NSABP B-38 Trial Shows No Benefit of Adding Fourth Drug to Standard Adjuvant Treatment in Women With Node-Positive Breast Cancer
Anthracycline- and taxane-based three-drug chemotherapy regimens have proven benefit as adjuvant therapy for early-stage breast cancer. As reported in Journal of Clinical Oncology by Sandra M. Swain, MD, FACP, of Washington Cancer Institute–MedStar Washington Hospital Center, and colleagues, the NSABP B-38 trial assessed whether the addition of a fourth drug to standard adjuvant therapy could improve outcomes compared with two standard regimens in women with early-stage node-positive breast cancer. The study found no significant differences in disease-free survival among the three regimens, although toxicity profiles differed.
Study Details
In NASBP B-38, 4,894 women with node-positive early-stage breast cancer were randomly assigned to receive six cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC; n = 1,630); four cycles of dose-dense doxorubicin and cyclophosphamide followed by four cycles of dose-dense paclitaxel (AC→P; n = 1,634); or dose-dense AC→P with four cycles of gemcitabine added to the dose-dense paclitaxel (AC→PG; n = 1,630). Patients were stratified according to number of positive lymph nodes, hormone receptor status, and type of surgery and planned radiotherapy. Primary granulocyte colony-stimulating factor support was required and erythropoiesis-stimulating agents were used at investigator discretion. The primary endpoint was disease-free survival.
Patients in each group had a median age of 54 years, and there were no differences among groups with regard to age distribution, menopausal status, number of positive nodes, hormone receptor status, pathologic tumor size, type of surgery, or type of radiation therapy.
The majority of patients completed protocol-specified chemotherapy (91% of patients in the TAC group, 88% in the AC→P group, and 88% in the AC→PG group). Treatment was discontinued due to adverse reactions in 4%, 9%, and 6% of patients, respectively. A total of 208 patients received trastuzumab (Herceptin), including 58 in the TAC group, 70 in the AC→P group, and 80 in the AC→PG group.
Disease-Free Survival Outcomes
After a median follow-up of 64 months, 5-year disease-free survival was 80.6% for AC→PG vs 82.2% for AC→P (hazard ratio [HR] = 1.07, P = .41) and vs 80.1% for TAC (HR = 0.93, P = .39). The hazard ratio for AC→P vs TAC was 0.87 (P = .07). No significant treatment interactions were observed for any stratification subgroup tested. There was a suggestion that AC→P might be better than TAC in patients with estrogen receptor (ER)-negative tumors (P = .09) and those with one to three positive nodes (P = .08). Exploratory analyses for erythropoiesis-stimulating agents showed no association with disease-free survival events (HR = 1.02, P = .95).
Overall Survival Outcomes
The 5-year overall survival was 90.8% for AC→PG vs 89.1% for AC→P (HR = 0.85, P = .13) and vs 89.6% for TAC (HR = 0.86, P = .17). The hazard ratio for AC→P vs TAC was 1.01 (P = .96). There were no differences in the three arms in any ER or nodal subset. Five-year recurrence-free intervals and distant recurrence-free intervals ranged from 85% to 87%, with no differences among the three arms.
Multiple Cox proportional hazards models adjusting for age at entry, number of positive nodes, ER status, and radiation therapy and type of surgery did not show significant differences in disease-free survival or overall survival among the three treatment groups. Overall, women with one to three positive nodes, ER-positive tumors, and smaller tumors and those who had received radiotherapy had significantly less risk of disease-free survival events or all-cause mortality. Among patients who received radiotherapy, there was no difference in the risk of disease-free survival events or death between those with regional radiotherapy and those without regional radiotherapy regardless of surgery type.
Toxicities
Grade 3 or 4 toxicities for TAC, AC→P, and AC→PG included febrile neutropenia (9%, 3%, 3%; P < .001), sensory neuropathy (< 1%, 7%, 6%; P < .001), diarrhea (7%, 2%, 2%; P < .001), anemia (< 1%, 2%, 2%; P < .001), and arthralgia/myalgia (4%, 11%, 12%; P < .001).
Erythropoiesis-stimulating agent use occurred in 35%, 47%, and 51% of patients, respectively, (P < .001) and 3.7%, 6.3%, and 9.3%, respectively, received transfusions (P < .001). Hospitalization occurred more frequently in the TAC group (7.2%, 4.9%, 5.5%; P < .001). Growth factor support was used in 98% of patients receiving TAC at each cycle and 98% of patients in the other two groups at each cycle up to cycle 6, and then in 94% and 97% at cycle 7 and 87% and 93% at cycle 8 for the AC→P and AC→PG groups, respectively.
Death on treatment occurred in 13 TAC patients, 5 AC→P patients, and 7 AC→PG patients (P = .2). Acute myeloid leukemia or myelodysplastic syndrome occurred in 5, 8, and 11 patients, respectively (P = .46).
The investigators concluded: “Adding G to dose-dense AC→P did not improve outcomes. No significant differences in efficacy were identified between dose-dense AC→P and TAC…. [H]owever, toxicity profiles differed with greater incidences of febrile neutropenia and diarrhea with TAC and greater incidences of neuropathy, anemia, transfusions, and [erythropoiesis-stimulating agent] use with dose-dense AC→P and AC→PG.”
The study was supported by the National Cancer Institute, and Eli Lilly and Amgen provided funding and/or drugs for the trial.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
