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If there is no overall survival benefit in metastatic breast cancer: Does it imply lack of efficacy? Taxanes as an example

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Abstract

In recent years, new drugs have shown activity in metastatic breast cancer, but not always resulting in an overall survival benefit. This has led to discussions if such drugs, mainly expensive drugs, should be reimbursed especially when also not leading to improvement in quality of life. For that reason, we decided to systematically review taxane-based chemotherapy studies in early and metastatic breast cancer, to assess which factors may have caused the differential outcome. Taxanes did not improve survival in metastatic breast cancer trials, whereas they did so in early breast cancer trials. We questioned if the differential outcome of taxanes in metastatic breast cancer might be caused by the chosen comparator and study design. We noticed that in the majority of metastatic breast cancer studies taxanes were used as a substitute for other active cytotoxic drugs, mainly cyclophosphamide, whereas in early breast cancer studies taxanes were generally delivered in addition to a standard regimen. We conclude from our analyses that use of taxanes instead of other active drugs explains the lack of overall survival benefit in metastatic breast cancer trials. Further, our results suggest that cyclophosphamide is an important drug in the treatment of breast cancer, being as effective as optimally dosed taxanes and anthracyclines. By studying the different study designs and comparators in both settings, we were able to demonstrate their impact on efficacy endpoints. We conclude, therefore, that re-assessment of studies of drugs both assessed in metastatic and early breast cancer provides a new tool for improved understanding.

Introduction

Taxanes are approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for use in metastatic and early breast cancer. Despite registration, it was concluded in the most recent Cochrane review that there was no evidence of a survival benefit in metastatic breast cancer for single-agent taxanes versus anthracyclines.1 And, although an overall survival benefit was seen in favour of taxane containing regimens, the superiority of taxane regimens over non-taxane containing regimens was not seen if the non-taxane regimens were largely limited to optimally-dosed anthracycline-based regimens.1 In a second review on taxanes in metastatic breast cancer, it was concluded that single-agent taxane was even less effective than single-agent anthracycline, based on the EORTC study 10923.2 On the other hand, it was concluded that first-line anthracycline–taxane combinations seemed slightly better than anthracycline-based regimens with regard to tumor response and progression-free survival, although not with regard to overall survival. However, the conclusions from meta-analyses on adjuvant taxane breast cancer trials were remarkably different, showing an improvement in both disease-free and overall survival.[3], [4], [5]

In recent years, new drugs have shown activity in metastatic breast cancer, but not always resulting in an overall survival benefit.6 In the oncology community this has led to discussions on whether such drugs should be reimbursed. A thorough analysis of drugs without a clear survival gain in metastatic breast cancer but with a survival gain in early breast cancer may help clarify this apparent discrepancy, and may prevent premature conclusions on the value of new drugs in this field. For that reason, we decided to systematically review taxane-based chemotherapy studies in early and metastatic breast cancer, to assess which factors may have caused the different outcomes between these patient groups.

Section snippets

Search strategy and selection criteria

A detailed search strategy, consisting of numerous MeSH heading and text word combinations, “breast cancer”, “chemotherapy”, “taxanes”, “docetaxel” and “paclitaxel”, was used to search the PubMed database. Publications of clinical phase III trials between 1995 and November 1, 2010 in the English language were included. Abstracts of the annual meetings of the American Society of Clinical Oncology (ASCO) and of the San Antonio Breast Cancer Symposium (SABCS) were searched for relevant trials (and

Overall efficacy of taxanes in metastatic and early breast cancer

In total 10 trials in the metastatic breast cancer setting were included, comparing taxane containing chemotherapy schemes with anthracycline containing schemes (Table 1). We calculated the pooled hazard ratio and found no significant difference for progression-free survival with a hazard ratio of 0.94 (95% CI 0.88–1.01) and for overall survival with a hazard ratio of 0.98 (95% CI 0.91–1.05) (Fig. A, Appendix).

In total 21 trials in the adjuvant breast cancer setting were included, comparing

Discussion

In our meta-analysis, we included 10 randomized trials that assessed the role of taxanes in the metastatic breast cancer setting, and 21 trials in the early breast cancer setting. We show that the use of taxanes did not improve overall survival in metastatic breast cancer trials (hazard ratio of 0.98; 95% CI 0.91–1.05), whereas it did so in early breast cancer (hazard ratio of 0.85; 95% CI 0.79–0.91). The primary goal of our review and meta-analysis was to determine whether the study design

Conflicts of interest statement

The authors indicated no potential conflicts of interest.

Funding

Netherlands Organization for Health Research and Development (ZonMw 80-82500-98-10901).

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    d

    Division of Medical Oncology, Department of Internal Medicine, Maastricht University Medical Centre, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. Tel.: +31 43 3877025; fax: +31 43 3876281.

    e

    Department of Internal Medicine, Maxima Medisch Centrum, P.O. Box 90052, 5600 PD Eindhoven, The Netherlands. Tel.: +31 40 8885320; fax: +31 43 3876281.

    f

    Department of Epidemiology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Tel.: +31 (0) 43 3882387; fax: +31 43 3876281.

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