The Era of High-Dose Chemotherapy for Breast Cancer: Revisiting a Troubled Quest

Substantial preclinical evaluation of many DNA-damaging agents, particularlyalkylatingagents,demonstratedsteepdose-responserelationships. Clinically, these agents caused dose-limiting hematologic toxicity; therefore, to maximize dosages, as justified by mathematical modeling, hematologic progenitor cell support was required. Results in hematologic malignancies such as non-Hodgkin’s lymphoma promoted the application of this treatment approach to many solid tumors, including breast cancer. Early phase II results were promising; a small subset of the enrolled patients became long-term survivors, and this invoked hope for betteroutcomesacrossbroaderpatientcohorts. Ultimately,breastcancer became the predominant indication for high-dose chemotherapy (HDC), which led to the randomized trials that were analyzed by Berry et al in the articles that accompany this editorial. Berry et al obtained individual patient data from 15 adjuvant and 6 metastatic breast cancer randomized trials that compared HDC to a control therapy without stem-cell support, thus allowing a more definitive meta-analysis with better statistical power overall and improved likelihood to find a subset effect. Of 6,210 patients with adjuvant node-positive or locally advanced breast cancers who participated in the 15 trials, HDC achieved a significant 13% reduction in the risk of recurrence (hazard ratio [HR], 0.87; 95% CI, 0.81 to 0.93; P .001) but without a significant reduction in the risk of death (HR 0.94; 95% CI, 0.87 to 1.02; P .13) after a median follow-up of 6 years. No patient subset achieved markedly greater benefit. The patient population was predominantly young and premenopausal. Although age, tumor size, lymph node involvement, histology, and hormonereceptor status were well known, and although the staging evaluation was rigorous, the human epidermal growth factor receptor 2 status was known for only 27% of patients. As pointed out, the design of the trials was quite heterogeneous, and for some trials, the standard dose arm had greater weekly dose intensity than the HDC arm. Notably, patients who were enrolled in the HDC arm experienced lower survival after relapse, which suggests either poorer tolerance to additional therapy, increased drug resistance, exclusion from clinical trials of targeted and other chemotherapy agents, or a decreased willingness on the part of the patient and/or the physician to continue treating the tumor. Of 866 patients with metastatic breast cancer who participated in one of the six randomized trials that compared HDC to a control arm, there was a statistically significant improvement in progressionfree survival (median, 11 v 8.3 months; HR, 0.76; P .001) but without a significant improvement in overall survival (median, 2.16 v 2.02 years; HR, 0.87; P .08). As with the adjuvant set of trials, no subset seemed to differentially benefit from HDC. In agreement with the authors, we would conclude that HDC with autologous support for breast cancer, as it was studied in these trials, does not produce sufficient benefit to be worthwhile. Moreover, the current generation of new treatments for breast cancer includes targeted agents and newer chemotherapies that do not possess a clear dose-response relationship and are not limited by hematopoietic toxicity. Thus, it is unlikely that HDC with autologous progenitor cell support will ever again play an important role in the treatment of breast cancer. The burgeoning of transplantation trials for breast cancer led to many achievements. Notably, advances in the understanding of hematologic cell differentiation and cytokines and other regulators of bone marrow were translated to the clinic by advances in peripheral blood progenitor cell support, mobilization, and harvesting methods. This allowed the delivery of tandem transplantations but also markedly improved the safety of HDC, which led to a reduction in autologous transplantation mortality from approximately 10% to close to 1%. Outpatient management became possible in sophisticated programs. All of this has benefitted patients with hematologic malignancies who receive HDC. The fields of circulating tumor cells and microscopic residual disease in bone marrow likewise were greatly stimulated by the research into HDC for breast cancer; increased knowledge in these areas is now applied clinically in the management of breast and other cancers. The meta-analyses that were provided by Berry et al demonstrate the absence of survival benefit and lack of a patient subset for whom this therapeutic modality may yet offer benefit, and requires a revisit to the era of HDC for breast cancer to understand the difficulties that surround the randomized trials. The potential to definitively define the role of HDC in breast cancer upfront was subverted by several intertwined factors in the research. First, the overall research effort in HDC did not include a well-developed link between breast cancer research and transplantation research. As evidence, the control arms of many of the trials were far from standardized because no consensus could be readily obtained. Second, legal channels were employed to force the funding of clinical care for patients enrolled onto research studies. Given the promise of the phase II trials and the excitement of new technology, patients sued their insurers to get onto the trials, at first in ovarian cancer and then in breast and other cancers. By winning these lawsuits, these patients were able to participate in the clinical trials but also de facto established HDC as a standard of care and also as a highly reimbursable therapeutic option that was available before phase III data determined its actual role in the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 29 NUMBER 24 AUGUST 2