We read with great interest the article by Cheson (The case against rituximab maintenance. Nat. Rev. Clin. Oncol. 6, 622–624; 2009).1 Unfortunately, we encountered a few inaccuracies in the article regarding the reference to our meta-analysis: 'Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials'.2 We would like to correct these inaccuracies. Cheson refers to the fact that we reported two versions of the same Eastern Cooperative Oncology Group (ECOG) trial. As stated in our meta-analysis, the results of the ECOG 1496 study were reported in a number of publications. Two of these publications refer to two different cohorts included in one trial: patients treated with fludarabine and cyclophosphamide induction, and patients treated with cyclophosphamide, vincristine, and prednisone induction.3,4,5 Thus, the data from both publications are complementary, rather than redundant.
At the time the systematic review and meta-analysis was accepted for publication the updated trial data from van Oers and coauthors had not been reported. We used the available published data at that time, as we could not get additional data from the researchers.6 Our meta-analysis was updated when additional data presented at the ASH meeting in 2008 were published.7 The updated data did not, however, change the results of overall survival.8
Cheson raises the concern that we confused event-free survival with overall survival. This is incorrect. The definition of mortality and as a consequence, that of overall survival is straightforward. This may be the only and most important objective outcome measure, and therefore it was chosen by us as the primary outcome. Cheson compares the results of the trial by Ghielmini et al. that were used in the meta-analysis to the results reported in the original study.2 This is challenging as Ghielmini et al. did not report survival data in their original manuscript, and specifically not survival data in patients with follicular lymphoma. The survival data were provided to us by Drs M. Ghielmini and S. F. Hsu Schmitz, co-authors of the meta-analysis.
Randomized trials have failed to support a survival benefit with maintenance rituximab but the pooling of their results in a meta-analysis has shown survival benefit for patients with relapsed or refractory follicular lymphoma, and these patients should be treated with maintenance rituximab.
References
Cheson, D. B. The case against rituximab maintenance. Nat. Rev. Clin. Oncol. 6, 622–624 (2009).
Vidal, L. et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J. Natl Cancer Inst. 101, 248–255 (2009).
Hochster, H. et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progession-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 study. J. Clin. Oncol. 27, 1607–1614 (2009).
Hochster, H. et al. Cyclophosphamide and fludarabine (CF) in advanced indolent lymphoma: results from the ECOG/CALGB intergroup E1496 trial. J. Clin. Oncol. ASCO Annual Meeting Proceedings Part I 25, 8004 (2007).
Hochster, H., Weller, E., Gascoyne, R. et al. Maintenance rituximab after CVP results in superior clinical outcome in advanced follicular lymphoma (FL): results of the E1496 phase III trial from the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group [abstract]. Blood 106, 349 (2005).
van Oers, M. H. et al. Rituximab maintenance improves clinical outcome of relapsed/refractory follicular non-Hodgkin's lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase III intergroup trial. Blood 108, 3295–3301 (2006).
Van Oers, M. H. J. et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study [abstract 836]. Blood 112, 309–310 (2008).
Vidal, L., Gafter-Gvili, A., Leibovici, L., Dreyling, M., Ghielmini, M., Shpilberg, O. Response: Re: Rituximab Maintenance for the Treatment of Patients With Follicular Lymphoma: Systematic Review and Meta-analysis of Randomized trials. J. Natl Cancer Inst. 101, 1289–1290 (2009).
Ghielmini, M. et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with weekly × 4 schedule. Blood 103, 4416–4423 (2004).
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Vidal, L., Gafter-Gvili, A. & Shpilberg, O. Rituximab maintenance for follicular lymphoma. Nat Rev Clin Oncol 7, 1 (2010). https://doi.org/10.1038/nrclinonc.2009.161-c1
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DOI: https://doi.org/10.1038/nrclinonc.2009.161-c1