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Malignant melanoma metastatic to the central nervous system is an important cause of morbidity and mortality. The management of these patients is rapidly evolving. This activity reviews the evaluation and management of malignant melanoma metastatic to the central nervous system, and reviews the role of the interprofessional team in evaluating and managing patients with this condition. Objectives: Review the etiology of malignant melanoma metastatic to the central nervous system. Describe the evaluation of patients with malignant melanoma metastatic to the central nervous system. Review the management considerations for patients with malignant melanoma metastatic to the central nervous system. Access free multiple choice questions on this topic.

Malignant melanoma is a serious form of skin cancer. It arises from the melanocytes which in turn originate from neural crest cells. The overall survival at 5 years depends on the extent and stage of the disease at diagnosis. Patients with advanced-stage melanoma are more likely to develop metastasis.[1] This topic will discuss the distant metastatic disease of malignant melanoma involving the central nervous system (CNS).

Multiple etiologies were proposed for melanoma. The common etiologies are: Ultraviolet radiation Indoor tanning PUVA therapy Light skin pigmentation, poor tanning ability FAMM syndrome and atypical mole syndrome Personal history of melanoma Familial history of melanoma Immunosuppressed patients with HIV, lymphoma, transplant history Drugs: TNF inhibitors, BRAF inhibitors Risk factors for CNS metastasis in Melanoma: Male gender and age > 60 years[2] Deep invasive or ulcerated primary lesions[2] Acral, lentiginous, or nodular histology Involvement of >3 lymph nodes[3] Visceral metastasis at diagnosis[2] BRAF mutation and NRAS mutation[4][5] Activation of the phosphoinositide 3-kinase/protein kinase B pathway (PI3K/AKT)[6] Elevated LDH[2]

The incidence of melanoma is increasing worldwide and is the fifth leading cause of cancer in men and women in the United States.[7] Even though the incidence of melanoma is increasing, the mortality rates are beginning to decrease likely due to screening measures. Melanoma is rare in children and adolescents and the incidence continues to increase with age.[8][9] Melanoma is more common in Whites than in Blacks or Asians.[10] Brain metastases (BM) is a common complication, especially with advanced-stage melanoma. Melanoma accounts for almost 10 percent of BM and the third leading cause after lung and breast cancer.[11] In a large multi-institutional adjuvant study, the incidence of BM is about 15 percent in Stage III melanoma, which predominantly occurred in the first 3 years after surgery.[12] The majority of the BM are supratentorial, with about 15 percent infratentorial.

BM has a highly variable clinical presentation. It should be suspected in a malignant melanoma patient with neurologic symptoms or behavioral abnormalities. The most common cause of the symptoms is due to the enlarging metastases and inflammatory edema surrounding the lesions in the brain. It is important to remember that the majority of patients initially can be asymptomatic. Headache is the most common presentation in BM and occurs in about 40% to 50% of patients.[13] Associated symptoms of nausea, vomiting, abnormal neurologic exam, and positional change are suggestive of a possible BM. Focal neurologic symptoms are presenting symptoms in about 20-40 percent of the patients.[14] Cognitive dysfunction, stroke, seizures are other symptoms. BM in melanoma also has a higher propensity for spontaneously bleeding.

BM must be distinguished from primary brain tumors. Imaging studies are very useful to further evaluate the symptoms, but rarely some patients may need a definitive brain biopsy for diagnosis. Contrast-enhanced magnetic resonance imaging (MRI) is the preferred imaging modality for the diagnosis of BM. Non-contrasted MRI or CT scans are less sensitive compared to the contrast MRI.[15][16][17] Radiological features help differentiate BM from other CNS lesions. The following features are helpful to accurately characterize the BM Presence of multiple lesions Tumor localization at the junction of the gray and white mater Large vasogenic edema compared with the size of the lesion Circumscribed margins

The multidisciplinary approach is the cornerstone for the optimal management of patients with BM in melanoma and is strongly recommended by the National Comprehensive Cancer Network (NCCN). Conventional treatment for BM consists of the use of whole-brain radiation therapy (WBRT) for multiple metastatic lesions in the brain and stereotactic radiosurgery (SRS) for a limited number of lesions. Although CNS has been thought to be a sanctuary site for traditional systemic therapy options, recent data suggests it is not the case and systemic therapy modalities are being considered for disease control in the CNS. Advances in the neurosurgical techniques and stereotactic radiosurgery (SRS) along with systemic therapy options of immunotherapy and BRAF with MEK inhibitors have led to the major improvement in control of the BM and also improved the OS in these group of patients. SRS also has the ability to treat lesions that are not amenable for surgical resection. The key factors to consider in a patient with a new diagnosis of BM are: The number, size, location, extent of CNS symptoms The extent of extracranial systemic disease BRAF mutation status Performance status of the patient and co-morbidities Prior systemic therapy Thus, the treatment is individualized depending on patient characteristics. Patients with new untreated BM and who are naive to systemic therapy, the initial therapy depends on the size of the lesions as well as if the patient is symptomatic. Patients with small, usually <1cm and minimally symptomatic or asymptomatic lesions, locoregional therapy (SRS or surgery) can be deferred and patients started on systemic therapy. A careful monitoring plan for intracranial progression is required. The choice of systemic therapy depends on if the melanoma harbors BRAF mutation. In BRAF – mutant tumors, both the targeted therapy with BRAF with MEK inhibitors as well as immunotherapy combination nivolumab with ipilimumab is effective.[18][19] In tumors that do not harbor the BRAF mutation, combination immunotherapy with nivolumab and ipilimumab is a reasonable option considering patients can tolerate the medications.[20] Rare patients with isolated BM SRS or surgery are still a reasonable front-line option.

Patients with new untreated BM and who are naive to systemic therapy, the initial therapy depends on the size of the lesions as well as if the patient is symptomatic. Patients with small, usually <1cm and minimally symptomatic or asymptomatic lesions, locoregional therapy (SRS or surgery) can be deferred and patients started on systemic therapy. A careful monitoring plan for intracranial progression is required. The choice of systemic therapy depends on if the melanoma harbors BRAF mutation. In BRAF – mutant tumors, both the targeted therapy with BRAF with MEK inhibitors as well as immunotherapy combination nivolumab with ipilimumab is effective.[18][19] In tumors that do not harbor the BRAF mutation, combination immunotherapy with nivolumab and ipilimumab is a reasonable option considering patients can tolerate the medications.[20] Rare patients with isolated BM SRS or surgery are still a reasonable front-line option. For patients with large, symptomatic lesions, local control is a high priority, thus SRS or surgery is considered as front-line prior to systemic therapy. These patients also will need supportive measures like the use of high dose steroids, to control the edema. Patients who are not surgical candidates, RT alone, usually SRS or WBRT depending on the number of lesions is reasonable. For patients with new brain metastases but on current or prior systemic therapy, the options for systemic therapy are more limited, and thus local control is best achieved by SRS or surgery. Also, patients who are not eligible for systemic therapy with intracranial efficacy, locoregional therapy is offered. Imaging surveillance with brain MRI or contrast-enhanced CT of the head is critical for the follow-up of the brain metastases. The duration between scans depends on if loco-regional therapy was deferred or not. In patients who didn't receive loco-regional therapy, a scan every 8 to 12 weeks is recommended. In patients who received loco-regional therapy, a scan every 12 weeks is reasonable.

About 10% of mass lesions in the brain in patients with a history of cancer are not metastases. The differential diagnosis for a BM includes: Abscess Acute demyelinating disorders Progressive multifocal leukoencephalopathy Radiation necrosis Granuloma Primary brain tumors like gliomas and astrocytoma Stroke Multiple sclerosis Nonbacterial thrombotic endocarditis

Advances in neurosurgical techniques over the years have contributed to improvement in the management of the BM.[21][22][23][24] Surgical resection is usually preferable for patients with a large lesion (usually > 3cm), solitary or very limited number of brain lesions, superficial lesions in areas where surgery do not lead to an unacceptable loss of function, posterior fossa metastatic lesions causing complications like brain herniation and with Karnofsky performance status 90 to 100 percent.[25] Post-surgical management usually involves SRS to the resection cavity to decrease the local recurrence. Even though no randomized controlled trials have been conducted, observational studies showed an increase in local control rates with SRS to the tumor bed.[26][27][28]

SRS is gaining importance in the management of the BM in Melanoma. Compared to Whole Brain Radiotherapy (WBRT), SRS has better long-term safety and a decline in the neurocognitive function.[29] SRS may be administered by itself as a primary treatment to control the BM or as adjuvant therapy after surgical removal of the brain lesions as discussed above. WBRT is not recommended as adjuvant therapy. SRS is often given as a single fraction SRS or given over two – five fractions. Usually, SRS is limited to patients with 3 -5 lesions, but recently some clinicians are using the SRS in patients with a higher number of lesions.[30][31] On one study in patients with melanoma and BM, local control at 6 and 12 months was 87% and 68% respectively in patients treated with SRS.[32]

Immunotherapy including ipilimumab, nivolumab, and pembrolizumab and targeted therapy with combination BRAF and MEK inhibitors are the first-line therapeutic options recommended for advanced melanoma. These groups of medications provided significant advances in the management of melanoma patients with untreated BM. Immunotherapy Since 2011, multiple immunotherapy medications were approved in patients with melanoma. Ipilimumab, a cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor and programmed cell death-1(PD-1) inhibitors nivolumab, and pembrolizumab are currently approved in advanced melanoma. The combination of ipilimumab and nivolumab has an approximately 50% response rates in patients with asymptomatic BM.[20] CHECKMATE – 204 is a phase II trial that enrolled melanoma patients with asymptomatic BM. Patients were given ipilimumab 3mg/kg every 3 weeks for 4 doses in combination with nivolumab 1 mg/kg. After the 4 doses, a maintenance nivolumab was given 3mg/kg every 2 weeks. The intracranial response rate was 55% with 29% complete response rates. The estimated OS at 18 months was 75%. ABC trial, another phase II trial similar to CHECKMATE -204, compared ipilimumab with nivolumab to single-agent nivolumab.[33] Combination therapy was noted to show a significantly higher intracranial response of 46% compared to 20% with single-agent nivolumab. A meta-analysis of patients with melanoma and BM showed the combination of ipilimumab and nivolumab was associated with improved PFS and OS.[18] Pembrolizumab as a single-agent demonstrated intracranial response rates of up to 26% and nivolumab up to 20% in patients with untreated BM in melanoma.[33][34][35] In symptomatic patients, there is limited data on the efficacy of immunotherapy as a sole initial therapy. Usually, these patients will require steroids with/without local CNS therapy before systemic therapy. It is recommended to decrease the dose of steroids to minimal or even discontinue them prior to the start of immunotherapy due to decreased efficacy of immunotherapy in combination with steroids.[36] BRAF and MEK Inhibitors

In symptomatic patients, there is limited data on the efficacy of immunotherapy as a sole initial therapy. Usually, these patients will require steroids with/without local CNS therapy before systemic therapy. It is recommended to decrease the dose of steroids to minimal or even discontinue them prior to the start of immunotherapy due to decreased efficacy of immunotherapy in combination with steroids.[36] BRAF and MEK Inhibitors Approximately 40% of melanomas harbor a BRAF mutation which is a component of the mitogen-activated protein kinase (MAPK) signaling pathway and activates the downstream MEK protein. By the use of molecularly targeted agents that inhibit the BRAF and MEK, the treatment of metastatic melanoma has improved significantly. The most common BRAF mutation is the V600E, but there are other mutations noted within the BRAF protein. Three combinations of BRAF plus MEK inhibitors are currently available which include dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib. To determine the efficacy of the combination of BRAF plus MEK inhibitors, a phase II COMBI-MB study evaluated dabrafenib and trametinib in multiple subsets of melanoma patients with BM. In the subset of patients with asymptomatic and no prior therapy to the BM with associated BRAF V600E mutation, intracranial response rates were about 60% with a median PFS of about 6 months.[19] Similar responses were also noted in other subsets of patients who received prior local therapy to the BM, harbor other BRAF mutations, and in symptomatic patients.[19] Due to radiation sensitization with BRAF inhibitors, it is recommended to hold the treatment with BRAF inhibitors with or without MEK inhibitors one to three days prior and one day after radiation therapy.[37][38][39] Chemotherapy Cytotoxic chemotherapy didn’t show any efficacy in patients with BM alone or in combination with RT and has no significant role in the management of these patients.[40][41]

Currently, the eighth edition of the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) is used to stage Melanoma. This is based on the evaluation of the primary tumor, regional lymph nodes, lymphatic drainage, and distant metastases. A separate distant metastases (M) category was created in the eighth edition of the AJCC staging based upon the presence of CNS metastases. Patients with CNS metastases with or without the involvement of the other sites are staged as M1d.[42]

Melanoma patients with BM historically had a dismal prognosis. Before 2000, the median survival was 3 to 4 months with one-year survival <10%.[43][44][45] Significant advances made in the last two decades with radiation therapy in BM as well as systemic therapy in melanoma has significantly improved the prognosis. One study enrolled 179 patients with BM secondary to melanoma who are subsequently treated with SRS and systemic therapy involving immunotherapy or targeted therapy. The one year and two-year OS were 50% and 27% respectively.[46] A variety of tools were developed for prognostication in individual melanoma patients. These include the Basic Score for Brain Metastases (BSBM), score index or radiosurgery in BM, and a diagnosis-specific graded prognostic assessment tool for patients with melanoma brain metastases.[47][48][49][50]

Patient education is paramount to the appropriate management of malignant melanoma prevention as well as after diagnosis. Skin cancer preventative education for patients as well as their families is important. Proper precautions, as well as regular sunscreen use, may diminish the incidence of subsequent melanoma. The diagnosis of metastasis to the CNS in melanoma patients is a difficult discussion and constitutes the incurable nature of the disease. Education should be given regarding the multi-disciplinary care and involvement of surgical oncology, radiation oncology, and medical oncology along with other allied health professionals. Educating patients regarding the goals of treatment, available treatment options, side effects associated with the various treatments help them choose their care according to their goals and beliefs with emphasis on compliance with follow up visits and surveillance scans. Education and resources regarding the end of life care should be provided to the patients and their families.

Management of metastatic melanoma to the CNS is complex and needs a multidisciplinary team approach involving surgical oncologists, neurosurgeons, medical oncologists, radiation oncologists, dermatology, pathologists, and radiologists. It is recommended these complex patients discussed in a multidisciplinary tumor board for a consensus treatment plan. This approach will facilitate optimal patient care, individualized treatment decisions, and also improve enrollment in the clinical trials. Medical oncology and radiation oncology play a critical role in the management of CNS metastases. Appropriate histopathologic diagnosis with associated harboring mutations helps direct targeted therapies to control the disease/ Medical oncologists make treatment decisions and oversee the administration of systemic medications like immunotherapy and targeted therapies. Radiation oncologists use WBRT or SRS to help manage the symptoms as well as control the growth of the BM. Oncologic pharmacists review medications, verify doses and play a very important role in the administration and side effect management. Oncology nurses staff the infusion center to administer the systemic medications and closely monitor for any associated side effects. The decision on when to stop treating a patient with CNS metastases as well as metastatic melanoma can be difficult, and this decision should involve the patient, family, friends, and the healthcare team. Extensive communication of interdisciplinary teams with the patient and families improve the outcomes of patients with metastatic melanoma to the CNS.[51][52][53]