HIGH-DOSE CHEMOTHERAPY

The rationale behind the use of high-dose chemotherapy (HDC) necessitating stem cell support comes from the work of Skipper, Schabel, and Frei.37-39 Skipper's rules summarize the scientific rationale for using HDC and stem cell support40:

•  Rule 1 The total tumor-cell-kill hypothesis: In order to achieve cure, it is necessary to eradicate all sensitive and resistant cancer cells.

•  Rule 2 The dose-response and first kinetics hypothesis: This rule states that a single dose of a specific chemotherapeutic regimen will kill a certain fraction of tumor cells. Therefore, administering a chemotherapy agent with a steep dose-response curve provides an advantage in achieving maximal cancer cell death.

•  Rule 3 The inverse rule: This rule states that there is an inverse correlation between the total cancer cell burden and the curability by chemotherapy.

These three rules helped investigators design an optimal setting for the use of HDC. Using a combination of chemotherapeutic agents, performing the procedure at the lowest possible tumor burden, and using high doses of the chemotherapeutic agents provide the ideal scenario.

The relationship of HDC and breast cancer has been a turbulent one. In the early to mid-1990s, a large number of women diagnosed with breast cancer were offered HDC followed by autologous stem cell transplantation (ASCT) for their breast cancer. In 1994 and 1995 alone, 4503 transplants were performed, and in 1996 and 1997 the number reached 5695.41 There was also a trend toward offering transplant to individuals with earlier stage disease. Although in 1989 only 7% of patients undergoing transplantation had localized disease, this number increased to 49% in 1995.42 However, only a small number of patients receiving transplantation for breast cancer did so in the context of a clinical trial. However, the enthusiasm for HDC/ASCT in breast cancer came to an end because of results of clinical trials presented at the 1999 American Society of Clinical Oncology (ASCO) meeting showing that the HDC approach offered no better outcomes for patients compared with standard-dose adjuvant chemotherapy. In addition, the highly publicized discrepancies found after an audit in the trials presented by Bezwoda and his colleagues fueled skepticism regarding the benefit associated with HDC. Media coverage portrayed the available results in the most negative way. Subsequently, trials that were ongoing at that time were unable to accrue patients and had to close prematurely.

There are still several unanswered questions regarding the role of transplantation. To achieve adequate statistical power to answer these questions, large randomized multicenter trials would be required, so it seems unlikely at the present time that these questions will ever be answered.

Patients were eligible if they had more than 10 positive axillary lymph nodes or 4 to 9 positive axillary lymph nodes with poor prognostic features. Adjuvant chemotherapy with either single agent doxorubicin (75 mg/m2 every 3 weeks for four cycles) or CAF (described previously) for four to six cycles was administered. All 132 patients received high-dose chemotherapy with Stamp V (cyclophosphamide 1500 mg/m2 plus thiotepa 125 mg/m2 plus carboplatin 200 mg/m2 continuous infusion [CI] for 96 h). There were no treatment-related deaths, and with median follow-up of 51 months, the DFS and OS were 72% and 81%, respectively.

Day 2 and 55 of the transplant, and another nine developed MDS or acute leukemia in the transplant arm. There was no statistical difference between standard chemotherapy and the HDC treatment arms with respect to DFS (47% vs. 49%), OS (62% vs. 58%) and time to recurrence (48% vs. 55%; Table 68-1). However, when analyzing only the 417 patients who did not have any protocol violations, time to recurrence was improved by 10% in the HDC and stem cell rescue arm (45% vs. 55%, respectively, P = 0.045).43 This large phase III trial did not show any benefit in performing stem cell transplant as part of the adjuvant treatment of women with high-risk breast cancer. The high incidence of treatment-related mortality and occurrence of secondary MDS/acute leukemia may be one of the reasons for the lack of effect observed in this study. Therefore, the development of less toxic preparative regimens could potentially show a benefit for HDC followed by stem cell rescue in resectable breast cancer. This study may also have been underpowered to detect a small difference between the two treatment arms. It will be up to the treating physicians and especially the patients to decide what a meaningful improvement in survival is given the increased toxicity with the addition of high-dose chemotherapy with stem cell rescue in breast cancer.

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