Upfront Surgical Resection of Melanoma Brain Metastases Provides a Bridge Toward Immunotherapy-Mediated Systemic Control

Abstract

Background: Immune checkpoint blockade has systemic efficacy in patients with metastatic melanoma, including those with brain metastases (MBMs). However, immunotherapy-induced intracranial tumoral inflammation can lead to neurologic compromise, requiring steroids, which abrogate the systemic efficacy of this approach. We investigated whether upfront neurosurgical resection of MBM is associated with a therapeutic advantage when performed prior to initiation of immunotherapy.

Material and methods: An institutional review board-approved, retrospective study identified 142 patients with MBM treated with immune checkpoint blockade between 2010 and 2016 at Massachusetts General Hospital, of whom 79 received surgery. Patients were classified based on the temporal relationship between immunotherapy, surgery, and development of central nervous system metastases. Overall survival (OS) was calculated from the date of diagnosis of MBM until death from any cause. Multivariate model building included a prognostic Cox model of OS, the effect of immunotherapy and surgical sequencing on OS, and the effect of immunotherapy and radiation sequencing on OS.

Results: The 2-year overall survival for patients treated with cytotoxic T-lymphocyte antigen 4, programmed death 1, or combinatorial blockade was 19%, 54%, and 57%, respectively. Among immunotherapy-naïve melanoma brain metastases, surgery followed by immunotherapy had a median survival of 22.7 months (95% confidence interval [CI], 12.6-39.2) compared with 10.8 months for patients treated with immunotherapy alone (95% CI, 7.8-16.3) and 9.4 months for patients treated with immunotherapy followed by surgery (95% CI, 4.1 to ∞; p = .12). On multivariate analysis, immunotherapy-naïve brain metastases treated with immunotherapy alone were associated with increased risk of death (hazard ratio, 1.72; 95% CI, 1.00-2.99) compared with immunotherapy-naïve brain metastases treated with surgery followed by immunotherapy.

Conclusion: In treatment-naïve patients, early surgical resection for local control should be considered prior to commencing immunotherapy. A prospective, randomized trial comparing the sequence of surgery and immunotherapy for treatment-naïve melanoma brain metastases is warranted.

Implications for practice: In this retrospective study of 142 patients with melanoma brain metastases treated with immune checkpoint blockade, the development of melanoma brain metastases following immunotherapy was associated with decreased survival compared with diagnosis of immunotherapy-naïve brain metastases. The benefit of surgical intervention was seen in immunotherapy-naïve brain metastases in contrast to brain metastases that developed on immunotherapy. These results suggest that upfront local control with surgery for immunotherapy-naïve melanoma brain metastasis may provide a bridge toward immunotherapy-mediated systemic control.

Keywords: Brain metastases; Immunotherapy; Metastatic melanoma.

Figure 1.

Kaplan‐Meier estimates of overall survival by timing of surgery. (A): Median overall survival for CNS‐IMTX (10.8 months; 95% confidence interval [CI], 7.8–16.3), CNS‐IMTX‐SURG (9.4 months; 95% CI, 4.1 to ∞), and CNS‐SURG‐IMTX (22.7 months; 95% CI, 12.6–39.2). (B): Median overall survival for IMTX‐CNS (9.1 months; 95% CI, 3.7 to ∞) and IMTX‐CNS‐SURG (9.0 months; 95% CI, 3.2–31.3). Abbreviations: CNS‐IMTX, brain metastasis diagnosis treated with immunotherapy alone; CNS‐IMTX‐SURG, brain metastasis diagnosis treated with immunotherapy followed by surgery; CNS‐SURG‐IMTX, brain metastasis diagnosis treated with surgery followed by immunotherapy; IMTX‐CNS, immunotherapy followed by brain metastasis diagnosis; IMTX‐CNS‐SURG, immunotherapy followed by brain metastasis diagnosis and subsequent surgery.

Figure 2.

Kaplan‐Meier estimates of overall survival by timing of radiation. The cohort was divided into patients who did not receive RT (median overall survival [OS], 4.0 months; 95% confidence interval [CI], 1.5–16.3), those who received RT within 2 months prior to starting ImTx (median OS, 13.2 months; 95% CI, 10.8–21.2), and all others (median OS, 16.5 months; 95% CI, 10.2–29.4). Although radiation was associated with an increase in overall survival, this was not dependent upon the timing of radiation and ImTx (overall p = .009; for the two RT groups, p = .76). Abbreviations: ImTx, immunotherapy; RT, radiotherapy.