E2197: Phase III AT (doxorubicin/docetaxel) vs. AC (doxorubicin/cyclophosphamide) in the adjuvant treatment of node positive and high risk node negative breast cancer
Reviewer: Christopher Dolinsky, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 15, 2005
Presenter: L.J. Goldstein
Presenter's Affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania
Type of Session: Keynote
- A number of recent studies have shown the benefit of taxane based chemotherapy given in combination with other active agents for high risk breast cancer.
- A regimen including doxorubicin (A) and docetaxel (T), a taxane, has been shown to be beneficial in metastatic breast cancer.
- Combination doxorubicin (A) and cyclophosphamide (C) has been well described as an effective regimen for adjuvant therapy after local treatment in high risk breast cancer patients.
- This trial was designed to compare AC to AT.
Materials and Methods
- Women with N1 disease (1-3 positive nodes) or node negative and T > 1cm disease were randomized to 4 cycles of AT (60mg/m2/60mg/m2) given every 3 weeks or 4 cycles of AC (60mg/m2/600mg/m2) given every 3 weeks.
- Patients with ER and/or PR positive tumors were treated with 5 years of tamoxifen.
- Patients were stratified by a variety of factors: menopausal status, nodal stage, hormone receptor status.
- The two arms were well balanced in terms of disease and demographic factors including: age, hormone receptor status, menopausal status, tumor size, nodal stage, tumor grade and type of surgery.
- 2885 patients were enrolled and eligible for analysis.
- Median age was 51 years old.
- 64% of patients were ER positive, and 65% of patients were node negative.
- Median tumor size was 2 cm.
- The primary endpoint was disease free survival.
- Median follow-up time was 59 months.
- There was no significant difference in either disease free survival (hazard ratio 1.03, p=0.48) or overall survival (hazard ratio 1.09)
- When subgroups were analyzed separately, no significant differences were noted between the two arms.
- The 4 year disease free survival for both arms was 87%.
- Febrile neutropenia was more common in the AT arm than the AC arm, 28% vs 10%.
- 2 deaths related to treatment were seen in the AT group, and no deaths related to treatment were seen in the AC group.
- 18 cases of congestive heart failure were noted in the AT group, and 10 were noted in the AC group, but this difference was not statistically significantly different.
- It does not appear that there is a significant difference between these two regimens in terms of disease free survival
- The disease free survival in the control AC arm of 87% was higher than expected based on historical controls, which would predict a disease free survival of 70% for this regimen.
- Longer follow-up will not likely alter these results.
- Analyses of various subsets will be performed and presented in the future.
This trial is a negative study. Based on these results, four cycles of AT should not be substituted for four cycles of AC given the increased toxicity and similar efficacy. These findings are not consistent with a number of recently reported studies that show a benefit of adding taxane based agents to anthracyclines for adjuvant therapy of high risk breast cancers. One may speculate as to why this is the case. The study design may have contributed to the negative findings. Previous research with the addition of taxanes has focused on high risk patients. Although the aim of this study was to study high risk patients, analysis of the data does not demonstrate that this was a particularly high risk group of patients. 65% of the patients were node negative, 64% were ER + and the median size of tumors was 2 cm. Although the data was not presented, one may speculate that a sizeable number of low risk T1N0 patients were included in this study. Another piece of information that argues against this dataset comprising a high risk population is the better than expected disease free survival noted with the control arm (87% vs 70% expected based on historical controls.) Perhaps if a higher risk group of patients were studied, the outcomes would have been different. Other potential reasons that this regimen may have failed include: insufficient dose and duration of chemotherapy and questions about sequential versus concurrent administration of the taxane. Regardless, it is unlikely that this regimen will be studied further given the success seen with other taxane based regimens.