Results of a pilot/phase II study of gamma knife radiosurgery for brain metastases and implications for future prospective clinical trials

Abstract

Gamma knife radiosurgery is a well established method of treating intracranial metastases. We created a dose algorithm based on our standard clinical practice, taking into account tumor volume, number of metastases, radiosensitivity, and prior whole brain radiation treatment. We performed a phase 2 study to validate this algorithm and to investigate the feasibility of a larger clinical trial. A total of 39 patients were prospectively enrolled at Yale New Haven Hospital (YNHH) between April 3, 2014 and November 21, 2016. There were 114 evaluable brain metastases. The pre-defined primary endpoint of this study was the control of all irradiated lesions for each patient. Survival was estimated using the method of Kaplan-Meier. Cox proportional hazard regression was performed to identify factors associated with survival and local control. The median patient age of enrolled patients was 64 years (range, 34–88). Of the 114 evaluable lesions, 58 (50.9%) had complete response, 16 (14.0%) had partial response, 33 (28.9%) had stable disease, and 7 (6.1%) had progression at last imaging follow-up. Therefore, there was a per-lesion local control rate of 93.9%. Six (15.3%) patients developed symptomatic radiation necrosis requiring steroids or surgery, with median time to occurrence of 6 months. Median survival after gamma knife was 11.4 months (95% CI 4.9–15.7). Age was the only significant variable in univariate and multivariate analysis. Having a bladder primary (vs. lung) was associated with a higher risk of death, although this was based on only two patients and therefore is of unclear significance. In this pilot/phase II study, we learned: (1) radiosurgery using radiation doses based on our algorithm provides good local control with low toxicity. (2) Despite the relative commonality of brain metastases, patients with brain metastases are difficult to enroll on clinical trials. (3) A prospective study that encompasses all potentially important clinical variables that go into radiosurgery dose selection will require large amounts of patients. Our findings have important implications for future clinical trials of radiosurgery for brain metastases.