|
Overview of randomized perioperative polychemotherapy trials in women with early-stage breast cancer |
Clahsen P C, van de Velde C J, Goldhirsch A, Rossbach J, Sertoli M R, Bijnens L, Sylvester R J |
|
|
Authors' objectives The objective was to determine whether peri-operative polychemotherapy (PeCT) could prolong overall survival in women with early breast cancer.
Searching MEDLINE was searched, but the dates and search terms were not reported. The authors handsearched proceedings of the American Society of Clinical Oncology, the European Society of Medical Oncology, and the European Cancer Conference. Experts in the field were also contacted to identify trials. Data had to be received by February 1994 to be included in the review.
Study selection Study designs of evaluations included in the reviewThe review included individual patient data (IPD) from randomised controlled trials (RCTs). The median follow-up in the studies included in the review was 5.3 years.
Specific interventions included in the reviewStudies of curative surgery followed by PeCT compared to surgery without PeCT were eligible for inclusion. The definition of PeCT was any regimen that started within 3 days after surgery. The PeCT drugs used in the included studies were cyclophosphamide, methotrexate, fluorouracil, leucovorin, epirubicin and doxorubicin, given less than 24 to 72 hours after surgery. One study compared PeCT plus prolonged chemotherapy (CT) to prolonged CT, the others compared PeCT with no PeCT. In all of the included studies, additional adjuvant systemic therapy (CT or tamoxifen) was given in both the PeCT and control groups on the basis of menopausal and axillary node status.
Participants included in the reviewStudies in women with early breast cancer were eligible for inclusion. Pre- and post-menopausal women, and women with positive and negative axillary nodes were included in the studies reviewed. The age of the participants ranged from 22 to 76 years.
Outcomes assessed in the reviewOverall survival was the main outcome of interest. Disease-free survival, time to local recurrence and time to distant metastases were also reported.
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 reported cross-checking the data and contacting trial investigators if inconsistencies needed to be corrected. No further details were reported. The authors did not state how the papers were assessed for validity, or how many reviewers performed the validity assessment.
Data extraction The data collected included age and menopausal status, type of surgery and axillary node status. If menopausal status was unknown it was assumed that women younger than 50 years of age were pre-menopausal. Women with unknown axillary node status were considered to have positive nodes. Outcome data were collected for survival and cause of death, second primary tumours, local recurrence and distant metastases.
Methods of synthesis How were the studies combined?IPD from the included studies were combined according to the treatment subgroups: PeCT versus no CT, and PeCT plus adjuvant treatment versus adjuvant treatment. The latter was further subgrouped into three categories: PeCT plus CT versus CT; PeCT plus tamoxifen (TAM) versus TAM; PeCT plus CT plus TAM versus CT plus TAM. Data from all the women randomised were analysed by intention-to-treat using Kaplan-Meier survival curves, log rank statistics and meta-analysis of hazard ratios (HRs) weighted by study variance. The analyses were stratified by study and treatment subgroup. In addition, predefined exploratory subgroup analyses were conducted for age, menopausal status and node status. Trends in survival across subgroups were assessed using a statistical test for trend.
How were differences between studies investigated?In addition to the stratified analyses, a chi-squared test was used to investigate statistical heterogeneity between studies in the meta-analyses.
Results of the review IPD from 5 RCTs were included. The total number of participants was 6,093.
Across all studies, no statistically-significant difference was shown in overall survival between PeCT and no PeCT (n=6,093). The HR was 0.97 (95% confidence interval, CI: 0.86, 1.10, P>0.1). The test for heterogeneity was not statistically significant.
Overall, PeCT was associated with a statistically-significant increase in disease-free survival (n=6,093). The HR was 0.89 (95% CI: 0.82, 0.98, P=0.02). Heterogeneity was not statistically significant. The absolute benefit at 5 years was 3.4% (standard deviation, SD=1.3). When the treatment subgroups were examined separately, PeCT compared with no CT (n=4,109) showed a significant benefit, while PeCT plus adjuvant treatment compared with adjuvant treatment alone (n=1,984) did not.
PeCT was associated with a statistically-significant increase in the time to local recurrence (n=6,093). The HR was 0.68 (95% CI: 0.58, 0.80, P<0.0001). There was no statistically-significant difference in the time to distant metastases (HR 0.90, 95% CI: 0.81, 1.00, P=0.06). In both analyses the test for heterogeneity was not statistically significant.
In the exploratory subgroup analysis for overall survival, the test for trend (P=0.04) indicated that PeCT was more beneficial among node-negative women (n=3,420) than node-positive women (n=2,673). In the subgroup analysis for disease-free survival, the test for trend was not statistically significant (P=0.07) although the improvement in disease-free survival reached statistical significance in women with negative nodes (18% reduction in HR, SD=8), but not in women with positive nodes (4% reduction in HR, SD=6). The data reported for the subgroup analyses by age and menopausal status was incomplete.
Authors' conclusions The authors concluded that there was no evidence that PeCT prolongs overall survival in early breast cancer patients. However, PeCT appears to prolong disease-free survival particularly in women with negative axillary nodes.
CRD commentary The review question and the inclusion criteria were clearly stated. While the authors' intention was to identify all relevant trials, and published and unpublished data were sought, the search described does not appear to be exhaustive. The process by which the studies were selected for inclusion and appraised for validity was unclear, although the authors did report that they checked the data they received for anomalies. The data included in the review were analysed using appropriate methods. The results support the authors' main conclusion, according to their stated objective concerning the impact of PeCT on overall survival. The subgroup analyses, and the conclusions about greater benefit in women with negative axillary nodes, need more cautious interpretation. Subgroup analyses generate hypotheses about treatment interactions, they do not compare prognosis between subgroups of patients. Further research involving node-negative women appears to be a reasonable recommendation given the evidence presented.
Implications of the review for practice and research Practice: The authors stated that the results show that a short-term intensive course of PeCT can have a significant effect on the risk of relapse among node-negative women. However, it was still unclear whether node-negative women who are not at extreme high or low risk of relapse should receive more aggressive adjuvant chemotherapy.
Research: The authors stated that future clinical trials would show whether longer-term CT could further improve the apparent benefits of short-term PeCT in node-negative women. In the meantime, node-negative women who are candidates for such trials should be offered the opportunity to participate.
Funding National Cancer Institute, grant numbers 2U10 CA11488-23 and 2U10 CA11488-24; European Community, Fourth Medical and Health Research Program; Dutch Cancer Society.
Bibliographic details Clahsen P C, van de Velde C J, Goldhirsch A, Rossbach J, Sertoli M R, Bijnens L, Sylvester R J. Overview of randomized perioperative polychemotherapy trials in women with early-stage breast cancer. Journal of Clinical Oncology 1997; 15(7): 2526-2535 Indexing Status Subject indexing assigned by NLM MeSH Antineoplastic Combined Chemotherapy Protocols /therapeutic use; Breast Neoplasms /drug therapy /pathology /surgery; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Neoplasm Staging; Odds Ratio; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome AccessionNumber 11997000914 Date bibliographic record published 31/03/2004 Date abstract record published 31/03/2004 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. |
|
|
|