Changing Treatment Paradigms for Brain Metastases From Melanoma-Part 1: Diagnosis, Prognosis, Symptom Control, and Local Treatment

Melanoma is the third most common cause of brain metastases, after lung and breast cancer. The management of melanoma brain metastases can be broadly divided into symptom control and therapeutic strategies. Supportive treatments include corticosteroids to reduce peritumoral edema, antiepileptics for seizure control, and medications to preserve cognitive function. Until recently, therapeutic strategies consisted primarily of local treatments, including surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). Surgery, WBRT, and SRS-alone and in various combinations-still play an important role in treatment, especially in patients with few and/or smaller brain lesions. Much work has been done recently to try to determine the optimal settings for these therapies, the most effective ways to combine them, and ideal radiation dose and fractions.

Introduction

Recent progress in the management of advanced melanoma has resulted in improved 5-year survival rates; however, melanoma brain metastases remain a significant cause of morbidity and mortality. Approximately 20% of patients with metastatic melanoma have brain metastases at diagnosis. Overall, about 50% of patients with stage IV melanoma will develop symptomatic brain metastases.[1,2] Cerebral hemispheres are the site of 80% of brain lesions from melanoma, followed by the cerebellum (15%) and brainstem (5%).[3] Common clinical manifestations include headache, neurologic deficits, cognitive impairment, and seizures. Until recently, patients with melanoma brain metastases had a dismal prognosis, with a median overall survival (OS) of 6 months.[4]

The management of melanoma brain metastases can be broadly divided into supportive management and therapeutic strategies. Supportive treatments include corticosteroids to reduce peritumoral edema, antiepileptics for seizure control, and medications to preserve cognitive function. Traditionally, therapeutic strategies focused on local treatments, including surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). Historically, systemic therapy has had limited utility in the management of melanoma brain metastases. However, the treatment paradigm has changed considerably with the advent of targeted therapy and immunotherapy. Approximately 50% of patients with advanced melanoma harbor a BRAF mutation, and a number of targeted agents for this mutation and the downstream pathway have shown promise in the management of metastatic melanoma. Immunotherapeutic agents such as those that target cytotoxic T-lymphocyte–associated antigen 4 and programmed death 1 (PD-1) have shown clinical efficacy in melanoma brain metastases and are now considered first-line treatment options for metastatic melanoma.

Biology of Brain Metastases

Until recently, melanoma brain metastases were believed to have the highest mutational discordance of any tumor type relative to the primary site.[5] However, Chen et al reported molecular profiling that included hot spot mutations, global microRNA expression patterns, quantitative analysis of protein expression, and reverse phase protein array analysis of samples from 16 patients.[6] The authors reported complete concordance in mutational profiles between intracranial and extracranial sites. Despite these similarities, expression of activation-specific protein markers of the phosphoinositide-3 kinase (PI3K)/AKT pathway was shown to be increased in brain metastases compared with extracranial metastases. Another study compared the expression of mutated BRAF at different metastatic sites in advanced melanoma and showed greater mutational concordance (16/20 patients) between brain metastases and the primary tumor than between other visceral/subcutaneous metastases and the primary site.[7] These studies provide an initial understanding of the molecular characteristics of melanoma brain metastases.

With the advent of immunotherapy, the tumor microenvironment and immune infiltration have been a focus of intense research. The brain has traditionally been thought of as an immune-privileged organ, but recent studies have established the existence of a neuro-immune axis, throwing this belief into question.[8] Our understanding of the unique interplay between the immune system and the central nervous system has evolved dramatically in recent years. Berghoff et al investigated the expression of PD-1, programmed death ligand 1 (PD-L1), CD3, CD8, CD45RO, forkhead box protein 3 (FoxP3), CD20, and BRAF V600E by immunohistochemistry in melanoma brain metastasis samples.[9] The tumor-infiltrating lymphocytes (TILs) present varied among the samples: out of 43 specimens, 33 stained positive for CD3 TILs, 39 for CD8, 32 for CD45RO, 27 for PD-1, 21 for FoxP3, and 19 for CD20 TILs. Tumoral PD-L1 expression was observed in 22 specimens, with significant PD-L1 expression (> 5% of cells) seen in 9 of these, suggesting a role for immunotherapeutic agents in melanoma brain metastases.

Prognostic Indices

Although the median OS of patients with melanoma brain metastases is dismal, approximately 5% of these patients are long-term survivors.[1] Hence, prognostic factors that predict outcomes and that can guide treatment decisions and enrollment in clinical trials are of value. Several large single-center series have examined various primary tumor, brain metastasis, and patient characteristics predictive of survival.[1,10,11] Age, performance status, number of brain metastases, presence of extracranial metastases, time from primary tumor diagnosis, presence of neurologic symptoms, and elevated lactate dehydrogenase level are factors that determine survival.[12]

Sperduto et al proposed a new disease-based scoring index based on data from 483 patients with newly diagnosed melanoma brain metastases from 8 different centers.[13] On multivariate analysis, performance status and number of brain metastases were prognostic for survival in these patients. The outcomes of this Diagnostic-Specific Graded Prognostic Assessment (DS-GPA) for patients with melanoma brain metastases varied from a median survival of 3.4 months for those in GPA class I to a median survival of 13.2 months for patients in GPA class IV.

Prognostic indices have inherent limitations. All of them have been evaluated retrospectively, have had only OS as the endpoint, have not included a molecular and genetic profile of the primary malignancy, and have not taken systemic therapy into consideration.[14] A large single-institution experience of 366 patients that included treatment of 1,336 brain metastases has also shed some light on the interplay of important prognostic variables in patients with melanoma brain metastases.[15] In this series, characteristics associated with survival included younger age, lack of extracranial metastases, performance status, and treatment with BRAF inhibitors or immunotherapies. This work specifically highlights the improved outcomes in patients who are eligible for and receive newer targeted therapies. For example, the 12-month survival estimate for patients treated with BRAF inhibitors was 37%, compared with 23% for those who did not receive these therapies (P = .01). Moreover, the 12-month survival estimate for patients treated with immunotherapies was 47%, compared with 22% for those who did not receive these therapies (P = .04).[15] Clearly, further work is needed to define the impact of mutation status, targeted drugs, and immunotherapy in the current era.

Diagnosis

The neurologic symptoms associated with brain metastases include headaches; seizures; and cranial nerve, motor, and sensory deficits. All melanoma patients with neurologic symptoms worrisome for melanoma brain metastases should undergo a gadolinium-enhanced MRI scan of the brain, provided no contraindications exist. Guidelines recommend routine MRI of the brain with and without gadolinium contrast for patients with stage IV melanoma because of the high prevalence of asymptomatic brain metastases.[16] CT of the brain with and without contrast can be used as an alternate imaging modality.

Management of Symptoms

Supportive care for patients with brain metastases typically consists of controlling the cerebral edema with steroids. Because of its minimal mineralocorticoid effect and long half-life, dexamethasone is the steroid of choice; however, other steroids at an equivalent dose can be used and tapered gradually over a 2-week period.[17] A randomized trial conducted in 1994 compared different doses of dexamethasone, ranging from 4 mg/day to 16 mg/day, and concluded that 4 to 8 mg/day would provide the same degree of clinical improvement in 1 week.[18] Routine use of prophylactic antiepileptics in patients with brain metastases is not recommended.[19] When patients have seizures, several antiepileptics are available, including phenytoin, carbamazepine, valproic acid, and levetiracetam. Non–enzyme-inducing agents such as levetiracetam are preferred so as to avoid interactions with systemic anticancer agents.

Neurosurgical Options

Surgery has traditionally been used for the management of solitary brain metastases and large symptomatic brain lesions. Multiple retrospective studies have reported improved survival with surgery compared with best supportive care.[12,20-22] Younger patients with good performance status, fairly well-controlled extracranial disease, solitary brain metastasis, and lesions in accessible locations and of small size generally have better outcomes with surgery.[21,23] Surgery is usually followed by a radiation boost to the surgical bed by either WBRT or SRS, with an intention of sterilizing the surrounding tissues and preventing local recurrence. Two randomized trials comparing adjuvant WBRT against surgery alone have shown an improvement in outcomes with the addition of WBRT.[24,25] Patchell et al evaluated the role of post-resection WBRT for a single brain metastasis compared with surgery alone.[25] Postoperative WBRT resulted in a significant reduction in local and distant intracranial failure. However, no difference in OS or in the duration of functional independence was noted. Similar results were seen in the European Organisation for Research and Treatment of Cancer 22952-26001 study, with decreased 2-year intracranial and resection site recurrence but without a significant survival benefit.[24] Multiple retrospective reports of postoperative SRS have shown improved patient outcomes; however, prospective data are awaited.[26,27] In a retrospective review of 56 selected patients with multiple metastases, Bindal et al showed a benefit for resection.[28] In practice, surgery plays an important role in debulking and in removal of life-threatening lesions. Surgery also provides immediate relief from intracranial hypertension by eliminating the mass effect, and it relieves symptomatic hydrocephalus by reestablishing the flow of cerebrospinal fluid.

WBRT

Brain metastases from melanoma are generally considered more radio-resistant than brain metastases of other histologies.[29] Randomized trials of WBRT have reported survivals in the range of 2.4 to 4.8 months.[30] The ideal dose and number of fractions, in order to achieve a balance between intracranial control and the risk of cognitive decline, has been the subject of intense debate. WBRT fraction sizes of ≤ 3 Gy do not lead to significant neurocognitive decline. A retrospective study compared a higher dose of radiation, 40 Gy in 20 fractions, against 30 Gy in 10 fractions.[31] The 40-Gy group had a median OS of 5.6 months compared with 3.1 months in the 30-Gy group. However, most trials have not been melanoma-specific and have included patients with all tumor types. Patients who are symptomatic, with changes in mentation, headaches, and/or seizures-but who are deemed unfit for surgery or SRS because of a large number of metastases, poor performance status, or uncontrolled extracranial metastases-are generally treated with WBRT.[32]

SRS

SRS has been increasingly used in the management of melanoma brain metastases in the last 2 decades. SRS in melanoma brain metastases results in local control rates of 50% to 75% at 1 year.[33-35] SRS is generally limited to lesions smaller than 4 cm in diameter.[36] A retrospective review of 333 patients with melanoma brain metastases treated with SRS showed a sustained tumor control rate of 73%.[35] The 12-month cumulative incidence of local failure was 28% in another single-institution experience of 103 patients with a total of 381 treated melanoma brain metastases.[37] The number of brain metastases that can be treated with SRS has been intensely investigated. SRS for solitary brain metastasis was compared with surgery plus WBRT in a phase III trial that closed prematurely due to poor accrual. The OS, freedom from local recurrence, and neurologic death rates were similar in both groups.[38] Several studies have evaluated the role of SRS in patients with 1 to 3 or 4 brain metastases.[39,40] Aoyama et al compared SRS alone with SRS followed by WBRT in patients with 1 to 4 brain metastases.[39] No difference in neurocognitive function or survival was observed. The SRS-alone arm had increased rates of local and distant intracranial failure. A phase III trial compared WBRT followed by SRS vs WBRT alone in 333 patients with 1 to 3 brain metastases from different histologies; only 13 patients with melanoma brain metastases were included.[41] Performance status at 6 months improved significantly with the addition of SRS to WBRT. SRS for patients with 5 to 10 brain lesions was evaluated in a multi-institution prospective observational Japanese study of 1,194 patients.[42] The median OS, neurocognitive function, and rate of post-SRS complications did not differ for patients with 5 to 10 brain lesions compared with those who had 2 to 4 brain lesions.[43]

An Approach to the Initial Management of Patients With Melanoma Brain Metastases

Appropriate care of patients with melanoma brain metastases begins with diagnosis. In melanoma, the brain is a common site of metastatic spread, both early and late. It is crucial to begin screening patients for brain metastases at the time melanoma is first diagnosed; National Comprehensive Cancer Network guidelines have recently been updated to reflect this changing diagnostic paradigm. The frequency at which to repeat imaging is still not known.

Enrollment in an appropriate clinical trial is the preferred management for eligible patients with good performance status. When appropriate clinical trials are unavailable or when patients are acutely symptomatic or have hemorrhagic brain metastases, upfront local therapies need to be considered. Surgical resection followed by SRS is suitable for patients with solitary large symptomatic brain metastases, whereas radiation therapy options are preferred for patients with multiple small brain metastases. Although the number of lesions that can be safely and effectively treated with SRS is a moving target, SRS is currently the preferred treatment for patients with 1 to 4 brain metastases and for patients with higher numbers of small-volume metastatic lesions (up to 10 lesions).[42] For patients with numerous lesions or poor performance status, WBRT can be considered. A treatment algorithm for patients with melanoma brain metastases will be provided with Part 2 of the article.

Conclusion

Brain metastases are a common occurrence in the natural history of metastatic melanoma; therefore, most guidelines recommend screening imaging studies to diagnose asymptomatic brain metastases. Considerable progress has been made in the genomic characterization of brain metastases from melanoma. Various prognostic factors and indices have been suggested. A key part of management of patients with brain metastases is management of symptoms caused by cerebral edema and seizures. Resection of brain metastases can be considered in select patients with single or oligometastatic disease. Although melanoma is thought to be resistant to radiation therapy, SRS continues to play an important role in the treatment of brain metastases. In Part 2, we will provide insights into the current state of systemic therapies for brain metastases from melanoma.

Financial Disclosure:Dr. Ahluwalia reports grants and personal fees from Monteris Medical, grants and personal fees from AbbVie, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from AstraZeneca, personal fees from Datar Genetics, personal fees from CBT Pharmaceuticals, personal fees from Kadmon Pharmaceuticals, personal fees from Elsevier, grants and personal fees from Novocure, grants from Novartis, grants and personal fees from Incyte, grants from Pharmacyclics, grants from TRACON Pharmaceuticals, personal fees from prIME Oncology, and personal fees from Caris Life Sciences. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Acknowledgment:Dr. Ahluwalia’s work was supported by the Dean and Diane Miller Family Chair in Neuro-Oncology.

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