Optimizing Whole Brain Radiotherapy Dose and Fractionation: Results from a Prospective Phase III Trial (NCCTG N107C (Alliance)/CEC.3)

Abstract

Whole brain radiotherapy (WBRT) remains a commonly employed cancer treatment today, although controversy exists regarding the optimal dose and fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits. We sought to utilize the results of N107C/CEC.3, a prospective clinical trial for patients with brain metastases, to evaluate the impact of WBRT dose and fractionation on tumor control, overall survival (OS), and toxicity. N107C/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the fractionation schedule that would be used for all patients treated at that site (either 30 Gy in 10 fractions (fx), or 37.5 Gy in 15 fx). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher’s exact tests, where appropriate. Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fx (53%), and 43 were treated with 37.5 Gy in 15 fx (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology more frequent with protracted WBRT, 74% vs. 47%, p=0.01), and 93% of patients completed the full course of WBRT. Protracted WBRT dose/fx did not impact time to cognitive failure (hazard ratio, HR=0.91, p=0.64), surgical bed control (HR=0.52, p=0.14), intracranial tumor control (HR=0.56, p=0.09), or OS (HR=0.73, p=0.18). Although there were no reports of radionecrosis, there is a statistically significant increase in the risk of at least one grade 3 or higher adverse event with 37.5 Gy/15 fx vs. 30 Gy/10 fx (54% vs. 31%, respectively, p=0.03). This unplanned analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with lengthened courses. For patients with brain metastases where WBRT is recommended, a short course hypofractionated regimen remains the current standard of care. Support: U10CA180821, U10CA180882; U10CA180863; U10CA180868; NCT01372774; Alliance NCORP grant UG1CA189823.