A U.S. Intergroup study (CLB-9344) randomly assigned women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m2) and a fixed dose of cyclophosphamide (600 mg/m2) every 3 weeks for four cycles. After AC chemotherapy, patients underwent a second randomization to paclitaxel (175 mg/m2) every 3 weeks for four cycles, and women with ER-positive tumors also received tamoxifen for 5 years. Although the dose-escalation of doxorubicin was not beneficial, the addition of paclitaxel resulted in statistically significant improvements in DFS (5%) and OS (3%).[Level of evidence: 1iiA] The results of a second trial, the NSABP-B-28 trial, have also been reported. This trial randomized 3,060 women with node-positive breast cancer to four cycles of postoperative AC or four cycles of AC followed by four cycles of paclitaxel. All women older than 50 years, and those younger than 50 years with receptor-positive disease, received tamoxifen. In this trial, DFS was significantly improved by the addition of paclitaxel (hazard ratio [HR] = 0.83; 95% CI, 0.72-0.96; P = .006; 5-year DFS = 76% vs. 72%). The difference in OS was small (HR = 0.93), however, and not statistically significant (P = .46).[Level of evidence: 1iiA]
The regimen of 5-FU, adriamycin, and cyclophosphamide (FAC) compared with docetaxel plus doxorubicin and cyclophosphamide (TAC) has been studied in 1,491 women with node-positive disease in the Breast Cancer International Research Group's (BCIRG-001) trial. Six cycles of either regimen were given as adjuvant postoperative therapy. A 75% DFS rate existed at 5 years in the TAC group compared with a 68% survival in the FAC group (P = .001). TAC was associated with a 30% overall lower risk of death (5% absolute difference) than FAC (HR = .70; 98% CI, 0.53-0.91; P < .008). Anemia, neutropenia, febrile neutropenia, and infections were more common in the TAC group. No deaths were associated with infections in either group.[192,193][Level of evidence: 1iiA] (For information on anemia, refer to the PDQ summary on Fatigue.)
The regimen of docetaxel and cyclophosphamide (TC) compared with doxorubicin plus cyclophosphamide (AC) was studied in 1,016 women with stage I or stage II invasive breast cancer. Patients were randomly assigned to receive four cycles of either TC or AC as adjuvant postoperative therapy. At 5 years, DFS was statistically significantly superior for TC compared with AC (86% vs. 80%, HR= 0.67; 95% CI, 0.50-0.94; P = .015).[Level of evidence: 1iiA] However, OS was not statistically significantly improved. With TC, patients had fewer cardiotoxic effects but other side effects included more myalgia, arthralgia, edema, and febrile neutropenia compared with AC.
The role of bisphosphonates as part of adjuvant therapy for early stage breast cancer is currently under clinical study. The ABCSG-12 (NCT00295646) trial was a 2 � 2 factorial-design randomized trial that assigned 1,803 premenopausal patients with ER+ breast cancer to receive ovarian function suppression with goserelin and tamoxifen versus goserelin and anastrozole. These patients then underwent a second randomization to receive zoledronic acid (4 mg intravenously every 6 months) versus no zoledronic acid.[Level of Evidence: 1iiA] There was no significant difference in DFS between the anastrozole and tamoxifen groups. However, the addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in a relative reduction of 36% in the risk of disease progression (HR = 0.64; P = .01) but did not significantly reduce the risk of death.