During the 1990s, perhaps no other therapy for women with breast cancer was more controversial than high-dose chemotherapy with autologous bone marrow and/or peripheral stem cell support. With encouraging results from late phase I and early phase II trials in the early to mid-1990s, high-dose chemotherapy was promoted by its many enthusiastic proponents as a potentially great leap forward for women with high-risk, node-positive or metastatic disease.
In the absence of controlled randomized phase III clinical trial data, as noted by Williams in this excellent review, breast cancer became the leading indication for autologous stem cell transplant in North America in the 1990s. Most of these stem cell transplants occurred outside of a clinical trial, which led to many heated and publicized battles between insurers and women for access to these therapies. Indeed, the battle became so heated, and positions so ingrained, that one investigator resorted to outright research fraud to make the case for high-dose therapy.
At the plenary session of the American Society of Clinical Oncology in 1999, investigators presented several abstracts detailing preliminary results from phase III randomized studies of high-dose therapy vs the more "standard" chemotherapy regimens for both high-risk node-positive breast cancer and metastatic breast cancer. After these studies demonstrated little or no apparent benefit for high-dose chemotherapy over the standard regimens, interest in high-dose therapy, both inside and outside the context of clinical trials, waned. After 3 years of reflection, is there currently a role for high-dose chemotherapy in the management of breast cancer?
Rational Basis, Disappointing Results
Williams correctly notes that high-dose therapy has a reasonable experimental and perhaps reasonable clinical rationale. Alkylating agents demonstrated a steep dose-response curve in experimental systems, and an early phase II clinical trial demonstrated high overall and complete response rates in metastatic breast cancer.
The data from randomized clinical trials presented to date, however, have been mixed. As noted, one randomized trial in metastatic disease was fraudulent. One trial enrolled women with metastatic disease and a complete response to initial standard-dose induction therapy to immediate or delayed high-dose therapy at progression. Immediate consolidation with high-dose therapy produced a better disease-free survival than delayed consolidation but a poorer over- all survival. Another study randomized women with metastatic breast cancer and a response to induction therapy to high-dose or standard chemotherapy. This trial demonstrated no difference in disease-free or overall survival between the arms.
Randomized trials of high-dose chemotherapy as adjuvant therapy for high-risk node-positive breast cancer have fared no better. To date, although there have been encouraging signs of a trend toward improved disease-free survival in one study, no trial randomizing women to high-dose vs standard-dose regimens has demonstrated a significant disease-free or overall survival benefit.