Clinical Investigation
Stereotactic Radiosurgery for Melanoma Brain Metastases in Patients Receiving Ipilimumab: Safety Profile and Efficacy of Combined Treatment

https://doi.org/10.1016/j.ijrobp.2015.01.004Get rights and content

Purpose

Ipilimumab (Ipi), a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, has been shown to improve survival in patients with metastatic melanoma. In this single-institution study, we investigated the safety and efficacy of stereotactic radiosurgery (SRS) for patients with melanoma brain metastases (BMs) who also received Ipi.

Methods and Materials

From 2005 to 2011, 46 patients with melanoma received Ipi and underwent single-fraction SRS for BMs. A total of 113 BMs (91% intact, 9% postoperative) were treated with a median dose of 21 Gy (range, 15-24 Gy). Ipi was given at 3 mg/kg (54%) or 10 mg/kg (46%) for a median of 4 doses (range, 1-21). Adverse events were recorded with the use of the Common Terminology Criteria for Adverse Events 3.0. Kaplan-Meier methods were used to estimate survival, and Cox regression was used to investigate associations.

Results

Fifteen patients received SRS during Ipi, 19 received SRS before Ipi, and 12 received SRS after Ipi. Overall survival (OS) was significantly associated with the timing of SRS/Ipi (P=.035) and melanoma-specific graded prognostic assessment (P=.013). Patients treated with SRS during or before Ipi had better OS and less regional recurrence than did those treated with SRS after Ipi (1-year OS 65% vs 56% vs 40%, P=.008; 1-year regional recurrence 69% vs 64% vs 92%, P=.003). SRS during Ipi also yielded a trend toward less local recurrence than did SRS before or after Ipi (1-year local recurrence 0% vs 13% vs 11%, P=.21). On magnetic resonance imaging, an increase in BM diameter to >150% was seen in 50% of patients treated during or before Ipi but in only 13% of patients treated after Ipi. Grade 3 to 4 toxicities were seen in 20% of patients.

Conclusion

Overall, the combination of Ipi and SRS appears to be well tolerated. Concurrent delivery of Ipi and SRS is associated with favorable locoregional control and possibly longer survival. It may also cause a temporary increase in tumor size, possibly because of an enhanced immunomodulatory effect.

Introduction

Ipilimumab (Ipi), a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), allows for T cell activation and proliferation, thereby enhancing immune response to cancer. In patients with metastatic melanoma, Ipi has been shown to improve overall survival (OS) in 2 phase 3 trials, 1 trial in comparison with the cancer vaccine gp100 and the other in combination with dacarbazine 1, 2. These trials led to the approval of Ipi by the U.S. Food and Drug Administration in 2011.

As many as 60% of patients with metastatic melanoma will experience brain metastases (BMs), and those with relatively good prognosis and few BMs often undergo treatment with stereotactic radiosurgery (SRS) 3, 4, 5, 6, 7. The rationale for combining Ipi and SRS is based on potential activity of Ipi in the brain, as demonstrated by Margolin et al (8) in a phase 2 trial, and on the possible abscopal effects of SRS that may enhance the systemic response to Ipi 8, 9, 10, 11, 12, 13, 14. Several series have reported promising preliminary results with the combination of SRS and Ipi, including a study by Knisely et al (5) showing median OS of 21.3 months in 27 patients 15, 16, 17, 18. Given our large institutional experience with Ipi and SRS, we conducted a retrospective study to investigate the safety and efficacy of this combination for treatment of melanoma BMs.

Section snippets

Methods and Materials

From an institutional melanoma database, 46 patients were identified who received Ipi and underwent single-fraction SRS for melanoma BMs between 2005 and 2011. Most of these patients (85%) received Ipi as part of a research protocol. Ipi was delivered intravenously every 3 weeks for 4 doses during the induction phase. After induction, 13 patients (28%) received maintenance therapy every 3 months.

Gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI) with 3-mm slices was performed

Patient and tumor characteristics

This study included 46 patients with metastatic melanoma who received Ipi and SRS for BMs between 2005 and 2011. The patient, tumor, and treatment characteristics are shown in Table 1. The median age was 57 years (range, 24-76 years), and the male:female ratio was 1.4:1. The median mGPA was 3 out of 4, because most patients had KPS 90% and 1 to 2 BMs (4). Only 37% of patients had elevated lactate dehydrogenase. Almost all patients had other non-brain metastasea and underwent prior systemic

Discussion

This retrospective, single-institution study is the largest series to date investigating the combination of brain SRS and Ipi immunotherapy for patients with melanoma BMs (n=46 patients). Our results suggest several important hypotheses. First, delivery of SRS during or before Ipi may yield comparatively favorable survival and regional control compared with delivery of SRS after Ipi. These effects clearly need to be investigated further. Second, SRS during or before Ipi may cause a temporary

Conclusion

This largest-to-date single-institution retrospective study investigated the safety and efficacy of SRS in 46 patients with melanoma BMs who also received Ipi immunotherapy. We found that delivery of SRS during or before Ipi was associated with comparatively favorable survival and regional control compared with delivery of SRS after Ipi. However, SRS during or before Ipi may also be associated with a temporary increase in size or hemorrhage of the irradiated lesion. Overall, the combination of

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    Conflict of interest: none.

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