Gradishar and colleagues [1] focused on the rationale for the randomized studies evaluating adjuvant high-dose chemotherapy in the early stages of breast cancer. They express the concern that few patients are entered into randomized trials even though there is no definite proof of the value of high-dose chemotherapy in the adjuvant setting. The authors reviewed the efforts to overcome physician and patient biases so that the trials can be completed. Somewhat to our surprise, the authors did not indicate that this patient and physician bias is particularly a problem in the United States but that several well-accruing, ongoing randomized trials of adjuvant breast cancer therapy are evaluating high-dose chemotherapy in Europe.

As we have previously [2], we would like to illustrate the situation in the Netherlands. The single Dutch randomized study of patients with four or more positive lymph nodes is comparing standard-dose chemotherapy (consisting of five cycles of 5-fluorouracil, epirubicin, and cyclophosphamide) with four cycles of these drugs and one cycle with high-dose chemotherapy (cyclophosphamide, thiotepa, and carboplatin) followed by blood progenitor reinfusion. Apart from clinical end points, a quality-of-life analysis and cost-effectiveness study are to be performed. All university hospitals and the two cancer centers in the Netherlands reached a consensus about the study design. The committee of investigative medicine of the Dutch Health Insurance Council approved the protocol and financially sponsored the high-dose regimen, growth factors, data management, and cost-effectiveness study. The Council is a public agency for the insurance companies and the ministries of health and science.

The study began in January 1994 and had randomly assigned 425 patients by October 1996. We expect the results to be available by the year 2000. An interim analysis will be done by an independent monitoring committee to determine whether results obtained thus far justify continuation of the study. The patients are treated in only 10 centers, and high-dose chemotherapy for the study indication is never administered outside of the protocol. In the Netherlands, medical specialists have reached consensus about the relevance of this study. In contrast to the situation in the United States, every eligible patient in the Netherlands can participate in this study. Outcome measurements from this study should therefore be applicable to the general Dutch population. Interest in and consensus about the study design also make it likely that the results of this study will lead to uniform acceptance of implications for the medical care in these women in the future. Although we are aware of the need for randomized studies in the United States, we anticipate that the Dutch approach to this clinical dilemma may also be of interest.