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, pe rhaps, 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 chemoth erapy correlates with curative therapy, while cumulative dose is associated with longer survival for those who are not cured [1]. These observations s uggests a strategy of using high doses when cure is the objective but small er doses over a prolonged period when palliation and survival are the goal. A strategy combining repetitive cycles of higher doses of cytotoxic therap y, followed by the optimal combination of hormonal and biological agents ba sed 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 subs equent modification for support after high dose therapy for other malignanc ies, has a long, complex and emotional history in medicine. At least partly because of firmly held opinions and the way large randomized trials are fu nded in the United States, few American randomized trials of BMT or high do se therapy strategies have been completed. The vast majority of published r andomized BMT and high dose studies are European. Interestingly, in contrast, two large American randomized trials of high do se chemotherapy for breast cancer had actually completed accrual. Accrual o n a third was on target until the presentation of five very small or very e arly randomized trials at the American Society of Clinical Oncology meeting in May of 1999. Results from some of these trials, which were analyzed aft er a relatively brief follow-up, are too premature to allow definitive conc lusions. Nevertheless, these data have been over and misinterpreted within the scientific and lay communities. The remaining studies included a limite d number of patients, thus restricting the statistical power of the observa tions. The desire for quick answers impeded dispassionate analysis of the availabl e data. The opportunity for collegial review of the data further deteriorat ed with another round of press coverage when the data from the South Africa n adjuvant study were found to be unreliable. Rather than increasing commit ment to accrual on randomized and appropriate pilot trials, accrual to the only large American study in existence at that time tricked to a halt. In response to press coverage, Susan Edmonds from the Fred Hutchinson Cance r Research Center observed that 'the NYT article tends to cast shadows gene rally on the therapy and those providing the therapy rather than pointing o ut early in the article (where the public will readily see it) that there a re a number of very credible research institutions conducting research dire cted at breast cancer, some looking at high dose chemotherapy and stem cell transplantation.' Dr. Rodenhuis, presenting the large positive Dutch Rando mized study (funded by the Dutch insurance industry) at ASCO in 2000, comme nted on the,unreasonably high expectations until 1999' and 'unreasonably ne gative [opinion-ed] since 1999' for high dose adjuvant chemotherapy for bre ast cancer. (C) 2001 Elsevier Science B.V. All rights reserved.