ORIGINAL ARTICLE CEOP-21 Versus CEOP-14 Chemotherapy With or Without Rituximab for the First-Line Treatment of Patients With Aggressive Lymphomas: Results of the HE22A99 Trial of the Hellenic Cooperative Oncology Group T. Economopoulos,† A. Psyrri,† M. A. Dimopoulos,‡ A. Kalogera-Fountzila,§ N. Pavlidis,¶ C. Tsatalas, C. Nikolaides,¶ S. Mellou,** N. Xiros,* and G. Fountzilas§ Abstract: Background: In this study we investigated whether administering CEOP (cyclophosphamide, epirubicin, vincristine [Oncovin], and prednisone) every 2 weeks (CEOP-14) instead of every 3 weeks (the standard CEOP-21 regimen) improves outcomes in patients with previously untreated aggressive lymphomas. In a secondary analysis we evaluated the impact of adding rituximab to CEOP-14/CEOP-21 chemotherapy. Study Design: The trial opened in March 1999, and patients were randomly assigned to either CEOP-14 or CEOP-21. All patients enrolled from May 2002 onward received rituximab with each chemotherapy cycle, and those attaining a complete response re- ceived rituximab consolidation. Results: Complete and overall response rates in the CEOP-21  rituximab (N  114) and CEOP-14  rituximab (N  103) arms were similar, as were the overall survival (P  0.769) and time to progression distributions (P  0.969). Rituximab was shown to have a beneficial effect both on the overall survival and on the time to progression. Conclusions: Thus far, no significant improvement in outcome has been demonstrated with CEOP-14  rituximab versus CEOP-21  rituximab. However, with addition of rituximab to CEOP-21/CEOP-14, significant improvements in time to progression and overall survival were achieved. Key Words: aggressive non-Hodgkin lymphoma, CEOP, dose- intensification, rituximab, overall survival (Cancer J 2007;13: 327–334) A fter decades of intensive clinical research, a significant proportion of patients with aggressive lymphoma still die of the disease. For many years the CHOP (cyclophospha- mide, doxorubicin, vincristine [Oncovorin], and prednisone) regimen was considered the standard of care for aggressive lymphomas, on the basis of a pivotal study demonstrating that the m-BACOD, ProMACE-CytaBOM, and MACOP-B regi- mens were not superior to CHOP in terms of complete response (CR) rates, disease-free survival (DFS), and overall survival (OS) and were more toxic than CHOP. 1 Our group 2 and others 3,4 have demonstrated that the substitution of doxorubicin by epirubicin in CHOP (CEOP) yields a cure rate similar to that of CHOP but with less myelosuppression and cardiotoxicity. However, the 5-year OS rates with CHOP or CEOP are only in the range of 30% to 40%, with 30% of patients failing to respond or experi- encing disease progression shortly after treatment. One strategy under investigation with the aim of im- proving cure rates in aggressive lymphomas is chemotherapy dose intensification—increasing the dose administered 5,6 or compressing the cycle interval. Another strategy is to add rituximab to the chemotherapy regimen. To investigate whether compressing the CEOP treat- ment interval from 3 to 2 weeks (CEOP-14) would im- prove patient outcome in previously untreated patients with aggressive lymphomas, we initiated a phase III ran- domized study comparing CEOP-14 with standard CEOP (CEOP-21). After the trial opened to accrual in March 1999, several studies conducted in patients with aggressive non-Hodgkin lymphoma (NHL) demonstrated significant improvements in outcomes associated with the addition of rituximab to CHOP or CHOP-like chemotherapy and a pivotal trial demonstrated that 8 cycles of rituximab (R) plus CHOP (R-CHOP) significantly improved complete remission rates, DFS, and OS in elderly patients with previously untreated diffuse large B-cell lymphoma (DLBCL) compared with CHOP alone and without a substantial in- crease in regimen toxicity. 7 Similar benefits were subse- quently confirmed in further studies in elderly patients with DLBCL 8,9 and in young patients with good-prognosis DLBCL, 10 leading to R-CHOP being accepted worldwide as From *Second Department of Internal Medicine–Propaedeutic, Athens Uni- versity Medical School, Attikon University Hospital; †Department of Medicine, Yale University, New Haven, CT; ‡Department of Clinical Therapeutics, University of Athens School of Medicine; §Department of Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Macedonia; ¶Oncology Department, Section of Internal Medicine, Medical School of the University of Ioannina, Ioannina; Hematology Department, Democritus University of Thrace School of Medicine, Alexandroupolis; and **Second Oncology Department Henry Dunant Hospital, Athens, Greece. Reprints: A. Psyrri, Assistant Professor of Medicine, Yale Cancer Center, Yale University, New Haven, CT. E-mail: diamando.psyrri@yale.edu. Copyright © 2007 by Lippincott Williams & Wilkins ISSN: 1528-9117/07/1305-0327 The Cancer Journal • Volume 13, Number 5, September/October 2007 327