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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

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.