Journal of Neuro-Oncology

, Volume 121, Issue 1, pp 159–165 | Cite as

Ipilimumab and whole brain radiation therapy for melanoma brain metastases

  • Naamit K. Gerber
  • Robert J. Young
  • Christopher A. Barker
  • Jedd D. Wolchok
  • Timothy A. Chan
  • Yoshiya Yamada
  • Leigh Friguglietti
  • Kathryn Beal
Clinical Study


Brain metastases (BM) frequently develop in patients with melanoma and are associated with a poor prognosis. Whole brain radiation therapy (WBRT) is a standard intervention for intracranial disease, particularly in patients with multiple BM. Ipilimumab improves survival in patients with advanced melanoma. The purpose of this study is to investigate the safety and efficacy of concurrent WBRT and ipilimumab. A retrospective analysis was conducted of 13 consecutive patients treated with WBRT within 30 days of ipilimumab administration. Radiographic response, as measured by serial magnetic resonance imaging scans post-treatment, was graded by modified World Health Organization (mWHO) and immune-related response criteria (irRC) in the 9 patients with follow-up imaging. Treatment-related toxicity was prospectively assessed during treatment. Four of nine patients (44 %) experienced partial response or stable central nervous system (CNS) disease as measured by mWHO criteria. This number increased to 5 patients (56 %) when irRC criteria were used. Rates of treatment-related neurologic toxicity were low with only one patient experiencing grade 3–4 neurologic toxicity. There was a high rate of intratumoral hemorrhage in this patient population, with 10 of 10 patients with post-treatment imaging demonstrating new or increased intratumoral bleeding after WBRT. This retrospective study demonstrates that the primary pattern of CNS response to WBRT and ipilimumab is stable disease and not regression of BM. Furthermore, while the combination of WBRT and ipilimumab may offer promising efficacy, prospective studies are needed to further assess efficacy and toxicity.


Melanoma Brain metastases Ipilimumab Immunotherapy Whole brain radiotherapy 



The authors would like to thank Lawrence A. Herman for his editorial assistance.

Conflict of interest

Dr. Wolchok is a paid consultant for and receives research funding from Bristol-Myers Squibb.


  1. 1.
    Bafaloukos D, Gogas H (2004) The treatment of brain metastases in melanoma patients. Cancer Treat Rev 30:515–520PubMedCrossRefGoogle Scholar
  2. 2.
    Fife KM, Colman MH, Stevens GN, Firth IC, Moon D, Shannon KF, Harman R, Petersen-Schaefer K, Zacest AC, Besser M, Milton GW, McCarthy WH, Thompson JF (2004) Determinants of outcome in melanoma patients with cerebral metastases. J Clin Oncol 22:1293–1300PubMedCrossRefGoogle Scholar
  3. 3.
    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 102:1213–1218PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Sampson JH, Carter JH Jr, Friedman AH, Seigler HF (1998) Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 88:11–20PubMedCrossRefGoogle Scholar
  5. 5.
    Mornex F, Thomas L, Mohr P, Hauschild A, Delaunay MM, Lesimple T, Tilgen W, Bui BN, Guillot B, Ulrich J, Bourdin S, Mousseau M, Cupissol D, Bonneterre ME, De Gislain C, Bensadoun RJ, Clavel M (2003) A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma. Melanoma Res 13:97–103PubMedCrossRefGoogle Scholar
  6. 6.
    Douglas JG, Margolin K (2002) The treatment of brain metastases from malignant melanoma. Semin Oncol 29:518–524PubMedCrossRefGoogle Scholar
  7. 7.
    Ellerhorst J, Strom E, Nardone E, McCutcheon I (2001) Whole brain irradiation for patients with metastatic melanoma: a review of 87 cases. Int J Radiat Oncol Biol Phys 49:93–97PubMedCrossRefGoogle Scholar
  8. 8.
    Hauswald H, Dittmar JO, Habermehl D, Rieken S, Sterzing F, Debus J, Combs SE (2012) Efficacy and toxicity of whole brain radiotherapy in patients with multiple cerebral metastases from malignant melanoma. Radiat Oncol 7:130PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Raizer JJ, Hwu WJ, Panageas KS, Wilton A, Baldwin DE, Bailey E, von Althann C, Lamb LA, Alvarado G, Bilsky MH, Gutin PH (2008) Brain and leptomeningeal metastases from cutaneous melanoma: survival outcomes based on clinical features. Neuro-Oncology 10:199–207PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Meyners T, Heisterkamp C, Kueter JD, Veninga T, Stalpers LJ, Schild SE, Rades D (2010) Prognostic factors for outcomes after whole-brain irradiation of brain metastases from relatively radioresistant tumors: a retrospective analysis. BMC Cancer 10:582PubMedCentralPubMedGoogle Scholar
  11. 11.
    Rades D, Heisterkamp C, Huttenlocher S, Bohlen G, Dunst J, Haatanen T, Schild SE (2010) Dose escalation of whole-brain radiotherapy for brain metastases from melanoma. Int J Radiat Oncol Biol Phys 77:537–541PubMedCrossRefGoogle Scholar
  12. 12.
    Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, Werner-Wasik M, Demas W, Ryu J, Bahary JP, Souhami L, Rotman M, Mehta MP, Curran WJ Jr (2004) 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 363:1665–1672PubMedCrossRefGoogle Scholar
  13. 13.
    Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, Markesbery WR, Macdonald JS, Young B (1990) A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494–500PubMedCrossRefGoogle Scholar
  14. 14.
    Soffietti R, Trevisan E, Ruda R (2012) Targeted therapy in brain metastasis. Curr Opin Oncol 24:679–686PubMedCrossRefGoogle Scholar
  15. 15.
    Robert C, Thomas L, Bondarenko I, O’Day S, DJ M, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526PubMedCrossRefGoogle Scholar
  16. 16.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Prins RM, Vo DD, Khan-Farooqi H, Yang MY, Soto H, Economou JS, Liau LM, Ribas A (2006) NK and CD4 cells collaborate to protect against melanoma tumor formation in the brain. J Immunol 177:8448–8455PubMedCrossRefGoogle Scholar
  18. 18.
    Wilson EH, Weninger W, Hunter CA (2010) Trafficking of immune cells in the central nervous system. J Clin Investig 120:1368–1379PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Grossman SA, Ye X, Lesser G, Sloan A, Carraway H, Desideri S, Piantadosi S (2011) Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res 17:5473–5480PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Barker C, Postow M (2014) Combinations of radiotherapy and immunotherapy for melanoma: a review of clinical outcomes. Int J Radiat Oncol Biol Phys 88:986–987PubMedCrossRefGoogle Scholar
  21. 21.
    Weber JS, Amin A, Minor D, Siegel J, Berman D, O’Day SJ (2011) Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial. Melanoma Res 21:530–534PubMedCrossRefGoogle Scholar
  22. 22.
    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 13:459–465PubMedCrossRefGoogle Scholar
  23. 23.
    Knisely JP, Yu JB, Flanigan J, Sznol M, Kluger HM, Chiang VL (2012) Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg 117:227–233PubMedCrossRefGoogle Scholar
  24. 24.
    Kiess A, Wolchok J, Barker C et al (2012) Ipilimumab and stereotactic radiosurgery for melanoma brain metastases. Int J Radiat Oncol Biol Phys 84:S115–S116CrossRefGoogle Scholar
  25. 25.
    Mathew M, Tam M, Ott PA, Pavlick AC, Rush SC, Donahue BR, Golfinos JG, Parker EC, Huang PP, Narayana A (2013) Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. Melanoma Res 23:191–195PubMedCrossRefGoogle Scholar
  26. 26.
    Muller-Brenne T, Rudolph B, Schmidberger H et al (2011) Successful therapy of a cerebral metastasized malign melanoma by whole-brain-radiation and therapy with ipilimumab. J Dtsch Dermatol Ges 9:787–788Google Scholar
  27. 27.
    Bot I, Blank CU, Brandsma D (2012) Clinical and radiological response of leptomeningeal melanoma after whole brain radiotherapy and ipilimumab. J Neurol 259:1976–1978PubMedCrossRefGoogle Scholar
  28. 28.
    Weber JS, O’Day S, Urba W, Powderly J, Nichol G, Yellin M, Snively J, Hersh E (2008) Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol 26:5950–5956PubMedCrossRefGoogle Scholar
  29. 29.
    Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, Sneed PK, Chao ST, Weil RJ, Suh J, Bhatt A, Jensen AW, Brown PD, Shih HA, Kirkpatrick J, Gaspar LE, Fiveash JB, Chiang V, Knisely JP, Sperduto CM, Lin N, Mehta M (2012) 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 30:419–425PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420PubMedCrossRefGoogle Scholar
  31. 31.
    Isiklar I, Leeds NE, Fuller GN, Kumar AJ (1995) Intracranial metastatic melanoma: correlation between MR imaging characteristics and melanin content. Am J Roentgenol 165:1503–1512CrossRefGoogle Scholar
  32. 32.
    Premkumar A, Marincola F, Taubenberger J, Chow C, Venzon D, Schwartzentruber D (1996) Metastatic melanoma: correlation of MRI characteristics and histopathology. J Magn Reson Imaging 6:190–194PubMedCrossRefGoogle Scholar
  33. 33.
    Hatzoglou V, Ulaner GA, Zhang Z, Beal K, Holodny AI, Young RJ (2013) Comparison of the effectiveness of MRI perfusion and fluorine-18 FDG PET-CT for differentiating radiation injury from viable brain tumor: a preliminary retrospective analysis with pathologic correlation in all patients. Clin Imaging 37:451–457PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Byrne TN, Cascino TL, Posner JB (1983) Brain metastasis from melanoma. J Neurooncol 1:313–317PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Naamit K. Gerber
    • 1
  • Robert J. Young
    • 2
  • Christopher A. Barker
    • 1
  • Jedd D. Wolchok
    • 3
    • 4
  • Timothy A. Chan
    • 1
  • Yoshiya Yamada
    • 1
  • Leigh Friguglietti
    • 1
  • Kathryn Beal
    • 1
  1. 1.Department of Radiation OncologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Department of RadiologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.Department of Medicine and Ludwig CenterMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  4. 4.Weill Cornell Medical CollegeNew YorkUSA

Personalised recommendations