Skip to main content
SpringerLink
Log in

The impact of timing of immunotherapy with cranial irradiation in melanoma patients with brain metastases: intracranial progression, survival and toxicity

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

Abstract

Immunotherapy (IT) is increasingly incorporated in the management of metastatic melanoma patients with brain metastases, but the impact of timing of IT with stereotactic radiosurgery (SRS) remains unclear. The aim of this study was to determine the temporal significance of IT in melanoma patients treated with cranial radiation therapy (RT) with respect to patterns of intracranial progression, overall survival (OS), and toxicity. We retrospectively reviewed consecutive melanoma patients with brain metastases undergoing cranial RT and IT between 2008 and 2015. Concurrent IT/RT was defined as IT administration within 30 days of RT. Intracranial progression, OS and radionecrosis were assessed. We identified 74 patients with 136 treated brain metastases. Median OS was 13.9 months. Performance status, pre-SRS surgery, and intracranial progression were correlated with OS. Concurrent IT/RT was used in 35 (47.3%) patients. Patients receiving concurrent IT/RT were less likely to have a BRAF mutation (p = 0.027) and more likely to be treated after 2013 (p = 0.010) compared to non-concurrently treated patients. Patients receiving concurrent IT/RT were more likely to have intracranial progression within 60-days (54.3% vs. 30.8%, p = 0.041). However, 25.7% of concurrent IT/RT patients attained ≥ 1 year intracranial progression-free survival. There were no significant differences in symptomatic radionecrosis (11.4% vs. 12.8%, p = 0.67). In conclusion, although melanoma patients with brain metastases receiving concurrent IT/RT were more likely to exhibit early intracranial disease progression, a significant proportion of non-early-progressors attained durable intracranial control. The combination of IT and cranial RT appears to be efficacious and safe. Prospective studies are required to clarify these retrospective findings.

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
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Johnson JD, Young B (1996) Demographics of brain metastasis. Neurosurg Clin N Am 7:337–344

    CAS  PubMed  Google Scholar 

  2. Sampson JH, Carter JH, Friedman AH, Seigler HF (1998) Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 88:11–20. https://doi.org/10.3171/jns.1998.88.1.0011

    Article  CAS  PubMed  Google Scholar 

  3. Schadendorf D, Hodi FS, Robert C et al (2015) Pooled analysis of long-term survival data from phase II and phase III trials of Ipilimumab in unresectable or metastatic melanoma. J Clin Oncol Off J Am Soc Clin Oncol 33:1889–1894. https://doi.org/10.1200/JCO.2014.56.2736

    Article  CAS  Google Scholar 

  4. 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  CAS  PubMed  Google Scholar 

  5. Schachter J, Ribas A, Long GV et al (2017) Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet Lond Engl. https://doi.org/10.1016/S0140-6736(17)31601-X

    Google Scholar 

  6. Goldberg SB, Gettinger SN, Mahajan A et al (2016) 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 17:976–983. https://doi.org/10.1016/S1470-2045(16)30053-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Long GV, Atkinson V, Menzies AM et al (2017) A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC). J Clin Oncol 35:9508

  8. Tawbi HA-H, Forsyth PA, Algazi AP et al (2017) Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: results of the phase II study CheckMate 204. J Clin Oncol 35:9507

  9. Sharabi AB, Lim M, DeWeese TL, Drake CG (2015) Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 16:e498-509. https://doi.org/10.1016/S1470-2045(15)00007-8

    Article  PubMed  Google Scholar 

  10. Qian JM, Yu JB, Kluger HM, Chiang VLS (2016) Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer 122:3051–3058. https://doi.org/10.1002/cncr.30138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 1–8. https://doi.org/10.3171/2016.9.JNS161585

    Google Scholar 

  12. Belcaid Z, Phallen JA, Zeng J et al (2014) Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model. PloS ONE 9:e101764. https://doi.org/10.1371/journal.pone.0101764

    Article  PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. Kato S, Goodman A, Walavalkar V et al (2017) Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res Off J Am Assoc Cancer Res 23:4242–4250. https://doi.org/10.1158/1078-0432.CCR-16-3133

    Article  CAS  Google Scholar 

  15. Berghoff AS, Preusser M (2017) Targeted therapies for melanoma brain metastases. Curr Treat Options Neurol 19:13. https://doi.org/10.1007/s11940-017-0449-2

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wolchok JD, Hoos A, O’Day S et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res Off J Am Assoc Cancer Res 15:7412–7420. https://doi.org/10.1158/1078-0432.CCR-09-1624

    Article  CAS  Google Scholar 

  17. Champiat S, Dercle L, Ammari S et al (2016) Hyperprogressive disease (HPD) is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-16-1741

    PubMed  Google Scholar 

  18. Patel KR, Lawson DH, Kudchadkar RR et al (2015) Two heads better than one? Ipilimumab immunotherapy and radiation therapy for melanoma brain metastases. Neuro-Oncol 17:1312–1321. https://doi.org/10.1093/neuonc/nov093

    Article  PubMed  PubMed Central  Google Scholar 

  19. Chandra RA, Wilhite TJ, Balboni TA et al (2015) A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab. Oncoimmunology 4:e1046028. https://doi.org/10.1080/2162402X.2015.1046028

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kohutek ZA, Yamada Y, Chan TA et al (2015) Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases. J Neurooncol 125:149–156. https://doi.org/10.1007/s11060-015-1881-3

    Article  PubMed  PubMed Central  Google Scholar 

  21. 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  Google Scholar 

  22. Fang P, Jiang W, Allen P et al (2017) Radiation necrosis with stereotactic radiosurgery combined with CTLA-4 blockade and PD-1 inhibition for treatment of intracranial disease in metastatic melanoma. J Neurooncol 133:595–602. https://doi.org/10.1007/s11060-017-2470-4

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study findings were presented at the American Society for Radiation Oncology 2017 Annual Meeting in San Diego, California.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 30 Fruit Street, Boston, MA, 02114, USA

    Rifaquat Rahman, Andrzej Niemierko, Kevin S. Oh & Helen A. Shih

  2. Hospital Universitario Ramon y Cajal, Madrid, Spain

    Alfonso Cortes

  3. Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA

    Keith T. Flaherty, Donald P. Lawrence & Ryan J. Sullivan

Authors
  1. Rifaquat Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alfonso Cortes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrzej Niemierko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kevin S. Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keith T. Flaherty
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Donald P. Lawrence
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ryan J. Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Helen A. Shih
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helen A. Shih.

Ethics declarations

Conflict of interest

Keith T. Flaherty is a consultant for Merck, Bristol-Myers Squibb, and Genentech. Ryan J. Sullivan is a consultant for Merck and Novartis. Kevin S. Oh has received research funding from Merck.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rahman, R., Cortes, A., Niemierko, A. et al. The impact of timing of immunotherapy with cranial irradiation in melanoma patients with brain metastases: intracranial progression, survival and toxicity. J Neurooncol 138, 299–306 (2018). https://doi.org/10.1007/s11060-018-2795-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-018-2795-7

Keywords

Search

Navigation