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Rituximab in lymphoma |
Imrie K, Esmail R, Buckstein R, Berinstein N, Meyer R, Hematology Disease Site Group |
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CRD summary This well-conducted review found that rituximab is generally well tolerated and may improve response in people with low-grade lymphoma. There were insufficient data on long-term outcomes or people with histological subtypes other than low-grade lymphoma. CHOP chemotherapy plus rituximab appears to improve response and survival more than CHOP alone in people with diffuse large B cell lymphoma. Authors' objectives To assess the groups of people with lymphoma in which rituximab has been studied, the benefits and toxicity of rituximab for people with lymphoma, and which groups are more or less likely to benefit from rituximab.
Searching The authors searched the following sources: MEDLINE (1966 to December 2003), PREMEDLINE (to December 2003), EMBASE (to December 2003), Cancerlit (1983 to March 2001), HealthSTAR (1975 to December 1999), CINAHL (1982 to December 2003), the Cochrane Library (Issue 4, 2003), European Organisation for Research and Treatment of Cancer (to December 2003), the UK Coordinating Committee on Cancer Research (to December 2003), the National Institute of Health Clinical Trials (to December 2003), the CMA Infobase (to July 2003), the National Guideline Clearinghouse (to July 2003) and PDQ (to December 2003). Also searched were conference proceedings of the American Society of Clinical Oncology (1997 to 2003) and the American Society of Hematology (1998 to 2003), the Lugano Proceedings (1999), and article bibliographies. The search terms were reported. Only studies reported in English were eligible.
Study selection Study designs of evaluations included in the reviewThe original review did not specify inclusion criteria for study design, but in regular updates the inclusion criteria were: phase III randomised trials of single agent rituximab or combination therapy with rituximab in any histology, and phase II trials reporting on new histologies. The authors did not specify how they defined phase II and phase III studies. Sample size was not a pre- specified criterion for inclusion, but at least 9 studies were excluded from the tabulation of results because they had less than 10 participants.
Specific interventions included in the reviewStudies of rituximab were eligible for inclusion. In the included studies, rituximab was administered as a single agent or combined with chemotherapy. The authors tabulated details of the regimens used in each study. The most common dose of rituximab was 375 mg/m2 weekly, repeated four or eight times.
Participants included in the reviewStudies were eligible for inclusion if they included patients with lymphoma. The included studies were of people with low-grade relapsed and bulky lymphoma, intermediate-grade lymphoma, follicular lymphoma, mantle cell lymphoma, Waldestrom's macroglobulinaemia, post-transplant lymphoproliferative disorders, diffuse large-cell lymphoma, and small lymphocylic subtypes.
Outcomes assessed in the reviewStudies were eligible for inclusion if they included data on at least one of the following outcomes: survival, quality of life, time-to-progression, response duration, response rate, or adverse effects.
How were decisions on the relevance of primary studies made?Two people independently reviewed the title and abstract of each citation, blinded to author name, institution, journal name, and whether the paper was available in full or as an abstract. When both reviewers agreed that an abstract met the inclusion criteria, the full paper was retrieved (where possible) and assessed further. In cases of disagreement, both people reassessed abstracts jointly to achieve consensus.
Assessment of study quality The authors did not state that they assessed validity. They reported that one member of the Hematology Disease Site Group and methodologists reviewed the papers. This review was developed using the Practice Guidelines Development Cycle reported elsewhere (see Other Publications of Related Interest).
Data extraction The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. Data on publication details, patient subtype, dosage, sample size, method and outcomes were extracted.
Methods of synthesis How were the studies combined?The response rates from patient groups with the same histologic subtypes were combined on an intention-to-treat basis. The number of people with complete or partial tumour responses was summed and divided by the total number of patients enrolled. Percentages and 95% confidence intervals (CIs) were calculated. Other findings were presented narratively.
How were differences between studies investigated?The authors divided their narrative summary according to whether single agent or combination therapy was used, whether papers were available in full or abstract form, and whether or not the studies were randomised trials. No investigation of heterogeneity was reported for the pooled analysis. However, pooling was stratified according to whether the studies included previously treated participants, participants not treated previously, or a mix of treated and untreated participants.
Results of the review The review comprised 66 studies: 5 randomised trials (one focused on quality of life), 45 single-arm phase II trials of rituximab monotherapy, 15 single-arm phase II trials of combination therapy with rituximab, and one economic analysis. The studies included a total of 3,262 participants. The size of the individual studies ranged from 2 to 328 participants.
Response to rituximab monotherapy: the pooled response rates for rituximab monotherapy ranged from 29% (95% CI: 12, 44) for people with small lymphocytic lymphoma to 60% (95% CI: 52, 68) for people with follicular lymphoma. All findings were based on phase II studies.
Response to combining rituximab with chemotherapy: a randomised trial in people with previously untreated diffuse large B cell lymphoma found that adding rituximab to CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) increased response rate over CHOP alone (76% versus 60%, P=0.004; n=328).
Another randomised trial found that rituximab alone had a lower response rate than rituximab followed by Zevalin in people with relapsed follicular or low-grade lymphoma (56% versus 80%, P=0.002; n=143).
Another randomised controlled trial in people with low-grade lymphoma who had a partial or minor response to rituximab monotherapy found that rituximab alone had a lower response rate than rituximab plus interferon (76% versus 100%, P<0.05; n=66).
A maximum of two phase II studies was available for pooling by disease subtype and treatment status. The findings for each combination were reported individually in the review.
Survival.
A randomised trial in people aged 60 to 80 years with previously untreated diffuse large B cell lymphoma found that the addition of rituximab to CHOP chemotherapy increased 1-year event-free survival (69% versus 49%, P<0.005) and 1-year survival (83% versus 68%, P<0.01).
No studies reported survival for follicular lymphoma. One phase II study reported 80% survival at one year in mantle cell lymphoma following single agent rituximab.
Toxicity.
Eight studies provided detailed toxicity data. Rituximab was generally well tolerated, but was associated with grade I to II toxic reactions. The majority of adverse effects occurred with the first infusion. These included fever, chills, nausea, headache, hypertension, hypotension, and allergic symptoms. Grade III to IV toxic reactions were rare.
The inter-rater agreement when selecting papers from the original search was 74% (kappa).
Cost information The authors identified an economic analysis during their search but did not report detailed cost information.
Authors' conclusions Most available evidence about rituximab focused on response rate and toxicity in people with low-grade lymphoma. There was insufficient data about long-term outcomes. There was insufficient evidence about people with histological subtypes of lymphoma other than low-grade lymphoma. People with follicular lymphoma appear to have the best response rates (about 60% of previously treated patients). CHOP chemotherapy plus rituximab appears to improve response and survival more than CHOP alone in people with diffuse large B cell lymphoma. Rituximab is generally well tolerated. CRD commentary This review comprised defined research questions, inclusion criteria, and a comprehensive search strategy. The authors did not report any language restrictions in the main text but, from the search terms listed in an appendix, it is evident that only English language studies were eligible. This might mean that some important studies were omitted or that language bias was introduced. Two authors independently assessed potential studies for relevance; however, no details were provided about how the authors assessed validity, if at all. Some of the samples were extremely small, involving 2, 3 or 7 people, for instance. It is unclear why some studies with less than 10 participants were excluded from the evidence tables while other studies with small samples were included.
Details of the primary studies were clearly tabulated; the tables have been updated to reflect more up-to-date literature. The authors pooled data on response rates and provided a narrative synthesis of other findings. It is unclear whether it was appropriate to pool the data as no heterogeneity analysis was reported.
The authors' conclusions appear to be supported by the data presented. They stated that there was insufficient evidence to answer their research questions in any depth. They also highlighted some of the limitations with the evidence-base.
Implications of the review for practice and research Practice: The authors stated that rituximab is generally well tolerated and may improve response in people with low-grade lymphoma. There was insufficient data on long-term outcomes or people with histological subtypes other than low-grade lymphoma.
Research: The authors did not explicitly state any implications for further research, although they highlighted the lack of data pertaining to long-term outcomes and people with histological subtypes other than low-grade lymphoma. They identified 23 ongoing trials. Rituximab alone or combined with chemotherapy is currently being compared in people with newly diagnosed low-grade or follicular lymphoma, relapsed lymphoma, and as initial therapy for intermediate-grade lymphoma.
Funding Cancer Care Ontario; Ontario Ministry of Health and Long-term Care.
Other publications of related interest 1. Browman GP, Levine MN, Mohide EA, Hayward RS, Pritchard KI, Gafni A, et al. The practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation. J Clin Oncol 1995;13:502-12. 2. Imrie K, Esmail R, Buckstein R, Berinstein N, Meyer R, and the Hematology Disease Site Group. Use of rituximab in the treatment of lymphoma: an evidence summary. Curr Oncol 1999;6:228-35.3. Cheung MC, Haynes AE, Meyer RM, Stevens A, Imrie KR, and the Members of the Hematology Disease Site Group of the Cancer Care Ontario Program in Evidence-Based Care. Rituximab in lymphoma: a systematic review and consensus practice guideline from Cancer Care Ontario. Cancer Treat Rev 2007;33:161-76. Indexing Status Subject indexing assigned by CRD MeSH Antibodies, Monoclonal /therapeutic use; Antineoplastic Agents /therapeutic use; Lymphoma, B-Cell /drug therapy; Lymphoma, Follicular /drug therapy; Lymphoma, Non-Hodgkin /drug therapy AccessionNumber 12003008180 Date bibliographic record published 31/03/2005 Date abstract record published 31/03/2005 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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