Review
Long-term efficacy of the CHVmP/BV regimen used for aggressive non-Hodgkin’s lymphoma in three randomised EORTC trials

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Abstract

We analysed data from 936 newly-diagnosed patients with advanced, aggressive non-Hodgkin’s lymphoma (NHL) treated in three randomised European Organisation for Research and Treatment of Cancer (EORTC) trials performed between 1980 and 1999 (median follow-up of 8.7 (0.2–20.4) years). The CHOP-like regimen CHVmP/BV (cyclophosphamide, doxorubicin, teniposide and prednisone with bleomycin and vincristine at mid-interval), was compared with CHVmP (CHVmP/BV without bleomycin and vincristine), ProMACE-MOPP (methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamide, vincristine, procarbazine and prednisone) and CHVmp/BV with additional, autologous stem-cell transplantation, respectively. Overall, treatment with CHVmP/BV resulted in a better long-term outcome with 63% complete responses being observed and an overall survival (OS) of 59 and 43% at 5 and 10 years, repectively. Remarkably, OS after CHVmP/BV improved across the trials, even after stratifying for the International Prognostic Index (IPI). This finding could not be directly related to better salvage treatments during the last decade. Selection bias appears to be responsible: stepwise corrections for small differences in inclusion criteria eliminated the difference in OS, especially when histological subgroups were studied. This systemic review underlines the difficulties encountered in retrospective sub-set analyses and the biases that can be introduced when recent studies are compared with older ones.

Introduction

Patients with advanced, aggressive non-Hodgkin's lymphoma (NHL) can be effectively treated with multi-agent chemotherapy. Although most (55–80%) patients below the age of 65 years will experience a complete remission (CR) after 6–8 courses of CHOP-like chemotherapy, less than 50% will be cured. Many trials have been performed, several within the European Organisation for Research and Treatment of Cancer (EORTC) [1], introducing new drugs and more aggressive approaches, with the aim of improving the outcome of this group of NHL patients. Since 1980, the CHVmP/BV scheme (eight cycles of cyclophosphamide, doxorubicin, teniposide and prednisone with bleomycin and vincristine in every cycle at the mid-interval), which contains cyclophosphamide, doxorubicin, teniposide and prednisone combined with vincristine and bleomycin, has been consistently used in three consecutive EORTC phase III trials 2, 3, 4, 5 Combining these trials resulted in a unique chance to review the efficacy of this regimen over a 20-year period. We observed remarkably large differences across the trials in long-term outcome data. By presenting our analyses, we want to underline the risk of comparing recent studies with older ones, showing the biases that can be introduced by retrospective sub-set analyses.

Section snippets

Eligibility

Between 1980 and 1999, 936 newly-diagnosed and untreated patients with advanced, aggressive NHL were registered in three prospective, phase III randomised EORTC-trials (20802, 20855 and 20901). Follow-up was missing or incomplete in 23 patients. Therefore, altogether, 913 patients could be analysed. All three trials were designed for intermediate or high-grade NHL classified by the Working Formulation (WF) as D-J [6]. Histological classification (Table 1) was performed by the local pathologist

Long-term efficacy

Out of 913 patients with advanced, aggressive NHL, 55 and 47% were still alive at 5 and 10 years, respectively (median follow-up of 8.7 (0.2–20.4) years). The median survival was 7.3 (0.2–20.4) years, with 388 (42%) patients still alive at the time of analysis. Protocol treatment was stopped in 168 (18%) patients after three cycles, showing no response; from the patients who continued protocol treatment, 63% of the patients treated with CHVmP/BV obtained a complete remission.

Randomised trials

Trial 20802 was

Discussion

Several different regimens have been applied in patients with advanced aggressive NHL. Fisher and colleagues [13] compared third generation regimens (m-BACOD, ProMACE-CytaBOM, MACOP-B) with the classical CHOP, and found no difference in outcome between all four regimens. Our findings were similar when we compared ProMACE-MOPP, as a third generation regimen, with the EORTC-based CHVmP/BV regimen. However, by adding bleomycin and vincristine to the CHVmP scheme, we improved the survival outcome

Acknowledgments

This project was partly financed by the Dutch Cancer Foundation. The help of all participating centres and local investigators is gratefully acknowledged (see the Appendix for details).

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