SAN ANTONIODocetaxel (Tax-otere) has produced higher response rates than doxorubicin in a large European clinical trial in women with advanced breast cancer, marking the first time doxorubicin has been outperformed by any other single chemotherapeutic agent, John Crown, MD, reported for the International 303 Study Group, at a general session of the San Antonio Breast Cancer Symposium. [See page 30 for a commentary on single-agent taxanes in this setting.]
Docetaxel resulted in a 48% response rate, compared with 33% for doxorubicin, in approximately 300 patients with metastatic breast cancer. The taxane led to quicker responses and achieved significantly more responses in all visceral metastases, in liver metastases, and in chemotherapy-resistant patients, said Dr. Crown, a consultant oncologist at St. Vincents Hospital, Dublin, Ireland.
Docetaxel also had a more favorable toxicity profile with respect to cardio-toxicity and hospitalization for febrile neutropenia and infection. The results of this study would seem to indicate that docetaxel is more effective and safer than doxorubicin in patients with advanced breast cancer, Dr. Crown said.
Docetaxel did not prove superior with respect to the primary endpoint of time to disease progression. Although it did prolong the time to progression, compared with doxorubicin, the difference did not achieve significance, Dr. Crown commented.
The trial involved breast cancer patients who had received previous treatment with alkylating agents. Half of the patients had chemotherapy-resistant disease, either primary (treatment failure) or secondary (disease progression after treatment). Patients who had a history of taxane or anthracycline therapy were excluded from the trial.
A Poor-Prognosis Population
Three-fourths of the patients had visceral metastases, more than 40% had liver metastases and involvement of at least three organs, and 80% had measurable disease. This was primarily a poor-prognosis population, Dr. Crown said.
Patients were randomized to receive one of two treatment regimens. Approximately half received docetaxel at a dose of 100 mg/m2 infused over 1 hour every 3 weeks. The rest received doxorubicin at a dose of 75 mg/m2 infused over 15 to 20 minutes every 3 weeks.
The protocol specified a treatment target of seven cycles of therapy. The trial did not allow routine use of growth factors or prophylactic antibiotics.
Response was assessed after every two cycles of therapy, at the end of the study, and then every 3 months until progression. Because of doxorubicins risk of cardiotoxicity, left ventricular ejection fraction was assessed at randomization, after a cumulative drug dose of 400 mg/m2, and at the end of the study.
Docetaxel produced complete responses in 7% of patients and partial responses in 41% for a cumulative response rate of 48%. Doxorubicin led to complete responses in 4% and partial responses in 29% for a total response of 33%.
Analysis by site showed a 46% response rate in visceral metastases for docetaxel, compared with 29% for doxorubicin. Docetaxel led to clinical responses to 54% of patients with liver metastases versus 27% for doxorubicin. Among resistant patients, 47% responded to docetaxel, compared to 24% with doxorubicin.
Responses occurred significantly faster with docetaxel (12 weeks vs 23 weeks). The time to progression favored docetaxel (26 weeks vs 21 weeks), but the difference was not significant, Dr. Crown said.
Hematologic toxicity occurred in 97% of patients in each treatment group, and the incidence of grades 3/4 neutropenia was similar in both groups (15% and 79%, respectively, for docetaxel, and 10% and 78%, respectively, for doxorubicin).
The incidence of hospitalization for infection or febrile neutropenia was significantly higher in the doxorubicin cohort (9% vs 3%), as was the incidence of thrombocytopenia (40% vs 4%).
With respect to nonhematologic toxicity, doxorubicin led to higher inci-dences of nausea, vomiting, and stomati-tis, whereas more patients in the docetaxel cohort had diarrhea. Neurosensory and neuromotor toxicity each occurred in 5% of docetaxel patients but in none of the patients treated with doxorubicin.
As expected, doxorubicin caused more cardiotoxicity. Dr. Crown said that almost 50% of the doxorubicin patients had a decline in left ventricular ejection fraction vs 8% of the docetaxel patients. Cardiotoxicity forced 9% of doxorubicin patients to withdraw from the study; 4% developed clinical heart failure, and 2% died from cardiotoxic complications. This type of clinical cardiotoxicity was not seen with Taxotere, he said.
QOL Data Not Yet Analyzed
Though quality of life data have not yet been analyzed, the findings appear to be similar in the two study arms. We have seen no evidence that the payoff of a higher response rate with Taxotere is any detriment in quality of life, compared to doxorubicin, Dr. Crown said.
This large randomized comparative trial confirms the high activity of Taxotere, which has been seen in many phase II, single-arm studies, he said. The fact that the two drugs had incompletely overlapping toxicities and both had prominent activity provides powerful rationale for their evaluation in combination and in sequence in patients with metastatic disease and, perhaps more importantly, in the adjuvant setting for patients with earlier-stage disease.