Abstract
BACKGROUND: This is the final report of the G-PCNSL-SG-1 trial after a median follow-up of 81.2 months. METHODS: G-PCNSL-SG-1 (www.clinicaltrials.gov NCT00153530) had randomised immunocompetent patients with newly diagnosed PCNSL to high-dose methotrexate (HDMTX) - based chemotherapy followed by whole-brain radiotherapy (WBRT) or chemotherapy alone. We hypothesized that the omission of WBRT from first-line treatment would not compromise overall survival (OS; primary endpoint), using a non-inferiority design with a margin of 0.9. FINDINGS: Of 551 patients who entered the study 524 fulfilled the eligibility criteria, 410 entered the post-HDMTX phase (intention-to-treat, ITT population), and 320 were treated per protocol (PP). OS with versus without WBRT was different neither in the ITT (HR 0.997, 95%CI 0.79-1.26, p = 0.98) nor in the PP population (HR 1.03, 95%CI 0.79-1.35, p = 0.82). In the ITT population CR patients experienced neither a progression-free survival (PFS) benefit from the last HDMTX-based CHT (PFS-2) (HR 0.84, 95% CI 0.60-1.19, p = 0.33) nor an OS benefit (HR 1.13, 95% CI 0.77-1.66, p = 0.53) with WBRT. In CR patients of the PP population, WBRT conferred a benefit for PFS-2 (HR 0.68, 95%CI 0.46-1.01, p = 0.057), but no OS benefit (HR 1.06, 95%CI 0.69-1.63, p = 0.78). In non-CR patients of the ITT population, a benefit of PFS-2 (HR 0.58, 95%CI 0.44-0.77, p < 0.001), but not of OS (HR 0.86, 95%CI 0.64-1.16, p = 0.32) was found with WBRT; in non-CR patients of the PP population, WBRT conferred a benefit of PFS-2 over CHT alone (HR 0.41, 95%CI 0.29-0.57, p < 0.001) and a trend for OS, too (HR 0.76, 95%CI 0.54-1.08, p = 0.12). INTERPRETATION: Despite improvement in PFS, particularly in patients without CR to HDMTX-based CHT, no significant difference in OS was found when WBRT was omitted from primary therapy in this long-term follow-up analysis. The PFS afforded by WBRT has to be balanced against its long-term toxicity.