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In Reply:

Breast Cancer Unit, Institut Gustave Roussy, Villejuif, France

Although they allow a demonstration of a drug efficacy in a defined setting, randomized trials fail to answer questions about the utility of these advances in daily practice. Indeed, inclusion criteria are often very restrictive, and at the end, it is not clear whether the population included in the trial is representative of the population treated in daily practice. In addition to these limitations related to inclusion criteria, it is not clear whether the investigated drug will be appropriately used in daily practice and therefore, whether it will provide a benefit similar to that observed in a clinical trial. From our knowledge of these limitations has arisen the need to control the external validity of randomized trials. Although they exhibit several limitations, the studies using historical cohorts as reference arms give important indications about two majors questions of our daily practice: (1) Are the results of randomized trials applicable to daily clinical practice? (2) Are diseases changing?

As reported in our article,¹ several drugs have been approved in metastatic breast cancer, but the impact of these drugs on survival in this population was still under debate. Comparing two populations of breast cancer patients presenting with synchronous metastases was a way to evaluate the impact of new drugs in daily practice. As usual, with this kind of study, several biases can be discussed. Voogd et al ask whether an imbalance in the number of untreated patients could be observed between the two periods, and suggest that the increased use of mammograms could have allowed an earlier detection of metastases. To rule out this latter bias, they suggested that one look at T stage in the two cohorts. In our study, 25 (3.4%) of 724 patients did not receive any systemic treatment. The number of cases did not differ between the two periods since 14 (4%) of 343 patients treated between 1987 and 1993, and 11 (2.9%) of 381 patients did not receive any systemic therapy (P = .4, ² test). The T stage was not recorded in our database. Nevertheless, as reported in our Discussion section, the sites of metastases were similar between the two populations, suggesting that the clinical presentation of these patients was similar and was not influenced by mammogram screening.

In our study, we were not able to detect any survival improvement for patients who presented a hormone receptor–negative (HR–) breast cancer. As reported in the Discussion section, a possible explanation was the fact that the most recent period stopped in 2000, and therefore, only a few patients received trastuzumab or capecitabin. D.G. Kirsch et al report a survival improvement for patients treated with trastuzumab and presenting with brain metastases, suggesting an impact of trastuzumab in daily practice. Although the results are interesting, the methodology used in this analysis is, from our viewpoint, debatable since the survival of patients with HER2+ disease was compared with that of patients with HER2– disease. The use of a historical cohort would have limited biases, but historical cohorts currently do not exist since the "HER2+ disease" born with the approval of trastuzumab. In our opinion, two different approaches could be used to evaluate the impact of trastuzumab in daily practice. First, HER2 overexpression could be determined in all patients presenting with stage IV breast cancer between 1996 and 2004, and median survival of patients with HER2+++/HR– disease could be compared between the 1996 to 2000, and 2000 to 2004 periods. The second approach could consist of comparing the survival of patients with stage IV HR– breast cancer diagnosed within the 1996 to 2000, and 2000 to 2004 periods.

In conclusion, although randomized trials give crucial information regarding the efficacy of a given drug, studies using comparisons with historical cohorts bring some important indications as to the impact of new drugs in daily practice. In our opinion, their cautious use should be more accepted in medical oncology.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCE

1. Andre F, Slimane K, Bachelot T, et al: Breast cancer with synchronous metastases: Trends in survival during a 14-year period. J Clin Oncol 22:3302-3308, 2004[Abstract/Free Full Text]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Andre, F. Articles by Spielmann, M. Search for Related Content PubMed Articles by Andre, F. Articles by Spielmann, M. Related Articles Related Correspondence Social Bookmarking                            What's this?