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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Continued chemotherapy after complete response to primary therapy among women with advanced ovarian cancer: a meta-analysis

LM Hess, N Rong, PO Monahan, P Gupta, C Thomaskutty, and D Matei.

Review published: 2010.

CRD summary

The review concluded that continued chemotherapy after completion of primary therapy for ovarian cancer improved progression-free survival and overall survival. The authors' conclusions reflect the evidence presented, but the limited search, differences between studies and lack of reporting of review methods mean their reliability is uncertain.

Authors' objectives

To assess the impact of consolidation and maintenance therapy on survival and toxicity among patients with ovarian cancer in first remission.

Searching

MEDLINE was searched from 1950 to December 2009 for published articles. Search terms were reported. Cochrane Central Register of Controlled Trials (CENTRAL), Society of Gynecologic Oncology abstracts and American Society of Clinical Oncology abstracts were searched for relevant articles.

Study selection

Clinical trials with continued therapy (either consolidation or maintenance therapy regimens of at least six treatment cycles) for ovarian cancer in first complete remission were eligible for inclusion. Continued therapy was defined as any post-primary treatment for ovarian cancer after completion of primary therapy. Eligible studies had to include at least two treatment groups and haveh continued therapy in at least one treatment group. Studies also had to include participants with ovarian or peritoneal cancer. The primary outcomes of interest were toxicity, progression-free survival and overall survival. Studies that evaluated treatment for persistent or recurrent ovarian cancer or post-frontline maintenance therapy regimen and studies that allowed an extended treatment-free interval were excluded.

Chemotherapy treatment regimens varied widely between studies. Comparison groups included observation, no treatment, radiotherapy, any other treatment and placebo. Over half of the included trials enrolled only patients who achieved complete response or pathologic complete response after primary surgery. Some trials were limited to patients with advanced ovarian cancer (stages III-IV). Only a few studies enrolled patients with early stage disease.

The authors did not state how studies were selected for inclusion.

Assessment of study quality

Validity was assessed using the Cho and Bero scale based on 24 criteria. Total quality score ranges from 0.0 to 1.0 (highest study quality).

The authors did not state how many reviewers assessed validity.

Data extraction

Two reviewers independently extracted data to enable calculation of hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for survival outcomes and odds ratios (ORs) and 95% CIs for toxicity. Survival data were limited to patients who had experienced a complete response after primary therapy. Median values were obtained from survival curves when not reported in the study. Discrepancies were resolved through discussion or recourse to a third reviewer. Primary study authors were contacted for missing information where necessary.

Methods of synthesis

Data were combined using a random-effects analysis. Chemotherapy was considered the experimental treatment where not explicitly stated. Heterogeneity was assessed using the Q statistic. Publication bias was assessed using the fail-safe N method together with a trim-and-fill analysis. Sensitivity analyses were conducted by subgroup to test stability of the survival analysis.

Results of the review

Twenty-nine trials (n=3,518 participants) were included in the review: 20 consolidation trials and nine maintenance therapy trials. The average quality score for consolidation trials was 0.68 (range 0.47 to 0.94) and for maintenance trials was 0.70 (range 0.37 to 0.92). Eleven (55%) of consolidation trials and seven (78%) of maintenance trials were reported to be randomised.

Progression-free survival: Continued therapy significantly improved progression-free survival (HR 0.81, 95% CI 0.73 to 0.91; 23 trials). This remained significant for consolidation therapy regimens (HR 0.79, 95% CI 0.68 to 0.93; 16 trials) and maintenance therapy regimens (HR 0.82, 95% CI 0.70 to 0.96; seven trials).

Overall survival: Continued treatment was significantly associated with improved overall survival (HR 0.69, 95% CI 0.58 to 0.81; 26 trials). This remained significant for consolidation regimens (HR 0.68, 95% CI 0.55 to 0.85; 17 trials) and maintenance therapy (HR 0.68, 95% CI 0.51 to 0.90; nine trials).

Toxicity: Neurotoxicity was significantly higher among patients treated with continued therapy (OR 2.25, 95% CI 1.25 to 4.07; six trials). There were no significant differences between continued therapy and control groups for nausea/vomiting (six trials), pain (five trials) and fatigue (four trials).

Results remained significant in sensitivity analyses when only RCTs were included. Other results of the sensitivity analyses were reported. There was evidence of statistical heterogeneity for the overall analysis (p=0.006), analysis of consolidation regimens (p=0.008) and maintenance regimens (p=0.02). Analysis of publication bias found that even if it was present it would not have changed the conclusion of the review. Trim-and-fill analysis suggested that 10 trials may have been suppressed in the literature.

Authors' conclusions

The results demonstrated that continued chemotherapy after completion of primary therapy for ovarian cancer improved progression-free survival and overall survival. Benefits were greatest in patients with advanced stage ovarian cancer who reached complete clinical or pathologic response after primary therapy.

CRD commentary

The review question was clear with clearly stated inclusion criteria. Inclusion for study design was broad and this resulted in a mix of randomised and other studies being included. Some relevant sources were searched, but relevant databases such as CANCERLIT, EMBASE and CINAHL were not searched. Assessment found some evidence of publication bias but analysis also indicated that it would not have changed the conclusion of the review. Validity was assessed, although full details of criteria and results for individual studies were not reported. The authors did not report whether they used methods to reduce reviewer error and bias during study selection, validity assessment and data extraction. Interventions and disease-state after primary therapy varied between studies. The overall analyses appeared to include studies that were not randomised alongside studies that were and this may have affected the reliability of the pooled effect sizes. However, the authors conducted a sensitivity analysis that included only RCTs and the results were unchanged.

The authors' conclusions reflect the evidence presented, but the limited search, differences between studies and lack of reporting of review methods mean their reliability is uncertain.

Implications of the review for practice and research

Practice: The authors stated that the burden of continuation therapy with relation to treatment-related toxicity and financial costs associated with prolonged therapy needed to be weighed against the anticipated clinical benefits.

Research: The authors stated that further prospective adequately powered trials were required. Future trials of maintenance therapy should include measures of patient quality of life and report adverse events in order to measure benefits and costs associated with continued therapy. The authors noted some of ongoing prospective trials.

Funding

Supported by a project development team within the Indiana Clinical and Translational Science Institute National Institutes of Health/National Center for Research Resource RR025761.

Bibliographic details

Hess LM, Rong N, Monahan PO, Gupta P, Thomaskutty C, Matei D. Continued chemotherapy after complete response to primary therapy among women with advanced ovarian cancer: a meta-analysis. Cancer 2010; 116(22): 5251-5260. [PMC free article: PMC3740230] [PubMed: 20665885]

Indexing Status

Subject indexing assigned by NLM

MeSH

Antineoplastic Agents /administration & dosage /adverse effects; Chemotherapy, Adjuvant /methods; Disease-Free Survival; Female; Humans; Ovarian Neoplasms /drug therapy /mortality /pathology; Remission Induction; Sensitivity and Specificity; Survival Analysis

AccessionNumber

12010008202

Database entry date

07/09/2011

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.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 20665885

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