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 followup 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] . 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. Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma ABSTRACTObjective: 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 5 320), WBRT nonsignificantly prolonged progressionfree survival (PFS) (median 18.2 vs 11.9 months, hazard ratio 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. Neurology ® 2015;84:1242-1248 GLOSSARY CHT 5 chemotherapy; CI 5 confidence interval; CR 5 complete response; G-PCNSL-SG 5 German PCNSL Study Group; HD-Ara-C 5 high-dose cytarabine; HDMTX 5 high-dose methotrexate; HR 5 hazard ratio; ITT 5 intent-to-treat; KPS 5 Karnofsky Performance Score; OS 5 overall survival; PCNSL 5 primary CNS lymphoma; PFS 5 progression-free survival; PP 5 per protocol; PR 5 partial remission; WBRT 5 whole-brain radiotherapy.Standards of care have not been well-defined for primary CNS lymphoma (PCNSL). Highdose methotrexate (HDMTX) is the only undisputed standard of care, whereas the addition of whole-brain radiotherapy (WBRT) has been increasingly questioned because of the high frequency of late neurotoxicity ...
We addressed the effect of post-transplant lymphoproliferative disorder (PTLD) treatment with rituximab monotherapy or CHOP-based chemotherapy (± rituximab) after upfront immunosuppression reduction (IR) on renal graft function in a longitudinal analysis of 58 renal transplant recipients with PTLD and 610 renal transplant controls. Changes in the estimated glomerular filtration rate over time were calculated from a total of 6933 creatinine measurements over a period of >1 year using a linear mixed model with random and fixed effects. Renal graft function significantly improved with treatment of PTLD, especially in the chemotherapy subgroup. Patients treated with IR + chemotherapy ± rituximab had a noninferior graft function compared with untreated controls suggesting that the negative impact of IR on the renal graft function can be fully compensated by the immunosuppressive effect of CHOP. The immunosuppressive effect of single agent rituximab may partially compensate the negative impact of IR on the graft function. Thus, it is possible to reduce immunosuppression when using chemotherapy to treat PTLD.
Interval reduction from 3 (CHOP-21) to 2 weeks (CHOP-14; Pfreundschuh et al., Blood, 2004) and the addition of rituximab to CHOP-21 (R-CHOP-21; Coiffier et al., NEJM, 2002) improved outcome in elderly patients with DLBCL to a similar extent without increasing toxicity compared to CHOP-21. In the RICOVER-60 trial, elderly patients (61–80 years, stages I–IV) were randomized to receive 6 or 8 cycles of CHOP-14 with or without 8 applications of 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. The primary endpoint was freedom from treatment failure (FFTF) with events defined as additional therapy, failure to achieve complete remission, progressive disease, relapse, or death. The trial was powered to show a 9% difference in FFTF rate after 3 years. Between 07/2000 and 06/2005, 1330 patients were recruited. A planned interim analysis was performed on 828 evaluable patients with CD20+ DLBCL (median age 68 years; IPI=1: 32%, IPI=2: 29%; IPI=3: 23%; IPI=4,5: 16%). As by intention to treat, there was no difference in FFTF between 6 (n=414) and 8 (n=413) cycles (p=0.23), but FFTF after R-CHOP-14 (n=414) was significantly better than after CHOP-14 (n=413) alone (p=0.000025). As the empirical p-value of the log rank test statistics for FFTF was considerably lower than the critical value for the interim analysis (pcrit=0.031), the formal criterion for stopping the trial according to the alpha spending function (O’ Brien and Fleming boundary) was met and the trial was stopped on June 17, 2005 with 50/1330 patients still under therapy. After a median observation time of 26 months, there was a trend for a better FFTF after 8 cycles of CHOP-14 (n=210) compared to 6 cycles (n=203; 58% vs. 53%; p=0.13), but this trend was neutralized after the addition of rituximab: 70% FFTF for both 6 (n=211) and 8 cycles R-CHOP-14 (n=203). The advantage of R-CHOP-14 over CHOP-14 with respect to overall survival after 26 months is not yet significant (74% vs. 78%; p=0.13). Excluding patients with stage I, the RICOVER-60 population is very similar to the one included in the GELA 98.5 trial; however, the projected 2.5-year survival rate for elderly stage II–IV patients after 6 x R-CHOP-14 (74%) compares favorably with 8 x R-CHOP-21 in the GELA trial (64%; Feugier et al. JCO 2005). The superiority of 6 x R-CHOP-14 over 8 x R-CHOP-21 is mostly due to the better 2.5-year survival of poor-prognosis patients (IPI=3,4,5: 64% in the RICOVER trial vs. 54% in the GELA trial). In conclusion, the results observed with 6 cycles of R-CHOP-14 in this largest randomized trial of DLBLC performed to date are the best ever reported for elderly patients with DLBCL. 6 x R-CHOP-14 should be considered as reference standard in future trials for elderly patients with DLBCL.
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