Taxane-Based Regimen Improves Disease-Free Survival in Early-Stage Breast Cancer

LOS ANGELES—Early data from a Breast Cancer International Research Group (BCIRG) study showed that docetaxel (Taxotere)-based combination therapy was significantly more effective than standard FAC (fluorouracil/doxorubicin [Adriamycin]/cyclophosphamide [Cytoxan, Neosar]) for the treatment of early-stage breast cancer (ASCO abstract 141). Reporting on behalf of BCIRG was its chairman Jean-Marc Nabholtz, MD, professor of medicine at the University of California at Los Angeles and director of Cancer Therapy Development at UCLA’s Jonsson Comprehensive Cancer Center.

The phase III trial compared TAC (Taxotere [docetaxel]/doxorubicin/cyclophosphamide (TAC) to FAC as adjuvant treatment for node-positive breast cancer. Dr. Nabholtz said that interim data analysis with a median follow-up of 33 months showed that TAC reduced breast cancer recurrence risk by 32% (relative risk 0.68 vs FAC, P = .0011) and reduced mortality for women with 1 to 3 positive nodes by 54% (P = .006).

"The observed early benefit that TAC provides over FAC in treatment of node-positive breast cancer is large enough to be of clinical significance, but final conclusions will require a longer period of follow-up," Dr. Nabholtz said.

Relapse Risk Reduced

The primary study endpoint is disease-free survival (DFS), assessed by Cox analysis. This showed a relative risk for TAC/FAC of 0.64 (CI 0.54-0.81, P = .0002). "Seventy-four percent of patients were alive and disease-free at 36 months on FAC and 82% on TAC," Dr. Nabholtz said.

There were 119 recurrences on TAC vs 170 on FAC. This constitutes a 32% reduction in relapse risk (P = .0011), but planned subset analysis showed that this improvement was accounted for entirely by better outcomes for women with three or fewer positive nodes. TAC cut the risk of relapse in half for these women but did not improve DFS for women with four or more positive nodes.

Dr. Nabholtz said the investigators were surprised to find that TAC reduced the risk of relapse almost equally in hormone-receptor positive (HR+) patients and in those who were hormone-receptor negative (32% reduction, P = .002, and 38% reduction, P = .005). "It was very unexpected to see such a difference in a group of patients with positive hormonal receptor status," he said.

TAC significantly improved DFS in HER2+ patients (RR 0.59, P = .02). DFS was also better in HER2- patients treated with TAC, but the difference did not reach statistical significance (RR 0.74, P = .06).

TAC appears to work in part by reducing the risk of distant metastasis. The site of first recurrence was distant in 80 patients on TAC vs 119 on FAC. First events were local or regional in 23 patients on TAC vs 31 on FAC.

Cox analysis of overall survival showed a relative risk for TAC/FAC of 0.71 (CI 0.50-1.00, P = .049).

Prospective Stratification

The study enrolled 1,491 node-positive patients after surgery to remove their primary tumor. Patients were randomized either to TAC (n = 745) or to FAC (n = 746) with prospective stratification according to number of positive nodes (1-3 vs 4 or more). Patients on the TAC arm were premedicated with dexamethasone (8 mg bid for 3 days) and with prophylactic ciprofloxacin (Cipro, 500 mg bid on days 5-14).

Dr. Nabholtz said that most patients had tumors smaller than 5 cm, that 69% of patients on each arm were estrogen-receptor positive and/or progesterone-receptor positive, and that 19% were HER2+. Patients with HR+ tumors also received 5 years of tamoxifen after completing chemotherapy.

Most patients (54%) were younger than 50, 62% had 1 to 3 positive lymph nodes, and 56% were premenopausal at study entry. The study was powered to permit statistically valid subgroup analysis according to number of positive nodes (1-3 vs 4 or more) and hormone receptor status.

Most patients were able to complete at least six cycles of treatment: 91% on TAC and 97% on FAC. Hematologic toxicities included neutropenia in 65.1% of patients on TAC vs 49% of patients on FAC, and febrile neutropenia in 23.9% on TAC vs 2.4% on FAC. "The absolute neutrophil count was low significantly more often with TAC than with FAC, and febrile neutropenia was significantly more frequent with TAC," Dr. Nabholtz said.

"There were no differences in grade 3/4 infections (2.8% vs 1.3%) or in infectious deaths between the two regimens. Nevertheless, this should raise our awareness of the importance of deciding who we want to treat with these regimens."

TAC as Standard Therapy?

Edith A. Perez, MD, the discussant for this paper, cut to the chase: "Should TAC be a standard therapy for node-positive breast cancer?" Dr. Perez is a professor of medicine, and director, Clinical Investigation and Breast Cancer Program, Mayo Medical School, Jacksonville, Florida. She pointed out that TAC improved disease-free survival, with a trend for improvement in overall survival compared to FAC and that this benefit was independent of hormone receptor status.

The importance of hormone receptor status is uncertain, and other researchers have reported different results.

"At this point," Dr. Perez said, " I would not exclude patients from consideration for taxanes based on hormone receptor status, and I also would not exclude them from consideration for taxanes based on the number of involved nodes in the axilla. The improvement in DFS with taxanes is clinically relevant, but the optimal way to use taxanes is not yet clear, and we cannot yet make definite conclusions regarding effect on overall survival."

Dr. Perez estimated that if all of the 200,000 women who will be diagnosed with breast cancer this year could be treated with taxanes, 16,000 additional patients would be free of recurrence at 3 years, based on the data presented by Dr. Nabholtz.