Response Adapted Assignment of the Number of Chemotherapy Cycles for the Treatment of Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Is Not Justified: Results of the RICOVER-60 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).
Authors: Schubert Joerg , Ziepert Marita , Lengfelder Eva , Mohren Martin , Peter Norma , Reiser Marcel , Clemens Michael , Nickenig Christina , deWit Maike , Ho Anthony , Eimermacher Hartmut , Truemper Lorenz , Hoffmann Martin , Mertelsmann Roland , Metzner Bernd , Mergenthaler Hans-Guenther , Liersch Ruediger , Duehrsen Ulrich , Balleisen Leopold , Hartmann Frank , Poeschel Viola , Schmitz Norbert , Loeffler Markus , Pfreundschuh Michael 
Published: October 2019

Background: While the CHOP regimen is widely accepted standard chemotherapy regimen of care for aggressive lymphomas, the optimal number of chemotherapy cycles for the treatment of aggressive lymphomas has not been determined. Since RICOVER-60 is the first randomized comparison between 6 and 8 cycles of chemotherapy, it allowed to analyze whether 8 cycles are better than 6 in patients with poor prognosis and/or those achieving less than a complete response after 4 cycles of chemotherapy.

Methods: In the RICOVER-60 trial, 1222 elderly patients (61–80 years, stages I–IV) were randomized to receive 6 or 8 cycles of CHOP-14 with or without rituximab given on days 1, 15, 29, 43, 57, 71, 85, and 99. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement.

Results: In a multivariate analysis adjusted for prognostic factors using 6xCHOP-14 without rituximab as the reference, all intensified regimens improved event-free survival. Compared to 6xCHOP-14, progression-free survival (PFS) improved after 6xR-CHOP-14 and 8xR-CHOP, while overall survival (OS) improved only after 6xR-CHOP-14 (Pfreundschuh et al., 2006, Blood 108: 64a, Abstract #205). Since 8 cycles of chemotherapy were not better than 6 in the overall RICOVER-60 population, we searched for subgroups who might have a benefit from the two additional cycles of chemotherapy. The outcome after 6 cycles was at least as good as 8 cycles, in any risk group according to IPI. Compared to patients in CR after 4 cycles (n=261), patients in PR after 4 cycles (n=459) had a significantly worse 3-year PFS (63% vs. 75%; p=.001) and OS (69% vs. 84%; p=0.001), while for patients in CRu (n=276) this applied to PFS (68% vs. 76%; p=0.043), but not to OS (78% vs. 84%; p=0.125). Among patients with mid-therapy CRu, the 3-year progression free rates receiving 6 cycles (6x-CHOP-14: 65%, 6xR-CHOP-14: 72%) and those receiving 8 cycles (8xCHOP-14: 63%; 8xR-CHOP-14: 71%) were not different (p=0.601 and p=0.815 without and with rituximab, respectively). The same was true with respect to overall survival (6xCHOP-14: 82%; 8xCHOP-14: 70%; 6xR-CHOP-14: 80%; 8xR-CHOP-14: 80%; p=0.422 and p=0.759 without and with rituximab, respectively).

Conclusion: Patients in CR after 4 cycles of therapy have a better outcome than those in CRu and PR at mid-therapy, with no difference between patients who received 6 and 8 cycles of (R−)CHOP-14. Response-adapted assignment of 8 cycles instead of 6 does not compensate for the worse prognosis of patients achieving less than a CR after 4 cycles. Response-adapted assignment of the number of chemotherapy cycles - either with or without rituximab - is not supported by our data.