received EGFR TKIs plus WBRT therapy	III	Compared with TKIs alone, EGFR TKIs plus WBRT had no superior intracranial PFS (P = .232) and systemic PFS (P = .546) but were associated with worse OS (P = .049) in NSCLC with EGFR mutation and BM. Chemotherapy plus WBRT was shown to have an intracranial PFS (P = .339) and OS (P = .977) similar to those with chemotherapy alone in patients with EGFR of unknown or WT status. Authors’ conclusions: The addition of WBRT to EGFR TKIs did not appear to have survival benefit superior to that of EGFR TKIs alone in with EGFR-mutant NSCLC with BM. WBRT also did not bring additional benefit to chemotherapy in patients with BM and EGFR of WT or unknown status. Conclusions: This retrospective study provides class III data.
1	Wolf et al, 201637	Therapy	Retrospective cohort, single-institution patients with metastatic melanoma to the brain who underwent SRS between 2012-2015	III	The time to progression/new metastasis was significantly longer for patients with a BRAF-M treated with a BRAFi compared with the BRAF-WT patients (P = .02). OS from diagnosis of BM metastasis comparing BRAF-M patients on inhibitors to BRAF-WT patients showed a statistically significant worse OS for patients with BRAF-WT melanoma (P = .04). Authors’ conclusions: patients with BRAF-mutation treated with both SRS and BRAF inhibitors, at or after SRS, have increased OS from the time of SRS. Conclusion: The retrospective nature of this study provides class III evidence.
1	Zhang et al, 2016122	Therapy	Retrospective comparative, single-institution, 60 HER2-positive breast cancer patients	III	Patients who received anti-HER2 therapy and chemotherapy after WBRT had significantly better survival compared with patients who did not receive further treatment (P < .001 and P = .002, respectively). Authors’ conclusions: Both chemotherapy and anti-HER2 therapy after WBRT could improve OS. Moreover, patients without prior exposure to adjuvant anti-HER2 treatment may have survival benefit superior to those of patients with prior exposure. Conclusion: The retrospective nature of this study provides class III evidence.

 

ALK = anaplastic lymphoma kinase; BM = brain metastasis; BRAFi = BRAF inhibitor; CNS = central nervous system; CR = complete response; DCR = disease control rate; DS-GPA = Diagnosis-Specific Graded Prognostic Assessment; EGFR = epidermal growth factor receptor; GKRS = Gamma Knife Radiosurgery; GPA = graded prognostic assessment; HER2 = human epidermal growth factor receptor 2; HR = hazard ratio; IMT = immunotherapy; IT = immunotherapy; NSCLC = non­–small-cell lung carcinoma; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PP = pemetrexed-platinum; PR = partial response; RCT = randomized controlled clinical trial; RR = response rate; SD = stable disease; SRS = stereotactic radiosurgery; TKI = tyrosine kinase inhibitor; TT = targeted therapy; WBRT = whole brain radiation therapy; WT = wild-type.

 

 

Table 4. Targeted Therapy for NSCLC With Leptomeningeal Brain Metastases

PICO Question	Author, Year	Type of Evidence	Study Type	Class of Evidence	Reviewer’s Conclusions
2	Zou et al, 202245	Therapy	Multicenter retrospective study of ALK-positive NSCLC patients with BM or LM with patients in 3 cohorts based on the treatment history before the administration of alectinib: ALK-TKI-naive patients (cohort 1)—patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib and (cohort 2), and patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs (cohort 3); 65 patients (cohort 1: 20, cohort 2: 32, cohort 3: 13)	III	Nine patients were diagnosed with LM (4 patients with LM, 5 patients with LM + BM), of whom 7 patients presented with typical clinical symptoms. In total, 21 patients (21/25, 84%) experienced significant improvement in CNS-related symptoms after the treatment with alectinib, of whom 13 patients (13/17, 76.5%) had BM and 8 (8/8, 100%) had LM ± BM. Seven of 7 were no longer in need of mannitol or corticosteroids following the administration of alectinib. In these patients treated with alectinib, with a median follow-up of 16.8 months (95% CI 4.1-28.7 months), CNS-time to progression (TTP) for patients with LM was 408 days. Authors’ conclusions: Results demonstrate favorable efficacy of alectinib in LM. Therefore, TKIs with robust intracranial activity should be deemed as the vital options for LM. Conclusions: This retrospective study provides class III data.
2	Yi et al, 202246	Therapy	A single-center retrospective study of 27 patients diagnosed with LM from EGFR-mutant NSCLC who received osimertinib with or without bevacizumab.	III	The median OS of the patients who received osimertinib and bevacizumab (n = 16) compared with osimertinib group (n = 11) was 18.0 months vs 13.7 months (log-rank test, P = .046, HR 2.867 [95% CI 1.007-8.162]). The median intracranial PFS (iPFS) was 10.6 months vs 5.5 months (log-rank test, P = .037, HR 3.401 [95% CI 1.079-10.720]). Authors’ conclusions: The findings indicate the potential benefit of osimertinib plus bevacizumab in LM with EGFR-mutant NSCLC. Conclusions: As a retrospective study, this provides class III data.
2	Li et al, 202247	Therapy	A single-center retrospective series of 53 patients with EGFR-mutated NSCLC treated with EGFR-TK inhibitors.	III	Median OS after LM diagnosis was 13.0 months, ranging from 0.5 to 42.0 months (95% CI 9.067-16.933), with 64.2% maturity. Patients who received osimertinib after developing LM (n = 35) had a significantly higher rate of LM disease control (P = .008) and significantly longer OS (15.0 vs 6.0 months; HR 2.4292 [95% CI 1.234-4.779]; P = .045) than those who received previous generations of EGFR TKIs or other localized therapies (n = 6). Authors’ conclusions: EGFR-mutated NSCLC diagnosed with LM who developed LM had better clinical outcomes with osimertinib therapy than older EGFR-TKIs Conclusions: This study provides class III evidence as it is retrospective.
2	Zhang et al, 202148	Therapy	Retrospective study of 78 patients with EGFR-mutated NSCLC and LM. Case data were collected and EGFR mutation status of circulating cell-free DNA from paired CSF, and plasma of 23 patients with LM was detected using droplet digital PCR.	III	The median OS was 8.08 months (95% CI 6.07-10.09) in the study. Forty-four osimertinib-treated patients had an improved median OS of 13.15 months (95% CI 5.74-20.57) and a median PFS (PFS) of 9.50 months (95% CI 6.77-12.23) when compared with patients treated with first- or second-generation EGFR-TKI (median OS 3.00 months [95% CI 1.32-4.68]) and median PFS = 1.50 months (95% CI 0.00-3.14). In the osimertinib group, median OS values for CSF with and without T790M mutation were 22.15 months (95% CI 9.44-4.87) and 13.39 months (95% CI 7.01-19.76), respectively, with no statistical differences. Authors’ conclusions: Regardless of the CSF T790M mutation status, osimertinib demonstrated significant efficacy against LM associated with NSCLC. Conclusion: This retrospective analysis provides class III evidence.
2	Miyawaki et al, 202149	Therapy	Single-institution retrospective case review of subjects comprising 50 patients treated with EGFR-TKI after LM diagnosis. 35 were treated with Switch-TKI. Switch-TKI: switch to previously unadministered EGFR-TKIs. 15 with Rechallenge-TKI. Rechallenge-TKI: rechallenge previously administered EGFR-TKIs	III	According to the treatment type, the median OS from the time of LM diagnosis: 6.9 months in switch-TKI patients; 4.9 months in rechallenge-TKI patients. There was no significant difference in the OS between the Switch-TKI and rechallenge-TKI groups (P = .864). 9 pts treated with switch-osimertinib with median OS was 11.3 months. 7 patients were treated with rechallenge-osimertinib with median OS of 9.1 months, 26 patients were treated with switch-erlotinib with median OS was 5.1 months. 8 patients were treated with Rechallenge-Erlotinib with median OS 4.1 months, In the multivariate analysis for OS, treatment with osimertinib following the onset of LM (HR 0.09 [95% CI 0.01-0.48]; P = .005) was associated with better OS. Authors’ conclusions: This study showed that patients treated with Osimertinib had significantly better OS and TTF than those treated with erlotinib. Therefore, rechallenge with osimertinib could be a better treatment option for LM development following the failure of osimertinib as a first-line treatment. Conclusions: This is a retrospective study representing class III data.
2	Lee et al, 202050	Therapy	Single-institution retrospective study of 351 patients with EGFR-mutated NSCLC and cytologically confirmed LM. T790M mutation was detected in 88 of 197 patients tested, and a total of 110 patients were treated with osimertinib after LM	III	For all patients with LM included in the analysis the median OS was 8.1 months (95% CI 7.2-9.0). Patients treated with osimertinib had a superior OS of 17.0 months (95% CI 15.13-18.94) compared with those not treated with osimertinib who had a median OS of 5.5 months (95% CI 4.34-6.63) regardless of T790M mutational status (HR 0.36 [95% CI 0.28-0.47], P < .001). This was also considerably longer even than the median OS of 8.7 months (95% CI: 7.01-10.39) of those who were never treated with osimertinib but had first- or second-generation EGFR tyrosine kinase inhibitors. Authors’ conclusions: Osimertinib is a promising treatment option for EGFR-mutated NSCLC with LM regardless of T790M mutational status. Conclusions: This is a retrospective study representing class III data.
2	Ahn et al, 202051	Therapy	Retrospective analysis of the multicenter AURA study. Patients with EGFR T790M-positive advanced NSCLC and progression after previous EGFR-tyrosine kinase inhibitor therapy received osimertinib (80 mg qd). Patients with CNS metastases (including LMs) were eligible if the lesions were neurologically asymptomatic and stable. Patients with evidence of LMs at the study entry were retrospectively included for the analysis. 22 patients included in the analysis	III	Of the 22 patients included in study, LM objective response rate was 55% (95% CI 32-76). Median LM duration of response was not reached (95% CI 2.8-not calculable [NC]). Median LM PFS 11.1 months (95% CI 4.6-NC). Median LM OS 18.8 months (95% CI 6.3-NC). Authors’ conclusions: Patients with EGFR T790M-positive NSCLC and radiologically detected LM obtained clinical benefit from osimertinib (80 mg daily). Conclusion: This is a retrospective study representing class III data.
2	Kwon et al, 202052	Therapy	Single-institution retrospective study of 117 patients with lung adenocarcinoma with EGFR mutations and cytologically confirmed LMC identified.	III	Median survival time from the date of LMC was 3.8 months (IQR 1.5-8.6 months). Median survival time was significantly longer in patients treated with EGFR-TKIs (7.1 months, IQR 3.3-11.4 months), followed by those treated with cytotoxic chemotherapy (3.1 months, IQR 1.3-7.9 months) and with best supportive care (1.2 months, IQR 0.7-3.2 months). The survival of patients treated with third-generation EGFR-TKIs was significantly longer than the other treatment groups. (P < .0001). In multivariate analysis, ECOG performance status score ≤2, treatment with EGFR-TKIs, and insertion of an Ommaya reservoir were significantly associated with favorable outcomes in terms of OS. In a subgroup analysis of EGFR-TKIs, there was no significant difference in OS between erlotinib and gefitinib (8.7 months [95% CI 5.0-12.3 months] vs 8.5 months [95% CI 5.111.9 months], P = .608; data not shown). Of the 62 patients treated with EGFR-TKIs, 11 (17.7%) received third-generation EGFR-TKIs, and the survival outcomes in these patients were significantly longer than with other treatments, including first-generation EGFR-TKIs and cytotoxic chemotherapy. Authors’ conclusions: These findings support the efficacy of third-generation EGFR-TKIs in patients with LMC. Although IT chemotherapy showed no survival benefit, it was associated with improved neurologic symptoms and signs and CSF negative conversion. Conclusion: This is a retrospective study representing class III data
2	Nosaki et al, 202053	Therapy	Single-center phase II trial evaluating the efficacy of erlotinib for patients with non-small cell lung cancer with leptomeningeal metastasis. 17 CSF specimens that were available for epidermal growth factor receptor mutation analysis were all negative for the resistance-conferring T790M mutation.	III	The primary outcome was the objective cytological clearance rate. The clearance rate was 30.0% (95% CI 11.9%-54.3%). Median TTP was 2.2 months. Median OS was 3.4 months. Significantly longer TTP and OS times were observed in patients with mutant EGFR (P = .0113 and P <. 0054). Authors’ conclusions: Erlotinib was active for LM and may be a treatment option for patients with EGFR-mutated NSCLC and LM. Conclusion: This phase II prospective trial provides class II data.
2	Flippot et al, 201954	Therapy	Multicenter retrospective study including 92 patients with EGFR-mutated NSCLC and LM. TKI failure was defined as diagnosis of LM on TKI, or progression of known LM on TKI.	III	Median OS from LM diagnosis was 6.1 months (95% CI 4.2-7.6 months). Among 87 patients with TKI failure, patients rechallenged with TKI had a median LM OS of 7.6 months (95% CI 5.7-10.9) compared with 4.2 months (95% CI 1.6-6.7) in patients without further therapy. Sixty percent of patients rechallenged with TKI experienced clinical benefit (clinical response or stable disease >2 months), and 23% were treatment failure-free at 6 months. Clinical benefit was reported in 11 of 20 (55%) patients treated with erlotinib after afatinib or gefitinib. Strategies based on increasing dose intensity yielded clinical benefit in 59% of patients. All 4 patients who received osimertinib after first- and second-generation TKI experienced clinical benefit. Authors’ conclusions: TKI rechallenge strategies, including dosing intensification, may improve clinical outcomes of patients with LM from EGFR-mutated NSCLC after initial TKI failure. Conclusions: This is class III data due to its retrospective nature.
2	Wu et al, 201955	Therapy	Retrospective, single-institution study of 29 advanced NSCLC patients with LM receiving effective first-generation EGFR TKI treatment (eg, treatment > 6 months)	III	The median OS after LM diagnosis was 5.2 months (95% CI 3.2-7.2). OS was also improved among patients who received, rather than did not receive, antitumor treatment (6.0 months vs 1.9 months, respectively; P < .001) or WBRT (6.0 months vs 3.9 months, respectively; P = .038). OS after LM did not differ between the patients who continued erlotinib treatment vs those who did not in our subset analysis (5.3 months vs 4.0 months, respectively; P = .941). OS after LM did not differ in patients who stopped taking gefitinib and those who did not (5.2 months vs 4.2 months, respectively; P = .330). Authors’ conclusions: There was no significant difference in OS in patients who continued first-generation EGFR TKI after LM compared with those patients who stopped treatment. A greater incidence of LM was observed in NSCLC patients harboring EGFR mutations after effective EGFR TKI treatment. Conclusions: This is class III data based upon its retrospective nature.
2	Yan et al, 201956	Therapy	Retrospective, single-institution study of 156 patients with pathology-proven NSCLC with either positive cerebrospinal fluid cytology or leptomeningeal enhancement by MRI. Fifty-one patients harbored EGFR mutations, and ALK rearrangement was detected in 6 patients. Treatment for LM consisted of EGFR-TKIs alone in 11 patients, WBRT alone in 19 patients, ChT alone in 12 patients, EGFR-TKIs plus WBRT in 30 patients, WBRT plus ChT in 25 patients, and EGFR-TKIs plus ChT in 24 patients.	III	The median PFS was 3.9 months (95% CI 3.178-4.622), and the median OS (OSLM) was 9.8 months (95% CI 7.5-12.1). Thirty patients who received WBRT plus EGFR-TKIs achieved longer survival than those who only received WBRT (median 13.6 vs 8.8 months; P = .027) but did not add any survival benefit than those only received EGFR-TKIs (median 13.6 vs 13.9 months; P = .352). A multivariate analysis indicated that KPS ≥80 (HR 0.592 [95% CI 0.369-0.95]; P = .03) and EGFR-TKIs (HR 0.507 [95% CI 0.283-0.908]; P = .022) after LM diagnosis were independent favorable predictors of survival. Authors’ conclusions: Results suggest that patients with good performance statuses, nonsmoking patients, and the administration of EGFR-TKIs might improve clinical outcomes in NSCLC patients with LM. Conclusions: The retrospective database analysis yields class III data.
2	Choi et al, 201957	Therapy	Single-center retrospective analysis of patients with LM from EGFR-mutant NSCLC with or without pemetrexed use.	III	In our patient cohort with EGFR-mutant NSCLC (n = 631), 17.4% (n = 110) developed LM. Post-LM survival was significantly longer with pemetrexed use after LM (median 13.7 months [95% CI 4.1-23.2 months]) than without pemetrexed use after LM (median 4.0 months [95% CI 2.2-5.7 months]; P = .008). Authors’ conclusions: Pemetrexed use after LM was independently associated with a longer post-LM survival in patients with EGFR-mutant NSCLC with LM. Conclusions: This retrospective study provides class III data.
2	Li et al, 201658	Therapy	Retrospective, single institutional study of 184 lung cancer patients with LM. The percentage of patients with LM harboring EGFR mutations (9.4% [118/1258]) was significantly higher than that of patients with a wild-type EGFR status (1.7% [42/2517])	III	The median OS after LM was 8.7 months (95% CI 7.3-10.1). Among the 109 patients with common EGFR mutations, the 88 patients who received TKI therapy demonstrated longer OS than those who did not (10.0 months vs 3.3 months [P < .001]). Forty-two patients who underwent WBRT did not show longer OS than those without WBRT, and a combination of WBRT and TKIs did not add any survival benefit beyond that in patients receiving only TKIs. A multivariate analysis indicated that TKI therapy (P < .001, HR 0.218) was an independent predictor of favorable survival. Authors’ conclusions: EGFR TKIs were the optimal treatment for LM, and active treatment with WBRT did not prolong OS for EGFR-mutated patients. Conclusions: The retrospective database analysis yields class III data.
2	Xu et al., 201559	Therapy	Retrospective, single-institution study of 108 patients who had been diagnosed with LM from NSCLC	III	The median survival time of the 108 patients was 5.3 months. Forty-nine patients received WBRT with median survival of 6.4 months compared with those who did not of 4.3 months (P = .022). Forty-two patients were treated with EGFR-TKIs after being diagnosed with LM and had prolonged survival (11.1 vs 4.4 months, P < .01). Patients who received concomitant WBRT and EGFR-TKIs had the longest median survival time (12.3 months). Authors’ conclusions: WBRT, EGFR-TKIs or combined therapy, could lead to better clinical outcomes for NSCLC patients with LM. EGFR-TKIs plus WBRT has the potential to be the standard strategy for LM in NSCLC patients. Conclusions: The retrospective database analysis yields class III data.

 

BM = brain metastases; ChT = chemotherapy; CI = confidence interval; CSF = cerebrospinal fluid; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; HR = hazard ratio; ICI = immune checkpoint inhibitor; LC = local control; LM = leptomeningeal metastasis; LMC = leptomeningeal carcinomatosis; MVA = multivariate analysis; NSCLC = non­–small-cell lung carcinoma; OS = overall survival; PFS = progression-free survival; RT = radiation therapy; SRT = stereotactic radiation therapy; TKI = tyrosine kinase inhibitor; WBRT = whole brain radiation therapy.

Table 5. Targeted Therapy for Metastatic Breast Cancer With Leptomeningeal Brain Metastases

PICO Question	Author, Year	Type of Evidence	Study Type	Class of Evidence	Review/Conclusions
2	Figura et al, 201960	Therapy	Single-institution, retrospective study of 56 patients with breast cancer LM disease treated with IT trastuzumab (n = 18; 32%), single-agent IT chemotherapy (methotrexate n = 14 or thiotepa n = 1; 27%), or WBRT alone (n = 23; 41%).	III	Significant differences were noted in Kaplan-Meier craniospinal PFS with 6-month rates of 44%, 18%, and 26% (P = .04) between IT trastuzumab, IT chemotherapy, and WBRT, respectively. Craniospinal control >10 months was achieved in 4 patients treated with IT trastuzumab. Twelve-month Kaplan-Meier OS rates were 54%, 10%, and 19% (P = .01) between IT trastuzumab, IT chemotherapy, and WBRT groups, respectively. Authors’ conclusions: IT trastuzumab should be considered in the management HER2+ breast leptomeningeal disease. Conclusions: The retrospective nature of this data provides class III data.

 

BM = brain metastases; IT = intrathecal; LC = local control; LM = leptomeningeal; MBC = metastatic breast cancer; MVA = multivariate analysis; OS = overall survival; PFS = progression-free survival; WBRT = whole brain radiation therapy.

Table 6. Immune Modulators for the Therapy of Non–Small-Cell Carcinoma Parenchymal Brain Metastases

PICO Question	Author, Year	Type of Evidence	Study Type	Class of Evidence	Reviewer’s Conclusions
3	Abdulhaleem et al, 202262	Therapy	Single-institution, retrospective analysis of 80 consecutive subjects treated with concurrent ICI and SRS compared with 235 individuals treated with SRS and alone or with other systemic therapies. Concurrent therapy defined as ICI given ± 30 days of SRS.	III	Median OS time was improved in patients receiving concurrent immunotherapy compared with the historical control group (40 months vs 8 months, P < .001). Cumulative incidence of local failure in the historical control group was 10% at 1 year, compared with 1.1% at 1 year in the concurrent immunotherapy group (P = .025). Authors’ conclusions: Local control and OS were both improved in patients receiving concurrent immune checkpoint inhibitors with radiosurgery compared with historical controls. Conclusions: This retrospective study provides class III data.
3	Wasilewski et al, 202269	Therapy	A single-center retrospective collection of subjects comparing effectiveness of ICI to chemotherapy in combination with radiation therapy from a group of 480 individuals having undergone craniotomy for the tumor. Propensity matching of the selected cohorts was then carried out.	III	The 2 cohorts of interest included 108 patients (31%) with radiation therapy and chemotherapy and 63 patients (16%) with radiation therapy and ICI following neurosurgical metastasis removal (before matching). After covariate equalization using propensity score matching (62 patients per group), patients receiving radiation therapy and chemotherapy after neurosurgery had significantly lower OS (11.8 months [95% CI 9.1-15.2]) compared with patients with radiation therapy and ICIs (23.0 months [95% CI 20.3-53.8]; P < .001). Authors’ conclusions:  Patients with NSCLC brain metastases undergoing neurosurgical resection had longer OS when treated with radiation therapy and ICIs following neurosurgery compared with those receiving platinum-based chemotherapy and radiation. Conclusions: As a retrospective study, this provides class III data.
3	Enright et al, 202167	Therapy	Retrospective study of individuals with newly diagnosed NSCLC brain metastases treated with stereotactic radiation therapy (SRT) alone versus SRT and immune checkpoint inhibitors (ICIs) at the University of Wisconsin for between June 2012 and August 2019	III	A selective analysis of subjects treated with ICI was carried out. Use of ICI predicted for decreased DBF (HR 0.45 [95% CI 0.24-0.84]; P = .01), decreased rates of neurologic death (HR 0.29 [95% CI 0.10-0.85]; P = .02), and better OS (HR 0.46 [95% CI 0.23-0.91]; P = .03). Two-year LC was 97% for the SRT + ICI group, and 86% for the SRT-alone group (P = .046). Actuarial 2-year DBF was 39% for the SRT + ICI group and 66% for the SRT alone group (P = .016). On MVA, ICI use persisted in predicting lower incidence of neurologic death (HR 0.25 [95% CI 0.09-0.72]; P = .01) and DBF (HR 0.47 [95% CI 0.25-0.85]; P = .01) when adjusted for competing risk of death. Authors’ conclusions: In this cohort of patients with NSCLC brain metastases, ICI use combined with SRT predicted for improved LC and OS and decreased DBF and risk of neurologic death. Conclusion: This retrospective analysis provides class III evidence.
3	Lau SCM et al, 202163	Therapy	Single-institution retrospective case review of subjects comprising 36 ICI- and 33 chemotherapy-treated patients with baseline CNS metastases. ICI therapy was PD-1/PD-L1 inhibitors in combination with CTLA-4 inhibitors were included. Radiation included SRS or WBRT	III	At the time of progression, CNS involvement was identified in 30 % of ICI-treated patients compared with 64 % of chemotherapy controls (P = .02). ICI-treated patients had superior iPFS (13.5 vs 8.4 months) that remained significant in multivariate analysis (HR 1.9 [95% CI 1.1-3.4]). Superior CNS outcomes in ICI-treated patients were driven by the PD-L1 high subgroup where the 12-month cumulative incidence rate of CNS progression was 19% in ICI-treated PD-L1 ≥50%, 50% in ICI-treated PD-L1 <50% and 58% in chemotherapy-treated patients (P = .03). Authors’ conclusions: Brain metastases control is seen with baseline RT plus ICIs in patients with PD-L1 ≥50%. Conclusions: The retrospective nature of this manuscript provides class III data.
3	Lauko et al, 202164	Therapy	Retrospective case series of patients treated with or without immune checkpoint inhibitors for NSCLC BM at a single tertiary care center from 2010 to 2019	Class III	ICI in addition to SRS led to significantly improved OS compared with no-ICI (12.5 months vs 9.1, P < .001). In the 109 patients who had both a known PD-L1 expression and KRAS status, 80.4% of patients with KRAS mutation had PD-L1 expression vs 61.9% in wild-type KRAS patients (P = .04). In patients without a KRAS mutation, there was no difference in OS between the ICI-90 vs no-ICI cohort with a one-year survival of 60.2% vs 54.8% (P = .84). However, in patients with a KRAS mutation, ICI-90 led to a one-year survival of 60.4% vs 34.1% (P = .004). Authors’ conclusions: Patients with NSCLC BM who received ICI had improved OS compared with no-ICI patients. In addition, this benefit appears to be observed primarily in patients with KRAS mutations that may drive the overall benefit. Conclusion: This retrospective study provides class III evidence
3	Liao et al, 202168	Therapy	Retrospective collection of subjects from 2 institutions treated with WBRT alone (n = 41) or in combination with anti-PD-1therapy (n = 29). Patients in the anti-PD-1 group only received anti- PD-1 antibody treatment (nivolumab) that was started within 30 days of WBRT induction	III	The median survival times for WBRT alone and WBRT plus anti-PD-1 therapy cohorts were 20 months (95% CI 11.6-28.3) and 27 months (95% CI 19.5-28.5), respectively (P = .035). There was no statistical difference in PFS for the treatment cohorts (median PFS for WBRT alone: 7 months vs 12 months for WBRT plus anti-PD-1, P = .247). In EGFR wild-type subgroup (n = 31), both PFS (P = .037) and OS (P = .012) were significantly improved. Authors’ conclusions: NSCLC patients with BM receiving additional anti-PD-1 therapy may derive better OS than WBRT alone. Conclusions: This is a retrospective collection of cases representing class III data.
3	Mansfield et al, 202171	Therapy	Post hoc pooled analysis of KEYNOTE- 001, 010, 024, and 042. This included patients with previously treated, stable brain metastases	III	Two hundred ninety-three subjects had baseline brain metastases. One hundred ninety-nine subjects (67.9%) were assigned to pembrolizumab and 94 (32.1%) to chemotherapy. Among patients with PD-L1 TPS >50% with brain metastases at baseline, the HR for OS (pembrolizumab vs chemotherapy) was 0.67 (95% CI 0.44-1.02); median OS was 19.7 (95% CI 12.1-31.4) and 9.7 (95% CI 7.2-19.4) months, respectively. OS also favored the pembrolizumab group among patients with PD-L1 TPS >1%. Among patients with brain metastases, the HR for OS was 0.83 (95% CI 0.62-1.10); median OS was 13.4 (95% CI 10.4-18.0) and 10.3 (95% CI 8.1-13.3) months, respectively. Authors’ conclusions: Pembrolizumab monotherapy improved outcomes and was associated with fewer adverse events than chemotherapy in patients with treatment-naive and previously treated PD-L1‒positive advanced/metastatic NSCLC in the presence of baseline treated, stable brain metastases. Conclusion: The post hoc nature of this analysis of data combined from multiple studies with different design provides class III data.
3	Powell SF et al, 202172	Therapy	Post hoc pooled analysis of KEYNOTE-021, -189, and -407. All studies permitted enrollment of patients with previously treated or untreated stable brain metastases. Patients with previously treated brain metastases were clinically stable for 2 or more weeks. Patients were assigned to carboplatin and pemetrexed with or without the addition of 35 cycles of pembrolizumab 200 mg every 3 weeks	III	In patients with brain metastases (n = 171), median OS was 18.8 months (95% CI 13.8-25.9) with pembrolizumab plus chemotherapy and 7.6 months (95% CI 5.4-10.9) with chemotherapy alone, and median PFS was 6.9 months and 4.1 months, respectively. Authors’ conclusions: With or without brain metastasis, pembrolizumab plus platinum-based histology-specific chemotherapy improved clinical outcomes versus chemotherapy alone. Conclusion: This post hoc, retrospective analysis represents class III data.
3	Scoccianti et al, 202165	Therapy	Multicenter, retrospective analysis of immunotherapy and stereotactic radiation therapy for NSCLC brain metastases. Stereotactic radiation therapy consisted of 1 to 5 fractions. Immunotherapy most frequently used was nivolumab, pembrolizumab, or atezolizumab.	III	Patients receiving SRT + IT had a longer intracranial local PFS (iLPFS, propensity score-adjusted P = .007). Among patients who, at the diagnosis of BM, received IT and had also extracranial progression (n = 24), IT administration after SRT was shown to be related to a better OS (P = .037). On multivariate analysis, non-adenocarcinoma histology, KPS = 70 and use of SRT of 3-5 fractions were associated with a significantly worse survival (P = .019, P = .017, and P = .007 respectively). Time interval between SRT and IT ≤7 days (n = 90) was shown to be related to a longer OS if compared with SRT-IT interval >7 days (n = 10) (propensity score-adjusted P = .008). Authors’ conclusions: Combined stereotactic radiation therapy + immunotherapy was associated with a better intracranial local PFS compared with stereotactic radiation therapy alone. Conclusion: The retrospective nature of this work provides class III data.
3	Shepard et al, 202070	Therapy	Retrospective, single institution, matched cohort study of subjects treated with SRS with (n = 17) or without ICI (n = 34). ICIs included nivolumab, pembrolizumab, and atezolizumab. Concurrent ICI administration was defined as their administration within 3 months of SRS	III	Seventeen patients (45 BMs) and 34 patients (92 BMs) composed the concurrent-ICI and ICI-naive cohorts, respectively. There was no statistically significant difference in OS (HR 0.99 [95% CI 0.39-2.52], P = .99) or CNS PFS (HR 2.18 [95% CI 0.72-6.62], P = .11) between the 2 groups. Similarly, the 12-month local tumor control rate was 84.9% for tumors in the concurrent-ICI cohort vs 76.3% for tumors in the ICI-naïve cohort (P = .94). The median time to individual BM regression was shorter in patients receiving ICIs (2.5 months) than in those who did not (3.1 months; P < .0001, log-rank test). BMs with peritumoral edema had a shorter median time to edema regression in patients who received ICI (2.4 vs 3.1 months; P < .001, log-rank test). Authors’ conclusions: Combining ICI and SRS does not necessarily lead to improved OS or PFS in patients with NSCLC-BM. The concurrent use of ICI and SRS to treat NSCLC-BM was well tolerated while providing more rapid BM regression and control of cerebral edema. Conclusions: This is class III data due to its retrospective nature.
3	Singh et al, 202066	Therapy	Retrospective, single-institution study of subjects with brain metastases from NSCLC treated with single fraction SRS and either immunotherapy, chemotherapy, or targeted therapy. Immunotherapy consisted of pembrolizumab, nivolumab or ipilimumab. Concurrent systemic therapy was that provided within 30 days of SRS	III	One-year distant intracranial PFS (DI-PFS) was improved with any use of immunotherapy (58% vs 39%; P = .03) and concurrent immunotherapy versus chemotherapy or targeted therapy (67% vs 37% vs 39%, respectively; P = .01). In the immunotherapy cohort, 1-year DI-PFS was improved for programmed death-ligand 1 expression >50% vs 1%-49% vs 0% (80% vs 49% vs 19%, respectively; P < .01). Authors’ conclusions: Immunotherapy concurrent with SRS, particularly in patients with high PD-L1 expression is associated with improved DI-PFS compared with other systemic therapies for NSCLC. Conclusions: This is class III data based upon its retrospective nature.
3	Takamori et al, 202073	Therapy	Propensity matched analysis of data extracted from the National Cancer Database. Population: 42,512 patients with stage IV NSCLC; 11,810 patients with BMs and 30,702 patients without BMs. ICIs included those targeting PD-1 or PD-L1	III	In univariate analysis, NSCLC patients with BMs treated with immunotherapy had a significantly longer OS than those without immunotherapy after propensity score matching (median OS: 12.8 vs 10.1 months, HR 0.80 [95% CI 0.72-0.89], P < .0001). Authors’ conclusions: ICI may be one of the promising treatment options for stage IV NSCLC patients with BMs and prospective studies are warranted. Conclusions: The retrospective data base analysis yields class III data.

 

BM = brain metastases; CI = confidence interval; CTLA-4 = cytotoxic T-lymphocyte antigen 4; DBF = distant brain failure; DI-PFS = distant intracranial PFS; HR = hazard ratio; ICI = immune checkpoint inhibitor; iLPFS = intracranial local PFS; IT = immunotherapy; LC = local control; MVA = multivariate analysis; NSCLC = non-small cell lung carcinoma, OS = overall survival; PD-1 = programmed cell death protein 1; PD-L1 = programmed death-ligand 1; RT = radiation therapy; SRT = stereotactic radiation therapy.

 

 

Table 7. Immune Modulators for the Therapy of Melanoma Parenchymal Brain Metastases

PICO Question	Author, Year	Type of Evidence	Study Type	Class of Evidence	Reviewer’s Conclusions
3	Pedersen et al, 202274	Therapy	Retrospective collection subjects with metastatic melanoma involving the brain (MBM) from multiple institutions in Denmark. Comparison of efficacy data from different treatment modalities from an unselected patient cohort	III	Patients receiving surgical excision as first choice of treatment had the best mOS of 10.9 months, whereas patients receiving WBRT had the worst outcome (mOS, 3.4 months). Postoperative SRS did not improve survival or local control after surgical excision of brain metastases. Of the 40 patients alive >3 years after diagnosis of MBM, 80% received immunotherapy at some point after diagnosis. Patients with meningeal carcinosis did not benefit from treatment with CPI. Authors’ conclusion: Most patients alive >3 years after diagnosis of MBM received immunotherapy. Conclusion: This is a retrospective collection cases with no particular goal other than describing how subjects were treated over the interval of the study and yields class III data.
3	Borzillo et al, 202180	Therapy	Single-institution, retrospective study of subjects undergoing single fraction SRS/SRT. Patients were grouped into those who had received radiation therapy and ipilimumab (RT+IPI) and those who had received radiation therapy alone (NO-IPI)	III	A total of 63 MBMs patients were analyzed: 53 received RT+IPI and 10 RT alone. Therefore, the patients were divided into 4 groups: RT PRE-IPI (>4 weeks before IPI) (18), RT CONC-IPI (4 weeks before/between first and last cycle/within 3 months of last cycle of IPI) (20), RT POST-IPI (>3 months after IPI) (15), and NO-IPI (10). A total of 127 lesions were treated: 75 with SRS (one fraction) and 24 with SRT (three to five fractions). The median follow-up was 10.6 months. The median OS was 10.6 months for all patients, 10.7 months for RT+IPI, and 3.3 months for NO-IPI (P = .96). One-year LC was 50% for all patients, 56% for RT+IPI, and 18% for NO-IPI (P = .08). The 1-year intracranial control was 45% for all patients, 44% for RT+IPI, and 51% for NO-IPI (P = .73). IPI with SRS/SRT in MBMs treatment could improve LC. Authors’ conclusions: IPI with SRS/SRT in MBMs treatment could improve LC. However, the impact and timing of the 2 modalities on patients’ outcomes are still unclear. Conclusions: The retrospective nature of this data provides class III data.
3	Di Giacomo et al, 202192	Therapy	Prospective, multi-institutional, randomized study of adult patients with active, untreated, asymptomatic brain metastases with fotemustine, ipilimumab plus fotemustine, or ipilimumab plus nivolumab	I	Twenty-seven, 26, and 27 patients received fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab, respectively. Median OS was 8.5 months in the fotemustine arm, 8.2 months in the ipilimumab plus fotemustine arm (P = .78 vs fotemustine), and 29.2 months in the ipilimumab plus nivolumab arm (P = .017 vs fotemustine). Four-year survival rate was significantly higher for ipilimumab plus nivolumab than fotemustine [(41.0% vs 10.9% (P = .015)], and was 10.3% for ipilimumab plus fotemustine. Authors’ conclusion: Compared with fotemustine, ipilimumab plus nivolumab significantly improved overall and long-term survival of patients with melanoma with asymptomatic brain metastases. Conclusion: The prospective, randomized, well designed and completed nature of this study provides class I data.
3	Hilbers et al, 202193	Therapy	A 4-institution, retrospective collection of 116 subjects with melanoma brain metastases treated with combined immune checkpoint inhibitor therapy ipilimumab/nivolumab (combi-ICI, n = 53), or combined targeted therapy or combined targeted therapy (combi-TT, dabrafenib/trametinib or vemurafenib/cobimetinib, n = 63) within 3 months after diagnosis of melanoma brain metastases	III	Of those that received combi-ICI the disease control rate was 60.3%. Intracranial response rate was 43.8% at 3-months with durable responses at 6-(46.5%) and 12-months (53.1%). Median PFS was 9.6 months and median OS (mOS) 44.8 months. Of those that received combi-TT the disease control rate was 60.4%. The intracranial response rate was 50% at 3-months, but dropped at 6-months (20.9%). Median PFS was 5.8 months and mOS 14.2 months. In cases with BRAFV600 mutations, 26.7% of patients received Combi-ICI and 73.3% Combi-TT with OS (median not reached, 14.2 months, respectively, P = .0053) and mPFS (14.7 and 3.1 months, respectively, P = .03) in favor to Combi-ICI. Authors’ conclusion: Combi-ICI showed prolonged mOS with sustainable IC responses. Combi- ICI appeared superior to Combi-TT for OS and PFS in BRAFV600 patients. Conclusion: This retrospective data providing class III data.
3	Wilson et al, 202194	Therapy	Single-institution, retrospective analysis of melanoma brain metastases (n = 70) treated with a broad range of therapies	III	Sixty-nine patients received systemic treatment. Patients treated with first-line dual immunotherapy had the best median OS (26.7 months), compared with anti-PD-1 (either nivolumab, or pembrolizumab, 14.1 months), ipilimumab alone (14.3 months) and kinase inhibitors (inhibitors of BRAF alone or in combination with MEK inhibitors, 10.9 months). Authors’ conclusions: Dual immunotherapy appears to be the most effective systemic treatment. Conclusions: This retrospective study of an inconsistently applied variety of therapy options provides class III data.
3	Amaral et al, 202075	Therapy	Retrospective case series of patients with melanoma brain metastases with nivolumab and ipilimumab as a portion of their management between 2015 and 2018	III	In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (P = .085). In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (P = .996). Local therapy with SRS or surgery led to an improvement in OS compared with not receiving local therapy (P = .009), regardless of the timepoint of the local therapy. Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (P = .119). Authors’ conclusions: Immunotherapy with nivolumab plus ipilimumab, particularly in combination with SRS or surgery improves OS in asymptomatic and symptomatic MBM. Conclusion: Although the authors conclude there is OS benefit from use of immunotherapy as described, this does not reach statistical significance in any subgroup analysis. This study provides class III evidence based on its retrospective nature.
3	Gatterbauer et al, 202081	Therapy	Single-institution, retrospective analysis of melanoma brain metastases subjects treated with gamma knife radiosurgery. Those who received only radiation was compared with those that received radiation and immunotherapy or targeted therapy during or after the radiation	III	Patients treated with anti-PD-1 or a combination of anti-CTLA-4/PD-1 showed a significantly longer survival after first GKRS compared with all other forms of treatment. In addition, patients treated with anti-PD-1, anti-CTLA-4, or a combination of anti-CTLA-4/PD-1 showed a significantly longer time to new MBM after radiation compared with patients treated with other forms and combinations of the oncological therapy. Authors’ conclusions: There was a clear benefit in distant control and survival in melanoma brain metastases patients treated with radiosurgery and checkpoint inhibitors Conclusions This is class III data based on its retrospective nature.
3	Moyers et al, 202082	Therapy	A retrospective analysis based on a query of the National Cancer Database for patients with melanoma brain metastases receiving cranial radiation alone, cranial radiation with immunotherapy or immunotherapy alone. This study included, and analyzed separately, SRS and WBRT, each of which had quite broad definitions. Immunotherapy included nivolumab, ipilimumab, nivolumab and ipilimumab, and pembrolizumab. Concurrent therapy was defined as IT given within 28 days before or after RT; nonconcurrent defined as IT administered within 28-90 days of RT	III	Median OS was SRS + IT 15.77 months, SRS alone 9.33 months, IT alone 7.29 months, WBRT +I T 4.89 months; no RT or IT 3.29 months, and WBRT alone 3.12 months. Median OS results were then propensity score adjusted: SRS +IT 15.5 months was greater than SRS alone 10.1 months (P = .010) median OS. WBRT  + IT 4.6 months was greater than WBRT alone 2.9 months (P < .001). SRS + IT group 24-month landmark survival was 47% for concurrent therapy vs 37% for nonconcurrent therapy (P = .40). Authors’ conclusions: Those who received IT in addition to WBRT and SRS experienced longer survival. Those receiving concurrent SRS and IT trended toward improved survival vs nonconcurrent therapy. Conclusions: The broad definitions of SRS and WBRT limit the ability to make conclusions about any one treatment methodology. The retrospective nature of these data provides class III data.
3	Rhun et al, 202090	Therapy	Two-institution, retrospective review of the charts of consecutive patients with histologically confirmed melanoma with newly diagnosed BM. This included 62 patients (including 26 patients with BRAF-mutant tumors) with newly diagnosed brain metastases treated with ICI alone (n = 10, group 1), SRT alone or in combination with other systemic therapies (n = 20, group 2) or ICI plus SRT (n = 32, group 3). Focus on comparing assessment methods for imaging response was emphasized.	III	Patients treated with ICI alone showed no objective responses and had worse outcome than patients treated with SRT without or with ICI. Pseudoprogression was documented in 7 patients: 3 patients in group 2 and 4 patients in group 3. Radionecrosis was documented in 7 patients: 2 patients in group 2 and 5 patients in group 3. Authors’ conclusions: Pseudoprogression is uncommon with ICI alone, suggesting that growing lesions in such patients should trigger an intervention. Pseudoprogression rates were similar after SRT alone or SRT in combination with ICI. Conclusion: Class III data based on its retrospective nature and mainly sheds light on measurement of SRT toxicity.
3	White et al, 202091	Therapy	A retrospective analysis based on a query of the National Cancer Database for patients with melanoma brain metastases receiving cranial radiation with immunotherapy or immunotherapy alone. Specific immunotherapy agent not stated. Timing of immunotherapy in relationship to radiation not stated	III	Radiation and immunotherapy: n = 528, immunotherapy alone: n = 142. Immunotherapy administration biased toward subjects with lower comorbidity scores (P = .0073). Median OS SRS + immunotherapy: 19.0 months (P = .006), WBRT + immunotherapy: 7.7 months (P = .0255). Immunotherapy alone: 11.5 months. Authors’ conclusion: For melanoma patients requiring WBRT, immunotherapy alone may be reasonable in asymptomatic patients. For those eligible for SRS, combination therapy may provide better outcomes. Conclusion: This database study is retrospective in nature, provides limited treatment detail, and provided class III data.
3	Diao et al, 201883	Therapy	Retrospective, single-institution study of patients with MBM treated with SRS with or without ipilimumab. This identified 91 patients treated with SRS from 2006 to 2015. Concurrent ipilimumab administration was defined as ±4 weeks of SRS procedure	III	Twenty-three patients received ipilimumab concurrent with SRS, 28 patients non-concurrently, and 40 patients did not receive ipilimumab. Patients who received ipilimumab had a median OS of 15.1 months compared with 7.8 months in patients who did not (P = .02). Authors’ conclusion: Patients who received ipilimumab had improved OS even after adjusting for prognostic factors. Conclusion: The retrospective nature of this data provides class III data.
3	Gabani et al, 201884	Therapy	Retrospective review of melanoma brain metastases cases extracted from the National Cancer Database from 2011-2013	III	A total of 1104 patients were identified: 912 received RT alone and 192 received RT plus immunotherapy. The median follow-up time was 6.4 (0.1-56.8) months. Patients with extracranial disease (OR 1.603 [95% CI 1.146-2.243], P = .006), and patients receiving SRS (OR 1.955 [95% CI 1.410-2.711], P < .001) as compared with WBRT, had a higher likelihood of being treated with immunotherapy. The median OS was 11.1 (8.9-13.4) months in RT plus immunotherapy vs 6.2 (5.6-6.8) months in RT alone (P < .001), which remained significant after propensity score matching. Authors’ conclusions: Addition of immunotherapy to RT is associated with improved OS in MBM. Conclusion: This database study is retrospective in nature, provides limited treatment detail, and is class III data.
3	Long et al, 201895	Therapy	A multicenter randomized phase II study of asymptomatic melanoma brain metastases. Cohort A: nivolumab plus ipilimumab; cohort B: nivolumab	III	With a median follow-up of 17 months intracranial responses were achieved by 16 of 35 (46%) patients in cohort A, and 5 of 25 (20%) in cohort B. Authors’ conclusions: Though the nivolumab plus ipilimumab arm had better results, no statistical inference was computed because the study was not designed for a formal comparison between cohorts. Conclusion: Class III data based on this being an underpowered phase II randomized study.
3	Schmidberger et al, 201885	Therapy	A retrospective analysis of a single institutions experience with radiation and ipilimumab. Radiation consisted of hypofractionated whole brain radiation therapy, stereotactic radiation therapy or both	III	We identified a total of 41 patients of whom 15 were treated with STX, 7 with a combination of STX and WBRT, and 19 with WBRT alone. All patients received at least 2 doses of IPI. The median time interval between radiation therapy and IPI was 2 months. Patients treated with IPI after radiation therapy had a censored median survival of 11 months, compared with 3 months for the patients who received IPI prior to radiation therapy. Patients who received IPI before radiation therapy showed a similar survival as historical controls, who had not received IPI. Authors’ conclusions: These data suggest that the sequence of RT and immune checkpoint inhibition with IPI may be crucial for the success of combined modality treatment of melanoma brain metastases. Conclusions: This is class III data based on its retrospective nature.
3	Stera et al, 201876	Therapy	Two-institution, retrospective study of SRS and immunotherapy in patients with MBM. Nivolumab, ipilimumab and pembrolizumab were used as immunotherapy, given every 2-3 weeks, and dabrafenib, trametinib, vemurafenib, cobimetinib and buparlisib as kinase inhibitors	III	Forty-eight patients with a total of 250 lesions (median: 3) were treated in 65 single fraction SRS sessions from 2012 to 2018. Immunotherapy and the application of systemic treatment directly before or concomitant to SRS were both associated with improved OS (P = .037 and .045, respectively). ICI medication showed only a trend for better results compared with kinase inhibitors (P = .112). Authors’ conclusions: The combination of SRS with novel targeted agents is a feasible option with an acceptable safety profile and good clinical outcome even for treating a higher number of metastases and could be used to defer WBRT. Conclusions: This retrospective study provides class III data.
3	Trommer-Nestler et al, 201886	Therapy	Single-institution, retrospective analysis of 26 MM patients harboring 48 brain metastases (1-5 lesions per patient) receiving PD-1 inhibitors and/or robotic SRS	III	SRS alone: n = 13; 20 lesions; SRS + anti-PD-1 therapy: n = 13; 28 lesions Local control after 6 months: SRS + anti-PD-1: 86%; SRS alone: 80% (NS) Six cases manifest imaging pseudoprogression in the SRS + anti-PD-1 group. The overall rates of acute toxicity were higher in the SRS + anti-PD-1 group, but neither exceeded CTCAE grade 2 adverse events, nor reached statistical significance. Authors’ conclusion: Concomitant SRS and checkpoint inhibition does not increase therapy-related toxicity and can be safely administered. Conclusion: Retrospective data providing class III data in this study showing no benefit from the addition of anti-PD-1 agents to SRS.
3	Vosoughi et al, 201877	Therapy	Two-institution, retrospective study of melanoma patients with brain metastases	III	Following a diagnosis of brain metastasis, 39 (49.4%), 28 (35.4%), and 24 (30.4%) patients were treated with anti-CTLA-4 antibody, anti-PD-1 antibody, or BRAF inhibitors (with or without a MEK inhibitor), with a median OS of 19.2 months, 37. 9 months and 12.7 months, respectively.   Factors associated with significantly reduced OS included: Male sex Cerebellar metastasis Higher number of brain lesions Treatment with WBRT Factors associated with significantly longer OS included Treatment with craniotomy SRS Or with anti-PD-1 antibody After initial diagnosis of brain metastasis   Authors’ conclusions: The activity of anti-PD-1 therapy specifically in the setting of brain metastasis can result in improved OS. Conclusions: This retrospective study provides class III data.
3	Acharya et al, 2017	Therapy	Single-institution, retrospective study of subjects undergoing single fraction SRS in combination with immunotherapy or targeted therapy. Combination therapy was defined as delivery of SRS within 3 months of IMT (anti-CTLA-4 /anti-PD-1 therapy) or targeted therapy (BRAF/MEK inhibitors)	III	One-year distant intracranial control rates for SRS, SRS + IMT, and SRS + targeted therapy were 11.5%,60%, and 10%, respectively (P < .001). On multivariate analysis, after adjusting for steroid use and number of MBMs, SRS + IMT remained associated with a significant reduction in distant intracranial failure compared with SRS (HR 0.48 [95% CI 0.29-0.80]; P = .003) and compared with SRS + targeted therapy (HR 0.41 [95% CI 0.25-0.68]; P = .001). One-year local control for SRS, SRS + IMT, and SRS + targeted therapy was 66%, 85%, and 72%, respectively (P = .044). On multivariate analysis, after adjusting for dose, SRS + IMT remained associated with a significant reduction in local failure compared with SRS alone (HR 0.37 [95% CI 0.14-0.95]; P = .04). Authors’ conclusion: SRS with immunotherapy is associated with decreased distant and local intracranial failure compared with SRS alone. Conclusion: This retrospective study provides class III data.
3	Choong et al, 201778	Therapy	Single-institution, retrospective study of patients receiving SRS. Outcomes of individuals who received immunotherapy or targeted therapy within 6 weeks of the SRS were then compared		The median OS were as follows: anti-CTLA4 = 7.5 months, anti-PD1 = 20.4 months, and BRAF inhibitor/MEK inhibitor = 17.8 months. Median brain control was as follows: anti-CTLA4 = 7.5 months, anti-PD1 = 12.7 months and BRAF inhibitor/MEK inhibitor = 12.7 months. Authors’ conclusion: Though not significant, favorable outcomes are seen in patients treated with SRS and with the best survival seen in patients treated with anti-PD1 agents. Conclusion: The retrospective nature of this data provides class III data.
3	Gaudy-Marqueste et al, 201779	Therapy	Single-institution, retrospective study of subjects undergoing single fraction SRS and then compared by use of ipilimumab and BRAF ± MEK inhibitors and anti-PD1 agents, which were applied without prescribed protocol	III	Among 179 consecutive pts treated by GK, 109 received IT and/or TT after the first GK. Median OS was 10.95 months and 1- and 2-year survival rates were 49.5% and 27.4%, respectively, versus a median OS of 2.29 months (P < .001) in those who did not receive IT or TT. Multivariate analysis for OS confirmed that IT and TT were significantly and highly protective. Best OS was observed in BRAF-wild-type pts receiving anti-PD1 or in BRAF-mutated pts receiving BRAF-inhibitors and anti-PD1 (12.26 and 14.82 months, respectively). Authors’ conclusions: GammaKnife therapy together with immunotherapy and/or targeted therapy provides improved survival over GammaKnife therapy. Conclusions: Class III data based on its retrospective nature.
3	Patel et al, 2017	Therapy	A single-institution, retrospective review of 54 subjects with brain metastases from melanoma treated with SRS alone or in combination with ipilimumab administered within 4 months of the radiation	III	Compared with patients in the nonipilimumab group, the SRS plus ipilimumab group had 1 year local control (71.4% vs 92.3%, P = .40) and intracranial control (12.7% vs 29.1%, P = 0.59) were also statistically similar. The ipilimumab cohort also had no difference in 1-year OS (37.1% vs 38.5%, P = 0.84). Patients administered ipilimumab within 14 days of SRS had higher 1-year (42.9%) and 2-year OS (42.9%) relative to ipilimumab delivered >14 days (33.8%, 16.9%) and SRS alone (38.5%, 25.7%) but these differences were not statistically significant. Authors’ conclusion: The addition of ipilimumab to SRS was not associated with improved outcomes. Conclusion: The retrospective nature of this study provides class III data.
3	Yusuf et al, 201788	Therapy	Retrospective, single-institution collection of subjects with intact brain metastases treated with SRS. Subjects were considered to have received peri-SRS treatment of immune checkpoint therapy (ipilimumab or prembrolizumab) with SRS if the first or last dose of immune checkpoint therapy was within 4 weeks of the date SRS was performed	III	Fifty-one patients with 167 metastases were evaluated. Eighteen patients (59 lesions) were treated with peri-SRS ICT with ipilimumab or prembrolizumab. Peri-SRS ICT was a significant favorable predictor for reduced hazard of local failure (HR 0.131 [CI 0.028-0.610]). Concurrent ICT given with SRS (HR 0.364 [CI 0.161-0.825]) significantly predicted freedom from DBF. Freedom from DBF at 6 months and 12 months for the overall cohort was 34.5% and 15.6%, respectively. Median OS for patients receiving peri-SRS ICT was 7.4 months (range 0.9-26.4 months) compared with 7.1 months (range 1-51.8 months) for patients receiving SRS alone (P = .212). Authors’ conclusion: ICT combined with SRS was associated with greater lesion regression of melanoma brain metastases and decreased LF and improved freedom from DBF. Conclusion: This is class III data based on its retrospective nature.

 

BM = brain metastases; CI = confidence interval; CTLA-4 = cytotoxic T-lymphocyte antigen 4; DBF = distant brain failure, GK = GammaKnife; HR = hazard ratio; ICI = immune checkpoint inhibition; ICT = immune checkpoint therapy; IMT = immunotherapy; IPI = ipilimumab; IT = immunotherapy; LC = local control; MBM = melanoma brain metastases; OS = overall survival; MEK = mitogen activate protein kinase; MM = malignant metastatic melanoma; PD-1 = programmed cell death protein 1; RT = radiation therapy; SRS = stereotactic radiosurgery; SRT = stereotactic radiation therapy; TT = targeted therapy; WBRT = whole brain radiation therapy.

 

 

Table 8. Studies of Immune Modulators in Studies of Parenchymal Brain Metastases Combining Histologies

PICO Question	Author, Year	Type of Evidence	Study Type	Class of Evidence	Reviewer’s Conclusions
3	Du et al, 202196	Therapy	Retrospective TriNetX data base analysis of subjects with brain metastases from NSCLC, TNBC, melanoma, and RCC. After matching patient baseline characteristics, OS of cohorts with or without exposure to ICIs was evaluated. Exposure to ICIs was defined as treatment with ≥1 dose with inhibitors of PD-1 or its ligand PD-L1 (nivolumab, pembrolizumab, atezolizumab, velumab, and durvalumab) or the CTLA-4 inhibitor ipilimumab	III	For all types of cancer, median OS durations for the ICI and no-ICI cohorts were 14.0 and 7.9 months, respectively (HR 0.88 [95% CI 0.85-0.91]). More specifically, OS was remarkably prolonged in patients with NSCLC (14.4 vs 8.2 months; HR 0.86 [95% CI 0.82-0.90]), TNBC (23.9 vs 11.6 months; HR 0.87 [95% CI 0.82-0.92]), and melanoma (27.6 vs 16.8 months; HR 0.80 [95% CI 0.73-0.88]) if patients had exposure to ICIs. In contrast, there was no significant difference in OS of patients with RCC treated with and without ICIs (16.7 vs 14.0 months; HR 0.96 [95% CI 0.86-1.10]). Authors’ conclusions: Treatment with ICIs improves survival of patients with NSCLC, TNBC, and melanoma and BM; however, no significant improvement was observed in RCC. Conclusions: Class III data based upon its retrospective nature.
3	Minniti et al, 2021	Therapy	A retrospective analysis of 154 consecutive subjects with either NSCLC or melanoma brain metastases treated with surgical resection of ≥1  lesion followed by 3 fraction stereotactic radiation. Those that received either nivolumab or pembrolizumab (63 patients) were compared with those that did not (66 patients). Twenty-five individuals were excluded due to lack of follow-up, or because they had already had WBRT or immunotherapy of some sort	III	Local control was similar between the groups. Distant brain failure and OS were significantly different. The 1-year distant brain failure rates were 31% (95% CI 20- 46%) in the fractionated SRS and immunotherapy group and 52% (95% CI 39- 68%) in the fractionated SRS group. Also, the median OS was 24.8 months in the combination treatment group and 14.7 months in the nonimmunotherapy group (P = .007). Authors’ conclusion: Postoperative fractionated SRS in combination with immunotherapy decreases the incidence of distant brain failure in patients with resected brain metastases from NSCLC and melanoma as compared with fractionated SRS alone, reducing the rate of neurological death and prolonging survival. Conclusions: This retrospective study provides class III data.
3	Amin et al, 202097	Therapy	Retrospective study of cases from the National Cancer Database	III	In the multivariable analysis, patients who received immunotherapy had significantly improved OS compared with no immunotherapy (HR 0.62 [95% CI 0.51-0.76]; P < .001). Treatment with RT plus immunotherapy was associated with significantly improved OS compared with RT alone (HR 0.59 [95% CI 0.42-0.84]; P = .003).
3	Kowalski et al, 202098	Therapy	Multi-institution, retrospective study of brain metastases subjects treated with single or multiple fraction stereotactic radiation looking at the effect of ICI therapy as additional interventions. Concurrent ICI therapy was defined as administration ± 3 months of the radiation therapy. ICIs included: CTLA-4, (ipilimumab), PD-1 (pembrolizumab, nivolumab) and PD-L1 (durvalumab, atezolizumab). Histologies included were renal cell, melanoma, squamous cell and adenocarcinoma	III	Lesions treated with SRT-ICI had significantly improved 1-year local control compared with SRT alone (98 and 89.5%, respectively, P = .0078). On subset analysis of NSCLC patients alone, addition of ICI was also associated with improved 1-year local control (100% vs 90.1%, P = .018). On MVA, only tumor size ≤2 cm was significantly associated with local control (P = .02), as was concurrent ICI with SRS (P = .08). For combined SRS and ICI, 1-year distant brain failure (41% vs 53%, P = .21), OS (58% vs 56%, P = .79), and RN incidence (7% vs 4%, P = .25) were similar to SRT alone for the population as a whole and for the subset of those patients with NSCLC. Authors’ conclusions: These results suggest SRT-ICI may improve local control of brain metastases. Conclusions: This is retrospective data and is therefore class III.
3	Chen et al, 201899	Therapy	Single-institution, retrospective study of SRS-SRT patients with brain metastases from NSCLC, melanoma and renal cell carcinoma who were treated with CTLA-4 (ipilimumab) and anti-PD-1 receptor (nivolumab or pembrolizumab). Concurrent therapy: ICI therapy within 2 weeks before or after SRS-SRT. Nonconcurrent therapy: ICI therapy >2 weeks before or after SRS-SRT	III	The median OS for patients treated with SRS-SRT alone, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (P = .002; HR 2.69) and compared with nonconcurrent SRS-SRT and ICI (P = .006; HR 2.40) on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (P = .002; HR 3.82) or after ICI (P = .021; HR 2.64). Authors’ conclusion: Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes. Conclusions: This retrospective data provides class III data. The data is further weakened as results from different histologies are reported in a mixed fashion.

 

HR = hazard ratio; ICI = immune checkpoint inhibitor; NSCLC = non–small-cell lung carcinoma; OS = overall survival; RCC = renal cell carcinoma; SRS-SRT = stereotactic radiosurgery-stereotactic radiation therapy; TNBC = triple-negative breast cancer; WBRT = whole brain radiation therapy.

Table 9. Immune Modulators for the Therapy of Parenchymal Brain Metastases of Primaries Other than Non–Small-Cell Carcinoma or Melanoma
 

PICO Question	Author, Year	Type of Evidence	Study Type	Class of Evidence	Review/Conclusions
3	Uezono et al, 2021100	Therapy	Single-institution retrospective analysis of subjects with renal cell carcinoma brain metastases treated with SRS alone or with immunotherapy. Forty-eight patients with 372 RCC BM were treated with SRS and divided into those ever treated with immunotherapy versus those who never received immunotherapy. Immunotherapy included ipilimumab or nivolumab, combined ipilimumab and nivolumab, or cytokine agents (interleukin 2 and/or interferon alpha)	III	Immunotherapy and nonimmunotherapy groups contained 29 and 19 patients, respectively. Median follow-up was 23.1 months (range 6-93.8). Demographic and treatment variables were similar except median prescribed margin dose was significantly lower in immunotherapy group (20 vs 22 Gy, P < .0001). Median OS was 27.2 months (immunotherapy) and 14.9 months (nonimmunotherapy), P = 0.14. Furthermore, patients treated with ICI had even better median OS compared with those who never received ICI (33 vs 16.7 mo, P = .03). Factors associated with improved LC were use of ICI (P = .002) and lesion size <1000 mm3 (P = .046). There was no difference in incidence of radiation necrosis between the 2 groups (P = .67). Authors’ conclusions: Patients with RCC BM undergoing SRS can experience prolonged survival when treated with ICI. Conclusions: Retrospective data providing class III evidence.

 

BM = brain metastases; ICI = immune checkpoint inhibitor; OS = overall survival; RCC = renal cell carcinoma; SRS = stereotactic radiosurgery.

 

 

Immunotherapy for Leptomeningeal Metastases

 

Table 10. Immunotherapy for Leptomeningeal Metastases From a Mixed Cohort of Tumor Types

PICO Question	Author, Year	Type of Evidence	Study Type	Class of Evidence	Review/Conclusions
4	Minniti et al, 2021101	Therapy	Single-center retrospective analysis of 129 patients with NSCLC and melanoma treated with fSRS in combination with immunotherapy vs fSRS alone. The primary end point of the study was the rate of LM after treatments.	III	Sixty-three patients received postoperative SRS and immunotherapy, either nivolumab or pembrolizumab, and 66 patients received postoperative SRS alone to the resection cavity. With a median follow-up of 15 months, LM occurred in 19 patients: fSRS group, 14; fSRS and immunotherapy, 5. Authors conclusions: Postoperative fSRS in combination with immunotherapy decreases the incidence of LM in patients with resected BM from NSCLC and melanoma as compared with fSRS alone. Conclusions: This retrospective study provides class III data.

 

 fSRS = fractionated SRS; LM = leptomeningeal carcinoma; NSCLC = non–small-cell lung carcinoma; SRS = stereotactic radiosurgery.

Table 11. Immune Modulators for the Therapy of Melanoma Leptomeningeal Metastases

 

PICO Question	Author, Year	Type of Evidence	Study Type	Class of Evidence	Review/Conclusions
4	Tétu et al, 2020102	Therapy	Single-center retrospective analysis of 29 melanoma patients diagnosed with LM. Among the 27 patients treated with systemic therapy, 17 patients were treated with immunotherapy, 5 patients received targeted therapy, 1 was treated with chemotherapy, and 4 patients were treated with anti–PD-1 in combination with BRAF inhibitor.	III	The median OS of the 10 patients in which treatment sequence after leptomeningeal tumor diagnosis included BRAF inhibitors was 6.4 months, while median OS was 5.1 months for the 22 patients in which treatment sequence after leptomeningeal tumor diagnosis included immune checkpoint inhibitors. Immunotherapy was not associated with significantly improved OS (P = .37). Authors’ conclusions: Targeted therapy and immunotherapy are promising new treatment options in LM from melanoma that can increase OS and may induce long lasting remission in some patients. Conclusions: Although the authors provide data explicitly stating immunotherapy provides inferior efficacy, they conclude it is promising. This retrospective study provides class III data.

 

LM = leptomeningeal carcinoma; OS = overall survival; PD-1 = programmed cell death protein 1.

Table 12. Evidence Table for Interstitial Modalities

PICO	Author, Year	Literature Type	Study Type/Description	Class of Evidence	Review/Conclusions
5	Julie et al, 2020103	Therapy	Retrospective case-control series of patients with BM treated with Cs-131 or SRS after GTR	III	LR rate was significantly lower with brachytherapy; 10% for the Cs-131 cohort compared with 28.3% for SRS patients (OR 0.281 [95% CI 0.082-0.949]; P = .049). Rates of regional recurrence, DR, and OS did not differ significantly between the 2 cohorts. Kaplan-Meier analysis with log-rank testing showed a significantly higher likelihood of freedom from LR (P = .027) as well as DR (P = .018) after Cs-131 compared with SRS treatment (P = .027), but no difference in likelihood of OS (P = .093). Six (10.0%) patients who underwent SRS experienced RN compared with 1 (3.3%) patient who received Cs-131 (P = .417). Authors’ conclusions: Postresection patients with BM treated with Cs-131 brachytherapy were more likely to achieve local control compared with SRS-treated patients. Conclusions: This study provides class III evidence as it is retrospective in nature.

 

BM = brain metastases; CI = confidence interval; DR = distant recurrence; GTR = gross-total resection; LR = local recurrence; OR = odds ratio; SRS = stereotactic radiosurgery.

Table 13. Evidence for the Use of Radiosensitizers in Metastatic Brain Tumors

PICO	Author, Year	Literature Type	Study Type/Description	Class of Evidence	Review/Conclusions
6	Tian et al, 2022115	Therapy	Single-institution prospective study of 20 HER2-positive confirmed breast cancer pts with BM were randomly assigned into 2 groups in a 1:1 ratio, receiving either pyrotinib + capecitabine + WBRT or capecitabine + WBRT	III	A significant difference was observed in the ORR between the 2 groups (P < .0001). In addition, median PFS, TTP, and DoR were all significantly improved for patients in the pyrotinib + capecitabine + WBRT group compared with the capecitabine + WBRT group (all P < .0001). Authors’ conclusions: Pyrotinib might be an effective medication to enhance the tumor radiosensitivity of patients with HER2-positive breast cancer. Conclusion: A small prospective study provides class III data.
6	Morikawa et al, 2021112	Therapy	Phase I trial of WBRT + sorafenib in patients (24 pts) with breast cancer BM (10 pts) was conducted using a 3+3 design with safety-expansion cohort. Sorafenib was given daily at the start of WBRT for 21 days. NCT01724606 (November 12, 2012) and NCT01621906 (June 18, 2012)	III	The overall response rate was 71%. A decline in average SUVmax of≥25% was seen in 9/10 (90%) of WBRT + sorafenib patients and 2/4 (50%) of WBRT only patients (5 pts). Authors’ conclusions: Concurrent WBRT and sorafenib appear safe at 200 mg daily dose with clinical activity. CNS response was favorable compared with historical controls (WBRT). Conclusion: A small phase I clinical trial provides class III data.
6	Zhang et al, 2021109	Therapy	Prospective, observational, open-label study for MBT patients. A total of 106 patients with MBTs were enrolled in this study, and according to the sequence of admission, they were randomized into the TMZ + WBRT (53 patients) or WBRT (53 patients) alone group	III	Short-term remission after treatment was higher in the TMZ +WBRT group compared with WBRT group (P < .05). During the 24-month follow-up, they found that patients in the TMZ + WBRT group had longer recurrence time and survival time than their counterparts in the WBRT group (P < .05). After treatment, the QOL scores of patients in the TMZ + WBRT group were better than those in the WBRT group (P < .05). Also, there was a lower rate of the incidence of the adverse reactions in the TMZ + WBRT group (P < .05). Authors’ conclusions: TMZ + WBRT is a safe and reliable strategy in prolonging the survival time, increasing life quality while reducing the adverse reactions. Conclusions: This prospective study provides class III data based on the lack of methodology for randomization and dosing of TMZ.
6	Liu et al, 2020123	Therapy	Single-institution, retrospective analysis of 128 patients with BM metastases originating from NSCLC 64 received synchronous SRS with TMZ + WBRT (TMZ group), and 64 underwent SRS + WBRT (radiation therapy group)	III	OS and PFS of patients in the TMZ group were prolonged than those in the radiation therapy group (P = .041, P = .025). Univariate and multivariate regression analyses suggested that the absence of extracranial metastasis (P = .001), number of intracranial metastases <3 (P = .001), RPA class I (P = .001), and MMSE score ≥27 points before radiation therapy (P = .001), and treatment with TMZ were statistically significant factors affecting the prognosis. Authors’ conclusions: Synchronous SRT with TMZ combined with WBRT is effective in treating patients with brain metastases originating from NSCLC, which can effectively improve the OS of patients and has tolerable adverse reactions. Conclusions: This single-site retrospective study provides class III data.
6	Sun et al, 202029	Therapy	Single-institution, prospective study of 58 patients with NSCLC with BM was treated with concurrent WBRT + chemotherapy, or WBRT + targeted therapy	III	ORR of the WBRT + targeted therapy group was 68.97%, significantly higher than 41.38% of the WBRT + chemotherapy group (P < .05); the total incidence of adverse reactions in the WBRT + targeted therapy was 6.90%, significantly lower than 24.14% of the WBRT + chemotherapy group (P < .05); the median survival time of the WBRT + targeted therapy group was (16.81 ± 5.32) months, significantly longer than that of the WBRT + chemotherapy group (9.76 ± 3.25) months). The 1-and 2-year survival rates in the WBRT + targeted therapy group were significantly higher than those in the WBRT + chemotherapy group (P < .05). Authors’ conclusion: WBRT combined with targeted therapy is superior to concurrent WBRT and chemotherapy in the treatment of NSCLC with BM. Conclusions: This small single site retrospective study provides class III data.
6	Lee et al, 2020114	Therapy	Retrospective series reviewed consecutive cases of NSCLC BM among 264 patients (1069 BMs) who underwent GKRS and for whom EGFR mutation status, demographics, performance status, and tumor characteristics were available	III	Intracranial response rate in the EGFR mutant group was approximately 3-fold higher than that in the wild-type group (P < .001, 2-year follow-up). Cox regression multivariate analysis identified EGFR mutation status, extracranial metastasis, primary tumor control, and prescribed margin dose as predictors of tumor control (P = .004, P < .001, P = .004, and P = .026, respectively). Treatment with a combination of GKRS and TKIs was the most important predictor of OS (P < .001). Authors’ conclusion: Treatment with a combination of GKRS and tyrosine kinase inhibitors (TKIs) was the most important predictor of OS (P < .001). Conclusion: This retrospective study provides class III data.
6	Yomo et al, 201931	Therapy	Retrospective case series of patients divided into 2 groups based on the use of EGFR-TKI. The definition of EGFR-TKI use includes concurrent use at the time of the first GKS and/or post-SRS use for ≥3 weeks	III	200 patient pairs with/without post-SRS EGFR-TKI use. EGFR-TKI use was associated with longer OS (median 25.5 vs 11.0 months, HR 0.60 [95% CI 0.48-0.75], P < .001), although the long-term OS curves eventually crossed. Distant intracranial recurrence was more likely in patients receiving EGFR-TKI (HR 1.45 [95% CI 1.12-1.89], P = .005). Neurological death, local recurrence, and SRS-related adverse event rates did not differ significantly between the 2 groups. Authors’ conclusions: Although patients receiving EGFR-TKI concurrently or after SRS had significantly longer OS, the local treatment efficacy and toxicity of SRS did not differ between patients with/without EGFR-TKI use. Conclusions: Conclusion: This study provides class III evidence due to its retrospective nature.
6	Lv et al, 2018108	Therapy	Single-institution, prospective study of 77 patients with confirmed primary of NSCLC and BM treated with concurrent WBRT + TMZ (40 pts) compared with WBRT alone (37 pts)	III	The use of TMZ + WBRT exhibited an advantage over the using WBRT alone in terms of objective response and OS (P < .5). Authors’ conclusion: TMZ concomitantly with WBRT was well-tolerated and may be recommended for the treatment of BM from NSCLC. Conclusion: A small prospective study provides class II data.
6	Schmidberger et al, 2018116	Therapy	Retrospective case series examined 2 cohorts of patients with brain metastasis of melanoma treated with received IPI before (20 patients) or after radiation therapy (21 patients)	III	Patients who received IPI after irradiation had the best OS as compared not only with the historical controls (3.0 months, P = .000001) but also with the patients who had received IPI before irradiation (3.0 months, P = .015). The difference between the 2 previously mentioned groups (IPI before radiation therapy vs historical controls) was only marginally significant (P = .045). Regarding CPFS, patients who had received IPI after radiation therapy again had a significantly more favorable outcome than those who had been treated with IPI before radiation therapy (6.0 vs 2.0 months, P = .019). Authors’ conclusion: The sequence of RT and ICI with IPI may be crucial for the success of combined modality treatment of melanoma brain metastases. Conclusions: This small single-site retrospective study provides class III data. Importantly, because immunotherapy was not provided concurrent with the radiation, it cannot be used for a recommendation related to radiosensitization.
6	Zhang et al, 2018107	Therapy	Single-institution prospective analysis of 256 BM patients were enrolled and divided into 2 groups treated with either WBRT plus TMZ, or WBRT alone	II	WBRT plus concomitant TMZ to treat patients with BM can improve their intracranial ORR (P = .03) and median OS better than the use of WBRT alone (P = .001). The proportion of patients with deterioration in cognition, was significantly lower in WBRT plus- MZ group than in WBRT-alone group (6 months) (P < .05). Authors’ conclusions: WBRT plus concomitant TMZ can improve their ORR and OS better than the use of WBRT alone and toxicities are tolerable and manageable. Conclusions: This prospective study provides class II data.
6	Zhu et al, 2018106	Therapy	Single-institution retrospective analysis of 78 NSCLC patients with BM were observed, including 45 patients who received WBRT plus TMZ and 33 patients who received WBRT alone	III	Concomitant TMZ + WBRT compared with WBRT alone significantly increases ORR (P = .0108) and median PFS in patients with NSCLC BM (P = .038)., but no remarkable difference in median OS was found. Adding TMZ to the treatment strategy could prevent neurocognitive function and quality of life from deteriorating in the short term timepoint (5 months). Authors’ conclusions: No remarkable difference in median OS was found. Addition of TMZ to the WBRT could prevent neurocognitive function and quality of life from deteriorating. Conclusion: As a small retrospective study, this provides class III data.
6	Deng et al, 2017105	Therapy	Single-institution retrospective analysis of 238 NSCLC patients with BM were reviewed and categorized into WBRT plus TMZ arm and WBRT alone, respectively	III	Adding TMZ to WBRT in the treatment of NSCLC patients with BM could improve the intracranial ORR (P = .01), disease control rate (P = .03), and median PFS compared with WBRT alone (P = .002). Authors’ conclusions: Although no remarkable difference on median OS was found, adding TMZ could prevent NCF and QOL from worsening. The side effects increased by adding TMZ, but the difference was not statistical significance and toxicities were well tolerated. Conclusions: A retrospective study, this provides class III data.
6	Liu et al, 20179	Therapy	Single-institution prospective study of 72 patients with intracranial metastases were randomly divided into WBRT plus TMZ group and WBRT group (each n = 36)	II	TMZ concomitant with WBRT can increase the ORR(P = .0074), prolong the OS(P < .001) and improve the QOL(P < .001) compared with those treated with WBRT alone of patients with BM. Authors’ conclusions: Concomitant TMZ with WBRT can prolong ORR, OS, and PFS time and improve the QOL of patients with BM. Conclusions: A small prospective study of all BM provides class II data
6	El-Hamamsy et al, 2016111	Therapy	Prospective randomized, controlled, open-label pilot study was conducted on 50 patients with BM who were randomly assigned to WBRT (25 pts, control group) WBRT+ simvastatin (25 pts, simvastatin group)	II	Response rates were 60% and 78.6% (P = .427), 1-year PFS rates were 5.2% and 17.7% (P = .392), and 1-year OS rates were 12% and 8% (P = .880) for the control group and simvastatin group, respectively. Authors’ conclusions: The addition of simvastatin 80 mg/day did not improve the clinical outcomes of patients with BM receiving WBRT. Conclusions: This RCT provides class II data.
6	Gupta et al, 2016113	Therapy	Double-blind, multicenter, phase 2 trial patients with melanoma BM were randomized to receive WBRT plus 3 weeks of concurrent vandetanib (9 pts) or placebo (7 pts)	III	Median PFS brain was 3.3 months (90% CI 1.6-5.6) in patients randomized to WBRT plus vandetanib and 2.5 months (90% CI 0.2-4.8) in patients randomized to WBRT plus placebo. Median OS was 4.6 months (90% CI 1.6-6.3) in patients randomized to the vandetanib group and 2.5 months (90% CI 0.2-7.2) in the placebo group, with a HR of 0.85 (90% CI 0.37-1.96; P = .54). Authors’ conclusions: Compared with WBRT alone, there was no significant improvement in PFS brain or OS, although we were unable to provide a definitive result due to poor accrual; vandetanib + WBRT vs placebo + WBRT for melanoma BM; study closed early due to poor accrual. Conclusions: This small RCT provides class III data.
6	Zeng et al, 2016110	Therapy	Single-institution prospective randomized clinical trial of 64 patients with multiple brain metastases from NSCLC were included: the study group (n = 32) received WBRT + sodium glycididazole; the control group (n = 32) received WBRT only	II	The CNS disease control rate was better (90.6% vs 65.6%, P = .016) in the study group than in the control group. The median CNS PFS was longer in the study group than in the control group (P = .038). Authors’ conclusions: The study indicated that sodium glycididazole improved CNS disease control rate, extended the median CNS PFS and was well tolerated in patients suffering from NSCLC with multiple BMs. Conclusion: The study provides class II evidence.

 

BM = brain metastases; CI = confidence interval; CPFS = cerebral progression-free survival; CR = complete response; DLT = dose-limiting toxicity; DoR = duration of response; GKRS = Gamma Knife radiosurgery; ICI = immune checkpoint inhibitor; IPI = ipilimumab; MMSE = Mini Mental Status Examination; NCF = neurocognitive function; NSCLC = non–small-cell lung carcinoma; OR = objective response; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; QOL = quality of life, RCT = randomized controlled trial; RPA = recursive partitioning analysis, RT = radiation therapy; TKI = tyrosine kinase inhibitor; TMZ = temozolomide; TTP = time to progression; WBRT = whole brain radiation therapy.

Table 14. Evidence for Use to Laser Interstitial Thermal Therapy in the Management of Metastatic Brain Tumors

PICO	Author, Year	Literature Type	Study Type/Description	Class of Evidence	Reviewer’s Conclusions
7	Hong et al, 2019124	Therapy	Retrospective case series, single-institution chart review of patients treated with LITT or craniotomy for previously irradiated BM	III	There was no significant difference between LITT and craniotomy in ability to taper off steroids or neurological outcomes. PFS and OS were similar for LITT vs craniotomy, respectively: %PFS-survival at 1 year = 72.2% vs 61.1%, %PFS-survival at 2 years = 60.0% vs 61.1%, P = .72; %OS-survival at 1 year = 69.0% vs 69.3%, %OS-survival at 2 years = 56.6% vs 49.5%, P = .90. Craniotomy resulted in higher rates of preoperative deficit improvement than LITT (P < .01). On subgroup analysis, the single factor most significantly associated with OS and PFS was pathology of the lesion. Authors’ conclusions: LITT was as efficacious as craniotomy in achieving local control of recurrent irradiated brain metastases and facilitating steroid taper, regardless of pathology. Craniotomy appears to be more advantageous for providing symptom relief in those with preoperative symptoms. Conclusion: The retrospective nature of this study provides class III evidence.
7	Sankey et al, 2022125	Therapy	Retrospective case series, multicenter, study was performed of SRS-treated patients with BM who developed biopsy-proven RN and were treated with LITT or MM	III	MM (27%) and LITT patients (5%) demonstrated radiographic progression (P = .031) at a median of 5.3 and 4.0 months (P = .40). There was no significant difference in OS (LITT median of 15.2 vs 11.6 months, P = .60) or PFS (13.6 vs 7.06 months, P = .40). Patients stopped steroid therapy earlier in the LITT cohort at a median of 37 days compared with 245 days for medical management (P < .001). When controlled for follow-up duration, patients treated with LITT were 3 times more likely to be weaned off steroids before the study end point (P = .003). Authors’ conclusions: LITT for treatment of biopsy-proven RN after SRS for BM significantly decreases time to steroid independence. Conclusion: The retrospective nature of this study provides class III evidence

 

BM = brain metastases; LITT = laser interstitial thermal therapy; MM = medical management; OS = overall survival; PFS = progression-free survival; RN = radiation necrosis.

 

Appendix V. Conflicts of interest

 

Name	Affiliation	Type of COI
Kristin Huntoon, PhD, DO	None	None
J. Bradley Elder, MD2,	None	None
D. Ryan Ormond, MD, PhD	None	None
Navid Redjal, MD	None	None
Mark E. Linskey, MD	None	None
Jeffrey J. Olson, MD	Verastem, Inc.  American Cancer Society	Research Grant Editorial Consultant

 

 

REFERENCES

1. Institute of Medicine Committee on Standards for Developing Trustworthy Clinical Practice G. In: Graham R, Mancher M, Miller Wolman D, Greenfield S, Steinberg E, eds. Clinical Practice Guidelines We Can Trust. Washington (DC): National Academies Press (US) Copyright 2011 by the National Academy of Sciences. All rights reserved.; 2011.
2. Elder JB, Nahed BV, Linskey ME, Olson JJ. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Emerging and Investigational Therapties for the Treatment of Adults With Metastatic Brain Tumors. Neurosurgery. 2019;84(3):E201-e203.
3. Ransohoff DF, M. Pignone, and H.C. Sox, . How to decide whether a clinical practice guideline is trustworthy. . JAMA. 2013;309(2):139-140.
4. Huang Y-H, Hsu K-H, Chin C-S, et al. The Clinical Outcomes of Different First-Line EGFR-TKIs Plus Bevacizumab in Advanced EGFR-Mutant Lung Adenocarcinoma. Cancer research and treatment. 2022;54(2):434-444.
5. Wu Y-L, Ahn M-J, Garassino MC, et al. CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non-Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3). Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018;36(26):2702-2709.
6. Chiou G-Y, Chiang C-L, Yang H-C, et al. Combined stereotactic radiosurgery and tyrosine kinase inhibitor therapy versus tyrosine kinase inhibitor therapy alone for the treatment of non-small cell lung cancer patients with brain metastases. Journal of neurosurgery. 2021:1-8.
7. He Z-Y, Li M-F, Lin J-H, Lin D, Lin R-J. Comparing the efficacy of concurrent EGFR-TKI and whole-brain radiotherapy vs EGFR-TKI alone as a first-line therapy for advanced EGFR-mutated non-small-cell lung cancer with brain metastases: a retrospective cohort study. Cancer management and research. 2019;11:2129-2138.
8. He Y, Sun W, Wang Y, et al. Comparison of erlotinib and pemetrexed as second-/third-line treatment for lung adenocarcinoma patients with asymptomatic brain metastases. OncoTargets and therapy. 2016;9:2409-2414.
9. Liu Y, Deng L, Zhou X, et al. Concurrent brain radiotherapy and EGFR-TKI may improve intracranial metastases control in non-small cell lung cancer and have survival benefit in patients with low DS-GPA score. Oncotarget. 2017;8(67):111309-111317.
10. Huang Y-H, Hsu K-H, Tseng J-S, et al. The Difference in Clinical Outcomes Between Osimertinib and Afatinib for First-Line Treatment in Patients with Advanced and Recurrent EGFR-Mutant Non-Small Cell Lung Cancer in Taiwan. Targeted oncology. 2022.
11. Chiu T-H, Tung P-H, Huang C-H, et al. The different overall survival between single-agent EGFR-TKI treatment and with bevacizumab in non-small cell lung cancer patients with brain metastasis. Scientific reports. 2022;12(1):4398.
12. Fan Y, Xu Y, Gong L, et al. Effects of icotinib with and without radiation therapy on patients with EGFR mutant non-small cell lung cancer and brain metastases. Scientific reports. 2017;7:45193.
13. Wang C, Lu X, Zhou Z, et al. The Efficacy of Upfront Intracranial Radiation with TKI Compared to TKI Alone in the NSCLC Patients Harboring EGFR Mutation and Brain Metastases. Journal of Cancer. 2019;10(9):1985-1990.
14. Jiang T, Su C, Li X, et al. EGFR TKIs plus WBRT Demonstrated No Survival Benefit Other Than That of TKIs Alone in Patients with NSCLC and EGFR Mutation and Brain Metastases. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2016;11(10):1718-1728.
15. Yang J-J, Zhou C, Huang Y, et al. Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN): a multicentre, phase 3, open-label, parallel, randomised controlled trial. The Lancet Respiratory medicine. 2017;5(9):707-716.
16. Chen Y, Yang J, Li X, et al. First-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor alone or with whole-brain radiotherapy for brain metastases in patients with EGFR-mutated lung adenocarcinoma. Cancer science. 2016;107(12):1800-1805.
17. Magnuson WJ, Lester-Coll NH, Wu AJ, et al. Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naive Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;35(10):1070-1077.
18. Cheng W-C, Shen Y-C, Chien C-R, et al. The optimal therapy strategy for epidermal growth factor receptor-mutated non-small cell lung cancer patients with brain metastasis: A real-world study from Taiwan. Thoracic cancer. 2022.
19. Wang J, Liu Z, Pang Q, et al. Prognostic analysis of patients with non-small cell lung cancer harboring exon 19 or 21 mutation in the epidermal growth factor gene and brain metastases. BMC cancer. 2020;20(1):837.
20. Chen G, Chen X, Zhang Y, et al. A large, single-center, real-world study of clinicopathological characteristics and treatment in advanced ALK-positive non-small-cell lung cancer. Cancer medicine. 2017;6(5):953-961.
21. Yin Q, Li P, Wang P, et al. Alectinib Together with Intracranial Therapies Improved Survival Outcomes in Untreated ALK-Positive Patients with Non-Small-Cell Lung Cancer and Symptomatic and Synchronic Brain Metastases: A Retrospective Study. OncoTargets and therapy. 2021;14:5533-5542.
22. Gadgeel S, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Annals of oncology : official journal of the European Society for Medical Oncology. 2018;29(11):2214-2222.
23. Thomas NJ, Myall NJ, Sun F, et al. Brain Metastases in EGFR- and ALK-Positive NSCLC: Outcomes of Central Nervous System-Penetrant Tyrosine Kinase Inhibitors Alone Versus in Combination With Radiation. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2022;17(1):116-129.
24. Shaw AT, Bauer TM, de Marinis F, et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. The New England journal of medicine. 2020;383(21):2018-2029.
25. Yang RF, Yu B, Zhang RQ, et al. Bevacizumab and gefitinib enhanced whole-brain radiation therapy for brain metastases due to non-small-cell lung cancer. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2017;51(1):e6073.
26. Tian Y, Zhai X, Tian H, Jing W, Zhu H, Yu J. Bevacizumab in Combination with Pemetrexed and Platinum Significantly Improved the Clinical Outcome of Patients with Advanced Adenocarcinoma NSCLC and Brain Metastases. Cancer management and research. 2019;11:10083-10092.
27. Li X, Abbas M, Li Y, et al. Comparative Effectiveness of Pemetrexed-platinum Doublet Chemotherapy With or Without Bevacizumab as First-line Therapy for Treatment-naive Patients With Advanced Nonsquamous Non-small-cell Lung Cancer in China. Clinical therapeutics. 2019;41(3):518-529.
28. Li M, Sun X, Dong J, Qi Y, Zhao Y, Guan L. Effect of endostar combined with gefitinib on multiple brain metastases of non-small cell lung cancer after whole brain radiotherapy. International Journal of Clinical and Experimental Medicine. 2021;14(1):618-624.
29. Sun Y, Guo X, Zhang L, Zhang W, Zuo Y. Evaluation of radiotherapy combined with targeted therapy and concurrent radiotherapy, chemotherapy in the treatment of non-small cell lung cancer with brain metastasis. Pakistan Journal of Medical Sciences. 2020;36(3).
30. Cho A, Untersteiner H, Hirschmann D, et al. Gamma knife radiosurgery for brain metastases in non-small cell lung cancer patients treated with immunotherapy or targeted therapy. Cancers. 2020;12(12):1-16.
31. Yomo S, Serizawa T, Yamamoto M, et al. The impact of EGFR-TKI use on clinical outcomes of lung adenocarcinoma patients with brain metastases after Gamma Knife radiosurgery: a propensity score-matched analysis based on extended JLGK0901 dataset (JLGK0901-EGFR-TKI). Journal of neuro-oncology. 2019;145(1):151-157.
32. Chabot P, Hsia T-C, Ryu J-S, et al. Veliparib in combination with whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer: results of a randomized, global, placebo-controlled study. Journal of neuro-oncology. 2017;131(1):105-115.
33. He Z, Liu J, Ma Y, et al. Anlotinib Combined with Cranial Radiotherapy for Non-Small Cell Lung Cancer Patients with Brain Metastasis: A Retrospectively, Control Study. Cancer management and research. 2021;13:6101-6111.
34. Ren Y, Wang S-B, Zhou L, et al. Continuous Low-Dose Apatinib Combined With WBRT Significantly Reduces Peritumoral Edema and Enhances the Efficacy of Symptomatic Multiple Brain Metastases in NSCLC. Technology in cancer research & treatment. 2021;20:15330338211011968.
35. Mastorakos P, Xu Z, Yu J, et al. BRAF V600 Mutation and BRAF Kinase Inhibitors in Conjunction With Stereotactic Radiosurgery for Intracranial Melanoma Metastases: A Multicenter Retrospective Study. Neurosurgery. 2019;84(4):868-880.
36. Xu Z, Lee C-C, Ramesh A, et al. BRAF V600E mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases. Journal of neurosurgery. 2017;126(3):726-734.
37. Wolf A, Zia S, Verma R, et al. Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases. Journal of neuro-oncology. 2016;127(3):607-615.
38. Forschner A, Eichner F, Amaral T, Keim U, Garbe C, Eigentler TK. Improvement of overall survival in stage IV melanoma patients during 2011-2014: analysis of real-world data in 441 patients of the German Central Malignant Melanoma Registry (CMMR). Journal of cancer research and clinical oncology. 2017;143(3):533-540.
39. Acharya S, Mahmood M, Mullen D, et al. Distant intracranial failure in melanoma brain metastases treated with stereotactic radiosurgery in the era of immunotherapy and targeted agents. Advances in radiation oncology. 2017;2(4):572-580.
40. Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. The Lancet Oncology. 2017;18(7):863-873.
41. Bergen ES, Binter A, Starzer AM, et al. Favourable outcome of patients with breast cancer brain metastases treated with dual HER2 blockade of trastuzumab and pertuzumab. Therapeutic advances in medical oncology. 2021;13:17588359211009002.
42. Zhang Q, Chen J, Yu X, et al. Survival benefit of anti-HER2 therapy after whole-brain radiotherapy in HER2-positive breast cancer patients with brain metastasis. Breast cancer (Tokyo, Japan). 2016;23(5):732-739.
43. Kim JM, Miller JA, Kotecha R, et al. Stereotactic radiosurgery with concurrent HER2-directed therapy is associated with improved objective response for breast cancer brain metastasis. Neuro-oncology. 2019;21(5):659-668.
44. Parsai S, Miller JA, Juloori A, et al. Stereotactic radiosurgery with concurrent lapatinib is associated with improved local control for HER2-positive breast cancer brain metastases. Journal of neurosurgery. 2019;132(2):503-511.
45. Zou Z, Xing P, Hao X, et al. Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases-a multicenter retrospective study. BMC medicine. 2022;20(1):12.
46. Yi Y, Cai J, Xu P, et al. Potential benefit of osismertinib plus bevacizumab in leptomeningeal metastasis with EGFR mutant non-small-cell lung cancer. Journal of translational medicine. 2022;20(1):122.
47. Li N, Bian Z, Cong M, Liu Y. Survival Outcomes of Patients With Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer With Leptomeningeal Metastasis. Frontiers in Oncology. 2022;11.
48. Zhang M, Ma W, Liu H, et al. Osimertinib Improves Overall Survival in Patients with Leptomeningeal Metastases Associated with EGFR-Mutated Non-Small-Cell Lung Cancer Regardless of Cerebrospinal Fluid T790M Mutational Status. Evidence-based complementary and alternative medicine : eCAM. 2021;2021:6968194.
49. Miyawaki T, Kenmotsu H, Yabe M, et al. Rechallenge with previously administered epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR-mutated non-small cell lung cancer with leptomeningeal metastasis. Investigational new drugs. 2021;39(6):1732-1741.
50. Lee J, Choi YL, Han J, et al. Osimertinib Improves Overall Survival in Patients With EGFR-Mutated NSCLC With Leptomeningeal Metastases Regardless of T790M Mutational Status. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2020;15(11):1758-1766.
51. Ahn M-J, Chiu C-H, Cheng Y, et al. Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2020;15(4):637-648.
52. Kwon BS, Cho YH, Yoon S-K, et al. Impact of clinicopathologic features on leptomeningeal metastasis from lung adenocarcinoma and treatment efficacy with epidermal growth factor receptor tyrosine kinase inhibitor. Thoracic cancer. 2020;11(2):436-442.
53. Nosaki K, Yamanaka T, Hamada A, et al. Erlotinib for Non-Small Cell Lung Cancer with Leptomeningeal Metastases: A Phase II Study (LOGIK1101). The oncologist. 2020;25(12):e1869-e1878.
54. Flippot R, Biondani P, Auclin E, et al. Activity of EGFR Tyrosine Kinase Inhibitors in NSCLC With Refractory Leptomeningeal Metastases. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2019;14(8):1400-1407.
55. Wu Y-L, Zhao Q, Deng L, et al. Leptomeningeal metastasis after effective first-generation EGFR TKI treatment of advanced non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands). 2019;127:1-5.
56. Yan W, Jing W, An N, et al. The clinical characteristic and prognostic factors of leptomeningeal metastasis in patients with non-small-cell lung cancer-a retrospective study from one single cancer institute. Cancer medicine. 2019;8(6):2769-2776.
57. Choi M, Keam B, Ock C-Y, et al. Pemetrexed in the Treatment of Leptomeningeal Metastasis in Patients With EGFR-mutant Lung Cancer. Clinical lung cancer. 2019;20(4):e442-e451.
58. Li Y-S, Jiang B-Y, Yang J-J, et al. Leptomeningeal Metastases in Patients with NSCLC with EGFR Mutations. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2016;11(11):1962-1969.
59. Xu Q, Chen X, Qian D, et al. Treatment and prognostic analysis of patients with leptomeningeal metastases from non-small cell lung cancer. Thoracic cancer. 2015;6(4):407-412.
60. Figura NB, Rizk VT, Mohammadi H, et al. Clinical outcomes of breast leptomeningeal disease treated with intrathecal trastuzumab, intrathecal chemotherapy, or whole brain radiation therapy. Breast cancer research and treatment. 2019;175(3):781-788.
61. Kumthekar PU, Avram MJ, Lassman AB, et al. A phase I/II study of intrathecal trastuzumab in human epidermal growth factor receptor 2-positive (HER2-positive) cancer with leptomeningeal metastases: Safety, efficacy, and cerebrospinal fluid pharmacokinetics. Neuro Oncol. 2023;25(3):557-565.
62. Abdulhaleem M, Johnston H, D'Agostino R, Jr., et al. Local control outcomes for combination of stereotactic radiosurgery and immunotherapy for non-small cell lung cancer brain metastases. Journal of neuro-oncology. 2022;157(1):101-107.
63. Lau SCM, Poletes C, Le LW, et al. Durability of CNS disease control in NSCLC patients with brain metastases treated with immune checkpoint inhibitors plus cranial radiotherapy. Lung cancer (Amsterdam, Netherlands). 2021;156:76-81.
64. Lauko A, Kotecha R, Barnett A, et al. Impact of KRAS mutation status on the efficacy of immunotherapy in lung cancer brain metastases. Scientific reports. 2021;11(1):18174.
65. Scoccianti S, Olmetto E, Pinzi V, et al. Immunotherapy in association with stereotactic radiotherapy for non-small cell lung cancer brain metastases: results from a multicentric retrospective study on behalf of AIRO. Neuro-oncology. 2021;23(10):1750-1764.
66. Singh SA, McDermott DM, Mattes MD. Impact of Systemic Therapy Type and Timing on Intracranial Tumor Control in Patients with Brain Metastasis from Non-Small-Cell Lung Cancer Treated With Stereotactic Radiosurgery. World neurosurgery. 2020;144:e813-e823.
67. Enright TL, Witt JS, Burr AR, Yadav P, Leal T, Baschnagel AM. Combined Immunotherapy and Stereotactic Radiotherapy Improves Neurologic Outcomes in Patients with Non-small-cell Lung Cancer Brain Metastases. Clinical lung cancer. 2021;22(2):110-119.
68. Liao G, Qian Y, Arooj S, et al. Radiation Plus Anti-PD-1 Therapy for NSCLC Brain Metastases: A Retrospective Study. Frontiers in oncology. 2021;11:742971.
69. Wasilewski D, Radke J, Xu R, et al. Effectiveness of Immune Checkpoint Inhibition vs Chemotherapy in Combination With Radiation Therapy Among Patients With Non-Small Cell Lung Cancer and Brain Metastasis Undergoing Neurosurgical Resection. JAMA network open. 2022;5(4):e229553.
70. Shepard MJ, Xu Z, Donahue J, et al. Stereotactic radiosurgery with and without checkpoint inhibition for patients with metastatic non-small cell lung cancer to the brain: a matched cohort study. Journal of neurosurgery. 2019:1-8.
71. Mansfield AS, Herbst RS, de Castro G, Jr., et al. Outcomes With Pembrolizumab Monotherapy in Patients With Programmed Death-Ligand 1-Positive NSCLC With Brain Metastases: Pooled Analysis of KEYNOTE-001, 010, 024, and 042. JTO clinical and research reports. 2021;2(8):100205.
72. Powell SF, Rodriguez-Abreu D, Langer CJ, et al. Outcomes With Pembrolizumab Plus Platinum-Based Chemotherapy for Patients With NSCLC and Stable Brain Metastases: Pooled Analysis of KEYNOTE-021, -189, and -407. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2021;16(11):1883-1892.
73. Takamori S, Komiya T, Powell E. Survival benefit from immunocheckpoint inhibitors in stage IV non-small cell lung cancer patients with brain metastases: A National Cancer Database propensity-matched analysis. Cancer medicine. 2021;10(3):923-932.
74. Pedersen S, Moller S, Donia M, Persson GF, Svane IM, Ellebaek E. Real-world data on melanoma brain metastases and survival outcome. Melanoma research. 2022;32(3):173-182.
75. Amaral T, Kiecker F, Schaefer S, et al. Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients. Journal for immunotherapy of cancer. 2020;8(1).
76. Stera S, Balermpas P, Blanck O, et al. Stereotactic radiosurgery combined with immune checkpoint inhibitors or kinase inhibitors for patients with multiple brain metastases of malignant melanoma. Melanoma Research. 2019;29(2):187-195.
77. Vosoughi E, Lee JM, Miller JR, et al. Survival and clinical outcomes of patients with melanoma brain metastasis in the era of checkpoint inhibitors and targeted therapies. BMC cancer. 2018;18(1):490.
78. Choong ES, Lo S, Drummond M, et al. Survival of patients with melanoma brain metastasis treated with stereotactic radiosurgery and active systemic drug therapies. European journal of cancer (Oxford, England : 1990). 2017;75:169-178.
79. Gaudy-Marqueste C, Dussouil AS, Carron R, et al. Survival of melanoma patients treated with targeted therapy and immunotherapy after systematic upfront control of brain metastases by radiosurgery. European journal of cancer (Oxford, England : 1990). 2017;84:44-54.
80. Borzillo V, Di Franco R, Giannarelli D, et al. Ipilimumab and Stereotactic Radiosurgery with CyberKnife R System in Melanoma Brain Metastases: A Retrospective Monoinstitutional Experience. Cancers. 2021;13(8).
81. Gatterbauer B, Hirschmann D, Eberherr N, et al. Toxicity and efficacy of Gamma Knife radiosurgery for brain metastases in melanoma patients treated with immunotherapy or targeted therapy-A retrospective cohort study. Cancer medicine. 2020;9(11):4026-4036.
82. Moyers JT, Chong EG, Peng J, et al. Real world outcomes of combination and timing of immunotherapy with radiotherapy for melanoma with brain metastases. Cancer medicine. 2021;10(4):1201-1211.
83. Diao K, Bian SX, Routman DM, et al. Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity. Journal of neuro-oncology. 2018;139(2):421-429.
84. Gabani P, Fischer-Valuck BW, Johanns TM, et al. Stereotactic radiosurgery and immunotherapy in melanoma brain metastases: Patterns of care and treatment outcomes. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2018;128(2):266-273.
85. Schmidberger H, Rapp M, Ebersberger A, et al. Long-term survival of patients after ipilimumab and hypofractionated brain radiotherapy for brain metastases of malignant melanoma: sequence matters. Langfristiges Uberleben nach Ipilimumab und hypofraktionierter Ganzhirnbestrahlung bei Hirnmetastasen maligner Melanome: die Reihenfolge ist relevant. 2018;194(12):1144-1151.
86. Trommer-Nestler M, Marnitz S, Kocher M, et al. Robotic Stereotactic Radiosurgery in Melanoma Patients with Brain Metastases under Simultaneous Anti-PD-1 Treatment. International journal of molecular sciences. 2018;19(9).
87. Patel KR, Shoukat S, Oliver DE, et al. Ipilimumab and Stereotactic Radiosurgery Versus Stereotactic Radiosurgery Alone for Newly Diagnosed Melanoma Brain Metastases. American journal of clinical oncology. 2017;40(5):444-450.
88. Yusuf MB, Amsbaugh MJ, Burton E, Chesney J, Woo S. Peri-SRS Administration of Immune Checkpoint Therapy for Melanoma Metastatic to the Brain: Investigating Efficacy and the Effects of Relative Treatment Timing on Lesion Response. World neurosurgery. 2017;100:632-640.e634.
89. Yusuf M, Rattani A, Gaskins J, et al. Stereotactic radiosurgery for melanoma brain metastases: dose-size response relationship in the era of immunotherapy. Journal of neuro-oncology. 2022;156(1):163-172.
90. Le Rhun E, Wolpert F, Fialek M, et al. Response assessment and outcome of combining immunotherapy and radiosurgery for brain metastasis from malignant melanoma. ESMO open. 2020;5(4).
91. White RJ, Abel S, Horne ZD, et al. Melanoma brain metastases: is it time to eliminate radiotherapy? Journal of neuro-oncology. 2020;149(1):27-33.
92. Di Giacomo AM, Chiarion-Sileni V, Del Vecchio M, et al. Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;27(17):4737-4745.
93. Hilbers M-L, Dimitriou F, Lau P, et al. Real-life data for first-line combination immune-checkpoint inhibition and targeted therapy in patients with melanoma brain metastases. European journal of cancer (Oxford, England : 1990). 2021;156:149-163.
94. Wilson TG, Winter H, Taylor H, Herbert C. Treating brain metastases in melanoma: What is the optimal CNS-directed and systemic management? Journal of radiosurgery and SBRT. 2021;7(4):279-285.
95. Long GV, Atkinson V, Lo S, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. The Lancet Oncology. 2018;19(5):672-681.
96. Du W, Sirbu C, Lucas BD, Jr., Jubelirer SJ, Khalid A, Mei L. A Retrospective Study of Brain Metastases From Solid Malignancies: The Effect of Immune Checkpoint Inhibitors. Frontiers in oncology. 2021;11:667847.
97. Amin S, Baine MJ, Meza JL, Lin C. Association of Immunotherapy With Survival Among Patients With Brain Metastases Whose Cancer Was Managed With Definitive Surgery of the Primary Tumor. JAMA network open. 2020;3(9):e2015444.
98. Kowalski ES, Remick JS, Sun K, et al. Immune checkpoint inhibition in patients treated with stereotactic radiation for brain metastases. Radiation oncology (London, England). 2020;15(1):245.
99. Chen L, Douglass J, Kleinberg L, et al. Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma. International journal of radiation oncology, biology, physics. 2018;100(4):916-925.
100. Uezono H, Nam D, Kluger HM, et al. Outcomes of Stereotactic Radiosurgery and Immunotherapy in Renal Cell Carcinoma Patients with Brain Metastases. American Journal of Clinical Oncology: Cancer Clinical Trials. 2021;44(9):495-501.
101. Minniti G, Lanzetta G, Capone L, et al. Leptomeningeal disease and brain control after postoperative stereotactic radiosurgery with or without immunotherapy for resected brain metastases. Journal for ImmunoTherapy of Cancer. 2021;9(12).
102. Tetu P, Sirven-Villaros L, Cuzzubbo S, et al. Impact of New Systemic Treatment and Radiotherapy in Melanoma Patients with Leptomeningeal Metastases. Cancers. 2020;12(9).
103. Julie DA, Lazow SP, Vanderbilt DB, et al. A matched-pair analysis of clinical outcomes after intracavitary cesium-131 brachytherapy versus stereotactic radiosurgery for resected brain metastases. Journal of neurosurgery. 2020;134(5):1447-1454.
104. Liu H-P, Zheng K-B, Wang J-W. Efficacy and safety of temozolomide plus whole-brain radiotherapy in the treatment of intracranial metastases. Journal of cancer research and therapeutics. 2017;13(5):785-789.
105. Deng X, Zheng Z, Lin B, et al. The efficacy and roles of combining temozolomide with whole brain radiotherapy in protection neurocognitive function and improvement quality of life of non-small-cell lung cancer patients with brain metastases. BMC cancer. 2017;17(1):42.
106. Zhu Y, Fu L, Jing W, Guo D, Kong L, Yu J. Effectiveness of temozolomide combined with whole brain radiotherapy for non-small cell lung cancer brain metastases. Thoracic cancer. 2018;9(9):1121-1128.
107. Zhan Y, Jiang X. Concomitant treatment of brain metastases with whole brain radiotherapy and temozolomide protects neurocognitive function and improve quality of life. Tropical Journal of Pharmaceutical Research. 2018;17(6):1209-1213.
108. Lv Y, Zhang J, Liu Z, Liang N, Tian Y. Quality of life and efficacy of temozolomide combined with whole-brain radiotherapy in patients with brain metastases from non-small-cell lung cancer. Molecular and Clinical Oncology. 2018;9(1):70-74.
109. Zhang J, Zhang D, Li Y, Zhang C, Yuan S, Zhu B. Observation of the clinical outcomes in Temozolomide and radiotherapy Combination against the metastatic brain tumors. International Journal of Radiation Research. 2021;19(3):737-741.
110. Zeng YC, Wu R, Xing R, et al. Radiation-enhancing effect of sodium glycididazole in patients suffering from non-small cell lung cancer with multiple brain metastases: A randomized, placebo-controlled study. Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique. 2016;20(3):187-192.
111. El-Hamamsy M, Elwakil H, Saad AS, Shawki MA. A Randomized Controlled Open-Label Pilot Study of Simvastatin Addition to Whole-Brain Radiation Therapy in Patients With Brain Metastases. Oncology research. 2016;24(6):521-528.
112. Morikawa A, Grkovski M, Patil S, et al. A phase I trial of sorafenib with whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases and a correlative study of FLT-PET brain imaging. Breast cancer research and treatment. 2021;188(2):415-425.
113. Gupta A, Roberts C, Tysoe F, et al. RADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases - results and lessons learnt. British journal of cancer. 2016;115(10):1193-1200.
114. Lee C-C, Hsu SPC, Lin C-J, et al. Epidermal growth factor receptor mutations: association with favorable local tumor control following Gamma Knife radiosurgery in patients with non-small cell lung cancer and brain metastases. Journal of neurosurgery. 2019:1-8.
115. Tian W, Hao S, Wang L, Chen Y, Li Z, Luo D. Pyrotinib treatment enhances the radiosensitivity in HER2-positive brain metastatic breast cancer patients. Anti-cancer drugs. 2022;33(1):e622-e627.
116. Schmidberger H, Rapp M, Ebersberger A, et al. Long-term survival of patients after ipilimumab and hypofractionated brain radiotherapy for brain metastases of malignant melanoma: sequence matters. Strahlentherapie und Onkologie. 2018;194(12):1144-1151.
117. Hong CS, Deng D, Vera A, Chiang VL. Laser-interstitial thermal therapy compared to craniotomy for treatment of radiation necrosis or recurrent tumor in brain metastases failing radiosurgery. Journal of neuro-oncology. 2019;142:309-317.
118. Sankey EW, Grabowski MM, Srinivasan ES, et al. Time to steroid independence after laser interstitial thermal therapy vs medical management for treatment of biopsy-proven radiation necrosis secondary to stereotactic radiosurgery for brain metastasis. Neurosurgery. 2022;90(6):684-690.
119. Chehade R, Nofech-Mozes S, Plotkin A, et al. Human Epidermal Growth Factor Receptor 2–Low Breast Cancer Brain Metastases: An Opportunity for Targeted Systemic Therapies in a High-Need Patient Population. JCO Precision Oncology. 2024(8):e2300487.
120. Nadal E, Rodríguez-Abreu D, Simó M, et al. Phase II Trial of Atezolizumab Combined With Carboplatin and Pemetrexed for Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer With Untreated Brain Metastases (Atezo-Brain, GECP17/05). Journal of Clinical Oncology. 2023;41(28):4478-4485.
121. Gong X, Zhou D, Liang S, Zhou C. Analyses of prognostic factors in cases of non-small cell lung cancer with multiple brain metastases. OncoTargets and Therapy. 2016;9:977-983.
122. Zhang C, Wang L, Wang L, Cui S. A Retrospective Study on the Efficacy of Trastuzumab in HER2-Positive and Tamoxifen-Refractory Breast Cancer with Brain Metastasis. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2016;30(1):33-40.
123. Liu P, Ren R, You D, Liu J. Efficacy of synchronous stereotactic radiotherapy with temozolomide combined with whole brain radiotherapy in treating brain metastases originating from non-small cell lung cancer. Journal of BUON : official journal of the Balkan Union of Oncology. 2020;25(4):1771-1778.
124. Hong CS, Deng D, Vera A, Chiang VL. Laser-interstitial thermal therapy compared to craniotomy for treatment of radiation necrosis or recurrent tumor in brain metastases failing radiosurgery. Journal of neuro-oncology. 2019;142(2):309-317.
125. Sankey EW, Grabowski MM, Srinivasan ES, et al. Time to Steroid Independence After Laser Interstitial Thermal Therapy vs Medical Management for Treatment of Biopsy-Proven Radiation Necrosis Secondary to Stereotactic Radiosurgery for Brain Metastasis. Neurosurgery. 2022.
126. Gorka E, Fabo D, Gezsi A, Czirbesz K, Fedorcsak I, Liszkay G. Dabrafenib Therapy in 30 Patients with Melanoma Metastatic to the Brain: a Single-centre Controlled Retrospective Study in Hungary. Pathology oncology research : POR. 2018;24(2):401-406.