Brain metastases in solid tumours: new guidelines for a new era

Abstract

Brain metastases (BM) in solid tumours are a common finding, particularly in melanoma, lung cancer, and breast cancer, traditionally heralding poor prognosis. Importantly, BMs are heterogeneous: presenting synchronous with diagnosis or over a lifetime, being symptomatic or asymptomatic, and ranging from solitary or small but miliary, to large volume with significant vasogenic oedema. Whatever the presentation, diagnosis is usually devastating as therapeutic options have historically been limited and survival poor. Indeed, the original recursive partitioning analysis (RPA) score personalizing prognosis on the basis of age, performance status, and systemic tumour burden, identified little difference between tumour types in an era when imaging was carried out when symptomatic, whole-brain radiotherapy (WBRT) was the typical treatment used and drug options were chemotherapy-based. In recent years, however, the prevalence of BM has been rising, in part driven by more frequent brain staging, but importantly driven hand in hand with increased patient survival through advances in tumour biology, drug therapies, and surgical and radiation technologies. In some diseases, such as anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), where the risk of baseline and lifetime BM is high, optimal brain management and intracranial control has been key to extending median survival, now measured in excess of 5 years.1Mok T. Camidge D.R. Gadgeel S.M. et al.Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study.Ann Oncol. 2020; 31: 1056-1064Abstract Full Text Full Text PDF PubMed Scopus (176) Google ScholarIt is against this backdrop that in this issue of the Annals of Oncology, Le Run et al.2Le Rhun E. Guckenberger M. Smits M. et al.EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours.Ann Oncol. 2021; 32: 1332-1347Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar report the joint European Association of Neuro-Oncology and European Society for Medical Oncology (EANO-ESMO) Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. These guidelines lay out the foundation of good practice, describing optimal diagnostics, pathology, and treatments including surgery, radiation, and pharmacotherapy. Importantly, recommendations are given on an integrated therapeutic approach recommending an individualized treatment plan, ideally discussed at a dedicated BM board, an objective that every oncologist treating solid tumours should align to. Finally, supportive care and surveillance recommendations are given, noting the importance of 2-3 monthly magnetic resonance imaging (MRI) monitoring. Indeed, with the improved outcomes of patients with BM, the guidelines recommend consideration of brain screening in all but stage I NSCLC, in stage IV melanoma, in metastatic human epidermal growth factor receptor 2 (HER2)-positive and in triple-negative breast cancers.Much has changed since the last EANO BM guidelines were published in 2017.3Soffietti R. Abacioglu U. Baumert B. et al.Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO).Neuro Oncol. 2017; 19: 162-174Crossref PubMed Scopus (254) Google Scholar We are now in an unprecedented new era of genomic medicine and immune checkpoint inhibitor (CPI) therapy. Advanced radiation techniques have developed allowing delivery of stereotactic radiosurgery (SRS) in a more refined and safer manner, with a greater consideration on patient quality of life given the expectation that many may still live a considerable time after radiotherapy, if not years. Nevertheless, many of the recommendations are based on expert opinion and low-level evidence, highlighting our difficult, heterogeneous, and modest evidence base. Historically, patients with BM have been excluded from trials, especially unlicensed drug trials, due to an inherent poorer prognosis and bias against risks of delayed commercialization. Whilst exclusion may be justified to isolate the potential effect of an investigational drug, this may well limit the generalizability of results to a broader population ultimately using the drug in real life. Fortunately, much has now changed for the better. The American Society of Clinical Oncology (ASCO)-Friends of Cancer Research Brain Metastases Working Group have proposed three key populations of BM patients for trials.4Lin N.U. Prowell T. Tan A.R. et al.Modernizing clinical trial eligibility criteria: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research Brain Metastases Working Group.J Clin Oncol. 2017; 35: 3760-3773Crossref PubMed Scopus (69) Google Scholar But if we are going to include such patients in trials, how should trials be designed, what endpoints should be considered, and by what criteria should brain efficacy be measured? Here, the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) group have made recommendations for both systemic5Camidge D.R. Lee E.Q. Lin N.U. et al.Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group.Lancet Oncol. 2018; 19: e20-e32Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar and local6Alexander B.M. Brown P.D. Ahluwalia M.S. et al.Clinical trial design for local therapies for brain metastases: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group.Lancet Oncol. 2018; 19: e33-e42Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar therapy trials, separating intracranial and extracranial compartments to allow a better determination of drug efficacy alongside risks of intracranial versus extracranial progression, adding clarity on competing risks and censoring needs to interpret this data.6Alexander B.M. Brown P.D. Ahluwalia M.S. et al.Clinical trial design for local therapies for brain metastases: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group.Lancet Oncol. 2018; 19: e33-e42Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar In addition, unique response assessment criteria for BM have been proposed.7Lin N.U. Lee E.Q. Aoyama H. et al.Response assessment criteria for brain metastases: proposal from the RANO group.Lancet Oncol. 2015; 16: e270-e278Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar Whilst the EANO-ESMO guidelines highlight the utility of these RANO-BM response criteria, RANO-BM defines measurable disease as ≥10 mm, however, and modern brain imaging now readily reveals much smaller metastases. Moreover, RANO-BM does not include any volumetric response assessment criteria, but changes in metastases volume with treatment are probably the best means of objectively determining response. BM are volumetrically delineated as part of the SRS planning process; though this is labour-intensive, emerging machine learning techniques have the potential to overcome this bottleneck and unlock the potential of longitudinal volumetric response assessment for BM.8Zhou M. Scott J. Chaudhury B. et al.Radiomics in brain tumor: image assessment, quantitative feature descriptors, and machine-learning approaches.AJNR Am J Neuroradiol. 2018; 39: 208-216Crossref PubMed Scopus (194) Google ScholarAdditionally, we urgently need trial data on brain-specific and systemic outcomes of patients with BM receiving newer treatments. For therapies with a strong intracranial effect (e.g. ALK inhibitors), trials in ALK-positive NSCLC have provided invaluable data. For drugs where the intracranial effect may be more modest, however, such data is lacking. For example, whilst CPIs have been standard for multiple cancer types for over 6 years, the precise intracranial efficacy of CPIs in patients within the three ASCO-Friends classes of BM remains poorly defined, as registrational trials largely mandated patients with BM only if previously treated and dedicated intracranial trial assessments were not mandated. Nevertheless, despite limited data, these EANO-ESMO guidelines have given a clear steer that pharmacotherapy should be considered for most patients with BM, and upfront systemic therapy for specific disease subtypes such as oncogene-addicted NSCLC. The guidelines have also given clear steer on indications for SRS, and importantly where WBRT may be futile.We believe that the guidelines could have gone further, however, to optimize BM treatments. The guideline authors have chosen to use the number of central nervous system (CNS) metastases as a criterion for SRS selection. Whilst this is a readily determined metric, it is likely not optimal for SRS patient selection and cost-effectiveness bodies have not used it.9NHS England Clinical Commissioning Policy: Stereotactic Radiosurgery/Radiotherapy for Cerebral Metastases, NHS Commissioning Board.https://www.england.nhs.uk/wp-content/uploads/2020/08/D05-P-d-comm-policy-srs-cerebral-metastases.pdfDate: 2013Google Scholar Dedicated SRS delivery platforms can safely deliver treatment to multiple CNS metastases. The JLGK0901 study showed that having only a single metastasis conferred a survival advantage relative to having >1 metastasis, but patients with 2–4 metastases and ≥5 metastases had equivalent survival. Cumulative tumour volume has been shown in multiple studies to be associated with survival after SRS for BM, and should ideally be used in selecting patients for SRS, though the suggested maximum cumulative volume of 15 ml is too conservative, especially when fractionated SRS is used.10Niranjan A. Monaco E. Flickinger J. Lunsford L.D. Guidelines for multiple brain metastases radiosurgery.Prog Neurol Surg. 2019; 34: 100-109Crossref PubMed Scopus (22) Google Scholar The importance of BM volume to outcomes following SRS reinforces the need to move to volumetric response assessment.Additionally, several additional questions still remain for SRS; principally around consistency in clinical decision-making, better defining risks of radionecrosis, its identification and treatment, interactions with CPIs, and timing. With highly penetrant intracranial systemic therapies, in patients with BM at baseline is systemic therapy alone adequate, or should SRS be given at baseline, too, or on demand? Indeed, given the heterogeneous nature of BMs, will ongoing trials be able to address all these clinically important issues? The EANO-ESMO guidelines highlight the limited role of WBRT, given the increasing role of SRS, and weighing the neurotoxicity of WBRT versus SRS or brain-penetrant systemic therapy, this is a most welcome move away from WBRT. Indeed, radiotherapy prophylaxis in tumours with high BM rates still remains an area of controversy, but the current recommendation for prophylactic cranial irradiation for small-cell lung cancer patients is also noted alongside scepticism against it favouring MRI monitoring.These EANO-ESMO guidelines are a welcome document. Much has changed in the management of patients with BM over recent years and there is great cause for optimism. Between now and the next update, we hope these guidelines will stimulate the generation of newer data to push forward treatments and technologies, to ensure better outcomes for patients and to continue to dispel nihilism. Brain metastases (BM) in solid tumours are a common finding, particularly in melanoma, lung cancer, and breast cancer, traditionally heralding poor prognosis. Importantly, BMs are heterogeneous: presenting synchronous with diagnosis or over a lifetime, being symptomatic or asymptomatic, and ranging from solitary or small but miliary, to large volume with significant vasogenic oedema. Whatever the presentation, diagnosis is usually devastating as therapeutic options have historically been limited and survival poor. Indeed, the original recursive partitioning analysis (RPA) score personalizing prognosis on the basis of age, performance status, and systemic tumour burden, identified little difference between tumour types in an era when imaging was carried out when symptomatic, whole-brain radiotherapy (WBRT) was the typical treatment used and drug options were chemotherapy-based. In recent years, however, the prevalence of BM has been rising, in part driven by more frequent brain staging, but importantly driven hand in hand with increased patient survival through advances in tumour biology, drug therapies, and surgical and radiation technologies. In some diseases, such as anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), where the risk of baseline and lifetime BM is high, optimal brain management and intracranial control has been key to extending median survival, now measured in excess of 5 years.1Mok T. Camidge D.R. Gadgeel S.M. et al.Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study.Ann Oncol. 2020; 31: 1056-1064Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar It is against this backdrop that in this issue of the Annals of Oncology, Le Run et al.2Le Rhun E. Guckenberger M. Smits M. et al.EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours.Ann Oncol. 2021; 32: 1332-1347Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar report the joint European Association of Neuro-Oncology and European Society for Medical Oncology (EANO-ESMO) Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. These guidelines lay out the foundation of good practice, describing optimal diagnostics, pathology, and treatments including surgery, radiation, and pharmacotherapy. Importantly, recommendations are given on an integrated therapeutic approach recommending an individualized treatment plan, ideally discussed at a dedicated BM board, an objective that every oncologist treating solid tumours should align to. Finally, supportive care and surveillance recommendations are given, noting the importance of 2-3 monthly magnetic resonance imaging (MRI) monitoring. Indeed, with the improved outcomes of patients with BM, the guidelines recommend consideration of brain screening in all but stage I NSCLC, in stage IV melanoma, in metastatic human epidermal growth factor receptor 2 (HER2)-positive and in triple-negative breast cancers. Much has changed since the last EANO BM guidelines were published in 2017.3Soffietti R. Abacioglu U. Baumert B. et al.Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO).Neuro Oncol. 2017; 19: 162-174Crossref PubMed Scopus (254) Google Scholar We are now in an unprecedented new era of genomic medicine and immune checkpoint inhibitor (CPI) therapy. Advanced radiation techniques have developed allowing delivery of stereotactic radiosurgery (SRS) in a more refined and safer manner, with a greater consideration on patient quality of life given the expectation that many may still live a considerable time after radiotherapy, if not years. Nevertheless, many of the recommendations are based on expert opinion and low-level evidence, highlighting our difficult, heterogeneous, and modest evidence base. Historically, patients with BM have been excluded from trials, especially unlicensed drug trials, due to an inherent poorer prognosis and bias against risks of delayed commercialization. Whilst exclusion may be justified to isolate the potential effect of an investigational drug, this may well limit the generalizability of results to a broader population ultimately using the drug in real life. Fortunately, much has now changed for the better. The American Society of Clinical Oncology (ASCO)-Friends of Cancer Research Brain Metastases Working Group have proposed three key populations of BM patients for trials.4Lin N.U. Prowell T. Tan A.R. et al.Modernizing clinical trial eligibility criteria: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research Brain Metastases Working Group.J Clin Oncol. 2017; 35: 3760-3773Crossref PubMed Scopus (69) Google Scholar But if we are going to include such patients in trials, how should trials be designed, what endpoints should be considered, and by what criteria should brain efficacy be measured? Here, the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) group have made recommendations for both systemic5Camidge D.R. Lee E.Q. Lin N.U. et al.Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group.Lancet Oncol. 2018; 19: e20-e32Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar and local6Alexander B.M. Brown P.D. Ahluwalia M.S. et al.Clinical trial design for local therapies for brain metastases: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group.Lancet Oncol. 2018; 19: e33-e42Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar therapy trials, separating intracranial and extracranial compartments to allow a better determination of drug efficacy alongside risks of intracranial versus extracranial progression, adding clarity on competing risks and censoring needs to interpret this data.6Alexander B.M. Brown P.D. Ahluwalia M.S. et al.Clinical trial design for local therapies for brain metastases: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group.Lancet Oncol. 2018; 19: e33-e42Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar In addition, unique response assessment criteria for BM have been proposed.7Lin N.U. Lee E.Q. Aoyama H. et al.Response assessment criteria for brain metastases: proposal from the RANO group.Lancet Oncol. 2015; 16: e270-e278Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar Whilst the EANO-ESMO guidelines highlight the utility of these RANO-BM response criteria, RANO-BM defines measurable disease as ≥10 mm, however, and modern brain imaging now readily reveals much smaller metastases. Moreover, RANO-BM does not include any volumetric response assessment criteria, but changes in metastases volume with treatment are probably the best means of objectively determining response. BM are volumetrically delineated as part of the SRS planning process; though this is labour-intensive, emerging machine learning techniques have the potential to overcome this bottleneck and unlock the potential of longitudinal volumetric response assessment for BM.8Zhou M. Scott J. Chaudhury B. et al.Radiomics in brain tumor: image assessment, quantitative feature descriptors, and machine-learning approaches.AJNR Am J Neuroradiol. 2018; 39: 208-216Crossref PubMed Scopus (194) Google Scholar Additionally, we urgently need trial data on brain-specific and systemic outcomes of patients with BM receiving newer treatments. For therapies with a strong intracranial effect (e.g. ALK inhibitors), trials in ALK-positive NSCLC have provided invaluable data. For drugs where the intracranial effect may be more modest, however, such data is lacking. For example, whilst CPIs have been standard for multiple cancer types for over 6 years, the precise intracranial efficacy of CPIs in patients within the three ASCO-Friends classes of BM remains poorly defined, as registrational trials largely mandated patients with BM only if previously treated and dedicated intracranial trial assessments were not mandated. Nevertheless, despite limited data, these EANO-ESMO guidelines have given a clear steer that pharmacotherapy should be considered for most patients with BM, and upfront systemic therapy for specific disease subtypes such as oncogene-addicted NSCLC. The guidelines have also given clear steer on indications for SRS, and importantly where WBRT may be futile. We believe that the guidelines could have gone further, however, to optimize BM treatments. The guideline authors have chosen to use the number of central nervous system (CNS) metastases as a criterion for SRS selection. Whilst this is a readily determined metric, it is likely not optimal for SRS patient selection and cost-effectiveness bodies have not used it.9NHS England Clinical Commissioning Policy: Stereotactic Radiosurgery/Radiotherapy for Cerebral Metastases, NHS Commissioning Board.https://www.england.nhs.uk/wp-content/uploads/2020/08/D05-P-d-comm-policy-srs-cerebral-metastases.pdfDate: 2013Google Scholar Dedicated SRS delivery platforms can safely deliver treatment to multiple CNS metastases. The JLGK0901 study showed that having only a single metastasis conferred a survival advantage relative to having >1 metastasis, but patients with 2–4 metastases and ≥5 metastases had equivalent survival. Cumulative tumour volume has been shown in multiple studies to be associated with survival after SRS for BM, and should ideally be used in selecting patients for SRS, though the suggested maximum cumulative volume of 15 ml is too conservative, especially when fractionated SRS is used.10Niranjan A. Monaco E. Flickinger J. Lunsford L.D. Guidelines for multiple brain metastases radiosurgery.Prog Neurol Surg. 2019; 34: 100-109Crossref PubMed Scopus (22) Google Scholar The importance of BM volume to outcomes following SRS reinforces the need to move to volumetric response assessment. Additionally, several additional questions still remain for SRS; principally around consistency in clinical decision-making, better defining risks of radionecrosis, its identification and treatment, interactions with CPIs, and timing. With highly penetrant intracranial systemic therapies, in patients with BM at baseline is systemic therapy alone adequate, or should SRS be given at baseline, too, or on demand? Indeed, given the heterogeneous nature of BMs, will ongoing trials be able to address all these clinically important issues? The EANO-ESMO guidelines highlight the limited role of WBRT, given the increasing role of SRS, and weighing the neurotoxicity of WBRT versus SRS or brain-penetrant systemic therapy, this is a most welcome move away from WBRT. Indeed, radiotherapy prophylaxis in tumours with high BM rates still remains an area of controversy, but the current recommendation for prophylactic cranial irradiation for small-cell lung cancer patients is also noted alongside scepticism against it favouring MRI monitoring. These EANO-ESMO guidelines are a welcome document. Much has changed in the management of patients with BM over recent years and there is great cause for optimism. Between now and the next update, we hope these guidelines will stimulate the generation of newer data to push forward treatments and technologies, to ensure better outcomes for patients and to continue to dispel nihilism.