What is the role of high-dose chemotherapy in the era of targeted therapies?

The development of high-dose chemotherapy treatment for breast cancer provides ample opportunity to reflect on the integration of science into medicine. It also exemplifies the ongoing tension in a clinical investigator between being a physician and a scientist. As physicians, we want to provide our patients with the most effective therapy and want to do so as soon as such therapy becomes available. For a scientist, the primary objective is the successful testing of hypotheses and the generation of proof that would lead one to either accept or reject such hypotheses. Clinical trials with high-dose chemotherapy were developed almost at the same time as the introduction of combination chemotherapy in the management of breast cancer. Although myelosuppression was identified as the doselimiting toxicity for most cytotoxic drugs available 30 years ago, the initial steps in bone marrow transplantation were taken in the early 1970s, during the same time as the first trials of adjuvant chemotherapy. Reports about decreased survival associated with reduced doses of chemotherapy provided additional stimulus for the concept of dose-intensification. Hryniuk and others were instrumental in crystallizing this concept, providing a scientific platform for the development of multiple approaches to dose enhancement. From these initial steps emerged substantial enthusiasm for testing high-dose chemotherapy with autologous bone marrow transplantation as a potentially curative therapeutic intervention for both solid tumors and hematologic malignancies. Early results provided information about tolerance and toxicity, as well as the criteria for optimal selection of patients likely to tolerate treatment without lifethreatening toxicity. The development of the technique to harvest, manipulate, and reinfuse peripheral hematopoietic stem cells facilitated the development of the field, improved the safety of the procedure, and resulted in the widespread application of the technology, well before the assessment of both benefits and risks had been definitely established. Throughout the 1980s, enthusiasm overtook discipline, and well-tested clinical trials methodology was shoved aside by the perception that randomized trials in patients with very poor prognosis were ethically unjustified. High-dose chemotherapy with autologous stem-cell support became established in clinical practice, to the extent that access to this unproven treatment strategy was legislated in several states, insurance companies were forced to provide coverage, and centers not offering this treatment were considered outdated. However, doubts ultimately emerged. High-dose chemotherapy was clearly not an option for all patients, as it was restricted to a highly selected population. Extensive pretreatment evaluation excluded patients with microscopic metastatic disease, resulting in stage migration, resulting in turn in a stage-by-stage improvement in outcome independent of the treatment administered. Eventually, randomized trials were initiated; some were completed despite substantial difficulties in accrual. Many randomized trials were closed before completing accrual, thus precluding the development of high-quality evidence. We now have the results of 10 randomized trials that tested the contribution of high-dose chemotherapy to the systemic adjuvant treatment of patients with high-risk breast cancer. In these trials, high-risk patients were usually defined as having 10 or more positive axillary lymph nodes, though some of the trials included patients with four or more nodes, while others required only biopsy confirmation of an apical axillary lymph node. The regimens were heterogeneous, the trial designs varied, and most trials were hopelessly underpowered to detect anything less than major clinical differences in outcome. In this issue of the Journal of Clinical Oncology, Zander et al provide additional information on adjuvant highdose chemotherapy for breast cancer. Patients initially reJOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 12 JUNE 15 2004