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Trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials |
Dahabreh IJ, Linardou H, Siannis F, Fountzilas G, Murray S |
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CRD summary The review found that adding trastuzumab to chemotherapy for early-stage breast cancer patients improved disease-free and overall survival, locoregional recurrence, and distant metastasis, but increased the risk of some adverse events compared with chemotherapy alone. The authors' conclusions reflected the evidence, but limitations in the review process and the unknown quality of included trials mean that their reliability is uncertain. Authors' objectives To compare treatment outcomes for human epidermal growth factor receptor (HER)-2-positive early-stage breast cancer patients receiving adjuvant chemotherapy with and without trastuzumab. Searching MEDLINE (up to June 2007) and Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2007) were searched for relevant studies with not language restriction; search terms were reported. The online proceedings of the American Society of Clinical Oncology Annual meetings (1992 to June 2007) and the San Antonio Breast Cancer Symposium (2004 to June 2007) were also searched. Oncology journals and the reference lists of retrieved articles were handsearched. Experts in the field were contacted to identify additional studies. Study selection Eligible studies were randomised controlled trials (RCTs) that evaluated the administration of trastuzumab with or following adjuvant chemotherapy versus chemotherapy alone in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer. Any type of chemotherapy was considered eligible provided the same drugs were given at the same dose in both trial arms and the arms differed only by trastuzumab administration. Trials were excluded if they included post-chemotherapy radiotherapy and adjuvant hormonal treatment protocols, evaluated neoadjuvant administration of trastuzumab or biological/targeted agents other than trastuzumab. Abstracts were included if they reported on the primary outcome.
The primary outcome was disease-free survival rate (defined as disease progression or death from any cause). Secondary outcomes included all-cause mortality (death from any cause), locoregional recurrence, distant recurrence, central nervous system recurrence (defined as the development of central nervous system involvement as the initial metastatic event), class III/IV congestive heart failure, and significant decline in left ventricular ejection fraction.
In the included trials, patients had early-stage breast cancer with a high risk of recurrence (as demonstrated by a high prevalence of hormone receptor negative disease and node positive disease). HER-2-positivity in patients was assessed by a combination of immunohistochemistry, fluorescence in situ hybridization, or chromogenic in situ hybridization. Chemotherapy regimens included: combination of doxorubicin plus cyclophosphamide followed by an anthracycline, with or without trastuzumab, vinorelbine or docetaxel plus trastuzumab or observation; and anthracycline based chemotherapy with a number of alternative agents with or without trastuzumab.
The authors did not state how study selection was undertaken. Assessment of study quality The authors did not state whether quality assessment of the included studies was undertaken. Data extraction Relative risks (RRs) with their 95% confidence intervals (CIs) were calculated for the primary outcome (disease-free survival rate) and secondary outcomes. Where multiple reports were available, data from the longest follow-up were extracted. Interim analyses were only included if they represented the most recently available data. Data from one trial were extracted only on a subgroup of participants which were HER-2-positive. Authors of some of the trials were contacted for missing data.
Two reviewers extracted data, with disagreements resolved by consultation with a third reviewer until consensus was reached. Methods of synthesis Trials were pooled in meta-analyses using the Mantel-Haenszel fixed-effects model to estimate summary effects. Random-effects models were used in sensitivity analysis. Analyses were undertaken according to the intention-to-treat principle, where data were available. A continuity correction of 0.5 was used for trials with zero total effects in one arm.
Between trial heterogeneity was tested with the Q statistic, with statistical significance defined as p<0.1; inconsistency was assessed using the I2 statistic. When extreme inconsistency was present (I2>75%), summary estimates were not presented. Fixed-effect meta-regression was used to explore heterogeneity, when detected.
Begg’s and Egger’s tests were used to assess publication bias for the primary outcome (disease-free survival rate). Results of the review Five RCTs were included in the review (total n=13,493 patients, with 8,627 in the trastuzumab arm and 4,866 in the chemotherapy alone arm); 9,748 patients (4,882 treated with chemotherapy plus trastuzumab; 4,866 treated with chemotherapy alone) were considered eligible for analysis. Results from two RCTs were combined and treated as a single larger study. One trial included a small group of patients that were treated with neoadjuvant chemotherapy which had similar outcomes to the eligible patients; data from these patients were included in the review. Median follow-up from the trials ranged from two to three years, but the two-year trial reported only data from follow-up for one year.
Patients treated with trastuzumab plus chemotherapy had significantly better disease-free survival rate compared with patients that received chemotherapy alone (RR 0.62, 95% CI 0.56 to 0.68; all RCTs). Patients treated with trastuzumab plus chemotherapy had significantly better overall survival (RR 0.66, 95% CI 0.57 to 0.77; all RCTs), a lower risk of locoregional recurrence (RR 0.58, 95% CI 0.43 to 0.77; three RCTs) and distant recurrence (RR 0.60, 95% CI 0.53 to 0.68; all RCTs) than patients that received chemotherapy alone. Patients treated with trastuzumab had a higher risk of developing central nervous system metastasis as the first recurrent event (RR 1.60, 95% CI 1.06 to 2.40; three RCTs), a higher risk of class III/IV congestive heart failure (RR 7.60, 95% CI 4.07 to 14.18; four RCTs) and greater risk of left ventricular ejection fraction decline (RR 2.09, 95% CI 1.84 to 2.37; all RCTs).
There was no evidence of statistically significant heterogeneity for any outcome, except left ventricular ejection fraction decline (I2=74.6%, Q=15.72, p=0.003); for this outcome, between trial heterogeneity was further explored by a fixed effects meta-regression analysis. This analysis suggested that duration of trastuzumab administration and cumulative trastuzumab dose contributed significantly to the between trial heterogeneity. For all outcomes, random-effects and fixed-effect models produced similar results.
There was no evidence of publication bias for disease-free survival rate using either Begg’s or Egger’s test. Authors' conclusions The addition of trastuzumab to adjuvant chemotherapy in early-stage breast cancer improved disease-free and overall survival, locoregional recurrence, and distant metastasis, but increased the risk of some adverse events compared with adjuvant chemotherapy alone. The use of trastuzumab should be considered an integral part of the adjuvant therapy of human epidermal growth factor receptor-2-positive breast cancer patients. CRD commentary The review addressed a clear research question and inclusion criteria appear appropriate. A number of relevant sources were searched for relevant studies without language restriction. Publication bias was assessed by formal tests, but the small number of trials included meant that the results from these tests were potentially unreliable. Appropriate methods were used for data extraction, but the method used for selection of studies was not reported, so reviewer error and bias could not be excluded.
The quality of trials was not assessed, so it was difficult to assess the reliability of the evidence presented. Most of the trials had large sample sizes, but subgroup analysis was only possible for one trial. Some of the trials reported results from interim analyses, which may have introduced additional bias. Appropriate methods were used to conduct the synthesis of trials and assess heterogeneity. The overall findings of the review (the summary estimates) were not markedly changed with addition of results from a trial which was presented at a meeting after the review had been completed; this added further weight to the authors’ conclusions.
The authors’ conclusions reflected the evidence presented, but potential bias from some aspects of the review process and lack of validity assessment mean the reliability of the conclusions is uncertain. Implications of the review for practice and research Practice: The authors stated that the combination of trastuzumab with or following chemotherapy should be strongly considered for human epidermal growth factor receptor-2-positive early-stage breast cancer, particularly in patients at low risk of cardiovascular morbidity.
Research: The authors stated that further research was required to identify the most effective drug combination and treatment schedule, including the optimal duration of trastuzumab administration, to clarify the balance of benefits and risks of the addition of trastuzumab. Bibliographic details Dahabreh IJ, Linardou H, Siannis F, Fountzilas G, Murray S. Trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials. Oncologist 2008; 13(6): 620-630 Indexing Status Subject indexing assigned by NLM MeSH Antibodies, Monoclonal /therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic Agents /therapeutic use; Breast Neoplasms /drug therapy /metabolism /mortality; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Gene Amplification; Humans; Immunoenzyme Techniques; Neoplasm Staging; Randomized Controlled Trials as Topic; Receptor, ErbB-2 /genetics /metabolism; Survival Rate; Trastuzumab; Treatment Outcome AccessionNumber 12008107883 Date bibliographic record published 29/04/2009 Date abstract record published 09/03/2011 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. |
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