Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma.

Objective: This is the final report of a phase III randomized study to evaluate whole-brain radiotherapy (WBRT) in primary therapy of primary CNS lymphoma (PCNSL) after a median follow-up of 81.2 months.

Methods: Patients with newly diagnosed PCNSL were randomized to high-dose methotrexate (HDMTX)-based chemotherapy alone or followed by WBRT. We hypothesized that the omission of WBRT would not compromise overall survival (OS; primary endpoint), using a noninferiority design with a margin of 0.9.

Results: In the per-protocol population (n = 320), WBRT nonsignificantly prolonged progression-free survival (PFS) (median 18.2 vs 11.9 months, hazard ratio [HR] 0.83 [95% confidence interval (CI) 0.65-1.06], p = 0.14) and significantly PFS from last HDMTX (25.5 vs 12.0 months, HR 0.65 [95% CI 0.5-0.83], p = 0.001), but without OS prolongation (35.6 vs 37.1 months, HR 1.03 [95% CI 0.79-1.35], p = 0.82). In the intent-to-treat population (n = 410), there was a prolongation by WBRT of both PFS (15.4 vs 9.9 months, HR 0.79 [95% CI 0.64-0.98], p = 0.034) and PFS from last HDMTX (19.4 vs 11.9 months, HR 0.72 [95% CI 0.58-0.89], p = 0.003), but not of OS (32.4 vs 36.1 months, HR 0.98 [95% CI 0.79-1.26], p = 0.98).

Conclusion: Although the statistical proof of noninferiority regarding OS was not given, our results suggest no worsening of OS without WBRT in primary therapy of PCNSL.

Classification Of Evidence: This study provides Class II evidence that in PCNSL HDMTX-based chemotherapy followed by WBRT does not significantly increase survival compared to chemotherapy alone. The study lacked the precision to exclude an important survival benefit or harm from WBRT.