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SECTION I: Adjuvant Therapy

Abstract 141
Phase III Trial Comparing TAC with FAC in the Adjuvant Treatment of Node-Positive Breast Cancer Patients: Interim Analysis of BCIRG 001
Jean-Marc A. Nabholtz, MD, MS, Professor, Department of Medicine, University of California at Los Angeles (UCLA) School of Medicine; Director, Cancer Therapy Development Program, UCLA Jonsson Comprehensive Cancer Center, Los Angeles California; Chairman and Founder, Breast Cancer International Research Group (BCIRG)

Taxotere-based adjuvant chemotherapy achieved a 32% (p=0.0011) risk reduction in cancer recurrence compared to standard adjuvant chemotherapy in women with early-stage, node-positive breast cancer, according to a three-year interim analysis of results from a large, international, phase III trial (BCIRG 001). A trend toward lower mortality was also observed in women who received Taxotere (docetaxel), doxorubicin (Adriamycin, Adiblastine, Adriablatina, Doxil, and others) and cyclophosphamide [Cytoxan, Cytokan, Endoxon, Neosar, Neosar For Injection] (TAC) compared with standard chemotherapy using 5-fluorouracil (5-FU; Adrucil, Efudex, Fluroplex), doxorubicin and cyclophosphamide (FAC).

The Breast Cancer International Research Group (BCIRG) 001 trial is the first phase III trial to evaluate Taxotere in the adjuvant setting, explained lead investigator Dr. Jean-Marc Nabholtz, who reported results from a planned interim analysis at the 38^th Annual Meeting of the American Association of Clinical Oncology (ASCO).

Several trials have previously demonstrated the activity and efficacy of Taxotere in patients with metastatic breast cancer (Chan S et al. J Clin Oncol 1999;17(8):2341-2354; Nabholtz JM et al. J Clin Oncol 1999;17(5):1413-1424; Nabholtz JMA et al. ASCO 1999. Abstract 485; Sjöström J et al. Eur J Cancer 1999;35(8):1194-1201; Nabholtz JMA et al. ASCO 2001. Abstract 83; Mackey JR et al. ASCO 2002. Abstract 137). Adding Taxotere to the standard adjuvant therapy of an anthracycline was therefore logical and full of promise in this setting.

"The observed early benefit of adjuvant chemotherapy with TAC in this interim analysis is large enough to be of value to patients with early-stage breast cancer. The evidence is robust enough to confirm incorporating Taxotere in the adjuvant setting," Dr. Nabholtz told attendees.

Trial Design
BCIRG 001 was a large, international trial that included 112 centers from 20 countries. The study enrolled 1,491 patients with early-stage, node-positive, operable breast cancer who were randomized to one of two regimens, administered every three weeks for six cycles:

Arm 1. Standard adjuvant chemotherapy with FAC (5-FU 500 mg/m², doxorubicin 50 mg/m², and cyclophosphamide 500 mg/m²);
Arm 2. Taxotere-containing chemotherapy with TAC (Taxotere 75 mg/m², doxorubicin 50 mg/m², and cyclophosphamide 500 mg/m²).

Patients in the TAC group received standard Taxotere premedication with dexamethasone (Decadron, Aeroseb-Dex, Corotason, Curson, and others) 8 mg twice daily for three days and prophylactic ciprofloxacin (Cipro [oral/injectable], Ciloxan [ophthalmic], Cyprobay) 500 mg bid on days 5 to 14. All patients with estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+) tumors received tamoxifen for five years after chemotherapy.

The primary study endpoint was disease-free survival at five years. Secondary endpoints included overall survival, toxicity, quality of life and biological markers. Survival and toxicity data were presented.

Demographic and disease characteristics were well balanced in both arms of the study. Overall, 54% of patients were under the age of 50, 62% had one to three positive nodes, 50% were premenopausal, and 69% were ER/PR+. Sixty percent of women had tumors greater than 2 cm, and 20% of tumors were human epidermal growth factor receptor 2 (HER-2) positive as detected by fluorescence in situ hybridization (FISH).

Both regimens were well tolerated, as reflected by the fact that 97% of the FAC group and 91% of the TAC group received the total planned cycles of chemotherapy.

Disease-Free Survival
A 32% reduction in the risk of disease recurrence was seen with the use of TAC (p=0.0011). At 33 months of follow-up, there were 289 events (cases of metastatic or locoregional recurrence, contralateral breast cancer, second primary cancer, etc.) — 170 in the FAC group and 119 in the TAC group. Seventy-four percent of the FAC patients compared to 82% of the TAC patients were alive and disease-free at 36 months (Figure 1). At three years, there was an absolute difference of 8% in disease-free survival in favor of the TAC group.

Figure 1. BCIRG 001 Disease-Free Survival (ITT) Median follow-up: 33 months

Figure 1. BCIRG 001 Disease-Free Survival (ITT) Median follow-up: 33 months

Source: Adapted from Jean-Marc Nabholtz, MD, as presented at the 38^th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 18-21, 2002, Orlando, Florida. Abstract 141.

Overall Survival
Women who received TAC had a 24% reduction in mortality with 92% surviving compared with 87% in the FAC group. This is important but not yet statistically significant, although the difference in overall survival may become significant with longer follow-up, Dr. Nabholtz noted.

Nodal Status
As part of the pre-specified analysis in the trial, patients were stratified according to nodal status (one to three nodes versus four or more nodes) prior to randomization.

"In the general population, women with one to three positive nodes account for 60% to 70% of all women with node-positive early-stage breast cancer. The subset analysis according to nodal status was prospectively planned, so we should be able to draw a conclusion from these data," Dr. Nabholtz explained.

Taxotere-based chemotherapy reduced the risk of relapse by 50% (p=0.0002) and reduced the mortality rate by 54% (p=0.006) in women with one to three positive nodes compared with FAC. In this subset, 90% of women in the TAC group were alive at 36 months compared with 79% of women in the FAC group. No difference in survival was seen between the two regimens in women with four or more positive nodes — 86% of TAC patients were alive at 36 months compared with 84% of FAC patients (Table 1).

Table 1. BCIRG 001 Disease-Free Survival and Overall Survival at Three Years

Table 1. BCIRG 001 Disease-Free Survival and Overall Survival at Three Years

Source: Adapted from Jean-Marc Nabholtz, MD, as presented at the 38^th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 18-21, 2002, Orlando, Florida. Abstract 141.

This benefit with TAC in disease-free survival was seen regardless of hormone receptor status. TAC reduced the risk of relapse by 38% in women who were ER/PR- (p=0.005) versus 32% in those who were ER/PR+ (p=0.02) (Figure 2). Patients also had a greater benefit with TAC regardless of HER-2 status. In the HER-2-positive group, there was a 41% reduction in the risk of recurrence (p=0.02); while in the HER-2-negative group, the risk reduction was 26% (p=0.06).

Figure 2. BCIRG 001 Disease-Free Survival by Hormonal Status

Figure 2. BCIRG 001 Disease-Free Survival by Hormonal Status

Source: Adapted from Jean-Marc Nabholtz, MD, as presented at the 38^th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 18-21, 2002, Orlando, Florida. Abstract 141.

Toxicity
The TAC group showed a higher incidence of neutropenia (i.e., absolute neutrophil counts<1,000) compared to the FAC group (65.1% vs. 49%, p=0.05), as well as a higher incidence of febrile neutropenia (23.9% vs. 2.4%, p=0.05). However, the incidence of grade 3 or 4 infections was not significantly different between the two arms (3.1% vs. 1.5%, p>0.05) and there were no cases of septic death.

"The incidence of neutropenia and febrile neutropenia should raise our level of awareness when using TAC. We were aware that one-third of metastatic breast cancer patients treated with Taxotere develop febrile neutropenia, so we were prepared to manage it in this trial," Dr. Nabholtz said. Another trial evaluating TAC in the metastatic setting (BCIRG 004) had a reduction in the rate of febrile neutropenia to 6.7% with the use of granulocyte-colony stimulating factor (G-CSF).

Regarding non-hematologic toxicity, more grade 3 or 4 nausea and vomiting was observed in the FAC arm, while diarrhea, stomatitis, and asthenia were more frequent in the TAC arm.

"Overall, this interim analysis showed that TAC was superior to FAC. I was struck by the difference between the two arms in disease-free survival at three years. The superior results with the Taxotere-based regimen indicate that it has the potential to cure more women than a standard anthracycline-containing polychemotherapy," Dr. Nabholtz said. "Although early, these results should be considered when selecting therapy for a large number of women with early-[stage] breast cancer."

Key Points In Focus:

BCIRG 001 was the first large, randomized phase III study of Taxotere in the adjuvant setting.
Interim analysis showed that TAC was superior to FAC in patients with node-positive breast cancer.
TAC reduced the risk of recurrence by 32% (p=0.001) compared with FAC.
Women with one to three positive nodes account for about two-thirds of all breast cancer patients. It is this group that experienced the greatest benefit from Taxotere-based therapy.
In women with one to three positive nodes, disease-free survival and mortality significantly improved with TAC as compared with FAC.
Regardless of hormone receptor status, patients in the TAC arm were noted to have a significant reduction of recurrence versus patients in the FAC arm.
Both HER-2-positive and -negative patients had substantial reductions in the risk of recurrence with the use of TAC.
Although a higher incidence of febrile neutropenia was noted in the TAC arm, there was no difference in the frequency of infection and no septic deaths were observed in either arm.

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