Use of adjuvant chemotherapy with docetaxel (Taxotere) and cyclophosphamide (TC) is associated with a 33% improvement in disease-free survival and trend for improvement in overall survival in early-stage breast cancer, compared with the standard doxorubicin (Adriamycin)/cyclophosphamide (AC) regimen, according to the final analysis of a study from US Oncology Research, Houston
SAN ANTONIO-Use of adjuvant chemotherapy with docetaxel (Taxotere) and cyclophosphamide (TC) is associated with a 33% improvement in disease-free survival and trend for improvement in overall survival in early-stage breast cancer, compared with the standard doxorubicin (Adriamycin)/cyclophosphamide (AC) regimen, according to the final analysis of a study from US Oncology Research, Houston, presented at the 28th Annual San Antonio Breast Cancer Symposium (abstract 40).
Stephen E. Jones, MD, principal investigator and medical director of US Oncology Research, commented that the experimental regimen "is clearly a significantly better treatment than standard AC. Based on these findings, the TC regimen should now be considered a standard nonanthra-cycline adjuvant regimen for operable breast cancer."
The study included 1,016 women with stage I-III operable breast cancer enrolled between June 1997 and December 1999. Subjects were followed through April 2005, at which time 165 events had occurred. Median follow-up was 5.5 years.
Patients were randomized to four adjuvant cycles of AC (60/600 mg/m2) or four cycles of TC (75/600 mg/m2) given every 3 weeks. All chemotherapy was administered before radiotherapy (if it was indicated), and patients received tamoxi-fen if indicated. The arms were well balanced with regard to major prognostic factors. Overall, 71% of cancers were hormone-receptor positive. Nodal status was negative in 48%, one to three nodes positive in 41%, and four or more nodes positive in 11%.
The findings were made 30 years after Dr. Jones and his colleagues published the first study establishing AC as the standard treatment for women with advanced breast cancer. Since then, docetaxel has demonstrated greater antitumor activity than doxorubicin in metastatic breast cancer; therefore, the investigators wanted to compare the TC regimen to AC in earlier stage disease, he said. "Today, on the 30th anniversary of the AC paper, I present to you TC, a novel nonanthracycline regimen that, I think, can replace AC as a better adjuvant regimen," he said.
Events (local or distant relapses, second cancers) numbered 59 with TC and 80 with AC (see Table). Deaths from all causes numbered 55 and 71, respectively, and deaths without relapse numbered 7 and 12, Dr. Jones reported. This resulted in disease-free survival rates at 5 years (the primary endpoint) of 86% with TC vs 80% with AC. The hazard ratio was 0.67, which was statistically significant (P = .015).
"We did an exploratory analysis of disease-free survival by subgroup-particularly because of the interest in receptor status and the effect of the taxanes. . . . We saw that patients with both ER-negative disease and ER-positive disease had a clear benefit of TC over AC. Some of the subgroups are small, but in fact the treatment effect was consistent throughout the subgroups," Dr. Jones said.
There were fewer deaths overall with TC, resulting in overall survival rates of 90% for TC, compared with 87% for AC. The hazard ratio was 0.76 (P = .13). "I think that possibly docetaxel and cyclophosphamide are more synergistic than suspected. The outcome is clearly positive," he noted.
The two regimens had different toxicity profiles, with the TC regimen being better tolerated overall. There were no significant differences between the regimens for neutropenia, anemia, or thrombocytopenia; however, febrile neutropenia was more common in the TC arm (6%) than in the AC arm (3%). Nonhematologic toxicities were similar, although there were significantly more cases of nausea and vomiting of all grades in the AC arm, and TC was associated with more low-grade edema, myalgia, and arthralgia. Although he did not present data on cardiotoxicity, Dr. Jones pointed out that TC is less cardiotoxic than AC.
In contrast to this study, ECOG 2197, which evaluated the same regimens, was not positive, he said. The US Oncology Study had more patients with positive lymph nodes, and the dose of docetaxel was higher than in ECOG 2197. "I think these are potential reasons to explain the differences in these trials," he said.