Anthracycline-containing regimens improve disease-free and overall survival of patients with early breast cancer, but the toxicity, especially the cardiotoxicity, of the anthracyclines make them unattractive in the adjuvant setting. Two large, randomized trials, one in unselected patients and one in those with HER2-positive tumors, suggest that a taxane combination without an anthracycline might be just as effective as more traditional regimens. These and other studies also suggest that the anthracyclines might reasonably be used only for those with more aggressive forms of breast cancer, as defined by molecular markers. The results of these studies are provocative but insufficient to justify the conclusion that anthracyclines can be either abandoned or used only for a very select group of patients.
The anthracyclines doxorubicin and epirubicin are among the most effective cytotoxic treatments developed for the treatment of breast cancer. In the adjuvant setting they significantly improve both disease-free and overall survival. Although all anthracycline regimens are not equally efficacious, when the results of all trials were pooled in an overview comparing anthracycline regimens to no chemotherapy at all, they reduced the odds of recurrence by 33% (standard error [SE] +/- 8%) and the odds of death by 26% (SE +/- 9%). Compared to chemotherapy regimens that did not contain an anthracycline, they reduced the odds of recurrence by an additional 11% (SE +/- 3%) and the odds of death by an additional 16% (SE +/- 3%) over what can be achieved with a CMF (cyclophosphamide, methotrexate, and 5-fluorouracil)-like combination.
The anthracyclines are also among the most toxic drugs ever developed. They induce nausea and vomiting that, in the days before the introduction of 5-HT3-receptor antagonist antiemetics, was severe enough to sometimes necessitate hospitalization and intravenous hydration. The majority of patients lose nearly all their scalp hair. Myelosuppression can be profound, although fortunately its time course is very predictable and short, so granulocyte colony-stimulating factors are rarely needed at doses that are of proven value. The incidence of leukemia associated with anthracycline use is clearly greater than that seen with older regimens such as CMF; depending on the acute and cumulative dose and type of anthracycline used, this incidence ranges between 0.4% and 1.7% in the 5 to 10 years following treatment. A cardiomyopathy related to the cumulative dose of the anthracycline limits the duration of drug treatment and is likely the greatest impetus to finding new, non-cardiotoxic alternatives. Adjuvant anthracycline regimens typically use 240 to 360 mg/m2 of doxorubicin or 240 to 720 mg/m2 of epirubicin over 4 to 6 cycles, and with these doses the percentage of patients who develop a cardiac event such as congestive heart failure within the 5 years following completion of chemotherapy ranges from 0.5% to 1.5%. Subclinical cardiac dysfunction has been reported to occur in 10% to 15% of patients. The frequency of cardiac events is about four times greater when trastuzumab (Herceptin) is administered with or following the anthracycline (Table 1). This cardiotoxicity is more often reversible and likely has a different underlying pathophysiology,[4, 5] but it is still a cause of considerable concern since it is as yet unknown whether the incidence of serious cardiac disease will expand as the normal risks of cardiovascular disease associated with aging are superimposed on the cardiac damage from anthracyclines and trastuzumab.
In the past decade it has been repeatedly shown that the addition of a taxane to an anthracycline combination reduces the hazard of recurrence by yet another 15%. However, the taxanes induce neurotoxicity, and in many cases the taxane regimen is more toxic because it is administered for a longer duration than the non-taxane combination. Most investigators have felt that this increased toxicity was justified by the increased benefit. Recently, a taxane has been substituted for the anthracycline in two trials in an effort to circumvent toxicity, especially cardiotoxicity.
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