Determining the Benefits of Rituximab + Chemotherapy for Patients with Untreated Follicular Lymphoma: A Comprehensive Meta-Analysis.

Background: Current guidelines offer numerous options for initiating therapy in patients with untreated, advanced stage follicular lymphoma (FL). Selecting among these options that include watchful waiting, single-agent and combination chemotherapy, monoclonal antibodies, and radioimmunotherapy, remains challenging. Recent data suggest that chemotherapy combined with a monoclonal antibody may alter patterns of relapse and overall survival for pts with FL (Fisher, Blood 2004). While rituximab (R) chemotherapy combinations have become commonly used for untreated pts with FL, to date, the optimal first-line therapy remains undefined. To address this issue, we updated a systematic literature review and performed a meta-analysis of first-line therapy for untreated FL that examined the effect of various chemotherapy regimens combined with R on response rates and survival in patients with untreated FL. Methods: The comprehensive systematic review included searches the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 1, 2003), MEDLINE (1/1996–6/2006), EMBASE (1/1980–7/2006), American Society of Hematology Annual Meeting abstracts (2002–2005), and American Society of Clinical Oncology Annual Meeting abstracts (1995–2006). Each database was searched using combinations of the term follicular lymphoma and the terms for medications and treatment regimens. Inclusion criteria for studies were as follows: 1) Inclusion of patients with untreated stage III/IV FL grades 1, 2, or 3; 2) Intervention with chemotherapy and/or immunotherapy, radioimmunotherapy, or watchful waiting; 3) Reporting in English of the following treatment outcome measures specifically for patients with FL: CR/CR-unconfirmed, overall response rate (OR), and at least one form of survival data. Abstracts subsequently published as papers were excluded. Extracted data included pre-treatment disease status, treatment regimen, median follow-up time, progression free survival, overall survival, CR and OR. The following treatment strategies from peer-review publications were analyzed: single agent R, R-CVP, R-CHOP, and fludarabine-combinations with R (R-Fcom). In meta-analyses of selected studies, we utilized the Mantel-Haenszel (fixed effects model) and DerSimonain and Laird (random effects) methods to calculate the risk difference comparing treatment regimens’ CR/CRu to the spontaneous CR in patients undergoing watchful waiting (4.6%; Ardeshna et al. Lancet, 2003). Results: In total, over 3135 abstracts were reviewed to identify 11 studies meeting the inclusion criteria for this analysis. These studies included data from 3144 patients. Only one study presenting CR data for R-CVP (36%, 95% confidence interval: 28%–44%) met inclusion criteria. The meta-analyses estimated the CR rate associated with single-agent R to be 30% (95% CI: 20%–40%), R-CHOP to be 62% (30%–94%), and R-Fcom to be 85% (76%–94%) (random effects; see Figure). Conclusions: R-CHOP and R-fludarabine combinations appear to produce the highest CR rates for untreated pts with FL. Meta-analysis can aid clinicians in therapeutic decision making as they weight the risks and benefits of various regimens for newly diagnosed pts.