Randomized trials of high dose chemotherapy for breast cancer

'Now is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning'Winston Churchill in a speech to the Canadian Senate and House of Commons, December 30, 1941. In laboratory models of cancer, dose of cytotoxic chemotherapy correlates with curative therapy, while cumulative dose is associated with longer survival for those who are not cured. These observations suggests a strategy of using high doses when cure is the objective but smaller doses over a prolonged period when palliation and survival are the goal. A strategy combining repetitive cycles of higher doses of cytotoxic therapy, followed by the optimal combination of hormonal and biological agents based on the tumor's receptors might contribute to both the highest possible cure rate and the longest survival. The development of bone marrow transplant (BMT) for leukemias, and its subsequent modification for support after high dose therapy for other malignancies, has a long, complex and emotional history in medicine. At least partly because of firmly held opinions and the way large randomized trials are funded in the United States, few American randomized trials of BMT or high dose therapy strategies have been completed. The vast majority of published randomized BMT and high dose studies are European. Interestingly, in contrast, two large American randomized trials of high dose chemotherapy for breast cancer had actually completed accrual. Accrual on a third was on target until the presentation of five very small or very early randomized trials at the American Society of Clinical Oncology meeting in May of 1999. Results from some of these trials, which were analyzed after a relatively brief follow-up, are too premature to allow definitive conclusions. Nevertheless, these data have been over and misinterpreted within the scientific and lay communities. The remaining studies included a limited number of patients, thus restricting the statistical power of the observations. The desire for quick answers impeded dispassionate analysis of the available data. The opportunity for collegial review of the data further deteriorated with another round of press coverage when the data from the South African adjuvant study were found to be unreliable. Rather than increasing commitment to accrual on randomized and appropriate pilot trials, accrual to the only large American study in existence at that time trickled to a halt. In response to press coverage, Susan Edmonds from the Fred Hutchinson Cancer Research Center observed that 'the NYT article tends to cast shadows generally on the therapy and those providing the therapy rather than pointing out early in the article (where the public will readily see it) that there are a number of very credible research institutions conducting research directed at breast cancer, some looking at high dose chemotherapy and stem cell transplantation.' Dr. Rodenhuis, presenting the large positive Dutch Randomized study (funded by the Dutch insurance industry) at ASCO in 2000, commented on the 'unreasonably high expectations until 1999' and 'unreasonably negative [opinion-ed] since 1999' for high dose adjuvant chemotherapy for breast cancer.