R‐CHOP +/‐RADIOTHERAPY IN NON‐BULKY LIMITED‐STAGE DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL): FINAL RESULTS OF THE PROSPECTIVE RANDOMIZED PHASE III 02‐03 TRIAL FROM THE LYSA/GOELAMS

Abstract

Introduction: The benefit of radiotherapy (RT) following chemotherapy in limited-stage diffuse large B-cell lymphoma (DLBCL) remains controversial. Before the Rituximab (R) era, randomized trials have reported conflicting results. We conducted a randomized trial in patients with non-bulky (tumor size Method(s): Patients were stratified according to the Miller modified IPI (mIPI) including LDH (normal/elevated), ECOG performance status (0-1/2-3), age (60 yrs) and disease stage (I/II). The patients received 4 or 6 consecutive cycles of R-CHOP delivered every two weeks, followed or not by RT at 40 Gy delivered 4 weeks after the last RCHOP cycle. All patients were evaluated by FDG-PETs performed at baseline, after 4 R-CHOP cycles and at the end of treatment. The primary objective of the trial was event-free survival (EFS) from randomization. Result(s): The trial randomized 165 patients in the R-CHOP arm and 169 in the R-CHOP + RT arm. Response assessment was performed after the fourth cycle of R-CHOP based on clinical examination, CTscan and PET. CR was observed in 281 patients (88%) and PR in 38 (12%), without any difference between the two arms. R-CHOP cycles 5 and 6 were delivered to 123 and 118 patients respectively (61/57 in the R-CHOP arm and 62/61 in the R-CHOP + RT arm). According to initial randomization, among the 281 patients in CR following R-CHOP, 144 received RT and 137 did not receive any further treatment. Eight patients declined RT for personal reasons. 27 out of the 38 partial responders received 2 additional cycles of R-CHOP and RT, 5 received 2 additional R-CHOP cycles without RT, and 3 were delivered high dose chemotherapy: complete response was finally documented in 28 cases and the 10 remaining patients were still considered in PR. In an intent to treat analysis, with a median follow-up of 64 months, five-year EFS was not statistically different between the two arms, with 89% +/- 2.9 in the R-CHOP arm vs 92% +/- 2.4 in the R-CHOP + RT arm (HR 0.61, 95%CI 0.3 to 1.2, p = 0.18). Five-year overall survival was also not different at 92% (95% CI: 89.5-94.5) for patients assigned to RCHOP alone, and 96% (95% CI: 94.3-97.7) for those assigned to R-CHOP + RT, (p = ns). Conclusion(s): R-CHOP alone is not inferior to R-CHOP14 followed by RT in patients with non-bulky limited-stage DLBCL. We recommend that these selected patients who reach complete remission based on PET evaluation after 4 or 6 R-CHOP cycles should be spared additional RT, thus avoiding long-term radiation-related toxicity. (ClinicalTrials. gov number, NCT00841945).