Top

17-08-2017 | Melanoma | Article

Metastatic melanoma: prognostic factors and survival in patients with brain metastases

Journal: Journal of Neuro-Oncology

Authors: E. Frinton, D. Tong, J. Tan, G. Read, V. Kumar, S. Kennedy, C. Lim, R. E. Board

Abstract

Brain metastases from malignant melanoma carry a poor prognosis. Novel systemic agents have improved overall survival (OS), but the value of whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) remains uncertain. The melanoma-specific graded prognostic assessment (msGPA) provides useful prognostic information, but the relevance to the modern-day population has not been validated. Since 2011, 53 patients received treatment for brain metastases from malignant melanoma at the Rosemere Cancer Centre medical oncology clinic. Data were collated on demographic factors and survival. Survival analyses were performed using Kaplan–Meier methods. Cox regression was used to identify prognostic factors on univariate and multivariate analysis. OS from the date of diagnosis of brain metastases was 4.83 months (range 0.27–30.4 months). On univariate analysis, BRAF, performance status and msGPA were significant prognostic indicators for OS (p = 0.0056, p = 0.0039 and p = 0.0001 respectively). msGPA remained significant on multivariate analysis (p = 0.0006). OS for BRAF-positive patients receiving targeted treatment (n = 22) was significantly better than for BRAF-negative patients (n = 26), with median survival times of 8.2 and 3.7 months respectively (p = 0.0039, HR 2.36). SRS combined with systemic agents (n = 16) produced an OS of 13.5 months. Patients receiving WBRT alone (n = 21) had a poor prognosis (2.2 months). The msGPA remains a valid prognostic indicator in the era of novel systemic treatments for melanoma. BRAF-positive patients receiving targeted agents during their treatment had favorable survival outcomes. WBRT alone should be use with caution in the active management of melanoma brain metastases.

Murrell J, Board R (2013) The use of systemic therapies for the treatment of brain metastases in metastatic melanoma: opportunities and unanswered questions. Cancer Treat Rev 39:833–838CrossRefPubMed

Davies MA, Liu P, McIntyre S et al [2011]. Prognostic factors for survival in melanoma patients with brain metastases. Cancer 117:1687–1696

Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS (2012) Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 13(5):459–465CrossRefPubMed

Wilkins A, Furness A, Corbett RW, Bloomfield A, Porta N, Morris S, Ali Z, Larkin J, Harrington K 2015. The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma. Br J Cancer 113(9):1275–1281CrossRefPubMedPubMedCentral

Dummer R, Goldinger SM, Turtschi CP, Eggmann NB, Michielin O, Mitchell L, Veronese L, Hilfiker PR, Felderer L, Rinderknecht JD (2014) Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer 50(3):611–621CrossRefPubMed

Bhatnagar AK, Kondziolka D, Lunsford LD, Flickinger JC (2007) Recursive partitioning analysis of prognostic factors for patients with four or more intracranial metastases treated with radiosurgery. Technol Cancer Res Treat 6(3):153–160CrossRefPubMed

Mori Y, Kondziolka D, Flickinger JC, Kirkwood JM, Agarwala S, Lunsford LD (1998). Stereotactic radiosurgery for cerebral metastatic melanoma: factors affecting local disease control and survival. Int J Radiat Oncol Biol Phys 42:581–589CrossRefPubMed

Yu C, Chen JC, Apuzzo ML, O’Day S, Giannotta SL, Weber JS, Petrovich Z (2002) Metastatic melanoma to the brain: prognostic factors after gamma knife radiosurgery. Int J Radiat Oncol Biol Phys 52:1277–1287CrossRefPubMed

Chang EL, Selek U, Hassenbusch SJ 3rd, Maor MH, Allen PK, Mahajan A, Sawaya R, Woo SY (2005) Outcome variation among “radioresistant” brain metastases treated with stereotactic radiosurgery. Neurosurgery 56:936–945 (discussion 936–945)CrossRefPubMed

10.

Doss LL, Memula N (1982) The radioresponsiveness of melanoma. Int J Radiat Oncol Biol Phys 8(7):1131–1134

11.

Dyer MA, Arvold ND, Chen YH, Pinnell NE, Mitin T, Lee EQ, Hodi FS, Ibrahim N, Weiss SE, Kelly PJ, Floyd SR, Mahadevan A, Alexander BM (2014) The role of whole brain radiation therapy in the management of melanoma brain metastases. Radiat Oncol 9:143CrossRefPubMedPubMedCentral

12.

Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W (2008). A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 70(2):510–514CrossRefPubMed

13.

Marcus DM, Lowe M, Khan MK, Lawson DH, Crocker IR, Shelton JW, Melton A, Maynard N, Delman KA, Carlson GW, Rizzo M (2014) Prognostic factors for overall survival after radiosurgery for brain metastases from melanoma. Am J Clin Oncol 37(6):580–584CrossRefPubMed

14.

Hauswald H, Stenke A, Debus J, Combs SE (2015) Linear accelerator-based stereotactic radiosurgery in 140 brain metastases from malignant melanoma. BMC Cancer 15:537CrossRefPubMedPubMedCentral

15.

Shultz DB, Modlin LA, Jayachandran P, Von Eyben R, Gibbs IC, Choi CY, Chang SD, Harsh GR, Li G, Adler JR, Hancock SL, Soltys SG (2015). Repeat courses of stereotactic radiosurgery (SRS), deferring whole-brain irradiation, for new brain metastases after initial SRS. Int J Radiat Oncol Biol Phys 92(5):993–999CrossRefPubMed

16.

StatsDirect Ltd. (2013) StatsDirect statistical software. StatsDirect Ltd., England. http://www.statsdirect.com

17.

Kaplan E, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53(282):457–481. Retrieved from http://www.jstor.org/stable/2281868

18.

Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG (1977) Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 35(1):1–39CrossRefPubMedPubMedCentral

19.

Cox D (1972) Regression models and life-tables. J R Stat Soc 34(2):187–220. Retrieved from http://www.jstor.org/stable/2985181

20.

Rubinstein JC, Sznol M, Pavlick AC, Ariyan S, Cheng E, Bacchiocchi A, Kluger HM, Narayan D, Halaban R (2010) Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med 8:67CrossRefPubMedPubMedCentral

21.

Ramanujam S, Schadendorf D, Long GV (2015) Systemic therapies for melanoma brain metastases: which drug for whom and when? Chin Clin Oncol 4(2):25PubMed

22.

Colombino M, Capone M, Lissia A, Cossu A, Rubino C, De Giorgi V, Massi D, Fonsatti E, Staibano S, Nappi O, Pagani E, Casula M, Manca A, Sini M, Franco R, Botti G, Caracò C, Mozzillo N, Ascierto PA, Palmieri G 2012. BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol 30(20):2522–2529CrossRefPubMed

23.

Capper D, Berghoff AS, Magerle M, Ilhan A, Wöhrer A, Hackl M, Pichler J, Pusch S, Meyer J, Habel A, Petzelbauer P, Birner P, von Deimling A, Preusser M (2012) Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases. Acta Neuropathol 123(2):223–233CrossRefPubMed

24.

Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D (2012) 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 13(11):1087–1095CrossRefPubMed

25.

Lwu S, Goetz P, Monsalves E, Aryaee M, Ebinu J, Laperriere N, Menard C, Chung C, Millar BA, Kulkarni AV, Bernstein M, Zadeh G (2013) Stereotactic radiosurgery for the treatment of melanoma and renal cell carcinoma brain metastases. Oncol Rep 29(2):407–412CrossRefPubMed

26.

Gallaher IS, Watanabe Y, DeFor TE, Dusenbery KE, Lee CK, Hunt MA, Lin HY, Yuan J (2016) BRAF mutation is associated with improved local control of melanoma brain metastases treated with gamma knife radiosurgery. Front Oncol 6:107CrossRefPubMedPubMedCentral

Medicine Matters Oncology

Abstract