- Melanoma ranks behind only small-cell carcinoma of the lung:
- As the most common tumor that metastasizes to the brain
- An unusual feature of brain metastases:
- Is their propensity for hemorrhage:
- Which occurs much more frequently with melanoma than other primary tumors
- Hemorrhage occurs in:
- 33% to 50% of patients with brain metastases from melanoma
- Is their propensity for hemorrhage:
- Prognosis worsens with an increasing number of lesions and the presence of neurologic symptoms:
- Median survival has historically:
- Been reported to be 3 to 4 months
- With the description of combined immune checkpoint blockade for patients with brain metastasis by Tawbi et al:
- The prognosis for such patients has significantly improved
- In this phase II study of 94 melanoma patients with nonirradiated measurable brain metastases, Tawbi et al:
- Described a rate of radiologic clinical benefit of 57% and complete response rate of 26%
- As such, surgical resection is utilized less commonly than it has been historically
- Currently, patients with brain metastases are generally treated with:
- A combination of immune checkpoint blockade and gamma knife radiation:
- With the use of additional systemic or local therapies under the guidance of a multidisciplinary treatment team
- A combination of immune checkpoint blockade and gamma knife radiation:
- The role of targeted therapy remains unclear:
- Although BRAF / MEK inhibition appears to have superior control in extracranial rather than intracranial disease
- Stereotactic radiosurgery:
- Is an important option for patients with small to medium brain metastases who have a reasonable life expectancy:
- With no signs of increased intracranial pressure
- Is an important option for patients with small to medium brain metastases who have a reasonable life expectancy:
- Whole brain radiation therapy:
- Is not commonly utilized in contemporary treatment strategies
- Median survival has historically:
- Epidemiology and Significance of Brain Metastases in Cutaneous Melanoma:
- Cutaneous melanoma has a high propensity for central nervous system involvement:
- With brain metastases occurring in over one third of patients with advanced disease and up to 75% at autopsy
- Brain metastases are a major cause of morbidity and mortality in this population:
- Contributing significantly to neurologic complications and death
- Cutaneous melanoma has a high propensity for central nervous system involvement:
- Historically, the prognosis for patients with melanoma brain metastases has been poor:
- But recent advances in systemic and local therapies have improved outcomes
- Prognosis and Prognostic Factors:
- Median overall survival for patients with melanoma brain metastases has improved from 4 to 6 months in the pre-immunotherapy era to:
- 8.9 to 13 months in recent cohorts
- Prognosis is adversely affected by the presence of:
- Leptomeningeal disease
- Elevated serum lactate dehydrogenase (LDH)
- Multiple brain metastases at diagnosis
- Extracranial disease
- The presence of neurological symptoms
- Notably, LDH levels greater than twice the upper limit of normal at the time of brain metastasis onset:
- Are associated with poor prognosis and predict limited benefit from radiotherapy
- Median overall survival for patients with melanoma brain metastases has improved from 4 to 6 months in the pre-immunotherapy era to:
- Management Strategies:
- Management of brain metastases in cutaneous melanoma is multimodal and individualized
- Key components include:
- Surgery
- Stereotactic radiosurgery (SRS)
- Whole-brain radiation therapy (WBRT)
- Immunotherapy
- Targeted therapy
- Stereotactic radiosurgery (SRS):
- Is preferred for patients with a limited number of brain metastases
- Whole-brain radiation therapy (WBRT):
- Is reserved for those with multiple or leptomeningeal metastases:
- Given its association with neurocognitive toxicity
- Is reserved for those with multiple or leptomeningeal metastases:
- Systemic therapies:
- Specifically immune checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembrolizumab) and BRAF / MEK inhibitors for BRAF-mutant melanoma:
- Have demonstrated intracranial activity and improved survival
- Combined modality therapy, particularly the integration of RT with systemic agents:
- Has been shown to improve local and distant intracranial control and overall survival:
- Especially when RT is administered before or during systemic therapy
- Has been shown to improve local and distant intracranial control and overall survival:
- The American Society of Clinical Oncology (ASCO), Society for Neuro-Oncology (SNO), and American Society for Radiation Oncology (ASTRO) recommend:
- Ipilimumab plus nivolumab (regardless of BRAF status) or dabrafenib plus trametinib (for BRAF V600E mutation) for asymptomatic patients:
- With local therapy deferred until intracranial progression
- Ipilimumab plus nivolumab (regardless of BRAF status) or dabrafenib plus trametinib (for BRAF V600E mutation) for asymptomatic patients:
- Management decisions should be tailored based on:
- BRAF status
- Number and size of metastases
- Presence of symptoms
- Extent of extracranial disease
- Specifically immune checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembrolizumab) and BRAF / MEK inhibitors for BRAF-mutant melanoma:
- Role and Timing of Radiation Therapy:
- Radiation therapy remains a cornerstone for local control of brain metastases in melanoma
- SRS:
- Is the standard for patients with a limited number of lesions, offering high rates of local control with minimal neurotoxicity
- WBRT:
- Is now less commonly used due to its detrimental neurocognitive effects and limited impact on overall survival
- The combination of RT with immunotherapy or targeted therapy:
- Improves outcomes without increasing the risk of radiation necrosis or other neurotoxicities
- The timing of RT is critical:
- Optimal results are observed when RT is delivered before or concurrently with systemic therapy
- RT is particularly important for:
- Symptomatic or progressive lesions
- When rapid local control is required
- Areas Needing Further Evidence:
- Despite these advances, there remains a need for additional randomized trials to define the optimal sequencing and combination of RT with systemic therapies:
- As well as to clarify the best management strategies for patients with multiple or symptomatic brain metastases
- Despite these advances, there remains a need for additional randomized trials to define the optimal sequencing and combination of RT with systemic therapies:
- In summary, brain metastasis in cutaneous melanoma:
- Is a common and serious complication with historically poor prognosis, but outcomes have improved with the advent of effective systemic and local therapies
- Radiation therapy, particularly SRS, remains central to management, especially when integrated with immunotherapy or targeted agents, and should be individualized based on patient and disease characteristics
- References:
- Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. Tawbi HA, Forsyth PA, Algazi A, et al. The New England Journal of Medicine. 2018;379(8):722-730. doi:10.1056/NEJMoa1805453.
- Melanoma Brain Metastasis Presentation, Treatment, and Outcomes in the Age of Targeted and Immunotherapies. Bander ED, Yuan M, Carnevale JA, et al. Cancer. 2021;127(12):2062-2073. doi:10.1002/cncr.33459.
- Melanoma Brain Metastases: A Retrospective Analysis of Prognostic Factors and Efficacy of Multimodal Therapies. Internò V, Sergi MC, Metta ME, et al. Cancers. 2023;15(5):1542. doi:10.3390/cancers15051542.
- Clinical Management of Multiple Melanoma Brain Metastases: A Systematic Review. Goyal S, Silk AW, Tian S, et al. JAMA Oncology. 2015;1(5):668-76. doi:10.1001/jamaoncol.2015.1206.
- The Impact of Current Treatment Modalities on the Outcomes of Patients With Melanoma Brain Metastases: A Systematic Review. van Opijnen MP, Dirven L, Coremans IEM, Taphoorn MJB, Kapiteijn EHW. International Journal of Cancer. 2020;146(6):1479-1489. doi:10.1002/ijc.32696.
- Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline. Vogelbaum MA, Brown PD, Messersmith H, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2022;40(5):492-516. doi:10.1200/JCO.21.02314.
- 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. Dohm AE, Nakashima JY, Kalagotla H, et al. European Journal of Cancer (Oxford, England : 1990). 2023;192:113287. doi:10.1016/j.ejca.2023.113287.
- Melanoma Brain Metastasis: The Impact of Stereotactic Radiosurgery, BRAF Mutational Status, and Targeted and/or Immune-Based Therapies on Treatment Outcome. Kotecha R, Miller JA, Venur VA, et al. Journal of Neurosurgery. 2018;129(1):50-59. doi:10.3171/2017.1.JNS162797.
- Systemic Therapy for Melanoma: ASCO Guideline Update. Seth R, Agarwala SS, Messersmith H, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2023;41(30):4794-4820. doi:10.1200/JCO.23.01136.
- Recommended First-Line Management of Brain Metastases From Melanoma: A Multicenter Survey of Clinical Practice. Jablonska PA, Fong CH, Kruser T, et al. Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 2022;168:89-94. doi:10.1016/j.radonc.2022.01.037.
- Changing Therapeutic Landscape for Melanoma With Multiple Brain Metastases. Jiang C, Wallington DG, Anker CJ, et al. Neurosurgery. 2020;87(3):498-515. doi:10.1093/neuros/nyaa076.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 