Breast cancer will strike over 203,000 American women in 2002.[1] Despite the awareness of screening and early detection, close to 40,000 women will die of disseminated disease. Once breast cancer has metastasized, median survival is about 2 years with standard therapy, although longer survival has been seen in some groups of patients.[2] In an attempt to improve upon standard combination chemotherapy, dose-intensive or high-dose myeloablative therapy with autologous stem cell rescue has been explored.
High-dose chemotherapy with autologous stem cell or peripheral blood rescue or transplant has increasingly been used in North America to treat breast cancer. Earlier data from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry (IBMTR/ABMTR) showed breast cancer to be the leading indication for an autologous stem cell transplant in North America in the 1990s.[3]
The use of this modality to treat breast cancer, however, led to many societal concerns. As its expense became apparent in light of the large number of eligible women with breast cancer, insurers attempted to limit access to this therapy. This resulted in many battles in and out of the courts and polarized physicians, payors, and breast cancer advocacy groups. These events, in turn, raised the following issues: When does "investigational" therapy become "standard" therapy, and should legislation specify the indications for which insurers should pay benefits?
This article will attempt to review the evidence for the use of high-dose chemotherapy with autologous stem cell rescue in the treatment of breast cancer.
Dose Intensity in Chemotherapy for Breast Cancer
In experimental systems, alkylating agents demonstrate a steep dose-response curve.[4] Alkylating agents are active against breast cancer and have become a main ingredient in many combination chemotherapy programs. Several analyses have demonstrated the value of dose intensity in treating breast cancer. In metastatic disease, higher response rates have been found as dose intensity increases.[5] In adjuvant trials, 3-year relapse-free survival seems to improve with most dose-intensive regimens.[6,7] Many other factors, however, can influence the dose-response effect outside the laboratory, including drug schedule, tumor volume and growth kinetics, and the emergence of drug resistance.
Chemotherapeutic agents used to treat breast cancer in high-dose therapy trials were chosen to fit certain characteristics: (1) a steep dose-response curve, (2) myelosuppression as the major dose-limiting toxicity, (3) lack of cross-resistance with previously administered agents, and (4) minimal long-term toxicity. Table 1 lists several commonly used chemotherapy agents and typical doses in many of these clinical trials.
Treatment of Metastatic Breast Cancer
In the mid-1980s, several investigators reported results of phase I high-dose therapy trials with autologous bone marrow rescue in patients with solid tumors.[8-12] Many of these patients had refractory breast cancer. Both single agents and combinations were explored. As in trials of conventional therapy, drug combinations appeared superior. Investigators reported a limited number of responses of short duration, but some patients obtained complete responses. These encouraging findings led to treatment strategies using this modality earlier in the course of disease, before the patient’s exposure to multiple chemotherapeutic agents.
A 52-year-old man presented with an erythematous lesion in the axilla of unknown duration. Surgical excision was performed. What is your diagnosis?
