The effect of timing of stereotactic radiosurgery treatment of melanoma brain metastases treated with ipilimumab

Abstract

OBJECTIVE Melanoma represents the third most common cause of CNS metastases. Immunotherapy has evolved as a treatment option for patients with Stage IV melanoma. Stereotactic radiosurgery (SRS) also elicits an immune response within the brain and may interact with immunotherapy. The authors report on a cohort of patients treated for brain metastases with immunotherapy and evaluate the effect of SRS timing on the intracranial response. METHODS All consecutively treated melanoma patients receiving ipilimumab and SRS for treatment of brain metastases at the University of Virginia between 2009 and 2014 were included in this retrospective analysis; data from 46 patients harboring 232 brain metastases were reviewed. The median duration of clinical follow-up was 7.9 months (range 3-42.6 months). The median age of the patients was 63 years (range 24.3-83.6 years). Thirty-two patients received SRS before or during ipilimumab cycles (Group A), whereas 14 patients received SRS after ipilimumab treatment (Group B). Radiographic and clinical responses were assessed at approximately 3-month intervals after SRS. RESULTS The 2 cohorts were comparable in pertinent baseline characteristics with the exception of SRS timing relative to ipilimumab. Local recurrence-free duration (LRFD) was significantly longer in Group A (median 19.6 months, range 1.1-34.7 months) than in Group B patients (median 3 months, range 0.4-20.4 months) (p = 0.002). Post-SRS perilesional edema was more significant in Group A. CONCLUSIONS The effect of SRS and ipilimumab on LRFD seems greater when SRS is performed before or during ipilimumab treatments. The timing of immunotherapy and SRS may affect LRFD and postradiosurgical edema. The interactions between immunotherapy and SRS warrant further investigation so as to optimize the therapeutic benefits and mitigate the risks associated with multimodality, targeted therapy.

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Malignant Melanomas: A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study (JLGK1501)

“…This result suggests that GKRS is a safe irradiation procedure for brain metastases from malignant melanomas, which is consistent with past reports of SRS for brain metastases [42]. However, the outcomes obtained in this series also showed that combining SRS with immune checkpoint inhibitors significantly increased the incidence of radiation injury, which supports results obtained in several prior studies [1,17,18,30,31,34,43,44]. We hypothesized that this observation might be attributable to the increased radiosensitivity of brain tumors, leading to subacute inflammatory changes and lymphocyte toxicity, as described in recent reports focusing on the novel systemic agents [1,17,18,31,32,35].…”

“…A high incidence is reported in Caucasians, with malignant melanoma being the third most frequent primary cancer, following lung and breast cancers. Australia, New Zealand, Europe, and the USA have high incidences of 15-20 per 100,000, while malignant melanoma remains rare in Japan at an incidence of 2 per 100,000 [17,24,25].…”

“…Brain metastasis from malignant melanoma occurs at a high incidence of almost 10%, and the rate exceeds 40% in patients with stage 4 disease [1,3,6,7,9,13,14,17,18,20,23,[26][27][28][29]. Single or multimodality therapies including surgical resection, whole-brain radiation therapy, and stereotactic radiosurgery (SRS) are generally performed for brain metastases depending on the systemic condition of the patient.…”

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

“…A retrospective analysis of patients treated for brain metastases of malignant melanoma revealed that inhibition of the PD-1 axis was more effective than inhibition of CTLA-4 in combination with external beam radiotherapy and that concurrent dosing (at least 4 weeks within the two treatments) was necessary to induce best responses [163]. Independent retrospective studies and one meta-analysis confirmed these results [145,[164][165][166][167][168][169][170][171] (Table 4), also showing the superiority of combining radiation with PD-1 inhibitors compared to combination with other agents such as v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) or dual specificity mitogen-activated protein kinase kinase (MEK) inhibitors [172,173] (Table 4). One retrospective study showed longer overall survival of patients irradiated more than 16 weeks after initiation of ipilimumab, compared to patients irradiated within 16 weeks of starting ipilimumab treatment [174].…”

Innovations in Metastatic Brain Tumor Treatment

“…Several studies have reported better outcomes after treating metastatic brain melanoma with combination radiosurgery and immunotherapy [221,222]. One downside to this treatment is the inflammatory response may be overactive resulting in elevated peritumoral edema and more severe neurologic symptoms [190,191]. Efficacy and safety of concurrent SRS and immunotherapy needs further investigation.…”