Melanoma in the brain: biology and therapeutic options

The development of brain metastases is a frequent occurrence in patients with disseminated melanoma and contributes to a disproportionate degree of morbidity and mortality. The prognosis is markedly reduced once a patient is diagnosed with central nervous system disease. Definitive therapeutic interventions with resection or stereotactic radiosurgery have improved outcomes and become standard approaches in the management of melanoma brain metastases. With the inclusion of whole-brain radiation in these interventions, there has been a reduction in local recurrences, but no improvement in the overall survival. Still, many patients are not candidates for surgery nor radiotherapy nor develop progressive central nervous system disease after definitive therapy. As new immune-based and targeted therapeutic agents are developed for the treatment of metastatic melanoma, understanding their activity in brain metastases is necessary for effective patient management. In this review, we discuss the biology of brain metastases in metastatic melanoma, current treatment approaches with surgery and radiotherapy, and future systemic therapeutic strategies.     

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.     

Radiation necrosis of the brain in melanoma patients successfully treated with ipilimumab,three case studies

Metastasis to the brain is a frequent event in patients with advanced melanoma. Despite treatment with neurosurgery, pancranial irradiation and high-precision conformal radiotherapy, the prognosis of patients suffering from melanoma brain metastasis has remained very poor. Ipilimumab is a new effective immunotherapy for the treatment of advanced melanoma and has demonstrated activity against brain metastases. We report three patients successfully treated with ipilimumab who subsequently developed focal necrosis of the brain following prior radiotherapy of their melanoma brain metastases. As new active systemic treatment options become available that improve the survival of patients with melanoma brain metastases, adequate diagnosis and management of the late sequela from radiation to the brain is likely to gain importance in the management of these patients.     

The use of systemic therapies for the treatment of brain metastases in metastatic melanoma: Opportunities and unanswered questions

The development of brain metastases is common in patients with metastatic melanoma and heralds a particularly poor prognosis. The development of the immunological agent ipilimumab and targeted treatments such as the selective BRAF inhibitor vemurafenib have revolutionised the treatment of metastatic disease. Evidence from clinical trials suggest these drugs may be effective in the treatment of brain metastases from melanoma. However efficacy may be limited by a lack of penetration of the blood brain barrier (BBB) and by multi substrate efflux pumps expressed on the BBB. The role and sequencing of radiotherapy, both whole brain and stereotactic radiotherapy, is yet to be determined but combinations of radiotherapy and systemic therapies may further increase the effects of these drugs on brain metastases. Considering the impact of brain metastases on morbidity and mortality in metastatic melanoma, future research into systemic drug therapy for the treatment of brain metastases and improvements in BBB penetrance should be a priority.     

Revisiting the role of systemic therapies in patients with metastatic melanoma to the CNS

The CNS is a common site of metastasis in patients with malignant melanoma. Locoregional control either with surgery or radiotherapy is first-line treatment for patients with brain metastasis should they be suitable candidates. For those patients who are not and those who progress after previous treatment, there is an unmet clinical need for effective systemic therapies. Systemic cytotoxics, such as temozolamide and fotemustine, have only modest activity, resulting in a median progression-free survival ranging from 1–2 months, in patients with metastatic melanoma to the brain. Newer systemic treatments such as vemurafenib and ipilimumab have been approved for the treatment of melanoma, but evidence regarding their activity in brain metastases is inconclusive due to the limited access of patients to clinical trials. This is now being revised and more data are emerging supporting the inclusion of patients with brain metastasis in trials. In this review, the authors present data regarding the efficacy of systemically administered therapies in patients with metastatic melanoma to the brain.     

The treatment of brain metastases in melanoma patients

The incidence of central nervous system (CNS) metastases in patients with melanoma ranges from 10% to 40% in clinical studies and is even higher in autopsy series with as many as two-thirds of patients with metastatic melanoma having CNS involvement. Treatment options for patients with cerebral metastases are limited and depend largely on the number and the size of the lesions and on the extracranial extension of metastatic disease. This report gives the results of different treatment modalities in patients with melanoma metastases to the brain. As data from prospective randomized studies are lacking, the general recommendations based on clinical series reports are: (i) the combination of surgery and whole-brain radiotherapy (WBRT) is superior to WBRT alone for the treatment of single brain metastasis in patients with limited or absent systemic disease and good neurological condition. (ii) Radio surgery, alone or in conjunction with WBRT, yields results which are comparable to those reported after surgery followed by WBRT, provided that the lesion's diameter does not exceed 3 cm. With the use of WBRT after surgery or radio surgery the local control seems better (with the combined approach), but the overall survival does not improve. (iii) WBRT alone or in combination with chemotherapy is the treatment of choice in patients with single brain metastasis not amenable to surgery or radio surgery, with an active systemic disease, and in patients with multiple brain metastases. Chemotherapy may be also offered to patients with a good performance status, or after recurrence to local therapy.     

Biochemotherapy of metastatic melanoma in patients with or without recently diagnosed brain metastases

BACKGROUND: Brain metastases are an alarming complication of advanced melanoma, frequently contributing to patient demise. The authors performed a retrospective analysis to determine whether the treatment of metastatic melanoma with biochemotherapy would result in similar outcomes if brain metastases were first controlled with aggressive, central nervous system (CNS)-directed treatment. METHODS: Seventy melanoma patients were treated with biochemotherapy for metastatic melanoma between 1999 and 2005. Of these, 20 patients had recently diagnosed brain metastases, whereas 50 did not. Brain metastases (if present) were treated with stereotactic radiosurgery >or=28 days prior to systemic therapy. All patients were treated with biochemotherapy consisting of either dacarbazine or temozolomide in combination with a 96-hour continuous intravenous infusion of interleukin-2 and subcutaneous interferon-alpha-2B. The primary endpoint was survival from the time of the initial diagnosis of metastatic disease. RESULTS: Median survival from the time of the diagnosis of metastatic melanoma was 15.8 months for patients with brain metastases and 11.1 months for those without CNS involvement (P = .26 by the log-rank test; P = .075 by the Gehan Wilcoxon test). Dacarbazine-based and temozolomide-based regimens appeared similar with regard to their effect on overall survival and CNS disease progression. A plateau in further brain recurrences was observed in patients who survived for > 20 months. CONCLUSIONS: Data from the current study suggest that the outcome of biochemotherapy is comparable in patients with and those without brain metastases, if brain metastases are controlled with multidisciplinary treatment. Prolonged survival can be achieved in approximately 15% of patients, regardless of whether or not brain metastases are present.     

Immune toxicities and long remission duration after ipilimumab therapy for metastatic melanoma: two illustrative cases

New antitumour immunotherapy strategies for stage iv metastatic melanoma include ipilimumab, a monoclonal antibody against ctla-4. Patterns of response with cancer immunotherapy differ from those with cytotoxic chemotherapy. We present two cases of long-duration immune-related responses with ipilimumab in a phase ii trial.A 66-year-old woman with multiple lung metastases from a scalp primary melanoma received 4 doses of ipilimumab with mixed clinical response. However, after the first maintenance dose, she developed severe ileitis and colitis that responded to steroid therapy. Four months later, she had surgery and radiotherapy for a single brain metastasis. Radiologically, stable disease continued for 36 months after the last ipilimumab dose, and partial response for 5 years after ipilimumab start.A 54-year-old man with cervical lymph node and pulmonary metastases from a scalp primary melanoma received three induction doses of ipilimumab. He developed alopecia universalis and widespread vitiligo, and he discontinued treatment because of hypophysitis. Maintenance ipilimumab was started after a 6-month drug-free interval, with no further adverse events over 15 cycles. At week 12, computed tomography imaging showed no lung metastases and partial response in a supraclavicular lymph node, which was positive on positron-emission tomography. Five years after starting ipilimumab, the supraclavicular lymph node was calcified, and the patient was off steroid therapy and asymptomatic.The foregoing patients demonstrate long responses with ipilimumab (in association with delayed severe colitis in one case, and a constellation of immune events, including alopecia universalis in another). Re-treatment with ipilimumab may be possible even after significant immune adverse events.     

Hirnmetastasen des Melanoms

Context

Brain metastases occur in the majority of patients with metastatic melanoma and are the most common cause of death. Until recently, local therapy (neurosurgery, radiosurgery and whole brain radiotherapy) was the only option for a chance of disease control in the brain. Systemic treatment options are now available.

Objective

The aim of this study is to discuss the treatment options for brain metastases from melanoma.

Material and methods

Treatment recommendations are given in consideration of the S3 guidelines on diagnosis, therapy and follow-up of melanoma and recent publications (Pubmed and manual search).

Results

In limited brain metastases, neurosurgery and radiosurgery are established treatments that can prolong survival. Immunotherapy with ipilimumab appears to have activity in patients with brain metastases, particularly when metastases are small and asymptomatic (response rate 16?% and median overall survival 7 months). The BRAF inhibitor dabrafenib achieved response rates of 30–40?% and a median overall survival of 7–8 months in patients with asymptomatic BRAF mutation brain metastases. The intracranial disease control rate was 80–90?%. In patients with symptomatic BRAF mutation brain metastases, the BRAF inhibitor vemurafenib showed activity with a disease control rate of >?80?% and a median overall survival of 5 months. In symptomatic multiple brain metastases, palliative whole brain radiotherapy is an established treatment even though it has failed to show an overall survival benefit. Corticosteroids and antiepileptic drugs are indicated for patients presenting with intracranial hypertension and epileptic seizures. Treatment of patients with metastatic melanoma and brain metastases should be discussed in a multidisciplinary team.

Conclusion

The therapeutic options for patients with brain metastases from melanoma have improved in recent years. Presently, there are several effective local and systemic treatments available.     

Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial

Melanoma has a high propensity to metastasize to the brain, and this is often responsible for treatment failure in patients with advanced disease. Melanoma patients with brain metastases are usually excluded from clinical trials because of their expected survival of approximately 5 months. A growing body of evidence suggests that ipilimumab, a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has activity against melanoma brain metastases. We conducted a retrospective analysis of data from a phase II study of ipilimumab in advanced melanoma patients. Twelve of 115 patients randomized in the parent trial had stable brain metastases at baseline, as identified by an Independent Review Committee, and were evaluated for efficacy. Two of the 12 patients achieved a partial response and three had stable disease. Both patients with a partial response and one with stable disease were alive at the last follow-up, with survival time of more than 4 years. The median overall survival of the 12 patients was 14 months (range: 2.7-56.4+). An additional four patients with stable brain metastases at baseline were identified by a secondary Independent Review Committee reviewer, and were evaluated for safety. Central nervous system-related adverse events of grade 3-4, specifically cerebral edema and convulsion/seizure, occurred in two of 16 patients. Although the present study is limited by the fact that it is a retrospective analysis of a small number of patients, the results provide further evidence for the safety and efficacy of ipilimumab in melanoma patients with stable brain metastases.     

Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma

Temozolomide (TMZ) is the first new chemotherapy agent to be approved for the treatment of high-grade malignant gliomas in more than 20 years. This novel oral alkylating agent has demonstrated promising activity not only in brain tumors, but in a variety of solid tumors, including malignant melanoma. TMZ is 100% bioavailable when taken orally and, because of its small size and lipophilic properties, it is able to cross the blood-brain barrier. Concentrations in the central nervous system are approximately 30% of plasma concentrations. Once it has entered the central nervous system, TMZ can be spontaneously converted to the active metabolite. These pharmacologic properties make it an ideal agent for treating central nervous system malignancies. In patients with advanced metastatic melanoma, brain metastases are a major cause of treatment failure. In this setting, TMZ has been shown to be as effective as dacarbazine, with a similar safety profile. More importantly, there is evidence to suggest that TMZ-treated patients have a lower incidence of central nervous system relapse compared with dacarbazine-treated patients. Therefore, TMZ is actively being investigated for the treatment and prevention of brain metastases in melanoma patients. TMZ may become an important part of treatment regimens for advanced metastatic melanoma.     

Targeting of melanoma brain metastases using engineered neural stem/progenitor cells

Brain metastases are an increasingly frequent and serious clinical problem for cancer patients, especially those with advanced melanoma. Given the extensive tropism of neural stem/progenitor cells (NSPCs) for pathological areas in the central nervous system, we expanded investigations to determine whether NSPCs could also target multiple sites of brain metastases in a syngeneic experimental melanoma model. Using cytosine deaminase-expressing NSPCs (CD-NSPCs) and systemic 5-fluorocytosine (5-FC) pro-drug administration, we explored their potential as a cell-based targeted drug delivery system to disseminated brain metastases. Our results indicate a strong tropism of NSPCs for intracerebral melanoma metastases. Furthermore, in our therapeutic paradigm, animals with established melanoma brain metastasis received intracranial implantation of CD-NSPCs followed by systemic 5-FC treatment, resulting in a significant (71%) reduction in tumor burden. These data provide proof of principle for the use of NSPCs for targeted delivery of therapeutic gene products to melanoma brain metastases.     

Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1

IntroductionIn CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years’ minimum follow-up.MethodsTreatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only).ResultsOverall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months’ minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43–0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66–0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed.ConclusionsWith all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.     

Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases

Patients with melanoma brain metastases have a poor prognosis and historically have been excluded from clinical trials. The Expanded Access Program (EAP) provided an opportunity to evaluate the feasibility of ipilimumab (3 mg/kg every 3 weeks for four doses) in patients with stage 3 (unresectable) or 4 melanoma and asymptomatic brain metastases, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Tumor assessments were conducted at baseline and week 12 using immune-related response criteria and patients were monitored for adverse events (AEs). Of 855 patients participating in the EAP in Italy, 146 had asymptomatic brain metastases. With a median follow-up of 4 months, the global disease control rate was 27 %, including 4 patients with a complete response and 13 with a partial response. Median progression-free survival and overall survival were 2.8 and 4.3 months, respectively and approximately one-fifth of patients were alive 1 year after starting ipilimumab. In total, 29 % of patients reported a treatment-related AE of any grade, which were grade 3/4 in 6 % of patients. AEs were generally reversible with treatment as per protocol-specific guidelines. Ipilimumab shows durable benefits in some patients with advanced melanoma metastatic to the brain, with safety results consistent with those previously reported in clinical trials.     

Development of a preclinical model of spontaneous human melanoma central nervous system metastasis

Metastatic spread of melanoma to the central nervous system (CNS) is associated with dismal prognosis. Preclinical testing of novel therapeutic approaches would be aided by the development of appropriate models of spontaneous CNS metastasis arising from primary tumors. A highly metastatic variant of the WM239A human melanoma cell line, designated 113/6-4L, was generated and used to test the efficacy of long-term, low-dose metronomic cyclophosphamide and vinblastine chemotherapy on advanced established metastatic disease in sites such as liver, lungs, and lymph node. This treatment resulted in control of advanced, systemic disease and prolongation of survival. Among long-term surviving mice, 20% showed the presence of spontaneous brain metastases. Two cell lines (131/4-5B1 and 131/4-5B2) were generated from such metastases, which were found to spontaneously metastasize to brain parenchyma with occasional localization to leptomeninges, after orthotopic transplantation and removal of the primary tumor. The cell lines were found to have increased ability to proliferate in brain-conditioned medium and displayed enhanced adhesion to lung and brain endothelial cells. These findings represent the first report of spontaneous CNS metastases generated from primary tumors of any human cancer in mice, which heritably maintains this phenotype, and as such, the variant cell lines generated should aid studies in the biology and treatment of CNS metastases, especially of melanoma origin.     

Central nervous system involvement in malignant melanoma

One hundred consecutive patients with cerebral metastases from malignant melanoma were studied in relation to survival from the time of diagnosis of central nervous system (CNS) involvement, response to treatment, characteristics of their primary lesion, and the course of the disease from initial diagnosis to the development of intracranial tumor. After treatment, clinical and investigational evidence of objective regression of cerebral lesions was demonstrable in ten patients who survived with a median of 11.5 months from diagnosis of CNS involvement. In 11 additional patients, CNS disease remained clinically stable for a median period of 7 months. Median survival for the entire group of 100 patients was 2.5 months. However, eight patients (8%) survived longer than 1 year from the time of diagnosis of cerebral metastases, four of whom (4%) survived longer than 2 years; the longest survivor being disease-free and incomplete neurologic remission at more than 82 months. Patients with malignant melanoma metastatic to the brain should be informed of the therapeutic options available for their disease.     

Management of brain metastases in patients with melanoma

PURPOSE OF REVIEW: Melanoma is the third most common metastatic brain tumor in the United States and is a major cause of morbidity and mortality. The development of more effective therapies for melanoma brain metastases is a major unmet clinical need and is summarized in this review. RECENT FINDINGS: Management strategies include symptomatic treatment with corticosteroids and anticonvulsants, and definitive therapy in the form of whole-brain radiation therapy, surgical resection, stereotactic radiosurgery, and systemic therapy. The data on whole-brain radiation therapy show little impact on survival, but there is evidence that it may improve neurologic deficits. Surgery may provide a survival advantage in combination with whole-brain radiation therapy in the management of a single brain melanoma metastasis, compared with whole-brain radiation therapy alone. Stereotactic radiosurgery may offer a survival advantage (in a select group of patients with limited disease) when used alone or in combination with whole-brain radiation therapy, compared with whole-brain radiation therapy alone. Fotemustine, temozolomide, and thalidomide are three agents with high central nervous system penetration that are being actively investigated as part of systemic therapy. SUMMARY: The currently available therapeutic options offer palliative relief of symptoms in most patients and a survival advantage in selected patients with melanoma and brain metastases. An urgent need exists to further define these treatments in the context of randomized trials, several of which are under way in the United States and abroad.     

Patterned distribution of metastases from malignant melanoma in humans

Malignant melanoma has an unpredictable clinical course in terms of metastatic behavior, and further understanding might lead to improved therapeutic intervention with immune agents or antagonists. To determine whether metastases show patterns or are randomly distributed, we analyzed the distributions of metastases in the 56 patients with metastatic malignant melanoma, subjected to complete autopsy at The Johns Hopkins Hospital, using parametric statistics and cluster analysis. Variables examined included age, race, sex, location of primary tumor, length of survival, mode of therapy, histology of tumor, location of metastases, and extent of tumor infiltration at each metastatic site. The results indicate that the distributions of metastases from malignant melanoma are patterned such that significant positive correlations (p less than 0.05 or better) were observed among various tissues and organs. We identified several aggregations with respect to the distributions of metastases: (a) central nervous system; (b) mesodermal; (c) endocrine; (d) reticuloendothelial; and (e) foregut. Organs and tissues comprising each aggregation were interrelated by their similar developmental origins or functions. A very highly significant negative correlation between central nervous system and hepatic metastases (p less than 0.001) was also demonstrated by cluster analysis. We concluded that the distributions of metastases from malignant melanoma are not random; the patterns of metastases may be related to the embryological derivation of tissues involved.     

Chemotherapy for breast cancer brain metastases

Breast cancer is the second most common cause of brain metastases, and 10-15% of patients develop clinically overt central nervous system disease. Radiotherapy is the standard treatment for patients with brain metastases. Surgical resection should be considered in patients with isolated brain metastasis and no extracranial disease. The role of chemotherapy in breast cancer brain metastases is not clearly defined; the results of the 8 trials found in the literature are reported. Most experience has been gained with the CMF (cyclophosphamide, methotrexate and fluorouracil) and PE (cisplatin and etoposide) regimens; here the median survival of 6 months is similar to radiotherapy. The blood-brain barrier, maintained by tight endothelial junctions and active transport mechanisms, is a major reason for the lower activity of most chemotherapeutic agents compared to other sites of metastatic disease. Most substances with good penetration of the blood-brain barrier have limited activity against breast cancer and some of the most active substances in breast cancer - including doxorubicine, the taxanes and trastuzumab - appear not to reach the central nervous system in sufficient concentrations. Approaches to overcome the blood-brain barrier are still experimental, and more research is clearly needed to identify chemotherapeutic agents both active in breast cancer and with good penetration of the blood-brain barrier. With the exception of patients with resectable brain metastases, danger of cranial herniation or poor general condition, chemotherapy should be offered to breast cancer patients with brain metastases that have progressive extracranial metastatic disease or relapse after radiotherapy.     

Two heads better than one? Ipilimumab immunotherapy and radiation therapy for melanoma brain metastases

Melanoma is an aggressive malignancy with a deplorable penchant for spreading to the brain. While focal therapies such as surgery and stereotactic radiosurgery can help provide local control, the majority of patients still develop intracranial progression. Novel therapeutic combinations to improve outcomes for melanoma brain metastases (MBM) are clearly needed. Ipilimumab, the anticytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, has been shown to improve survival in patients with metastatic melanoma, but many of these trials either excluded or had very few patients with MBM. This article will review the efficacy and limitations of ipilimumab therapy for MBM, describe the current evidence for combining ipilimumab with radiation therapy, illustrate potential mechanisms for synergy, and discuss emerging clinical trials specifically investigating this combination in MBM.