Research presented at the 37^th annual meeting of the American Society of Clinical Oncology (ASCO) in San Francisco showed that after long-term evaluation (at 5 years), the cardiotoxic potential of the AT regimen (doxorubicin [Adriamycin], paclitaxel [Taxol]) for breast cancer patients is low.

"Our findings confirm that congestive heart failure only occurs during treatment and mainly in patients who are given doxorubicin for six or more cycles. By contrast, the level of cardiotoxicity is very low in patients who receive between four and six cycles of doxorubicin (up to a maximum dose of 360 mg/m²)," said presenter Pinuccia Valagussa of the Istituto Nazionale Tumore, Milan, Italy, and lead author of the study. "This is an important finding since we know that the majority of patients respond to the doxorubicin/paclitaxel regimen within the first four cycles of treatment."

A total of 141 patients were enrolled in three trials conducted at the Istituto Nazionale Tumori from 1993 to 1998. Patients were evaluated every 3 months during therapy and subsequently every 12 months for up to 5 years (median: 52 months). All patients entering the trials were screened for evidence of active heart disease, and only patients with left-ventricular ejection fractions within the normal range, good blood pressure control, and no history of significant heart disease were entered into these studies.

Cardiac Events Resolved After Treatment

The three studies found that although asymptomatic signs of decreased cardiac function (as measured by left-ventricular ejection fraction) increased progressively during treatment, these events resolved within an average of 18 months after the completion of treatment. Congestive heart failure occurred only during treatment and in a disproportionately high number of patients (5 of 7) who received the highest cumulative dose of doxorubicin (420 to 480 mg/m²).

"Doxorubicin and paclitaxel are highly active agents in the treatment of advanced breast cancer. While early studies demonstrated a high incidence of congestive heart failure due to a high dose of doxorubicin, more recent trials limiting the dose of doxorubicin to 360 mg/m² have not observed any increase in cardiotoxicity," said Dr. Valagussa.

In clinical practice, this means that up to six courses of therapy with doxorubicin (60 mg/m²) and paclitaxel (175 mg/m²) by 3-hour infusion can be administered followed by paclitaxel monotherapy without any significant cardiac risk.

Doxorubicin and paclitaxel in combination are the most cytotoxic agents in the treatment of metastatic breast cancer. Given their clinical efficacy, relative non-cross-resistance, and differing mechanisms of action, there is a clear rationale for combining these two agents in both advanced and early-stage disease. In clinical trials, it has been found that up to 94% of patients respond to this treatment regimen, and up to 30% of patients achieve a complete response.

Other Study Confirms Findings

A study published in the Journal of Clinical Oncology by Jassem et al (19:1707-1715, 2001) supported the findings observed at the Istituto Nazionale Tumori. The AT regimen was found to be safe and well-tolerated and resulted in no increase in the incidence of congestive heart failure. The study also showed that paclitaxel in combination with doxorubicin significantly improved survival and prolonged median time to disease progression in women with metastatic breast cancer. The study compared the AT regimen with FAC (fluorouracil, doxorubicin, cyclophosphamide [Cytoxan, Neosar]). Survival was superior among patients receiving AT: 23.3 vs 18.3 months. Median time to disease progression was also significantly superior in the AT arm: 8.3 vs 6.2 months.