Elsevier

The Lancet Oncology

Volume 9, Issue 2, February 2008, Pages 105-116
The Lancet Oncology

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Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60)

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Summary

Background

Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is used to treat patients with non-Hodgkin lymphoma. Interval decrease from 3 weeks of treatment (CHOP-21) to 2 weeks (CHOP-14), and addition of rituximab to CHOP-21 (R-CHOP-21) has been shown to improve outcome in elderly patients with diffuse large B-cell lymphoma (DLBCL). This randomised trial assessed whether six or eight cycles of R-CHOP-14 can improve outcome of these patients compared with six or eight cycles of CHOP-14.

Methods

1222 elderly patients (aged 61–80 years) were randomly assigned to six or eight cycles of CHOP-14 with or without rituximab. Radiotherapy was planned to sites of initial bulky disease with or without extranodal involvement. The primary endpoint was event-free survival; secondary endpoints were response, progression during treatment, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat. The trial is registered on National Cancer Institute website, number NCT00052936 and as EU-20243.

Findings

3-year event-free survival was 47·2% after six cycles of CHOP-14 (95% CI 41·2–53·3), 53·0% (47·0–59·1) after eight cycles of CHOP-14, 66·5% (60·9–72·0) after six cycles of R-CHOP-14, and 63·1% (57·4–68·8) after eight cycles of R-CHOP-14. Compared with six cycles of CHOP-14, the improvement in 3-year event-free survival was 5·8% (−2·8–14·4) for eight cycles of CHOP-14, 19·3% (11·1–27·5) for six cycles of R-CHOP-14, and 15·9% (7·6–24·2) for eight cycles of R-CHOP-14. 3-year overall survival was 67·7% (62·0–73·5) for six cycles of CHOP-14, 66·0% (60·1–71·9) for eight cycles of CHOP-14, 78·1% (73·2–83·0) for six cycles of R-CHOP-14, and 72·5% (67·1–77·9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by −1·7% (−10·0–6·6) after eight cycles of CHOP-14, 10·4% (2·8–18·0) after six cycles of R-CHOP-14, and 4·8% (−3·1–12·7) after eight cycles of R-CHOP-14. In a multivariate analysis that used six cycles of CHOP-14 without rituximab as the reference, and adjusting for known prognostic factors, all three intensified regimens improved 3-year event-free survival (eight cycles of CHOP-14: RR [relative risk] 0·76 [0·60–0·95], p=0·0172; six cycles of R-CHOP-14: RR 0·51 [0·40–0·65], p<0·0001; eight cycles of R-CHOP-14: RR 0·54 [0·43–0·69], p<0·0001). Progression-free survival improved after six cycles of R-CHOP-14 (RR 0·50 [0·38–0·67], p<0·0001), and eight cycles of R-CHOP-14 (RR 0·59 [0·45–0·77], p=0·0001). Overall survival improved only after six cycles of R-CHOP-14 (RR 0·63 [0·46–0·85], p=0·0031). In patients with a partial response after four cycles of chemotherapy, eight cycles were not better than six cycles.

Interpretation

Six cycles of R-CHOP-14 significantly improved event-free, progression-free, and overall survival over six cycles of CHOP-14 treatment. Response-adapted addition of chemotherapy beyond six cycles, though widely practiced, is not justified. Of the four regimens assessed in this study, six cycles of R-CHOP-14 is the preferred treatment for elderly patients, with which other approaches should be compared.

Introduction

For more than 25 years, the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen1 has been standard care for aggressive lymphomas.2 The French Groupe de l'Etude des Lymphomes de l'Adulte (GELA) added the monoclonal anti-CD20 antibody rituximab to eight cycles of CHOP (CHOP-21),3 whereas the German High-Grade Non-Hodgkin Lymphoma Study Group (Deutsche Studiengruppe Hochmaligne Lymphome; DSHNHL) shortened intervals between six cycles of treatment with CHOP from 3 weeks to 2 weeks (CHOP-14).4 Both approaches have been shown to improve the outcome of elderly patients, notably without relevant additional toxicity. To compare six cycles with eight cycles of chemotherapy and to address the question whether further improvement could be achieved by adding rituximab to the dose-dense CHOP-14 regimen, the DSHNHL designed the rituximab with CHOP over age 60 years (RICOVER-60) trial, in which elderly patients with diffuse large B-cell lymphoma (DLBCL) were randomly assigned to receive six or eight cycles of chemotherapy, both with and without eight cycles of rituximab. The number of rituximab cycles was kept constant in both R-CHOP-14 arms because we intended to compare the numbers of chemotherapy cycles without the confounder of differing rituximab regimens.

Section snippets

Patients

Patients were eligible if they had previously untreated, biopsy-confirmed aggressive non-Hodgkin lymphoma of the B-cell type according to the Revised European–American Lymphoma Classification5 (translated into the WHO classification6) and were aged between 61 years and 80 years. Histological diagnosis was reviewed centrally by a panel of five expert haematopathologists. Patients with previous lymphoma associated with acquired immunodeficiency syndrome, diagnosis or history of indolent lymphoma

Results

Between July 1, 2000, and June 14, 2005, 1242 patients were enrolled in 203 institutions in Germany, Czech Republic, and Switzerland. 20 patients were excluded because of missing or retracted informed consent, leaving 1222 for the intention-to-treat analysis (figure 1). There were no significant differences in numbers of excluded patients between treatment regimens. Of the 1222 eligible patients, 307 patients were randomly assigned to receive six cycles of CHOP-14, 305 patients to eight cycles

Discussion

To our knowledge, this trial is the first randomised study to compare six and eight cycles of chemotherapy and assess the role of rituximab in combination with a dose-dense CHOP-14 regimen. Of the three intensified regimens, only six cycles of R-CHOP-14, but not eight cycles of R-CHOP-14, improved event-free survival, progression-free survival, and overall survival over six cycles of CHOP-14. 3-year overall survival of eight cycles of R-CHOP-14 was 5·6% lower than after six cycles of R-CHOP-14.

References (17)

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