Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer

Abstract

Background: Chemotherapy regimens that combine anthracyclines and taxanes result in improved disease-free and overall survival among women with operable lymph-node-positive breast cancer. The effectiveness of concurrent versus sequential regimens is not known.

Methods: We randomly assigned 5351 patients with operable, node-positive, early-stage breast cancer to receive four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (sequential ACT); four cycles of doxorubicin and docetaxel (doxorubicin-docetaxel); or four cycles of doxorubicin, cyclophosphamide, and docetaxel (concurrent ACT). The primary aims were to examine whether concurrent ACT was more effective than sequential ACT and whether the doxorubicin-docetaxel regimen would be as effective as the concurrent-ACT regimen. The secondary aims were to assess toxic effects and to correlate amenorrhea with outcomes in premenopausal women.

Results: At a median follow-up of 73 months, overall survival was improved in the sequential-ACT group (8-year overall survival, 83%) as compared with the doxorubicin-docetaxel group (overall survival, 79%; hazard ratio for death, 0.83; P=0.03) and the concurrent-ACT group (overall survival, 79%; hazard ratio, 0.86; P=0.09). Disease-free survival was improved in the sequential-ACT group (8-year disease-free survival, 74%) as compared with the doxorubicin-docetaxel group (disease-free survival, 69%; hazard ratio for recurrence, a second malignant condition, or death, 0.80; P=0.001) and the concurrent-ACT group (disease-free survival, 69%; hazard ratio, 0.83; P=0.01). The doxorubicin-docetaxel regimen showed noninferiority to the concurrent-ACT regimen for overall survival (hazard ratio, 0.96; 95% confidence interval, 0.82 to 1.14). Overall survival was improved in patients with amenorrhea for 6 months or more across all treatment groups, independently of estrogen-receptor status.

Conclusions: Sequential ACT improved disease-free survival as compared with doxorubicin-docetaxel or concurrent ACT, and it improved overall survival as compared with doxorubicin-docetaxel. Amenorrhea was associated with improved survival regardless of the treatment and estrogen-receptor status. (ClinicalTrials.gov number, NCT00003782.)

Figure 1

Enrollment, Randomization, and Follow-up of Study Participants.

Figure 2. Overall Survival and Disease-free Survival

Panels A and B show the Kaplan–Meier estimates of survival and disease-free survival in the three treatment groups over the follow-up period. P values are by two-sided log-rank tests. At the prespecified significance level of 0.05, a significant improvement in overall survival was associated with doxorubicin and cyclophosphamide followed by docetaxel (sequential ACT) as compared with doxorubicin–docetaxel (P = 0.03), and a marginal benefit was associated with sequential ACT over concurrent administration of doxorubicin, docetaxel, and cyclophosphamide (concurrent ACT) (P = 0.09) (Panel A). There was a statistically significant decrease in disease recurrence, a second malignant condition, or death in the sequential-ACT group as compared with the concurrent-ACT group (P = 0.01). In addition, the rate of disease-free survival was significantly higher among patients in the sequential-ACT group than among patients in the doxorubicin–docetaxel group (P = 0.001) (Panel B). Panels C and D show the effect of amenorrhea on overall survival and disease-free survival, respectively, for the combined treatment groups adjusted for treatment, estrogen-receptor status, age, lymph-node status, tumor size, and use or nonuse of hormone therapy. Overall survival (hazard ratio for death, 0.76; P = 0.04) and disease-free survival (hazard ratio for disease recurrence, a second malignant condition, or death, 0.70; P<0.001) were improved among patients with amenorrhea for 6 months or more.

Figure 3. Hazard Ratios for Various Subgroups, According to Treatment

Panel A shows the reduced risk of death associated with doxorubicin and cyclophosphamide followed by docetaxel (sequential ACT) as compared with concurrent administration of all three agents (concurrent ACT). Panel B shows the reduced risk of disease recurrence, a second malignant condition, or death associated with sequential ACT as compared with concurrent ACT. Panel C shows the reduced risk of death associated with sequential ACT as compared with doxorubicin–docetaxel. Panel D shows the reduced risk of disease recurrence, a second malignant condition, or death associated with sequential ACT as compared with doxorubicin–docetaxel. Panels E and F show data from the menstrual-history study. Panel E shows the risk of death according to subgroups, adjusted for lymph-node status and tumor size. Panel F shows the risk of disease recurrence, a second malignant condition, or death according to subgroups, adjusted for lymph-node status and tumor size. The size of the squares is proportional to the size of the subgroups. CI denotes confidence interval, and ER estrogen receptor.

Figure 3. Hazard Ratios for Various Subgroups, According to Treatment

Panel A shows the reduced risk of death associated with doxorubicin and cyclophosphamide followed by docetaxel (sequential ACT) as compared with concurrent administration of all three agents (concurrent ACT). Panel B shows the reduced risk of disease recurrence, a second malignant condition, or death associated with sequential ACT as compared with concurrent ACT. Panel C shows the reduced risk of death associated with sequential ACT as compared with doxorubicin–docetaxel. Panel D shows the reduced risk of disease recurrence, a second malignant condition, or death associated with sequential ACT as compared with doxorubicin–docetaxel. Panels E and F show data from the menstrual-history study. Panel E shows the risk of death according to subgroups, adjusted for lymph-node status and tumor size. Panel F shows the risk of disease recurrence, a second malignant condition, or death according to subgroups, adjusted for lymph-node status and tumor size. The size of the squares is proportional to the size of the subgroups. CI denotes confidence interval, and ER estrogen receptor.