LOS ANGELES--Taxane therapy lengthens survival in breast cancer patients, both in the metastatic and adjuvant settings, according to the results of two phase III trials presented at the 34th Annual Meeting of the American Society of Clinical Oncology (ASCO).
An interim analysis of an intergroup trial found that adding paclitaxel(Drug information on paclitaxel) (Taxol) to the standard adjuvant AC chemotherapy regimen--doxorubicin (Adriamycin) and cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar)--not only significantly improved survival but also decreased the rate of recurrences.
In a trial conducted by the International 304 Study Group in patients with anthracycline-refractory metastatic disease, salvage therapy with docetaxel (Taxotere) proved superior to the combination of mitomycin (Mutamycin) and vinblastine(Drug information on vinblastine) (MV) with respect to every outcome assessed.
The intergroup trial, led by the Cancer and Leukemia Group B (CALGB), randomized 3,170 women with operable, node-positive breast cancer to adjuvant therapy with 600 mg/m² of cyclophosphamide plus one of three doses of doxorubicin(Drug information on doxorubicin) (60, 75, or 90 mg/m²), I. Craig Henderson, MD, principal investigator, said in his report.
After this therapy was completed, patients were randomized a second time to either paclitaxel (175 mg/m² over 3 hours) or no consolidation therapy. Receptor-positive women also were given 5 years of tamoxifen(Drug information on tamoxifen) (Nolva-dex) therapy.
An interim analysis of the data showed no impact of doxorubicin dose on either disease-free survival or overall survival, said Dr. Henderson, of the University of California, San Francisco. However, consolidation with paclitaxel lowered mortality by 26% and decreased the disease recurrence rate by 22%.
Kaplan-Meier plots at 18 months revealed a 2% absolute improvement in overall survival afforded by paclitaxel (97% for paclitaxel vs 95% for no paclitaxel; P = .0077) and a 4% absolute improvement in disease-free survival (90% vs 86%; P = .039).
The investigators saw no differences in the incidence of cardiotoxicity during or after chemotherapy that could be attributed to either the dose of doxorubicin used or the addition of paclitaxel.
"This may represent the largest increase in benefit from adjuvant therapy since the first CMF trials in the 1970s," Dr. Henderson said, but he warned that this statement should be taken with "great caution" due to the preliminary nature of the results. The benefits of paclitaxel are unlikely to disappear with further follow-up, he asserted, although the magnitude of those benefits may change.
Obvious Clinical Importance
"I think that these are tremendously exciting data and of obvious clinical importance," George Sledge Jr., MD, of Indiana University, said in his critical discussion of the two trials. "Its certainly reasonable and ethical to discuss these findings with all lymph-node-positive patients entering our clinics."
Emphasizing the inadequate follow-up and limited number of events thus far, however, he concluded that "we simply need further follow-up before considering adjuvant taxane therapy the proven standard of care."
Moreover, the majority of patients in the trial had four or more positive nodes and therefore were a high-risk group. Thus, the results may not be applicable to all subgroups, Dr. Sledge stated, adding that, as yet, there are not enough events to perform meaningful subgroup analyses.
Metastatic Disease Trial
Presenting the results of the 17-country, international trial, lead investigator Jean-Marc A. Nabholtz, MD, noted that the 392 patients who participated in the study had progressed during or after treatment with an anthracycline regimen for metastatic disease or had relapsed within 1 year of receiving anthracycline-based adjuvant therapy.
About half of the patients had visceral involvement, added Dr. Nabholtz, chairman of the Northern Alberta Breast Cancer Program, and senior medical oncologist, Cross Cancer Institute, Edmonton, Alberta, Canada.
These patients were randomized, in nonblinded fashion, to either docetaxel(Drug information on docetaxel) (100 mg/m² over 1 hour every 3 weeks) or mitomycin(Drug information on mitomycin) (12 mg/m² every 6 weeks) plus vinblastine (6 mg/m² for 3 weeks) for a maximum of 10 cycles.
An intention-to-treat analysis conducted in the 350 evaluable patients showed a 50% improvement in overall survival at 12 months, with 49% of docetaxel-treated patients alive at this juncture, compared with 33% of the MV recipients (P = .0037).
The survival benefit afforded by docetaxel therapy was maintained at 18 months, Dr. Nabholtz said. The 18-month survival rates were 33% for the docetaxel group and 21% for the combination therapy group--nearly a 60% improvement.
The docetaxel-treated patients also enjoyed significantly better response rates than the MV-treated patients (30% vs 11.6%; P < .0001), as well as a significantly longer time to progression (19 vs 11 weeks; P = .001).
Dr. Nabholtz described toxicity in both arms as "manageable and tolerable." Neutropenia was more common in the docetaxel group than in the MV group, as were febrile neutropenia and infection. Thrombocytopenia, however, occurred more frequently in the MV-treated patients.
With respect to nonhematologic toxicities, asthenia, stomatitis, and diarrhea were significantly more frequent with docetaxel. Fluid retention also was more common in the docetaxel arm, but this rarely led to drug discontinuation.
The risk-to-benefit ratio favors the taxane, Dr. Nabholtz concluded. "Clearly, we have to consider that, in this type of patient, this is the first large phase III trial showing that one chemotherapy agent is able to improve survival, as opposed to another type of treatment," he commented.
Survival Results Impressive
These sentiments were echoed by Dr. Sledge in his discussion of the paper. Dr. Sledge characterized the survival results as "particularly impressive."
"The salvage chemotherapy setting is a graveyard--both figuratively and literally," Dr. Sledge commented.
Responses to chemotherapeutic agents in this setting are infrequent, usually of short duration, and often accompanied by significant toxicity, he said. "Rarely is any real survival advantage observed."
In sharp contrast to this typically grim picture for these patients, Dr. Sledge said, "Taxotere provided superior results in every category--response rate, time to disease progression, and overall survival."