Stereotactic Radiosurgery and Ipilimumab Versus Stereotactic Radiosurgery Alone in Melanoma Brain Metastases

Abstract

Benefits of stereotactic radiosurgery (SRS) have been well established in melanoma brain metastases (MBM). Immunotherapy agents such as ipilimumab (ipi) have recently demonstrated clinical efficacy in advanced disease as well. The theoretical synergistic effects of combining these therapies in MBM have not been explored in detail, however, we conducted a systematic review with meta-analysis of studies that compared combined SRS and ipi versus SRS alone in MBM. Medical Literature Analysis and Retrieval System Online (MEDLINE) and Central databases were used for our literature search, which was conducted by three reviewers. We included studies that examined SRS and ipilimumab compared to SRS alone in MBM. Pertinent results were tabulated in a standardized spreadsheet. Newcastle-Ottawa Scale (NOS) Risk of Bias Assessment and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method for rating evidence quality were used for qualitative analysis. Review Manager was used for statistical analysis. We identified four cohort studies that compared SRS plus ipi versus SRS alone in MBM. As per the GRADE criteria, we found low-quality evidence for survival benefits associated with combined treatment. Meta-analysis confirmed a significant benefit in survival for SRS and ipilimumab (hazard ratio 0.38, 95% confidence interval 0.28 - 0.52, p < 0.01). There were no significant differences between comparison groups for local control, distant brain control, radiation necrosis, or intracranial bleeding. We conclude that low-quality evidence exists for superior overall survival in MBM treated with SRS and ipilimumab compared to SRS without ipilimumab. There is also no increased risk of radiation necrosis and/or intracranial bleeding with combining radiation and immunotherapy in this setting.

Keywords: brain mets; ipilimumab; melanoma; meta-analysis; stereotactic radiosurgery.

Figure 1. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flowchart of the literature search and study selection

The studies by Tazi, et al., Cohen-Inbar, et al., and Kiess, et al. were excluded. Their study arms were incompatible for our review [25-27]. Silk, et al. abstract was excluded due to results not being reported [28]

Figure 2. Pooled analysis for median survival

Forest plot of hazard ratios and 95% confidence intervals for pooled estimates of Silk, et al., Patel, et al., and Knisely, et al. studies [29-30,32]. Abbreviations: SRS = stereotactic radiosurgery; ipi = ipilimumab; SE = standard error; CI = confidence interval