Skip to main content
SpringerLink
Log in

Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity

  • Clinical Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Introduction

There is evidence that the combination of ipilimumab and stereotactic radiosurgery (SRS) for brain metastases improves outcomes. We investigated clinical outcomes, radiation toxicity, and impact of ipilimumab timing in patients treated with SRS for melanoma brain metastases.

Methods

We retrospectively identified 91 patients treated with SRS at our institution for melanoma brain metastases from 2006 to 2015. Concurrent ipilimumab administration was defined as within ± 4 weeks of SRS procedure. Acute and late toxicities were graded with CTCAE v4.03. Overall survival (OS), local failure, distant brain failure, and failure-free survival were analyzed with the Kaplan–Meier method. OS was analyzed with Cox regression.

Results

Twenty-three patients received ipilimumab concurrent with SRS, 28 patients non-concurrently, and 40 patients did not receive ipilimumab. The median age was 62 years and 91% had KPS ≥ 80. The median follow-up time was 7.4 months. Patients who received ipilimumab had a median OS of 15.1 months compared to 7.8 months in patients who did not (p = 0.02). In multivariate analysis, ipilimumab (p = 0.02) and diagnosis-specific graded prognostic assessment (p = 0.02) were associated with OS. There were no differences in intracranial control by ipilimumab administration or timing. The incidence of radiation necrosis was 5%, with most events occurring in patients who received ipilimumab.

Conclusions

Patients who received ipilimumab had improved OS even after adjusting for prognostic factors. Ipilimumab did not appear to increase risk for acute toxicity. The majority of radiation necrosis events, however, occurred in patients who received ipilimumab. Our results support the continued use of SRS and ipilimumab as clinically appropriate.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Siegel R, DeSantis C, Virgo K et al (2012) Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 62:220–241. https://doi.org/10.3322/caac.21149

    Article  PubMed  Google Scholar 

  2. Fonkem E, Uhlmann EJ, Floyd SR et al (2012) Melanoma brain metastasis: overview of current management and emerging targeted therapies. Expert Rev Neurother 12:1207–1215. https://doi.org/10.1586/ern.12.111

    Article  PubMed  CAS  Google Scholar 

  3. Fife KM, Colman MH, Stevens GN et al (2004) Determinants of outcome in melanoma patients with cerebral metastases. J Clin Oncol 22:1293–1300. https://doi.org/10.1200/JCO.2004.08.140

    Article  PubMed  CAS  Google Scholar 

  4. Staudt M, Lasithiotakis K, Leiter U et al (2010) Determinants of survival in patients with brain metastases from cutaneous melanoma. Br J Cancer 102:1213–1218. https://doi.org/10.1038/sj.bjc.6605622

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723. https://doi.org/10.1056/NEJMoa1003466

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Robert C, Thomas L, Bondarenko I et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526. https://doi.org/10.1056/NEJMoa1104621

    Article  PubMed  CAS  Google Scholar 

  7. Di Giacomo AM, Margolin K (2015) Immune checkpoint blockade in patients with melanoma metastatic to the brain. Semin Oncol 42:459–465. https://doi.org/10.1053/j.seminoncol.2015.02.006

    Article  PubMed  CAS  Google Scholar 

  8. Wilson EH, Weninger W, Hunter CA (2010) Trafficking of immune cells in the central nervous system. J Clin Invest 120:1368–1379. https://doi.org/10.1172/JCI41911

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Engelhardt B, Coisne C (2011) Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids Barriers CNS 8:4. https://doi.org/10.1186/2045-8118-8-4

    Article  PubMed  PubMed Central  Google Scholar 

  10. Cohen JV, Kluger HM (2016) Systemic Immunotherapy for the treatment of brain metastases. Front Oncol. https://doi.org/10.3389/fonc.2016.00049

    Article  PubMed  PubMed Central  Google Scholar 

  11. Margolin K, Ernstoff MS, Hamid O et al (2012) Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 13:459–465. https://doi.org/10.1016/S1470-2045(12)70090-6

    Article  PubMed  CAS  Google Scholar 

  12. Golden EB, Demaria S, Schiff PB et al (2013) An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 1:365–372. https://doi.org/10.1158/2326-6066.CIR-13-0115

    Article  PubMed  PubMed Central  Google Scholar 

  13. Postow MA, Callahan MK, Barker CA et al (2012) Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366:925–931. https://doi.org/10.1056/NEJMoa1112824

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Stamell EF, Wolchok JD, Gnjatic S et al (2013) The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys 85:293–295. https://doi.org/10.1016/j.ijrobp.2012.03.017

    Article  PubMed  Google Scholar 

  15. Tazi K, Hathaway A, Chiuzan C, Shirai K (2015) Survival of melanoma patients with brain metastases treated with ipilimumab and stereotactic radiosurgery. Cancer Med 4:1–6. https://doi.org/10.1002/cam4.315

    Article  PubMed  CAS  Google Scholar 

  16. Silk AW, Bassetti MF, West BT et al (2013) Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med 2:899–906. https://doi.org/10.1002/cam4.140

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Knisely JP, Yu JB, Flanigan J et al (2012) Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg 117:227–233

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kiess AP, Wolchok JD, Barker CA et al (2015) Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Phys 92:368–375. https://doi.org/10.1016/j.ijrobp.2015.01.004

    Article  PubMed  PubMed Central  Google Scholar 

  19. Shoukat S, Marcus D, Rizzo M et al (2014) Outcome with stereotactic radiosurgery (SRS) and ipilimumab (Ipi) for malignant melanoma brain metastases (mets). J Clin Oncol 32:9076

    Google Scholar 

  20. Shaw E, Scott C, Souhami L et al (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

    Article  PubMed  CAS  Google Scholar 

  21. Edge SB, Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17:1471–1474. https://doi.org/10.1245/s10434-010-0985-4

    Article  PubMed  Google Scholar 

  22. Sperduto PW, Chao ST, Sneed PK et al (2010) Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys 77:655–661. https://doi.org/10.1016/j.ijrobp.2009.08.025

    Article  PubMed  Google Scholar 

  23. Salama AKS, Postow MA, Salama JK (2016) Irradiation and immunotherapy: from concept to the clinic. Cancer 122:1659–1671. https://doi.org/10.1002/cncr.29889

    Article  PubMed  Google Scholar 

  24. Twyman-Saint Victor C, Rech AJ, Maity A et al (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373–377. https://doi.org/10.1038/nature14292

    Article  PubMed  CAS  Google Scholar 

  25. Frey B, Rubner Y, Kulzer L et al (2014) Antitumor immune responses induced by ionizing irradiation and further immune stimulation. Cancer Immunol Immunother 63:29–36. https://doi.org/10.1007/s00262-013-1474-y

    Article  PubMed  CAS  Google Scholar 

  26. Mathew M, Tam M, Ott PA et al (2013) Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. Melanoma Res 23:191–195. https://doi.org/10.1097/CMR.0b013e32835f3d90

    Article  PubMed  CAS  Google Scholar 

  27. Patel KR, Shoukat S, Oliver DE et al (2017) Ipilimumab and stereotactic radiosurgery versus stereotactic radiosurgery alone for newly diagnosed melanoma brain metastases. Am J Clin Oncol 40:444–450

    Article  PubMed  CAS  Google Scholar 

  28. Diao K, Bian SX, Routman DM et al (2018) Combination ipilimumab and radiosurgery for brain metastases: tumor, edema, and adverse radiation effects. J Neurosurg. https://doi.org/10.3171/2017.7.JNS171286

    Article  PubMed  Google Scholar 

  29. An Y, Jiang W, Kim BYS et al (2017) Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control. Radiother Oncol 125:80–88. https://doi.org/10.1016/j.radonc.2017.08.009

    Article  PubMed  CAS  Google Scholar 

  30. Cohen-Inbar O, Shih H-H, Xu Z et al (2017) The effect of timing of stereotactic radiosurgery treatment of melanoma brain metastases treated with ipilimumab. J Neurosurg 127:1007–1014. https://doi.org/10.3171/2016.9.JNS161585

    Article  PubMed  Google Scholar 

  31. Cairncross JG, Kim J-H, Posner JB (1980) Radation therapy for brain metastases. Ann Neurol 7:529–541. https://doi.org/10.1002/ana.410070606

    Article  PubMed  CAS  Google Scholar 

  32. Nguyen SM, Castrellon A, Vaidis O, Johnson AE (2017) Stereotactic radiosurgery and ipilimumab versus stereotactic radiosurgery alone in melanoma brain metastases. Cureus 9:e1511. https://doi.org/10.7759/cureus.1511

    Article  PubMed  PubMed Central  Google Scholar 

  33. Williams NL, Wuthrick EJ, Kim H et al (2017) Phase I study of ipilimumab combined with whole brain radiation therapy or radiosurgery for melanoma patients with brain metastases. Int J Radiat Oncol. https://doi.org/10.1016/j.ijrobp.2017.05.028

    Article  Google Scholar 

  34. Colaco RJ, Martin P, Kluger HM et al (2016) Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases? J Neurosurg 125:17–23. https://doi.org/10.3171/2015.6.JNS142763

    Article  PubMed  CAS  Google Scholar 

  35. Du Four S, Wilgenhof S, Duerinck J et al (2012) Radiation necrosis of the brain in melanoma patients successfully treated with ipilimumab, three case studies. Eur J Cancer 48:3045–3051. https://doi.org/10.1016/j.ejca.2012.05.016

    Article  PubMed  CAS  Google Scholar 

  36. Siddiqui ZA, Johnson MD, Baschnagel AM et al (2016) Predictors of radiation necrosis in long-term survivors of stereotactic radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 96:E104. https://doi.org/10.1016/j.ijrobp.2016.06.855

    Article  Google Scholar 

Download references

Acknowledgements

We wish to gratefully acknowledge the research support of the Kozak, Ginsburg, and Phillip families for the research stipend of Kevin Diao. Our sponsors were not involved in the research project.

Author information

Authors and Affiliations

  1. Harvard Medical School, Boston, MA, USA

    Kevin Diao

  2. Department of Radiation Oncology, Keck School of Medicine of USC, Los Angeles, CA, USA

    Kevin Diao, Shelly X. Bian, David M. Routman, Cheng Yu, Jason C. Ye & Eric L. Chang

  3. Department of Clinical Neurology, Keck School of Medicine of USC, Los Angeles, CA, USA

    Naveed A. Wagle

  4. Division of Medical Oncology, Keck School of Medicine of USC, Los Angeles, CA, USA

    Michael K. Wong

  5. Department of Neurological Surgery, Keck School of Medicine of USC, Los Angeles, CA, USA

    Gabriel Zada

Authors
  1. Kevin Diao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shelly X. Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David M. Routman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cheng Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jason C. Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naveed A. Wagle
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael K. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gabriel Zada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eric L. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kevin Diao.

Ethics declarations

Conflict of interest

Eric L. Chang received speaker’s honorarium from Brainlab.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Diao, K., Bian, S.X., Routman, D.M. et al. Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity. J Neurooncol 139, 421–429 (2018). https://doi.org/10.1007/s11060-018-2880-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-018-2880-y

Keywords

Search

Navigation