Docetaxel Adds to Benefit of Anthracycline-Based Adjuvant Chemotherapy in Node-Positive Breast Cancer: BIG 2-98

ATLANTA—Adding docetaxel (Taxotere) to anthracycline-based adjuvant chemotherapy reduces the risk of relapse, new primaries, and death among women with node-positive breast cancer, first data from the BIG 2-98 trial show. Furthermore, the risk reduction is greater if taxotere is given sequentially instead of concurrently, John P. Crown, MD, an oncologist with the Irish Clinical Oncology Research Group, said at the American Society of Clinical Oncology 42nd Annual Meeting (abstract LBA519).

The randomized, open-label, phase III trial enrolled women who had node-positive, nonmetastatic, T1-3 breast cancer that had been resected with clean margins.

It tested different regimens containing doxorubicin (A), cyclophosphamide (C), and docetaxel (T). Patients were randomized in a 1:2 ratio to a pair of control arms (A and AC) or a pair of experimental arms (A-T and AT). All regimens finished with CMF (cyclophosphamide, methotrexate, and 5-FU), as follows.

Arm A: A 75 mg/m² X 4 → CMF X 3

Arm AC: AC 60/600 mg/m² X 4 → CMF X 3

Arm A-T: A 75 mg/m² X 3 → T 100 mg/m² X 3 → CMF X 3

Arm AT: AT 50/75 mg/m² X 4 → CMF X 3

The analyses reported were conducted after a median follow-up of 62.5 months, earlier than initially planned, because the rate of relapse was slower than expected, Dr. Crown said. Analyses were based on 481 patients in arm A, 487 in arm AC, 960 in arm A-T, and 959 in arm AT. "Please note that this was an unusually high risk group of patients, with nearly one-half of each group having four or more involved axillary lymph nodes," Dr. Crown remarked.

In terms of the trial's primary endpoint, patients in the arms that received docetaxel (A-T and AT) had a borderline significant reduction in the risk of events (breast cancer relapse, a new primary, or death), compared with patients in the arms that did not receive docetaxel (A and AC) (HR 0.86; P = .051). In terms of secondary endpoints, a comparison of the two sequential arms showed that A-T was associated with a reduction in the risk of events relative to A (HR 0.79; P = .035), whereas a comparison of the two concurrent arms, AT and AC, showed that this outcome was statistically indistinguishable. Finally, a comparison of the arms with differing docetaxel schedules showed that the risk of events was lower with sequential A-T than with concurrent AT (HR 0.83; P = .047).

Analyses of overall survival showed no significant differences between the arms, as compared for event-free survival, Dr. Crown said. However, there was a trend toward a reduced risk of death with sequential A-T relative to concurrent AT (HR 0.80; P = .069).

Toxicity Profiles

The percentage of patients who experienced grade 3-4 toxicities or other severe or life-threatening toxicities during treatment or follow-up was lowest in the A arm (26%) followed by AC (27%), AT (32%), and A-T (38%). The incidence of grade 3-4 asthenia and stomatitis was highest in the A-T arm; infection was highest in the AT arm; and nausea/vomiting was highest in the AC arm.

About 12% of patients in the AT arm, 8% in the A-T arm, 5% in the A arm, and 4% in the AC arm developed febrile neutropenia. There were two treatment-related deaths in the AT arm, one each in the A-T and A arms, and none in the AC arm; all of these deaths were attributable to neutropenia, according to Dr. Crown.

"Adding docetaxel to sequential anthracycline, CMF chemotherapy resulted in improved disease-free survival, which was of borderline significance," he said. The findings favor sequential A-T over both AT and A, when each is followed by CMF. "This is the first demonstration of an improved outcome for sequential over combination anthracycline- and taxane-containing chemotherapy, a result that is consistent with the Norton-Simon hypothesis," he said (see Vantage Point).