Management Of Melanoma Brain Metastases Research Articles

Stereotactic radiosurgery and anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitors, or conventional chemotherapy for the management of melanoma brain metastases

BackgroundImmunotherapy and targeted BRAF/MEK inhibitors (i) have revolutionised the systemic management of advanced melanoma. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and various systemic therapies. MethodsPatients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1+CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy. Comparisons between groups were made for overall survival (OS), distant MBM control, local MBM, systemic progression-free survival (sPFS), and neurotoxicity. ResultsIn total, 257 patients with 1048 MBM treated over 368 SRS sessions between 2011 and 2020 were identified. On MVA, treatment with anti-PD1+anti-CTLA-4, anti-PD-1, and BRAF/MEK-i improved distant intracranial control over conventional chemotherapy. No significant differences were noted in local control (LC) between groups (p = 0.78). Kaplan–Meier OS at 12 months for anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, and conventional chemotherapy was 68%, 59%, 45%, 62%, 21%, and 15%, respectively (p = <0.0001). The sPFS rates at 12 months were 57%, 53%, 42%, 45%, 14%, and 6% (p = <0.0001). No significant differences were noted in rates of radiation necrosis (p = 0.93). ConclusionsThis is among the largest series evaluating MBM treated with SRS and various systemic therapy regimens. Our analysis noted significant differences in OS, distant MBM control, and sPFS by systemic therapy. No differences in LC or radiation necrosis risk were noted.

Identification of Epigenetically Regulated Genes Distinguishing Intracranial from Extracranial Melanoma Metastases

Despite remarkable advances in treating patients with metastatic melanoma, the management of melanoma brain metastases remains challenging. Recent evidence suggests that epigenetic reprogramming is an important mechanism for the adaptation of melanoma cells to the brain environment. In this study, the methylomes and transcriptomes of a cohort of matched melanoma metastases were evaluated by integrated omics data analysis. The identified 38 candidate genes displayed distinct promoter methylation and corresponding gene expression changes in intracranial compared with extracranial metastases. The 11 most promising genes were validated on protein level in both tumor and surrounding normal tissue using immunohistochemistry. In accordance with the underlying promoter methylation and gene expression changes, a significantly different protein expression was confirmed for STK10, PDXK, WDR24, CSSP1, NMB, RASL11B, phosphorylated PRKCZ, PRKCZ, and phosphorylated GRB10 in the intracranial metastases. The observed changes imply a distinct intracranial phenotype with increased protein kinase B phosphorylation and a higher frequency of proliferating cells. Knockdown of PRKCZ or GRB10 altered the expression of phosphorylated protein kinase B and decreased the viability of a brain-specific melanoma cell line. In summary, epigenetically regulated cancer-relevant alterations were identified that provide insights into the molecular mechanisms that discriminate brain metastases from other organ metastases, which could be exploited by targeting the affected signaling pathways.

Management of melanoma brain metastases: Evidence-based clinical practice guidelines by Cancer Council Australia.

The brain is a common site of metastatic disease for patients with advanced melanoma. Brain metastasis portends a poor prognosis, often causing deterioration in neurological function and quality of life, and leading to neurological death. Treatment approaches including surgery, radiotherapy and systemic therapy can lead to better control of this problem. Therefore, appropriate guidelines for the management of melanoma brain metastases need to be established, with regular updating when new treatment options become available. A multidisciplinary working party established by Cancer Council Australia has produced up-to-date, evidence-based clinical practice guidelines for the management of melanoma. After selecting key clinical questions, a comprehensive literature search for relevant studies was conducted, followed by systematic review of those studies. Data were summarised and the evidence was assessed, leading to the development of recommendations. Symptomatic lesions are best treated with surgery, when possible; this provides safe and effective local control. For patients with single or a small number of asymptomatic brain metastases, stereotactic radiotherapy is recommended, but in asymptomatic patients who have not previously received systemic treatment, drug therapy can be considered as a first-line treatment option. Whole brain radiotherapy may provide palliative benefits in patients with multiple brain metastases. Whenever possible, melanoma patients with brain metastases should be managed by a multidisciplinary team of melanoma specialists that considers the optimal combination and sequencing of surgery, radiotherapy and systemic therapy.

Stereotactic radiosurgery combined with anti-PD1 for the management of melanoma brain metastases: A retrospective study of safety and efficacy

BackgroundBrain metastases can be effectively treated with stereotactic radiosurgery (SRS). Immune checkpoint inhibitors are now pivotal in metastatic melanoma care, but some concerns have emerged regarding the safety of their combination with radiation therapy. MethodsWe present a retrospective analysis of a cohort of patients treated by anti-PD1 and SRS as a sole modality of radiation therapy (no whole brain radiation therapy at any time) in a single institution. We included patients on anti-PD1 at the time of SRS or patients who started anti-PD1 within a maximum period of 3 months following SRS and were treated at least one year before the analysis. Clinical and serial imaging data were reviewed to determine the efficacy and the rate of adverse radiation effectss of the combination. ResultsA total of 50 patients were included. SRS targeted 1, 2 to 3 and >3 brain metastases in 17, 16 and 17 patients, respectively. Two patients died before the first evaluation. Nine patients presented with an increase in peritumoral oedema, three with intracranial haemorrhage and one patient with both oedema and haemorrhage. Median follow-up was 38.89 months (interquartile range 24.43; 45.28). Median overall survival from SRS was 16.62 months with 1-, 2- and 3-year rates of 60%, 40% and 35%, respectively. Median brain-Progression Free Survival was 13.2 months with 1, 2 and 3-year rates of 62.1%, 49.7% and 49.7%, respectively. ConclusionsThis real-world cohort of patients treated with a homogeneous strategy combining upfront stereotactic radiosurgery and anti-PD1 shows remarkable survival rates and does not reveal unexpected toxicity.

CMET-23. IMPACT OF SYSTEMIC THERAPY IN MELANOMA BRAIN METASTASIS

Abstract BACKGROUND Melanoma is the third most common malignancy that results in brain metastasis and is associated with a median overall survival (OS) of approximately 9 months. In recent years, management of melanoma brain metastases (MBM) by surgery and radiation [stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT)] has been bolstered by targeted therapy and immune checkpoint inhibitors (ICI). METHODS 351 patients, treated for MBM at our tertiary care center from 2000–2018, were grouped into: received chemotherapy, ICI, or targeted therapy. 34% of patients treated with ICI had received other systemic therapies as well as part of their management. OS was calculated from the date of diagnosis of the brain metastases. The Kaplan Meier analysis was utilized to determine median OS and difference in OS was determined by utilizing the Cox proportional hazard model. RESULTS The median survival after the diagnosis of brain metastasis was 10.4, 11.96, and 7.06 months in patients who received ICI, chemotherapy and targeted therapy respectively. A multivariate model was developed including the type of systemic therapy, presence of extracranial metastases, age, KPS and number of intracranial lesions. 114 patients underwent SRS alone, 56 underwent SRS and WBRT, 43 underwent SRS and surgical removal, 28 had surgical removal, SRS and WBRT, and 78 had no intracranial therapy. Compared to patients who received chemotherapy, patients who received immunotherapy had a hazard ratio, HR = 0.628 (confidence interval = 0.396 – 0.994, p-value = 0.047). Presence of EC metastases (HR= 1.25, p-value &lt; .001), lower KPS (HR = .97, p-value &lt; .0001) and multiple brain lesions (HR = 1.117, p-value &lt; .0001) were associated with significantly worse OS. CONCLUSIONS Addition of ICI significantly improves the OS in MBM compared to chemotherapy. Lower performance status, multiple brain metastases, and EC metastases are associated with poor OS.

THER-02. IMPACT OF SYSTEMIC THERAPY IN MELANOMA BRAIN METASTASIS

BACKGROUND: Melanoma brain metastasis is associated with a median overall survival (OS) of approximately 9 months. In recent years, management of melanoma brain metastases (MBM) by surgery and radiation [stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT)] has been bolstered by targeted therapy and immune checkpoint inhibitors (ICI). METHODS: 351 patients, who underwent treatment for MBM at our tertiary care center from 2000 to 2018, were grouped into those that received chemotherapy, ICI, or targeted therapy. Thirty-four percent of patients treated with ICI had received other systemic therapies as well as part of their management. OS was calculated from the date of diagnosis of the brain metastases. The Kaplan Meier analysis was utilized to determine median OS and difference in OS was determined by utilizing the Cox proportional hazard model. RESULTS: The median survival after the diagnosis of brain metastasis was 10.4, 11.96, and 7.06 months in patients who received ICI, chemotherapy and targeted therapy respectively. A multivariate model was developed including the type of systemic therapy, presence of extracranial metastases, age, KPS and number of intracranial lesions. 114 patients underwent SRS alone, 56 underwent SRS and WBRT, 43 underwent SRS and surgical removal, 28 had surgical removal, SRS and WBRT, and 78 had no intracranial therapy. Compared to patients who received chemotherapy, patients who received immunotherapy had a hazard ratio, HR = 0.628 (confidence interval = 0.396 – 0.994, p-value = 0.047). Presence of EC metastases (HR= 1.25, p-value < .001), lower KPS (HR = .97, p-value < .0001) and multiple brain lesions (HR = 1.117, p-value < .0001) were associated with significantly worse OS. CONCLUSIONS: Addition of ICI significantly improves the OS in MBM compared to chemotherapy. Lower performance status, multiple brain metastases, and EC metastases are associated with poor OS.

Incidence, features and management of radionecrosis in melanoma patients treated with cerebral radiotherapy and anti-PD-1 antibodies.

Brain radiotherapy is used in the management of melanoma brain metastases (MBM) and can result in radionecrosis. Anti-PD-1 is active in the brain and may increase the risk of radionecrosis when combined with radiotherapy. We studied the incidence, associated factors and management of radionecrosis in longer-term survivors with MBM treated with this combination. Patients with MBM treated with radiotherapy and anti-PD-1 who survived >1year were identified to determine radionecrosis incidence (Cohort A, n=135). Cohort A plus additional radionecrosis cases were examined for factors associated with radionecrosis and management (Cohort B, n=148). From Cohort A, 17% developed radionecrosis, with a cumulative incidence at 2years of 18%. Using Cohort B, multivariable analysis confirmed an association between radionecrosis and elevated lactate dehydrogenase (p=0.0496) and prior treatment with ipilimumab (p=0.0319). Radionecrosis was diagnosed based on MRI (100%), symptoms (69%) and pathology (56%). Treatment included corticosteroids, bevacizumab and neurosurgery. Radionecrosis is a significant toxicity in longer-term melanoma survivors with MBM treated with anti-PD-1 and radiotherapy. Identification of those at risk of radionecrosis who may avoid radiotherapy is required.

New Era in the Management of Melanoma Brain Metastases.

The remarkable advances in the systemic therapy of metastatic melanoma have now extended the 1-year overall survival rate from 25% to nearing 85%. Systemic treatment in the form of BRAF-targeted therapy and immunotherapy is slowly but surely proving its efficacy in the treatment of metatstatic brain metastases (MBM). Single-agent BRAF inhibitors provide an intracranial response rate of 25% to 40%, whereas the combination of BRAFi/MEKi leads to responses in up to 58%. However, the durability of responses induced by BRAFi/MEKi seems to be even shorter than in extracranial disease. On the other hand, single-agent ipilimumab provides comparable clinical benefit in MBMs as it does in extracranial metastases. Single-agent PD-1 anitbodies induce response rates of approximately 20%, and those responses appear durable. Similarly the combination of CTLA-4+ PD-1 antibodies induces durable responses at an impressive rate of 55% and is safe to administer. Although the local treatment approaches with radiation and surgery remain important and are critically needed in the management of MBM, systemic therapy offers a new dimension that can augment the impact of those therapies and come at a potentially lower cost of neurocognitive impairment. Considerations for combining those modalities are direly needed, in addition to considering novel systemic combinations that target mechanisms specific to MBM. In this report, we will discuss the underlying biology of melanoma brain metastases, the clinical outcomes from recent clinical trials of targeted and immunotherapy, and their impact on clinical practice in the context of existing local therapeutic modalities.

Melanoma Brain Metastases: Local Therapies, Targeted Therapies, Immune Checkpoint Inhibitors and Their Combinations-Chances and Challenges.

Recent phase II trials have shown that BRAF/MEK inhibitors and immune checkpoint inhibitors are active in patients with melanoma brain metastases (MBM), reporting intracranial disease control rates of 50–75%. Furthermore, retrospective analyses suggest that combining stereotactic radiosurgery with immune checkpoint inhibitors or BRAF/MEK inhibitors prolongs overall survival. These data stress the need for inter- and multidisciplinary cooperation that takes into account the individual prognostic factors in order to establish the best treatment for each patient. Although the management of MBM has dramatically improved, a substantial number of patients still progress and die from brain metastases. Therefore, there is an urgent need for prospective studies in patients with MBM that focus on treatment combinations and sequences, new treatment strategies, and biomarkers of treatment response. Moreover, further research is needed to decipher brain-specific mechanisms of therapy resistance.

Metastatic melanoma: prognostic factors and survival in patients with brain metastases

Brain metastases from malignant melanoma carry a poor prognosis. Novel systemic agents have improved overall survival (OS), but the value of whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) remains uncertain. The melanoma-specific graded prognostic assessment (msGPA) provides useful prognostic information, but the relevance to the modern-day population has not been validated. Since 2011, 53 patients received treatment for brain metastases from malignant melanoma at the Rosemere Cancer Centre medical oncology clinic. Data were collated on demographic factors and survival. Survival analyses were performed using Kaplan–Meier methods. Cox regression was used to identify prognostic factors on univariate and multivariate analysis. OS from the date of diagnosis of brain metastases was 4.83 months (range 0.27–30.4 months). On univariate analysis, BRAF, performance status and msGPA were significant prognostic indicators for OS (p = 0.0056, p = 0.0039 and p = 0.0001 respectively). msGPA remained significant on multivariate analysis (p = 0.0006). OS for BRAF-positive patients receiving targeted treatment (n = 22) was significantly better than for BRAF-negative patients (n = 26), with median survival times of 8.2 and 3.7 months respectively (p = 0.0039, HR 2.36). SRS combined with systemic agents (n = 16) produced an OS of 13.5 months. Patients receiving WBRT alone (n = 21) had a poor prognosis (2.2 months). The msGPA remains a valid prognostic indicator in the era of novel systemic treatments for melanoma. BRAF-positive patients receiving targeted agents during their treatment had favorable survival outcomes. WBRT alone should be use with caution in the active management of melanoma brain metastases.

Metastatic melanoma: prognostic factors and survival in patients with brain metastases

Brain metastases from malignant melanoma carry a poor prognosis. Novel systemic agents have improved overall survival (OS), but the value of whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) remains uncertain. The melanoma-specific graded prognostic assessment (msGPA) provides useful prognostic information, but the relevance to the modern-day population has not been validated. Since 2011, 53 patients received treatment for brain metastases from malignant melanoma at the Rosemere Cancer Centre medical oncology clinic. Data were collated on demographic factors and survival. Survival analyses were performed using Kaplan–Meier methods. Cox regression was used to identify prognostic factors on univariate and multivariate analysis. OS from the date of diagnosis of brain metastases was 4.83 months (range 0.27–30.4 months). On univariate analysis, BRAF, performance status and msGPA were significant prognostic indicators for OS (p = 0.0056, p = 0.0039 and p = 0.0001 respectively). msGPA remained significant on multivariate analysis (p = 0.0006). OS for BRAF-positive patients receiving targeted treatment (n = 22) was significantly better than for BRAF-negative patients (n = 26), with median survival times of 8.2 and 3.7 months respectively (p = 0.0039, HR 2.36). SRS combined with systemic agents (n = 16) produced an OS of 13.5 months. Patients receiving WBRT alone (n = 21) had a poor prognosis (2.2 months). The msGPA remains a valid prognostic indicator in the era of novel systemic treatments for melanoma. BRAF-positive patients receiving targeted agents during their treatment had favorable survival outcomes. WBRT alone should be use with caution in the active management of melanoma brain metastases.

From the Guest Editors: Recent Advances and Evolving Challenges in Treating Unresectable Melanoma.

The dramatic progress recently made in the treatment of metastatic melanoma seemed unachievable only 10 years ago. Until 2011, few effective therapies existed for metastatic melanoma, and overall survival was on the order of months. Dacarbazine was US Food and Drug Administration (FDA) approved in 1975 and remains the only chemotherapy ever approved for melanoma, with response rates of up to 15%, but with limited durability.1 Approval of high-dose interleukin 2 followed in 1998, with the potential for long-term durable responses in a minority of patients (up to 15%), but at the expense of significant toxicity.2 After decades of drought, the advent of genomic profiling combined with breakthroughs in understanding immune escape mechanisms has led to approval of more effective therapies based on immunologic manipulation and identification of targetable oncogenic drivers.3 Optimism in the field has soared since the 2011 FDA approval of the CTLA-4 inhibitor ipilimumab and the BRAF inhibitor vemurafenib, both of which provided unmatched options for disease control. Since then, dual immune checkpoint blockade with CTLA-4 and PD-1 inhibitors and vertical mitogen-activated protein kinase pathway inhibition with BRAF and MEK inhibitors are now standards of care. The challenges in melanoma therapeutics have shifted from finding an effective drug to understanding which drug to use first, how to combine drugs to induce a synergistic anti-tumor effect, how to overcome primary or acquired drug resistance, and how to mitigate treatment-related toxicity. This comprehensive special issue is composed of thoughtful perspectives from leading melanoma experts. Beginning with a focus on immunotherapy, Loo et al. review the use of single and dual-agent immune checkpoint blockade in advanced melanoma and the ongoing research efforts to personalize these approaches. Hu-Lieskovan et al. build off this chapter to explore combination therapy strategies using CTLA-4 and/or PD-1 inhibitors as a backbone, whereas Giuroiu et al. segue into a discussion of novel drugs in early clinical development that target new immune molecules. An exploration of adjunctive therapies follows, including radiation’s role in amplifying the antitumor immune response by Escorcia et al. and the use of and rationale for intratumoral approaches by Bommareddy et al. Merhavi-Shoham et al. review the experience with adoptive cell therapy including use of tumor infiltrating lymphocytes, T-cell receptor gene manipulation, and T cells with genetically modified chimeric antigen receptors. The edition’s focus then shifts to an update on molecularly targeted therapies by Iams et al. and Gibney et al. and transitions to current investigations for the management of melanoma brain metastases by Oliva et al. Despite the groundbreaking progress that has transpired in systemic therapies for advanced melanoma over the past decade, multiple barriers remain, as highlighted in Izar and colleagues’ commentary on clinical trial design and Sznol’s reflection on the challenges of clinical research in melanoma. We have reached an unprecedented era in advanced melanoma in which objective response rates to frontline combination CTLA-4 and PD-1 immunotherapy reach 57.7%, whereas response rates to monotherapy PD-1 inhibitors reach 43.7%.4 This success has stimulated the rapid investigation and/or FDA approval of these drugs in other immunogenic malignancies. However, no reliable predictive biomarkers currently exist to aid in patient selection, and the rate of grade 3-4 toxicity remains high, potentially precluding patients from receiving subsequent immunotherapies. Even after melanoma progression on immunotherapy, other options include BRAF/MEK inhibition in the setting of a driver BRAF mutation, immunotherapy reinduction, or alternative immune therapies. Therefore, as patient and clinician access to numerous effective standard-of-care treatment options has dramatically increased, the pool of melanoma clinical trial participants can decrease.

Initial experience with combined BRAF and MEK inhibition with stereotactic radiosurgery for BRAF mutant melanoma brain metastases.

The combined use of the BRAF inhibitor dabrafenib and MEK inhibitor trametinib has been found to improve survival over dabrafenib alone. The management of melanoma brain metastases continues to present challenges. In this study, we report our initial experience in the management of melanoma brain metastases with stereotactic radiosurgery (SRS) with the use of BRAF and MEK inhibitors. We identified six patients treated with SRS for 17 brain metastases within 3 months of BRAF and MEK inhibitor administration. The median planning target volume was 0.42 cm (range: 0.078-2.08 cm). The median treatment dose was 21 Gy (range 18-24 Gy). The median follow-up of all lesions from SRS was 10.6 months (range 5.8-28.5 months). One lesion was found to undergo local failure 21.7 months following SRS treatment. The median overall survival was 20.0 months (range 6.1-31.8 months) from the time of SRS treatment and 23.1 months (range: 12.1-30.9 months) from the date of BRAFi and MEKi administration. There was no evidence of increased nor unexpected toxicity with the two modalities combined. In this initial experience of melanoma brain metastases treated with BRAF and MEK inhibition with SRS, we find the two modalities can be combined safely. These outcomes should be assessed further in prospective evaluations.

Management of melanoma brain metastases.

Relapses in the brain remain a major obstacle to cure in many patients with advanced melanoma. At present, the management of melanoma brain metastases continues to rely heavily on surgical and radiotherapeutic interventions, which have become safer and more effective with modern imaging, surgery and radiation technologies. Additionally, novel targeted and immunotherapeutic agents, shown to generate meaningful intracranial response and survival benefit in patients with melanoma brain metastases when compared with historical controls, expand systemic treatment options for this subset of patients. These systemic therapies become particularly important when intracranial disease burden precludes neuro- or radio-surgery. Considerable multidisciplinary research effort is ongoing to improve outcomes for melanoma patients with brain metastases, a key challenge in the management of advanced melanoma.

Recommandations de l’Anocef pour la prise en charge des métastases cérébrales

The incidence of brain metastases is increasing because of the use of new therapeutic agents, which allow an improvement of overall survival, but with only a poor penetration into the central nervous system brain barriers. The management of brain metastases has changed due to a better knowledge of immunohistochemical data and molecular biological data, the development of new surgical, radiotherapeutic approaches and improvement of systemic treatments. Most of the time, the prognosis is still limited to several months, nevertheless, prolonged survival may be now observed in some sub-groups of patients. The main prognostic factors include the type and subtype of the primitive, age, general status of the patient, number and location of brain metastases, extracerebral disease. The multidisciplinary discussion should take into account all of these parameters. We should notice also that treatments including surgery or radiotherapy may be proposed in a symptomatic goal in advanced phases of the disease underlying the multidisciplinary approach until late in the evolution of the disease. This article reports on the ANOCEF (French neuro-oncology association) guidelines. The management of brain metastases of breast cancers and lung cancers are discussed in the same chapter, while the management of melanoma brain metastases is reported in a separate chapter due to different responses to the brain radiotherapy.

The role of whole brain radiation therapy in the management of melanoma brain metastases.

BackgroundBrain metastases are common in patients with melanoma, and optimal management is not well defined. As melanoma has traditionally been thought of as “radioresistant,” the role of whole brain radiation therapy (WBRT) in particular is unclear. We conducted this retrospective study to identify prognostic factors for patients treated with stereotactic radiosurgery (SRS) for melanoma brain metastases and to investigate the role of additional up-front treatment with whole brain radiation therapy (WBRT).MethodsWe reviewed records of 147 patients who received SRS as part of initial management of their melanoma brain metastases from January 2000 through June 2010. Overall survival (OS) and time to distant intracranial progression were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model.ResultsWBRT was employed with SRS in 27% of patients and as salvage in an additional 22%. Age at SRS > 60 years (hazard ratio [HR] 0.64, p = 0.05), multiple brain metastases (HR 1.90, p = 0.008), and omission of up-front WBRT (HR 2.24, p = 0.005) were associated with distant intracranial progression on multivariate analysis. Extensive extracranial metastases (HR 1.86, p = 0.0006), Karnofsky Performance Status (KPS) ≤ 80% (HR 1.58, p = 0.01), and multiple brain metastases (HR 1.40, p = 0.06) were associated with worse OS on univariate analysis. Extensive extracranial metastases (HR 1.78, p = 0.001) and KPS (HR 1.52, p = 0.02) remained significantly associated with OS on multivariate analysis. In patients with absent or stable extracranial disease, multiple brain metastases were associated with worse OS (multivariate HR 5.89, p = 0.004), and there was a trend toward an association with worse OS when up-front WBRT was omitted (multivariate HR 2.56, p = 0.08).ConclusionsMultiple brain metastases and omission of up-front WBRT (particularly in combination) are associated with distant intracranial progression. Improvement in intracranial disease control may be especially important in the subset of patients with absent or stable extracranial disease, where the competing risk of death from extracranial disease is low. These results are hypothesis generating and require confirmation from ongoing randomized trials.

The role of systemic therapies in the management of melanoma brain metastases

Brain metastases in metastatic melanoma are highly prevalent and are associated with significant morbidity and a poor prognosis. Local therapy (surgery or radiotherapy) has been the mainstay of treatment, due in part to the lack of efficacy of systemic therapy. This review will focus on new systemic therapies for metastatic melanoma and their evolving role in the management of brain metastases. BRAF inhibitors have demonstrated efficacy in active (i.e. untreated or progressing) brain metastases in BRAF mutated metastatic melanoma. The cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody, ipilimumab, has also shown activity, particularly in asymptomatic metastases. Studies of programmed death 1/programmed death ligand 1 checkpoint inhibitors and combination BRAF and MEK inhibitor therapy in brain metastases are planned. Emerging evidence on the molecular biology of melanoma brain metastases, particularly the role of the phosphatidylinositol 3-kinase-AKT pathway, may identify additional therapeutic targets. The development of systemic therapy effective in controlling both intra-cranial and extra-cranial melanoma metastases has resulted in a change in the paradigm of management. More research is required in patients with active brain metastases to improve patient outcomes, including studies early in the development of novel therapies, and studies to determine the safe and effective combination or sequencing of local and systemic therapies.

The treatment of melanoma brain metastases before the advent of targeted therapies

The management of melanoma brain metastases (MBM) includes different therapeutic modalities, such as surgery, radiotherapy and chemotherapy. Despite the choice of treatments, survival remains poor, exceeding 1 year only in patients with solitary metastases and absence of extracranial disease. A total of 115 consecutive MBM patients observed between 1994 and 2010 were included in an historical cohort study. Demographic, clinical data and tumour characteristics were collected and survival status was ascertained across the follow-up window. The statistical associations between individual and tumour data and overall survival were investigated using Kaplan-Meier survival function and Cox's multiple regression analysis. The median survival was 4.3 months (95% confidence interval 2.6-6.1). Patients who underwent surgery or stereotactic radiosurgery showed a significantly (P<0.001) better prognosis than those who received chemotherapy and/or radiotherapy or supportive therapies. Patients without clinical symptoms experienced a statistically significant better survival (P=0.02) than patients with clinical symptoms; analogue difference was observed to be in favour of patients whose symptoms improved after the first treatment of MBM (P<0.001). The presence of symptoms, clinical outcome and first treatment received were the only independent variables to predict survival. Patients who cannot receive surgery or stereotactic radiosurgery have the worst overall survival.

Multidisciplinary Approach to Brain Metastasis from Melanoma; Local Therapies for Central Nervous System Metastases

The overall treatment paradigm for melanoma brain metastases continues to evolve and reflects the relative radioresistance of this histology, as well as the effect of emerging systemic therapies with central nervous system (CNS) activity. Local therapies, including surgery, whole brain radiotherapy (WBRT), and stereotactic radiosurgery (SRS), play an important role in the multidisciplinary management of melanoma brain metastases. Treatment selection for local therapies must consider many factors: (1) size, number, and location of lesions, (2) presence or absence of neurological symptoms, (3) extracranial disease status, expected survival, age, and performance status, (4) prior treatment history, (5) expected treatment toxicities, and (6) predicted response to systemic therapies. The choice of treatment modalities for brain metastases is among the most controversial areas in oncology. There has been a trend toward reduced use of WBRT and increased reliance on SRS and surgery for melanoma brain metastases. Although no prospective randomized data exist comparing local therapies for melanoma brain metastases, several large retrospective studies suggest aggressive local treatment with modalities including surgery and SRS are associated with favorable outcomes in select patients. Multidisciplinary collaboration is required to facilitate a treatment plan that balances reduction in risk of neurological death and symptomatic progression against the risk of treatment-related toxicity.

Stratégies thérapeutiques et traitements systémiques des métastases cérébrales du mélanome

Brain metastases affect 37% of patients suffering from metastatic melanoma, and their prognosis remains poor, with an overall survival lower than six months. At the moment, there is no standard therapeutic strategy for management of melanoma brain metastases. In some cases, having recourse to a systemic treatment is justified, for example, when brain metastases are combined with a progressive peripheral disease, or with unresecable brain lesions. In France, the use of fotemustine, which received the AMM approval, for metastatic melanoma treatment, is one of the treatments recommended in the case of brain metastases as this chemotherapy, that is active on the melanoma passes the blood-brain barrier. Temozolomide also shows some activity in the brain metastases treatment of melanoma that remains modest in monotherapy but seems interesting when it is combined with radiotherapy. The place of new drugs, in particular ipilimumab and vemurafenib, in the strategy of melanoma brain metastases treatment, still has to be defined and may improve the prognosis of these patients and their quality of life. The new targeted therapies, the widespread use of stereotactic radiosurgery and the improvement in neurosurgical operations would need a prospective clinical assessment, all the more so, in most of clinical studies, the presence of metastases is an exclusion criterion.