Home: Educational Supplement: Appendix

Overview of the Six Randomized Adjuvant Trials of
High-Dose Chemotherapy in Breast Cancer

Karen H. Antman, M.D.

There are six reports of randomized trials of high-dose chemotherapy in high-risk primary and metastatic breast cancer (see table 1). However, the South African study has been discredited, and two of the remaining studies randomized fewer than 100 patients and thus could not exclude a survival difference of 30 percent. The Scandinavian study did not compare high-dose versus conventional dose therapy. Thus, there have been two reasonably large trials, but both with only about 3 years of median followup at the time of the last analysis.

Mortality was consistently low, in the 0 to 2.5 percent range, for the high-dose regimens except for the CALGB/Intergroup study, which had a 7.4 percent toxic mortality rate. Mortality for the more conventional dose arms was in the range of zero to 1 percent.

The Dutch trial was the largest of the six studies (885 patients randomized) and therefore had the greatest statistical power to detect modest differences (Rodenhuis, Bontenbal, Beex, et al., 2000; McNamee, 2000). It compared four courses of FEC (5-fluorouracil, epirubicin, cyclophosphamide) to either an additional cycle of FEC or to CTCb (cyclophosphamide, thiotepa, carboplatin) with stem cell support followed by surgery, radiation, and tamoxifen for 2 years. In a planned analysis of the first 284 patients, at a median followup of 6 years, disease-free and overall survival were significantly better for the group receiving high-dose therapy. In the study as a whole, the mortality was 1 of 443 patients on standard dose FEC and 4 of 442 on high dose CTCb. At a median of 3 years followup, a trend (p=.057) emerged favoring high-dose therapy.

The CALGB/Intergroup study compared high versus intermediate dose cyclophosphamide, BCNU, and cisplatin (CBP) after a CAF (cyclophosphamide, Adriamycin, 5 fluorouracil) induction (Peters, Rosner, Vredenburgh, et al., 1999). Although the study can be criticized on grounds that intermediate dose CBP is not a standard regimen, this design in scientific terms is a pure comparison between high and intermediate dose CBP.

This first generation BCNU-containing regimen (as noted earlier) had a 7.4 percent mortality rate, which varied with the experience of the transplant center and increased with patient age. Substantial pulmonary and hepatic toxicity also occurred. With a median of 3.6 years of followup at the time of presentation, the differences in the PFS and OS rates in the two groups were not significant. Fewer events occurred than would have been predicted from historical series, suggesting either patient selection or an effect of the intermediate dose CBP. Significantly, fewer relapses occurred in the high-dose arm, but the survival rate of the two arms was similar at 70 percent because of the early toxic mortality of 7.4 percent. Increased mortality neutralized this early benefit. The study group was selected to have a tumor mortality of ~80 percent. Survival in both arms will fall with time, and significant differences may or may not emerge.

The Scandinavian trial compared induction FEC followed by one high-dose cycle of CTCb versus six additional cycles of moderately high dose FEC. The doses (in mg/M²) of FEC were tailored to individual tolerance up to 600 of 5-FU, 120 of epirubicin, and 1,800 of cyclophosphamide per cycle. The planned cumulative doses for tailored therapy actually exceeded that for the BMT arm. Therefore, this study assessed the role of high-dose therapy as compared to intermediate-dose chemotherapy with a higher cumulative dose (Bergh, 1999). Three percent of the patients on the tailored dose arm developed leukemia or myelodysplasia, compared with none on the marrow transplant arm.

Ongoing or unpublished randomized studies of high-dose therapy for breast cancer are shown in table 2.

Additional followup of the two large randomized trials and the completion of ongoing randomized trials will provide more reliable data to determine the role of high-dose chemotherapy regimens in the management of high-risk primary breast cancer.

References

Bergh J. Results from a randomized adjuvant breast cancer study with high dose chemotherapy with CTCb supported by autologous bone marrow stem cells versus dose escalated and tailored FEC therapy. Proc Am Soc Clin Oncol 1999;18:2a. Abstract.

Bezwoda WR. Randomised, controlled trial of high dose chemotherapy versus standard dose chemotherapy for high risk, surgically treated, primary breast cancer. Proc Am Soc Clin Oncol 1999;18:2a. Abstract.

Hortobagyi GN, Buzdar AU, Theriault RL, Valero V, Frye D, Booser DJ, et al. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 2000;92:225-33. Abstract.

McNamee D. High dose chemotherapy positive in breast cancer trial. Lancet 2000;355:1973. Abstract.

Peters WP, Rosner G, Vredenburgh J, et al. A prospective, randomized comparison of two doses of combination alkyating agents as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes: preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13. Proc Am Soc Clin Oncol 1999;18:1a. Abstract.

Rodenhuis S, Bontenbal M, Beex L, et al. Randomized phase III study of high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin in operable breast cancer with 4 or more axillary lymph nodes. [abstract]. Proc Am Soc Clin Oncol 2000;19:74. Abstract.

Rodenhuis S, Richel DJ, van der Wall E, Schornagel JH, Baars JW, Konniq CC, et al. Randomised trial of high-dose chemotherapy and haematopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph node involvement. Lancet 1998;352:515-21. Abstract.

Weiss RB, Rifkin RM, Stewart FM, Theriault RL, Williams LA, Herman AA, et al. High-dose chemotherapy for high-risk primary breast cancer: an on-site review of the Bezwoda study. Lancet 2000;355:999-1003. Abstract.