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Is There a Role for Dose-Intensive Chemotherapy With Stem Cell Rescue in Breast Cancer?

Is There a Role for Dose-Intensive Chemotherapy With Stem Cell Rescue in Breast Cancer?

ABSTRACT: Over the past decade, high-dose chemotherapy with autologous bone marrow and/or peripheral blood rescue has been increasingly used to treat women with breast cancer. Laboratory and clinical studies have shown that dose intensity may be important in treating selected patients with breast cancer. Initial phase I studies showed good response rates of short durations. Further trials in metastatic disease with high-dose chemotherapy and stem cell rescue earlier in the treatment course had been encouraging. However, the optimal timing of high-dose chemotherapy remains a question. In addition, randomized trials in high-risk early-stage breast cancer have completed accrual. Technologic improvements in stem cell procurement and hematopoietic growth factors have contributed to decreased morbidity and mortality. This review will discuss the role of such therapy in the treatment of women with breast cancer. [ONCOLOGY 16:1643-1656, 2002]

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.

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