Abstract
While selective BRAF inhibitors have demonstrated improved outcomes in patients with metastatic BRAF V600E mutant melanoma, management of brain metastases prior to and during therapy presents challenges. Stereotactic radiosurgery (SRS) is an effective treatment for melanoma brain metastases, but there is limited safety and efficacy data on the use of SRS during BRAF therapy. An analysis was performed of patients with metastatic melanoma and brain metastases treated with SRS while on vemurafenib. MRI scans were reviewed post-SRS to evaluate local control (LC) as well as distant control. We identified 80 metastatic melanoma brain lesions treated in 24 patients. The median planning target volume was 0.28 cm3 (range 0.05–4.19 cm3), and lesions were treated to a median dose of 24 Gy (range 15–24 Gy). The median follow up was 5.1 months (range 2–25.2 months). Eight (10 %) lesions showed progression at a median of 6.1 months (range 2–20.1 months) following SRS. Kaplan–Meier LC estimates at 6 and 12 months were 92 and 75 %, respectively. Fourteen (58 %) patients were noted to have distant brain failure at a median of 3.4 months (range 1.9–16.1 months) following treatment with SRS. Median overall (OS) from the date of SRS was 7.2 months (range 1.5–26.8 months) with a median of 11.9 months (range 1.5–28.5 months) since the date of brain metastases diagnosis. There was no evidence of increased toxicity with the combination of SRS and vemurafenib. SRS to brain metastases appears to be both safe and effective for patients treated concurrently with BRAF inhibitors.
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References
Staudt M, Lasithiotakis K, Leiter U, Meier F, Eigentler T, Bamberg M, Tatagiba M, Brossart P, Garbe C (2010) Determinants of survival in patients with brain metastases from cutaneous melanoma. Br J Cancer 102:1213–1218. doi:10.1038/sj.bjc.6605622
Hwu WJ, Lis E, Menell JH, Panageas KS, Lamb LA, Merrell J, Williams LJ, Krown SE, Chapman PB, Livingston PO, Wolchok JD, Houghton AN (2005) Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study. Cancer 103:2590–2597. doi:10.1002/cncr.21081
Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker EB, LeBoit PE, Pinkel D, Bastian BC (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353:2135–2147. doi:10.1056/NEJMoa050092
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954. doi:10.1038/nature00766
Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, Burton EA, Wong B, Tsang G, West BL, Powell B, Shellooe R, Marimuthu A, Nguyen H, Zhang KY, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D’Andrea K, Koehler A, Stumm M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, Chapman PB, Flaherty KT, Xu X, Nathanson KL, Nolop K (2010) Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596–599. doi:10.1038/nature09454
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA, Group BS (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516. doi:10.1056/NEJMoa1103782
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 13:1087–1095. doi:10.1016/S1470-2045(12)70431-X
Kefford RMM, Arance A, Nathan P, Blank C, Francoise MA, Gonzalez R, Schachter J, Margolin K, Lasserre SF, Veronese L, McArthur G Vemurafenib (2013) Metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicenter study. In: 10th international meeting of the Society for Melanoma Research, Philadelphia
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 50:611–621. doi:10.1016/j.ejca.2013.11.002
Anker CJ, Ribas A, Grossmann AH, Chen X, Narra KK, Akerley W, Andtbacka RH, Noyes RD, Shrieve DC, Grossmann KF (2013) Severe liver and skin toxicity after radiation and vemurafenib in metastatic melanoma. J Clin Oncol 31:e283–e287. doi:10.1200/JCO.2012.44.7755
Boussemart L, Boivin C, Claveau J, Tao YG, Tomasic G, Routier E, Mateus C, Deutsch E, Robert C (2013) Vemurafenib and radiosensitization. JAMA Dermatol 149:855–857. doi:10.1001/jamadermatol.2013.4200
Schulze B, Meissner M, Wolter M, Rodel C, Weiss C (2014) Unusual acute and delayed skin reactions during and after whole-brain radiotherapy in combination with the BRAF inhibitor vemurafenib. Two case reports. Strahlenther Onkol 190:229–232. doi:10.1007/s00066-013-0474-3
Narayana A, Mathew M, Tam M, Kannan R, Madden KM, Golfinos JG, Parker EC, Ott PA, Pavlick AC (2013) Vemurafenib and radiation therapy in melanoma brain metastases. J Neurooncol 113:411–416. doi:10.1007/s11060-013-1127-1
Gaudy-Marqueste C, Carron R, Delsanti C, Loundou A, Monestier S, Archier E, Richard MA, Regis J, Grob JJ (2014) On demand Gamma-knife strategy can be safely combined with BRAF-inhibitors for the treatment of melanoma brain metastases. Ann Oncol. doi:10.1093/annonc/mdu266
Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, Farnan N (2000) Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 47:291–298
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247. doi:10.1016/j.ejca.2008.10.026
Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366:707–714. doi:10.1056/NEJMoa1112302
Rochet NM, Dronca RS, Kottschade LA, Chavan RN, Gorman B, Gilbertson JR, Markovic SN (2012) Melanoma brain metastases and vemurafenib: need for further investigation. Mayo Clin Proc 87:976–981. doi:10.1016/j.mayocp.2012.07.006
Rochet NM, Kottschade LA, Markovic SN (2011) Vemurafenib for melanoma metastases to the brain. N Engl J Med 365:2439–2441. doi:10.1056/NEJMc1111672
Sambade MJ, Peters EC, Thomas NE, Kaufmann WK, Kimple RJ, Shields JM (2011) Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032. Radiother Oncol 98:394–399. doi:10.1016/j.radonc.2010.12.017
Harding JJ, Barker CA, Carvajal RD, Wolchok JD, Chapman PB, Lacouture ME (2014) Cutis verticis gyrata in association with vemurafenib and whole-brain radiotherapy. J Clin Oncol 32:e54–e56. doi:10.1200/JCO.2013.49.3528
Huang V, Hepper D, Anadkat M, Cornelius L (2012) Cutaneous toxic effects associated with vemurafenib and inhibition of the BRAF pathway. Arch Dermatol 148:628–633. doi:10.1001/archdermatol.2012.125
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 42:581–589
Seung SK, Sneed PK, McDermott MW, Shu HK, Leong SP, Chang S, Petti PL, Smith V, Verhey LJ, Wara WM, Phillips TL, Larson DA (1998) Gamma knife radiosurgery for malignant melanoma brain metastases. Cancer J Sci Am 4:103–109
Selek U, Chang EL, Hassenbusch SJ 3rd, Shiu AS, Lang FF, Allen P, Weinberg J, Sawaya R, Maor MH (2004) Stereotactic radiosurgical treatment in 103 patients for 153 cerebral melanoma metastases. Int J Radiat Oncol Biol Phys 59:1097–1106. doi:10.1016/j.ijrobp.2003.12.037
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Ahmed, K.A., Freilich, J.M., Sloot, S. et al. LINAC-based stereotactic radiosurgery to the brain with concurrent vemurafenib for melanoma metastases. J Neurooncol 122, 121–126 (2015). https://doi.org/10.1007/s11060-014-1685-x
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DOI: https://doi.org/10.1007/s11060-014-1685-x