Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial

Abstract

Purpose: Anthracycline- and taxane-based three-drug chemotherapy regimens have proven benefit as adjuvant therapy for early-stage breast cancer. This trial (NSABP B-38; Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Positive Breast Cancer) asked whether the incorporation of a fourth drug could improve outcomes relative to two standard regimens and provided a direct comparison of those two regimens.

Patients and methods: We randomly assigned 4,894 women with node-positive early-stage breast cancer to six cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC), four cycles of dose-dense (DD) doxorubicin and cyclophosphamide followed by four cycles of DD paclitaxel (P; DD AC→P), or DD AC→P with four cycles of gemcitabine (G) added to the DD paclitaxel (DD AC→PG). Primary granulocyte colony-stimulating factor support was required; erythropoiesis-stimulating agents (ESAs) were used at the investigator's discretion.

Results: There were no significant differences in 5-year disease-free survival (DFS) between DD AC→PG and DD AC→P (80.6% v 82.2%; HR, 1.07; P = .41), between DD AC→PG and TAC (80.6% v 80.1%; HR, 0.93; P = .39), in 5-year overall survival (OS) between DD AC→PG and DD AC→P (90.8% v 89.1%; HR, 0.85; P = .13), between DD AC→PG and TAC (90.8% v 89.6%; HR, 0.86; P = .17), or between DD AC→P versus TAC for DFS (HR, 0.87; P = .07) and OS (HR, 1.01; P = .96). Grade 3 to 4 toxicities for TAC, DD AC→P, and DD AC→PG, respectively, were febrile neutropenia (9%, 3%, 3%; P < .001), sensory neuropathy (< 1%, 7%, 6%; P < .001), and diarrhea (7%, 2%, 2%; P < .001). Exploratory analyses for ESAs showed no association with DFS events (HR, 1.02; P = .95).

Conclusion: Adding G to DD AC→P did not improve outcomes. No significant differences in efficacy were identified between DD AC→P and TAC, although toxicity profiles differed.

Trial registration: ClinicalTrials.gov NCT00093795.

Fig 1.

CONSORT diagram for enrollment, random assignment, and follow-up of study participants in National Surgical Adjuvant Breast and Bowel Project B-38 trial. AC→P, doxorubicin and cyclophosphamide followed by paclitaxel; AC→PG, doxorubicin and cyclophosphamide followed by paclitaxel and gemcitabine; ER, estrogen receptor; PR, progesterone receptor; TAC, docetaxel, doxorubicin, and cyclophosphamide. (*) No follow-up available on 35 patients.

Fig 2.

Disease-free survival and overall survival in National Surgical Adjuvant Breast and Bowel Project B-38 trial. Results of Kaplan-Meier analyses for (A) disease-free survival and for (B) overall survival across all three treatment arms. AC→P, doxorubicin and cyclophosphamide followed by paclitaxel; AC→PG, doxorubicin and cyclophosphamide followed by paclitaxel and gemcitabine; HR, hazard ratio; TAC, docetaxel, doxorubicin, and cyclophosphamide.

Fig 3.

Hazard ratios (HRs) for disease-free survival in the National Surgical Adjuvant Breast and Bowel Project B-38 trial, according to stratification groups for (A) doxorubicin and cyclophosphamide followed by paclitaxel and gemcitabine (AC→PG) compared with concurrent administration of all three agents (TAC); (B) AC→PG compared with doxorubicin and cyclophosphamide followed by paclitaxel (AC→P); and (C) AC→P compared with TAC. LN, lymph node.

Fig 4.

Kaplan-Meier analyses of disease-free survival with respect to erythropoiesis-stimulating agent usage in the National Surgical Adjuvant Breast and Bowel Project B-38 trial. There was no association with risk of disease-free survival with a hazard ratio (HR) of 1.02 (95% CI, 0.90 to 1.17; P = .95) after adjusting for treatments, age, tumor size, number of positive nodes, and surgery type. EPO, epoetin alfa or darbepoetin alfa (erythropoiesis-stimulating agent). W/O, without.

Fig A1.

Kaplan-Meier estimates of disease-free survival among patients with (A) estrogen receptor (ER) –negative tumors or (B) ER-positive tumors across all three treatment arms in the National Surgical Adjuvant Breast and Bowel Project B-38 trial. AC→P, doxorubicin and cyclophosphamide followed by paclitaxel; AC→PG, doxorubicin and cyclophosphamide followed by paclitaxel and gemcitabine; HR, hazard ratio; TAC, docetaxel, doxorubicin, and cyclophosphamide.

Fig A2.

Kaplan-Meier estimates of disease-free survival among patients with (A) 1 to 3 or (B) 4+ positive lymph nodes across all three treatment arms in the National Surgical Adjuvant Breast and Bowel Project B-38 trial. AC→P, doxorubicin and cyclophosphamide followed by paclitaxel; AC→PG, doxorubicin and cyclophosphamide followed by paclitaxel and gemcitabine; HR, hazard ratio; TAC, docetaxel, doxorubicin, and cyclophosphamide.

Fig A3.

Kaplan-Meier estimates of overall survival in patients with (A) estrogen receptor (ER) –negative or (B) ER-positive tumors across all treatment arms in the National Surgical Adjuvant Breast and Bowel Project B-38 trial. AC→P, doxorubicin and cyclophosphamide followed by paclitaxel; AC→PG, doxorubicin and cyclophosphamide followed by paclitaxel and gemcitabine; HR, hazard ratio; TAC, docetaxel, doxorubicin, and cyclophosphamide.

Fig A4.

Kaplan-Meier estimates of overall survival in patients with (A) 1 to 3 or (B) 4+ positive lymph nodes across all treatment arms in the National Surgical Adjuvant Breast and Bowel Project B-38 trial. AC→P, doxorubicin and cyclophosphamide followed by paclitaxel; AC→PG, doxorubicin and cyclophosphamide followed by paclitaxel and gemcitabine; HR, hazard ratio; TAC, docetaxel, doxorubicin, and cyclophosphamide.

Fig A5.

Kaplan-Meier estimates of (A) recurrence-free interval and (B) distant recurrence-free interval across all treatment arms in the National Surgical Adjuvant Breast and Bowel Project B-38 trial. AC→P, doxorubicin and cyclophosphamide followed by paclitaxel; AC→PG, doxorubicin and cyclophosphamide followed by paclitaxel and gemcitabine; HR, hazard ratio; TAC, docetaxel, doxorubicin, and cyclophosphamide.