|Benefit of taxanes as adjuvant chemotherapy for early breast cancer: pooled analysis of 15,500 patients
|Bria E, Nistico C, Cuppone F, Carlini P, Ciccarese M, Milella M, Natoli G, Terzoli E, Cognetti F, Giannarelli D
The review assessed the benefit of adding taxanes to standard chemotherapy for early breast cancer. The authors concluded that paclitaxel and docetaxel significantly improved disease-free survival and overall survival, albeit by a small amount. The results were based on trials involving more than 15,000 patients, but the quality of the review leaves some reservations about the reliability of the conclusions.
The main objective was to quantify the benefit of taxanes as adjuvant chemotherapy for early breast cancer.
MEDLINE and the websites of the following organisations were searched: American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), Federation of European Cancer Societies (FECS), San Antonio Breast Cancer Symposium (SABCS). The searches were conducted up to the end of October 2005; the search terms were reported. References in reviews and original articles, and lectures presented at ASCO, ESMO, SABCS and European Cancer Conference (ECCO) meetings on the topics 'adjuvant chemotherapy for breast cancer' or 'early breast cancer' were checked for additional studies. Studies published by October 2005 were eligible for inclusion in the review. The search was not restricted by language. Full articles and abstracts were included in the review.
Study designs of evaluations included in the review
Phase III trials, prospective and randomised by definition, were eligible for inclusion.
Specific interventions included in the review
Studies of chemotherapy with or without sequential or concomitant paclitaxel or docetaxel were eligible for inclusion. The studies reviewed included trials of sequential and concomitant paclitaxel and docetaxel. The standard chemotherapy regimens varied: in the paclitaxel trials these were doxorubicin plus cyclophosphamide with or without 5-fluorouracil (5-FU), and cyclophosphamide plus methotrexate and 5-FU with either doxorubicin or epirubicin; in the docetaxel trials these were doxorubicin plus cyclophosphamide, and 5-FU plus cyclophosphamide with either doxorubicin or epirubicin.
Participants included in the review
Studies of previously untreated patients who had undergone curative surgical resection for early breast cancer were eligible for inclusion. Studies were excluded if they enrolled only lymph node-negative patients. Four of the included trials were in node-positive populations, and in one other trial 98% of the patients enrolled were node positive.
Outcomes assessed in the review
The stated primary outcome was disease-free survival, defined as the time in months between randomisation and the appearance of recurrence or death from any cause. Recurrence could be local, distant or both. The secondary outcome was overall survival, defined as the time between randomisation and death from any cause. In the review event rates, not time-to-event data, appeared to have been used to determine the treatment effects. All of the included trials reported data on disease-free survival and all but one reported overall survival. The median follow-up in the included trials ranged from 43 to 69 months.
How were decisions on the relevance of primary studies made?
The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.
Assessment of study quality
The authors did not state that they assessed validity.
The data extraction procedure was not reported in full, although it appeared that two reviewers independently extracted the outcomes data. The numbers of deaths and recurrence events in the treatment and control groups were extracted from each trial.
Methods of synthesis
How were the studies combined?
Meta-analysis was used to calculate pooled estimates of the relative risk (RR) and a 95% confidence interval (CI) for each outcome. The analysis was based on the risk of an adverse outcome occurring. Analysis was ostensibly by intention-to-treat. Fixed-effect and random-effects analyses were conducted. The reported estimates appeared to have been calculated using the Mantel-Haenszel fixed-effect model. The pooled estimates were then expressed as absolute differences and the number-needed-to-treat.
How were differences between studies investigated?
A chi-squared test of statistical heterogeneity was applied in the meta-analysis. The application of fixed-effect and random-effects analyses constituted a sensitivity analysis. Estimates of effect were calculated overall and within the subgroups node positive, sequential taxane therapy, concomitant taxane therapy, paclitaxel and docetaxel. The authors referred to the subgroup analysis as a sensitivity analysis to decrease differences between the trials.
Results of the review
Nine randomised controlled trials involving 15,598 patients were included.
A meta-analysis of 9 trials (15,598 participants) showed a statistically significant improvement in disease-free survival with adjuvant taxanes compared with standard chemotherapy (RR 0.86, 95% CI: 0.81, 0.90, p<0.00001). There was no statistically significant heterogeneity between the studies. The absolute benefit was 3.3% and the NNT was 30.
A meta-analysis of 8 trials (15,074 participants) showed a statistically significant improvement in overall survival with adjuvant taxanes compared with standard chemotherapy (RR 0.87, 95% CI: 0.81, 0.93, p<0.0001). There was no statistically significant heterogeneity between the studies. The absolute benefit was 2.0% and the NNT was 49.
All of the subgroup analyses showed a statistically significant (p<0.05) benefit in favour of adjuvant taxanes for both outcomes and no statistically significant heterogeneity between the studies. The absolute benefit in the node-positive subgroup analyses were 4.3% in disease-free survival and 2.8% in overall survival (4 trials, 9,670 participants).
The authors noted that most of the trials did not report in detail on toxicity.
Taxanes as adjuvant chemotherapy seemed to confer a significant benefit in disease-free and overall survival compared with standard chemotherapy.
The review addressed a clear question and clearly stated the inclusion criteria. Although a number of topic specific websites were targeted in the search for studies, a wider search of electronic databases would have given more reassurance that relevant trials were not missed. From the information reported, the potential for bias in the study selection process of the review cannot be assessed and neither can the potential for bias in the studies included.
Sparse details of the individual studies were reported. The data used to calculate the individual study results used in the analysis were not shown. Poor reporting raises uncertainty as to how exactly the quantitative estimates of treatment effect were derived. Without adequate details of the individual studies the NNT derived from meta-analysis can be misleading. Despite the large number of participants included in the review, too many questions remain about the methods to be confident that the conclusions are reliable.
Implications of the review for practice and research
Practice: The authors stated that sequential or concurrent paclitaxel or docetaxel adjuvant to standard chemotherapy should be one of the standard options for patients undergoing surgery for early breast cancer. The magnitude of the expected benefit balanced against toxicity should be discussed with patients.
Research: The authors stated that the effect of hormone receptor status and overexpression of HER-2 on the benefit of adjuvant taxanes needs further exploration.
Bria E, Nistico C, Cuppone F, Carlini P, Ciccarese M, Milella M, Natoli G, Terzoli E, Cognetti F, Giannarelli D. Benefit of taxanes as adjuvant chemotherapy for early breast cancer: pooled analysis of 15,500 patients. Cancer 2006; 106(11): 2337-2344
Other publications of related interest
Cuppone F, Bria E, Carlini P, Milella M, Felici A, Sperduti I, Nistico C, Terzoli E, Cognetti F, Giannarelli D. Taxanes as primary chemotherapy for early breast cancer: meta-analysis of randomized trials. Cancer 2008;113(2):238-246.
Subject indexing assigned by NLM
Antineoplastic Agents, Phytogenic /therapeutic use; Breast Neoplasms /drug therapy /pathology /surgery; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Disease-Free Survival; Female; Humans; Neoplasm Staging; Paclitaxel /therapeutic use; Survival Rate; Taxoids /therapeutic use
Date bibliographic record published
Date abstract record published
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.