This trial showed that the sequential administration of ACT in the adjuvant treatment of operable node-positive breast cancer provided a significant 17% reduction in mortality over doxorubicin–docetaxel (P = 0.03) and a nonsignificant 14% reduction in mortality over concurrent ACT (P=0.09). The sequential-treatment schedule had a more pronounced advantage for disease-free survival.
The findings of this trial suggest that a shorter course of treatment is not as effective as a longer course. One explanation is that a higher total dose of docetaxel (400 mg per square meter vs. 240 or 300 mg per square meter) or a higher dose per cycle (100 mg per square meter vs. 60 or 75 mg per square meter) was delivered in the sequential-ACT regimen as compared with the other groups (before and after the dosage amendment, respectively). A dose–response relationship has been established between docetaxel and outcome in metastatic breast cancer across a dose range of 60 to 100 mg per square meter per treatment cycle; this supports the findings of this trial.15
However, this per-cycle dose–response effect would not explain the results of the Breast Cancer International Research Group 005 trial (ClinicalTrials.gov number, NCT00312208), which showed that six cycles of concurrent ACT (docetaxel dose per cycle, 75 mg per square meter; cumulative dose, 450 mg per square meter) was as effective as sequential ACT (docetaxel dose per cycle, 100 mg per square meter; cumulative dose, 400 mg per square meter).16
The results of the studies taken together suggest that the cumulative dose of docetaxel may be more important than the dose intensity per cycle.
A second possible explanation for the inferiority of the doxorubicin–docetaxel and concurrent-ACT regimens is the lower cumulative dose of doxorubicin at 200 mg per square meter, after the amendment, as compared with 240 mg per square meter in the sequential-ACT group. Initially, this trial was designed to compare equal cumulative doses and numbers of cycles of doxorubicin among all three treatment groups; however, because of toxicity, the dose of doxorubicin in the doxorubicin–docetaxel and concurrent-ACT groups was reduced. Although randomized trials have established a threshold dose of doxorubicin, with no dose–response effect noted above 60 mg per square meter, the Cancer and Leukemia Group B 8541 trial reported that “low” doses (30 mg per square meter) of doxorubicin, as compared with high doses (60 mg per square meter) and moderate doses (40 mg per square meter) were associated with inferior survival.17,18
The cumulative dose for the low-dose doxorubicin regimen was 120 mg per square meter versus 240 mg per square meter for the high-dose and moderate-dose regimens. Despite these findings, we found no evidence that the dose change of doxorubicin in this trial affected the outcome. Taken together, the results of these trials suggest that a longer course (sequential ACT), a higher dose of docetaxel, or both are important for maximum efficacy.
Ovarian ablation or suppression has been associated with an improved outcome in premenopausal women,2,19
and the incidence and effect of amenorrhea have been reported in studies of adjuvant treatment of breast cancer.20
A remaining question is whether ovarian suppression is needed in addition to chemotherapy. In an overview analysis, a significant reduction in both disease recurrence and death was seen with the addition of a luteinizing hormone–releasing hormone (LHRH) agonist and tamoxifen to chemotherapy in premenopausal women with ER-positive tumors.19
There was a significant reduction in disease recurrence and death among women 40 years of age or younger with the addition of an LHRH agonist to chemotherapy with or without tamoxifen. One study21
evaluated chemotherapy followed by goserelin versus either agent alone and showed a nonsignificant improvement in disease-free survival among premenopausal women with ER-positive tumors who received the combination. Prolonged amenorrhea occurred in patients who received chemotherapy and goserelin. Another study22
showed that the addition of tamoxifen to chemotherapy and goserelin improved outcomes in premenopausal women with node-positive, ER-positive breast cancer, whereas the addition of goserelin alone to chemotherapy did not. Our large prospective study with menstrual history data provides support for the added benefit of ovarian suppression induced by chemotherapy to improve outcome. However, one cannot rule out that the association of improved outcome with increased frequency of ovarian suppression might be correlative rather than cause and effect. Another possibility includes altered drug metabolism in individual patients which could lead to differences in efficacy or rates of ovarian suppression.
One of the most intriguing findings of this trial was that the outcome improved regardless of the treatment received or the ER content of the tumor in patients in whom protocol-defined amenorrhea developed. Inaccuracy of the determination of ER status by local laboratories is not an explanation. Tumor specimens from 66% of the premenopausal women in this study were provided to the central pathology laboratory. Among these cases, agreement in ER status between local and central testing was 94%. When the analysis was restricted to the use of data from central testing, the findings among pre-menopausal women were confirmed (data not shown). It has been hypothesized that the benefit of chemotherapy in premenopausal women may be due in part to ovarian suppression. Other factors associated with improved overall survival among patients with hormone-sensitive and hormone-insensitive tumors besides estrogen deprivation have been postulated, including modulation of the immune system.
The findings from this trial have clinical implications for women with early-stage, node-positive breast cancer (approximately 27% of women with breast cancer23
), regardless of their menopausal status. Taken in context with other recently reported trials, sequential-ACT therapy, as compared with four cycles of concurrent chemotherapy, is a highly effective treatment option for women with operable node-positive breast cancer.