Despite improvements in disease-free and overall survival resulting from the use of adjuvant chemotherapy in patients with lymph node-positive breast cancer, a significant number of patients develop tumor recurrence and die from the disease. Therefore, there is a need to develop new treatment regimens that combine active drugs for the treatment of such patients and to test alternative schedules and agents.I am very actively involved with the NSABP and am the Protocol Chair for NSABP B30. The primary aims of this Phase III multinational trial are 1) to determine whether four cycles of post-operative doxorubicin (A), docetaxel (T), and cyclophosphamide (C) administered concurrently will more effectively prolong disease-free survival and overall survival of patients with lymph node-positive breast cancer than will 4 cycles of AC followed by 4 cycles of T, and 2) to determine whether 4 cycles of AT is at least as efficacious as the above two regimens. The rationale for the design of the study was the significant efficacy of docetaxel in patients withmetastatic breast cancer and the improved activity when used in combination with anthracyclines. The hypothesis is that concurrent combination with an active taxane is more important than the sequence or duration of therapy. The second hypothesis for the study is that cyclophosphamide is not essential for a survival benefit when used in combination with the two most active agents for breast cancer. The standard arm for this study is the AC followed by T arm because it was the experimental arm for the NSABP B27 study. The secondary aims of the study are to compare toxicities, to examine differences in amenorrhea in premenopausal women in each treatment arm and its relationship to symptoms, quality of life (QOL), disease-free survival and overall survival, and finally to compare the quality of life among patients in each of the three treatment arms.Ovarian damage is considered the most significant long-term sequela of adjuvant chemotherapy in premenopausal breast cancer survivors, and alkylating agents such as cyclophosphamide are often the cause of ovarian dysfunction. Furthermore, drug-induced amenorrhea may be a favorable prognostic factor in patients with breast cancer, although this is controversial. NSABP B-30 will compare the incidence of amenorrhea in each treatment arm of the study and will assess the association of amenorrhea with symptoms and quality of life. (Because the AT arm does not include cyclophosphamide, there may be less ovarian dysfunction with this regimen.) Documenting menstrual history in women participating in this protocol will provide a unique opportunity to assess the effect of induced menopause on disease-free and overall survival. A menstrual history study, which included a baseline and follow-up questionnaires at cycle 4, and at 6, 12, 18, and 24 months, was implemented in this trial. QOL assessments are an attempt to measure and scientifically analyze the impact of a disease and its treatment on patients' perception of their well-being. Studies have shown that, at the end of primary treatment for breast cancer, women report decreased physical functioning after chemotherapy. QOL will be assessed in NSABP B-30 by Functional Assessment of Cancer Therapy - Breast (FACT-B), Treatment-Specific Symptom Checklist, Vitality Scale (SF -36) and Quality of Life Rating Scale at the same time points as those for the menstrual history study. QOL assessment can be helpful in weighing the risk and benefits of treatment options, particularly when differences in disease-free and overall survival among the treatment options are small. The NSABP B-30 study began accrual in March 1999 and completed accrual of 5351 patients in March 2004. The expected reporting of the results is in 2007. The follow-up study is NSABP B-38 for which I am the Protocol Chair.NSABP B-38 is the follow-up adjuvant trial to NSABP B-30 for patients with lymph node-positive breast cancer. This Phase III adjuvant therapy trial will compare three regimens of chemotherapy: TAC (docetaxel, doxorubicin, and cyclophosphamide) every 3 weeks for 6 cycles, dose dense AC followed by P (paclitaxel) every 2 weeks for 4 cycles followed by paclitaxel every 2 weeks for 4 cycles, or dose dense AC followed by PG (paclitaxel and gemcitabine) every 2 weeks for 4 cycles. The hypothesis is that a dose dense regimen with the addition of another active agent (i.e., gemcitabine) in breast cancer will be superior in disease-free survival to a standard dose dense regimen and a standard docetaxel-containing regimen.The primary aims of the study are 1) to determine whether the dose dense AC followed by PG regimen is superior to the TAC regimen and to the dose dense AC followed by P regimen in improving disease-free survival, and 2) to compare the relative disease-free survival among patients in the TAC and dose dense AC followed by P arms. Secondary aims are to determine whether dose dense AC followed by PG is superior to TAC and to dose dense AC followed by P in improving survival, to compare survival among patients in the TAC and dose dense AC followed by P regimens, and to compare the toxicities of the three regimens.The rationale for this study is the high interest among breast cancer community clinicians in determining whether dose dense therapy with paclitaxel is more effective than a combination therapy with a different yet related taxane, docetaxel. Results for the second interim analysis at 55 months for Breast Cancer International Research Group (BCIRG) 001 study have recently been reported with 399 events, revealing a significant increase in disease-free survival for patients in the TAC arm compared with patients in the FAC arm in 1,491 patients with lymph node-positive disease. There was an increase in 5-year disease-free survival of 28% and overall survival of 30% with the use of TAC. The 5-year disease-free survival with TAC versus FAC was 75% versus 68%, respectively, and overall survival was 87% versus 81%, respectively.The Norton-Simon hypothesis suggests that the smallest tumor size or best response is accomplished if the entire therapy is given over a short time period. The concept of "dose dense" therapy, which is based on this hypothesis, was tested prospectively in a phase III trial (CALGB 9741) in which the same doses were given over a 2 versus 3-week period of time. Citron et al. reported the results in 1973 women with lymph node-positive breast cancer designed to test two hypotheses with a 2 X 2 factorial design. The first hypothesis was to determine whether 2 weeks of AC followed by P was more effective than 3 weeks of the same therapy, and the second hypothesis was to evaluate sequential versus concurrent therapy. The results indicated a 26% increase in disease-free survival with the use of dose dense (i.e., 2 week) AC followed by P, a 31% improvement in survival with dose dense therapy compared with every 3 weeks, but no difference in sequential versus concurrent therapy. This corresponded to an absolute increase in disease-free survival at 3 years from 81% to 85% and survival from 90% to 92% with the dose dense regimen. The rationale for the third arm of the NSAPB B-38 study to include gemcitabine is the recent data showing increased efficacy and improved survival with the combination of gemcitabine and paclitaxel compared with paclitaxel alone in the metastatic disease setting and the ability to administer the drugs every 2 weeks with minimal toxicity. Results for the second interim analysis at 55 months for Breast Cancer International Research Group (BCIRG) 001 study have recently been reported with 399 events, revealing a significant increase in disease-free survival for patients in the TAC arm compared with patients in the FAC arm in 1,491 patients with lymph node-positive disease. There was an increase in 5-year disease-free survival of 28% and overall survival of 30% with the use of TAC.
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