Management of brain metastases in melanoma
- Wolfram E Samlowski, MD
Wolfram E Samlowski, MD
- Comprehensive Cancer Centers of Nevada (Las Vegas)
- Clinical Professor
- University of Nevada (Reno)
- Kevin Oh, MD
Kevin Oh, MD
- Assistant Professor of Radiation Oncology
- Harvard Medical School
- Attending Radiation Oncologist
- Massachusetts General Hospital
- Julian K Wu, MD
Julian K Wu, MD
- Professor of Neurosurgery
- Tufts University School of Medicine
- Section Editors
- Michael B Atkins, MD
Michael B Atkins, MD
- Section Editor — Malignant Melanoma and Other Cutaneous Neoplasms; Cancer of the Kidney
- Deputy Director
- Georgetown Lombardi Comprehensive Cancer Center
- Russell S Berman, MD
Russell S Berman, MD
- Section Editor — Skin and Soft Tissue Surgery
- Chief of Surgical Oncology
- New York University Langone Medical Center
Brain metastases are a frequent complication in patients with melanoma. In the past, brain metastases almost invariably contributed to the patients' death. However, major advances in neuroimaging, improved options for the neurosurgical and radiotherapeutic management of brain metastases, improved management of metastatic disease at systemic sites, and demonstrated activity of systemic treatments against central nervous system metastases have substantially improved the prognosis for many patients.
The management of patients with melanoma and brain metastases will be reviewed here. General aspects of the clinical manifestations, diagnosis, and management of cancer-related brain metastases are discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases" and "Overview of the treatment of brain metastases".)
EPIDEMIOLOGY AND CLINICAL PRESENTATION
Melanoma accounts for approximately 10 percent of all patients who develop brain metastases. In the United States, only lung and breast cancers are more frequent primary sites associated with brain metastases .
In the eighth edition of the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system for melanoma, brain metastases are separated from other sites of metastasis and form a separate M category, M1d (table 1).
Patients with melanoma limited to the skin and without lymph node involvement (stage I, II (table 2 and table 3)) have a low incidence of brain metastases , although younger patients with thick primaries may have an increased risk of late central nervous system (CNS) failure . In patients who presented with advanced regional melanoma (stage IIIB and C), a retrospective analysis of data from the large multi-institutional S0008 adjuvant trial observed a 15 percent incidence of subsequent brain metastases, which occurred predominantly in the first three years after surgery .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
Subscribers log in hereLiterature review current through: Sep 2017. | This topic last updated: Sep 25, 2017.References
- Johnson JD, Young B. Demographics of brain metastasis. Neurosurg Clin N Am 1996; 7:337.
- Zakrzewski J, Geraghty LN, Rose AE, et al. Clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post-brain metastases survival. Cancer 2011; 117:1711.
- Osella-Abate S, Ribero S, Sanlorenzo M, et al. Risk factors related to late metastases in 1,372 melanoma patients disease free more than 10 years. Int J Cancer 2015; 136:2453.
- Samlowski WE, Moon J, Witter M, et al. CNS metastases as a site of progression during SWOG Intergroup Study S0008: A Phase III Trial comparing High Dose Interferon Alpha-2b versus Cisplatin, Vinblastine, DTIC plus IL-2 and Interferon in Patients with Stage IIIB and C Melanoma. Submitted for publication.
- Chiarion-Sileni V, Guida M, Ridolfi L, et al. Central nervous system failure in melanoma patients: results of a randomised, multicentre phase 3 study of temozolomide- and dacarbazine- based regimens. Br J Cancer 2011; 104:1816.
- Sloan AE, Nock CJ, Einstein DB. Diagnosis and treatment of melanoma brain metastasis: a literature review. Cancer Control 2009; 16:248.
- Raizer JJ, Hwu WJ, Panageas KS, et al. Brain and leptomeningeal metastases from cutaneous melanoma: survival outcomes based on clinical features. Neuro Oncol 2008; 10:199.
- http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf (Accessed on December 24, 2014).
- Sampson JH, Carter JH Jr, Friedman AH, Seigler HF. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 1998; 88:11.
- Bedikian AY, Wei C, Detry M, et al. Predictive factors for the development of brain metastasis in advanced unresectable metastatic melanoma. Am J Clin Oncol 2011; 34:603.
- Ballo MT, Ross MI, Cormier JN, et al. Combined-modality therapy for patients with regional nodal metastases from melanoma. Int J Radiat Oncol Biol Phys 2006; 64:106.
- Bottoni U, Clerico R, Paolino G, et al. Predictors and survival in patients with melanoma brain metastases. Med Oncol 2013; 30:466.
- Huismans AM, Haydu LE, Shannon KF, et al. Primary melanoma location on the scalp is an important risk factor for brain metastasis: a study of 1,687 patients with cutaneous head and neck melanomas. Ann Surg Oncol 2014; 21:3985.
- El-Osta H, Falchook G, Tsimberidou A, et al. BRAF mutations in advanced cancers: clinical characteristics and outcomes. PLoS One 2011; 6:e25806.
- Thumar J, Shahbazian D, Aziz SA, et al. MEK targeting in N-RAS mutated metastatic melanoma. Mol Cancer 2014; 13:45.
- Fife KM, Colman MH, Stevens GN, et al. Determinants of outcome in melanoma patients with cerebral metastases. J Clin Oncol 2004; 22:1293.
- Carlino MS, Fogarty GB, Long GV. Treatment of melanoma brain metastases: a new paradigm. Cancer J 2012; 18:208.
- Davies MA, Liu P, McIntyre S, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer 2011; 117:1687.
- Gaudy-Marqueste C, Dussouil AS, Carron R, et al. Survival of melanoma patients treated with targeted therapy and immunotherapy after systematic upfront control of brain metastases by radiosurgery. Eur J Cancer 2017; 84:44.
- Staudt M, Lasithiotakis K, Leiter U, et al. Determinants of survival in patients with brain metastases from cutaneous melanoma. Br J Cancer 2010; 102:1213.
- Ewend MG, Carey LA, Brem H. Treatment of melanoma metastases in the brain. Semin Surg Oncol 1996; 12:429.
- Mori Y, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for cerebral metastatic melanoma: factors affecting local disease control and survival. Int J Radiat Oncol Biol Phys 1998; 42:581.
- Gupta G, Robertson AG, MacKie RM. Cerebral metastases of cutaneous melanoma. Br J Cancer 1997; 76:256.
- Buchsbaum JC, Suh JH, Lee SY, et al. Survival by radiation therapy oncology group recursive partitioning analysis class and treatment modality in patients with brain metastases from malignant melanoma: a retrospective study. Cancer 2002; 94:2265.
- Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 2012; 30:419.
- Serizawa T, Higuchi Y, Nagano O, et al. A new grading system focusing on neurological outcomes for brain metastases treated with stereotactic radiosurgery: the modified Basic Score for Brain Metastases. J Neurosurg 2014; 121 Suppl:35.
- Lorenzoni JG, Devriendt D, Massager N, et al. Brain stem metastases treated with radiosurgery: prognostic factors of survival and life expectancy estimation. Surg Neurol 2009; 71:188.
- Salvetti DJ, Nagaraja TG, McNeill IT, et al. Gamma Knife surgery for the treatment of 5 to 15 metastases to the brain: clinical article. J Neurosurg 2013; 118:1250.
- Rava P, Leonard K, Sioshansi S, et al. Survival among patients with 10 or more brain metastases treated with stereotactic radiosurgery. J Neurosurg 2013; 119:457.
- Serizawa T, Hirai T, Nagano O, et al. Gamma knife surgery for 1-10 brain metastases without prophylactic whole-brain radiation therapy: analysis of cases meeting the Japanese prospective multi-institute study (JLGK0901) inclusion criteria. J Neurooncol 2010; 98:163.
- Hunter GK, Suh JH, Reuther AM, et al. Treatment of five or more brain metastases with stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 2012; 83:1394.
- Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014; 15:387.
- Kim JM, Miller JA, Kotecha R, et al. The risk of radiation necrosis following stereotactic radiosurgery with concurrent systemic therapies. J Neurooncol 2017; 133:357.
- Minniti G, Paolini S, D'Andrea G, et al. Outcomes of postoperative stereotactic radiosurgery to the resection cavity versus stereotactic radiosurgery alone for melanoma brain metastases. J Neurooncol 2017; 132:455.
- Geukes Foppen MH, Brandsma D, Blank CU, et al. Targeted treatment and immunotherapy in leptomeningeal metastases from melanoma. Ann Oncol 2016; 27:1138.
- Smalley KS, Fedorenko IV, Kenchappa RS, et al. Managing leptomeningeal melanoma metastases in the era of immune and targeted therapy. Int J Cancer 2016; 139:1195.
- Ryken TC, McDermott M, Robinson PD, et al. The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010; 96:103.
- Millar BM, Bezjak A, Tsao M, et al. Defining the impact and contribution of steroids in patients receiving whole-brain irradiation for cerebral metastases. Clin Oncol (R Coll Radiol) 2004; 16:339.
- Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012; 13:459.
- Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372:320.
- Mikkelsen T, Paleologos NA, Robinson PD, et al. The role of prophylactic anticonvulsants in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010; 96:97.
- Goldlust SA, Hsu M, Lassman AB, et al. Seizure prophylaxis and melanoma brain metastases. J Neurooncol 2012; 108:109.
- Samlowski WE, Watson GA, Wang M, et al. Multimodality treatment of melanoma brain metastases incorporating stereotactic radiosurgery (SRS). Cancer 2007; 109:1855.
- Noël G, Proudhom MA, Valery CA, et al. Radiosurgery for re-irradiation of brain metastasis: results in 54 patients. Radiother Oncol 2001; 60:61.
- Chao ST, Barnett GH, Vogelbaum MA, et al. Salvage stereotactic radiosurgery effectively treats recurrences from whole-brain radiation therapy. Cancer 2008; 113:2198.
- Ammirati M, Cobbs CS, Linskey ME, et al. The role of retreatment in the management of recurrent/progressive brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 2010; 96:85.
- Stockham AL, Tievsky AL, Koyfman SA, et al. Conventional MRI does not reliably distinguish radiation necrosis from tumor recurrence after stereotactic radiosurgery. J Neurooncol 2012; 109:149.
- McDonald JD, Chong BW, Lewine JD, et al. Integration of preoperative and intraoperative functional brain mapping in a frameless stereotactic environment for lesions near eloquent cortex. Technical note. J Neurosurg 1999; 90:591.
- Lee JY, Lunsford LD, Subach BR, et al. Brain surgery with image guidance: current recommendations based on a 20-year assessment. Stereotact Funct Neurosurg 2000; 75:35.
- Hatiboglu MA, Chang EL, Suki D, et al. Outcomes and prognostic factors for patients with brainstem metastases undergoing stereotactic radiosurgery. Neurosurgery 2011; 69:796.
- Iwadate Y, Namba H, Yamaura A. Significance of surgical resection for the treatment of multiple brain metastases. Anticancer Res 2000; 20:573.
- Sills AK. Current treatment approaches to surgery for brain metastases. Neurosurgery 2005; 57:S24.
- Paek SH, Audu PB, Sperling MR, et al. Reevaluation of surgery for the treatment of brain metastases: review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques. Neurosurgery 2005; 56:1021.
- Choi CY, Chang SD, Gibbs IC, et al. Stereotactic radiosurgery of the postoperative resection cavity for brain metastases: prospective evaluation of target margin on tumor control. Int J Radiat Oncol Biol Phys 2012; 84:336.
- Ling DC, Vargo JA, Wegner RE, et al. Postoperative stereotactic radiosurgery to the resection cavity for large brain metastases: clinical outcomes, predictors of intracranial failure, and implications for optimal patient selection. Neurosurgery 2015; 76:150.
- Li J, Bentzen SM, Li J, et al. Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis. Int J Radiat Oncol Biol Phys 2008; 71:64.
- Skeie BS, Skeie GO, Enger PØ, et al. Gamma knife surgery in brain melanomas: absence of extracranial metastases and tumor volume strongest indicators of prolonged survival. World Neurosurg 2011; 75:684.
- Yu C, Chen JC, Apuzzo ML, et al. Metastatic melanoma to the brain: prognostic factors after gamma knife radiosurgery. Int J Radiat Oncol Biol Phys 2002; 52:1277.
- Motzer RJ, Bacik J, Mariani T, et al. Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol 2002; 20:2376.
- Selek U, Chang EL, Hassenbusch SJ 3rd, et al. Stereotactic radiosurgical treatment in 103 patients for 153 cerebral melanoma metastases. Int J Radiat Oncol Biol Phys 2004; 59:1097.
- Bernard ME, Wegner RE, Reineman K, et al. Linear accelerator based stereotactic radiosurgery for melanoma brain metastases. J Cancer Res Ther 2012; 8:215.
- Anker CJ, Grossmann KF, Atkins MB, et al. Avoiding Severe Toxicity From Combined BRAF Inhibitor and Radiation Treatment: Consensus Guidelines from the Eastern Cooperative Oncology Group (ECOG). Int J Radiat Oncol Biol Phys 2016; 95:632.
- Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004; 363:1665.
- Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006; 295:2483.
- Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 2011; 29:134.
- Welzel G, Fleckenstein K, Schaefer J, et al. Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys 2008; 72:1311.
- Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009; 10:1037.
- Liu J. A novel hypothesis of blood-brain barrier (BBB) development and in vitro BBB model: Neural stem cell is the driver of BBB formation and maintenance. journal of experimental and integrative medicine 2012; 2:39.
- Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 2016; 17:976.
- Weber JS, Amin A, Minor D, et al. Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial. Melanoma Res 2011; 21:530.
- Queirolo P, Spagnolo F, Ascierto PA, et al. Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J Neurooncol 2014; 118:109.
- Tazi K, Hathaway A, Chiuzan C, Shirai K. Survival of melanoma patients with brain metastases treated with ipilimumab and stereotactic radiosurgery. Cancer Med 2015; 4:1.
- Silk AW, Bassetti MF, West BT, et al. Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med 2013; 2:899.
- Knisely JP, Yu JB, Flanigan J, et al. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg 2012; 117:227.
- Samlowski, W. Unpublished data.
- Long GV, Atkinson V, Menzies AM, et al. A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients with melanoma brain metastases: the Anti-PD1 Collaboration (ABC) (abstract 9508). 2017 American Society of Clinical Oncology annual meeting.
- Tawbi HA, Forsyth PA, Algazi AP, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with melanoma metastatic to the brain: results of the phase II study Checkmate 204 (abstract 9507). 2017 American Society of Clinical Oncology annual meeting.
- Chu MB, Fesler MJ, Armbrecht ES, et al. High-Dose Interleukin-2 (HD IL-2) Therapy Should Be Considered for Treatment of Patients with Melanoma Brain Metastases. Chemother Res Pract 2013; 2013:726925.
- Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012; 379:1893.
- Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13:1087.
- Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017; 18:863.
- McArthur GA, Maio M, Arance A, et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol 2017; 28:634.
- Merten R, Hecht M, Haderlein M, et al. Increased skin and mucosal toxicity in the combination of vemurafenib with radiation therapy. Strahlenther Onkol 2014; 190:1169.
- Boussemart L, Boivin C, Claveau J, et al. Vemurafenib and radiosensitization. JAMA Dermatol 2013; 149:855.
- Satzger I, Degen A, Asper H, et al. Serious skin toxicity with the combination of BRAF inhibitors and radiotherapy. J Clin Oncol 2013; 31:e220.
- Agarwala SS, Kirkwood JM, Gore M, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 2004; 22:2101.
- Margolin K, Atkins B, Thompson A, et al. Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group. J Cancer Res Clin Oncol 2002; 128:214.
- Jacquillat C, Khayat D, Banzet P, et al. Final report of the French multicenter phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastases. Cancer 1990; 66:1873.
- EPIDEMIOLOGY AND CLINICAL PRESENTATION
- RISK FACTORS
- APPROACH TO MANAGEMENT
- Multidisciplinary approach
- Asymptomatic small brain metastases
- Symptomatic or large brain metastases
- Leptomeningeal disease
- Symptom control
- Patient selection
- Management following surgery
- STEREOTACTIC RADIOSURGERY
- Radiation sensitization
- Role of WBRT after SRS
- SYSTEMIC THERAPY
- - Anti-PD-1 inhibitors
- - Ipilimumab
- - Nivolumab plus ipilimumab
- - Adoptive cell therapy
- Targeted agents
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS