Response at 3–months after whole brain radiation therapy predicts survival in brain metastases patients

Abstract

To assess the validity of using response in the brain after whole brain radiation therapy (WBRT) to predict survival in brain metastases patients. A randomized open–label Phase 3 study was designed to compare the efficacy and safety of RSR13 (efaproxiral) combined with WBRT and supplemental O2 versus WBRT and supplemental O2 alone in patients with brain metastases. WBRT, stereotactic radiosurgery naı̈ve patients with good performance status (KPS ≥70) and at least one measurable lesion were eligible. In addition to survival, response rate at 1–month post WBRT, 3–months post–WBRT, and every 3 months thereafter using consistent MRI or CT studies was evaluated until progression or death. Response evaluations were made by an independent central review relative to the baseline scan on up to 3 indicator lesions. Progressive disease was defined as an increase in the bi–dimensional product of 25% in at least one target lesion; or, the progression of any treated lesion not enumerated as a target lesion; or, progression of any unevaluable but treated lesion. The appearance of new lesions (reseeding) did not constitute a progression. Imaging studies that did not meet the definition of progressive disease were evaluated as complete response (CR), partial response (PR), or stable disease (SD). Complete disappearance of all target lesions was required for CR. A PR was defined as at least a 50% reduction in the bi–dimensional products of all indicator lesions. All other evaluations were SD. For the purposes of this analysis, CRs and PRs were combined into one group (“Responders”). All other responses were defined as “Non–responders”. Survival time was measured from date of randomization until date of death or the last date known alive. Between 2/2000 and 7/2002, 538 patients were randomized in 82 sites in 12 countries to receive either RSR13 plus WBRT and supplemental O2 (N = 271) or WBRT plus supplemental O2 without a placebo (N = 267). Twenty–three patients were in violation of eligibility criteria and were therefore excluded from analysis. Of the 515 eligible patients, 510 patients had a baseline scan, 399 patients had a 1–month scan, and 236 patients had a 3–month scan. 124/236 (53%) patients alive and with a scan at the 3–month follow–up visit were responders. Responders at 3–months had a 37% reduction in risk of death compared to non–responders subsequent to this visit (HR = 0.63, p = 0.004 unadjusted log–rank), which translated into an additional 2.8 months of survival (median survival time from 3–month scan: 8.0 months vs. 5.2 months for responders vs. non–responders, respectively). Response at 1–month was not a significant predictor of survival. Response as a predictor of survival was not assessed at time–points beyond the 3–month follow–up visit due to the poor compliance resulting from short survival times. Response in the brain at the 3–month post–WBRT brain imaging assessment is a statistically significant predictor of additional survival time and may be used as a surrogate for survival in future studies of patients with brain metastases and good performance status