Annals of Oncology Advance Access published online on January 22, 2008
Annals of Oncology, doi:10.1093/annonc/mdm497
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Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: I. A randomized dose escalation and feasibility study with bi- and tri-weekly regimens
1 Hematology and Oncology, University Hospital Göttingen
2 Internal Medicine I, Saarland University Medical School, Homburg
3 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig
4 Oncology, University Hospitals of Magdeburg, Magdeburg
5 Oncology, University Hospital Münster, Münster
6 Oncology, City Hospital of Karlsruhe, Karlsruhe
7 Oncology, Kliniken Maria-Hilf, Mönchengladbach
8 Helios-Kliniken, Bad Saarow
9 Oncology, Städtische Kliniken Ludwigshafen, Ludwigshafen
10 Department of Internal Medicine, Städtische Kliniken Oldenburg, Germany
* Correspondence to: Dr M. Pfreundschuh, Innere Medizin I, Saarland University Medical School, D-66421 Homburg, Germany. Tel: +49-6841-162-3002; Fax: +49-6841-162-3101; E-mail: inmpfr{at}uniklinikum-saarland.de
Background: To determine the maximum tolerated dose of a bi- and tri-weekly combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone plus etoposide (CHOEP) regimen without stem-cell support.
Patients and methods: Randomized phase I/II multicenter four-level (cyclophosphamide: 1000–1200–1400–1600 mg/m2; doxorubicin: 55–60–65–70 mg/m2; etoposide: 375–450–525–600 mg/m2) dose escalation study with CHOEP-14 and CHOEP-21 in young patients (18–60 years) with newly diagnosed aggressive non-Hodgkin's lymphoma. Dose-limiting toxicity was defined as thrombocytopenia <80 000/mm3 and leukocytopenia <2500/mm3 on days 16 (CHOEP-14) and 23 (CHOEP-21) or prolonged (>4 days) leukocytopenia (<1000/mm3) or thrombocytopenia (<20 000/mm3).
Results: One hundred and thirty-nine patients (high-CHOEP-14: 47, high-CHOEP-21: 92) were randomly allocated to the study. Maximal tolerated dose was level 2 for CHOEP-14 and level 4 for CHOEP-21. With a less favorable profile of patients in CHOEP-14, 4-year event-free survival was 47.9% after high-CHOEP-14 and 66.2% after high-CHOEP-21, 4-year overall survival 62.1% after high-CHOEP-14 and 73.4% after high-CHOEP-21, respectively.
Conclusion: Significant dose escalations of CHOEP are possible with granulocyte colony-stimulating factor support, with different chemotherapy models favoring the maximally escalated bi- or tri-weekly regimen, respectively. Because a higher total dose can be achieved with six cycles of the tri-weekly compared with the biweekly regimen, CHOEP-21 at dose escalation level 3 was chosen for a nationwide randomized comparison with baseline CHOEP-21 in a subsequent phase III trial.
aggressive NHL, chemotherapy models, clinical trials, dose escalation
Both authors contributed equally to this manuscript. Received for publication September 18, 2007. Accepted for publication September 21, 2007.