To the Editor

Given the historically poor prognosis associated with brain metastases in patients with melanoma, better therapeutic options are needed. Can Tawbi et al. (Aug. 23 issue)1 address the following methodologic and logistic considerations pertaining to their study? Considering that 22% of the patients had died at the time of the analysis, could accounting for the competing risk of death have altered the results? Adverse events of grade 3 or 4 were noted in 55% of the patients, and one patient died from immune-related myocarditis. Although most of these adverse events were reversible, managing them inevitably affects patient safety, quality of life, and medical costs.

The experience of one of us (a radiation oncologist) and the literature suggest that stereotactic radiosurgery is safe and effective for the treatment of lesions of the sizes of those in patients enrolled in this study, with minimal to no side effects, even when combined with single-agent immunotherapy.2 Can the authors expand on their rationale to initiate immunotherapy without first starting with stereotactic radiosurgery? Given the considerable financial ramifications associated with their strategy, do the authors think the data are mature enough to replace the existing standard of care, which includes stereotactic radiosurgery?3,4

Alireza Mansouri, M.D.
Toronto Western Hospital, Toronto, ON, Canada

Fabio Y. Moraes, M.D.
Princess Margaret Hospital, Toronto, ON, Canada

Gelareh Zadeh, M.D., Ph.D.
Toronto Western Hospital, Toronto, ON, Canada

No potential conflict of interest relevant to this letter was reported.

  1. 1. Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med 2018;379:722730.

  2. 2. Kiess AP, Wolchok JD, Barker CA, et al. Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Phys 2015;92:368375.

  3. 3. Long GV, Atkinson V, Lo S, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol 2018;19:672681.

  4. 4. Yoo SH, Keam B, Kim M, et al. Low-dose nivolumab can be effective in non-small cell lung cancer: alternative option for financial toxicity. ESMO Open 2018;3(5):e000332e000332.

Response

The authors and a colleague reply: Mansouri and colleagues raise several issues regarding the role of stereotactic radiosurgery in patients with asymptomatic brain metastases. Approximately 90% of brain metastases occur along with other systemic metastases. Over the past decade, systemic therapy for melanoma has dramatically increased the rate of survival and durable disease control has been achieved with immunotherapy, even among patients with extracranial visceral metastases. Our data confirm the safety and feasibility of deferring initial stereotactic radiosurgery in favor of treatment that has efficacy for both intracranial and extracranial disease in patients with asymptomatic brain metastases. In our study, close surveillance with magnetic resonance imaging of the brain was performed 6 weeks after the first dose of nivolumab plus ipilimumab, so local therapy could be offered if definitive progression in the central nervous system occurred. We therefore advocate for a multidisciplinary approach involving medical oncologists, neurosurgeons, and radiation oncologists to use the most effective tools and maximize benefit for our patients. Further investigation is necessary to determine the best timing and sequence for combining stereotactic radiosurgery with effective systemic therapy for brain metastases.

Hussein A. Tawbi, M.D., Ph.D.
Caroline Chung, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX

Kim Margolin, M.D.
City of Hope, Duarte, CA

Dr. Chung reports receiving grant funding from Elekta; and Dr. Margolin, consulting fees from ImaginAb, fees for serving on an advisory board from Iovance Biotherapeutics, consulting fees and fees for serving on an advisory board from Nektar Therapeutics, and clinical research support from Bristol-Myers Squibb, Genentech, Viralytics, Checkmate Pharmaceuticals, and Amgen. An updated disclosure form for Dr. Margolin has been posted with the original article at NEJM.org. No further potential conflict of interest relevant to this letter was reported.



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