Evolution of adjuvant chemotherapy of breast cancer from Bonadonna to the taxanes

Abstract

The author summarizes the progress of adjuvant chemotherapy of breast cancer from the classical Bonadonna-type CMF over the anthracyclines to the taxanes. The CMF regimen represented the prototype of combination chemotherapy which significantly improved early and long term results. After 20 years the patients given adjuvant combination chemotherapy with CMF had significantly better rates of relapse-free survival (p<0.001) and overall survival (p=0.03) compared with no chemotherapy. 6 cycles of CMF was the gold standard of adjuvant chemotherapy in breast cancer for decades. The Milan research group decided in the early 1980s to challange this popular CMF combination by introducing doxorubicin within the adjuvant program. Compared with standard CMF, anthracyclin-containing regimens reduced the annual risk of recurrence by 12% and the annual risk of death by 11%, equating to a 3.2% absolute reduction in recurrence and a 2.7% absolute reduction in mortality at 5 years. This small but real difference seen with regimens containing three or more agents (e.g. CEF and CAF, FAC, FEC, etc.), whereas 4 cycles of 2-drug regimens (e.g. AC or EC) appears to be equivalent to 6 cycles of CMF. Among the novel chemotherapeutic drugs introduced in the 1990s the taxanes have emerged as the most powerful compounds in breast cancer. Several large, adjuvant clinical trials are currently ongoing or have recently completed accrual. The available results from innumerable clinical studies are still inconclusive and do not support the routine use of taxanes in the adjuvant setting - with the exception of the BCIRG 001 docetaxel trial, in which significant improvement was documented in disease free survival with 6 x TAC compared with 6 x FAC (82% vs 74%). Studies on the effect of the new trastuzumab (an antibody against the extracellular domain of the HER2) in adjuvant setting was initiated in early 2000. The Herceptin adjuvant trial programme is extensive, involving more than 12,000 patients worldwide. This trials will potentially offer many women with HER2-positive disease the chance of improved survival.