No Advantage to Longer Adjuvant Chemotherapy in Women with Early Breast Cancer: CALGB 40101 Trial

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Patients can be spared longer and more toxic treatment with these [adjuvant] regimens without fear of compromising breast cancer outcome.

The ideal duration of adjuvant therapy for women with lower-risk primary breast cancer remains unknown. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-15 trial, reported more than 20 years ago, found no difference in outcomes between six cycles of cyclophosphamide, methotrexate, and fluorouracil and four cycles of doxorubicin plus cyclophosphamide (AC)—although some believed that the AC arm might have fared better had they received six cycles of AC. Since then, several trials of adjuvant therapy have compared four cycles vs four cycles and six cycles vs six cycles of various regimens, but until recently, none has compared four vs six cycles of identical regimens using the same dose per cycle and schedule of treatment.

The Cancer and Leukemia Group B (CALGB) 40101 trial compared four and six cycles of AC or single-agent paclitaxel in early breast cancer and found no difference in 4-year relapse-free survival or overall survival between four-cycle and six-cycle regimens. The study was a 2×2 factorial design trial that also examined the effects of AC vs single-agent paclitaxel. The results from the four- vs six-cycle comparison were reported by Shulman and colleagues in a recent Journal of Clinical Oncology article.1

Study Details

CALGB 40101 enrolled 3,171 women with operable primary breast cancer and zero to three positive nodes between 2002 and 2008. Patients were randomly assigned to receive four cycles of AC (n = 1,142; 1,002 in 2-week and 140 in 3-week cycles), six cycles of AC (n = 789; 645 in 2-week and 144 in 3-week cycles), four cycles of paclitaxel (n = 1,151; 1,005 in 2-week and 146 in 3-week cycles), or six cycles of paclitaxel (n = 789; 648 in 2-week and 141 in 3-week cycles).

A year after the start of enrollment, study regimens were changed from 3-week to 2-week cycles based on the finding of superiority of dose-dense regimens in another major trial (CALGB 9741). AC was given as doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 once every 2 or 3 weeks, and paclitaxel was given at 80 mg/m2 when given weekly (with three weekly doses constituting a 3-week cycle) and at 175 mg/m2 when given every 2 weeks.

Initially, only women with node-negative disease were enrolled; patients with one to three positive axillary nodes were permitted to enter the study as of 2005. After 2005, when trastuzumab was recommended for treatment of patients with HER2-positive disease, patients randomly assigned to AC could receive trastuzumab after completing AC treatment and women assigned to paclitaxel could receive trastuzumab concurrently with or after completing paclitaxel treatment.

The 1,593 patients receiving four cycles of therapy (either AC or paclitaxel) were evenly matched with the 1,578 patients receiving six cycles for proportions of patients who were aged 50 years or older (59% vs 59%), nonwhite (16% vs 15%), premenopausal (44% vs 44%), and node-negative (94% vs 93%) and who had tumor size ≤ 2 cm (66% vs 62%), estrogen receptor (ER)-positive tumors (65% vs 64%), HER2-negative tumors (77% vs 77%), and high-grade tumors (47% vs 48%).

No Difference in Survival

The primary endpoint of the trial was relapse-free survival. The median follow-up for surviving patents was 5.3 years, with a maximum of 8.9 years. Four-year relapse-free survival rates were 90.9% in the six-cycle arms and 91.8% in the four-cycle arms, and 4-year overall survival rates were 95.3% and 96.3%, respectively.

Multivariate proportional hazards modeling showed that six cycles of treatment was not superior to four cycles for either relapse-free or overall survival after adjustment for tumor size, number of positive nodes, hormone receptor status, and menopausal status. The adjusted hazard ratios (worse:better) for six vs four cycles were 1.03 (95% CI = 0.84–1.28, P = .77) for relapse-free survival and 1.12 (95% CI = 0.84–1.49, P = .44) for overall survival.

Unplanned subset analyses showed no interaction between the number of cycles of therapy and tumor ER or HER2 status, suggesting that no subgroup benefited from more prolonged therapy. At the time of reporting, the Data and Safety Monitoring Board had not released results for the comparison of AC vs paclitaxel. However, investigators were informed that there was no interaction between number of treatment cycles and chemotherapy regimen with regard to outcome.

Greater Toxicity with Six Cycles

Hematologic toxicities were more common with AC and were somewhat more common in patients receiving six cycles of AC compared with four cycles. Grade 3 and 4 neutropenia occurred in 11% and 23%, respectively, of patients receiving six cycles of AC and in 9% and 17%, respectively, of those receiving four cycles. Other grade 3 and 4 hematologic toxicities in the group receiving six AC cycles included anemia (6% and < 1%, respectively), and thrombocytopenia (3% and 1%).

Neuropathy was more common in the paclitaxel arms. Grade 3 sensory neuropathy occurred in 4% of patients receiving four cycles of paclitaxel and 10% of patients receiving six cycles. Grade 3 and 4 motor neuropathy occurred in 2% and < 1%, respectively, of patients receiving four cycles and 3% and < 1%, respectively, of patients receiving six cycles.

Cardiac toxicity was infrequent but more common with six cycles of AC treatment; grade 3, 4, and 5 left-ventricular systolic dysfunction occurred in 18%, 5%, and 1%, respectively, of patients receiving six cycles of AC and in 5%, 0%, and 0%, respectively, of patients receiving four cycles. Acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) occurred in six patients in total, consisting of five patients receiving six cycles of AC and one patient receiving four cycles of AC.

Death occurred in 100 patients receiving six cycles of therapy, in 60 as a result of breast cancer–related causes, and in 91 patients receiving four cycles of therapy, in 55 due to breast cancer–related causes. There were seven treatment-related deaths, all occurring in the AC study arms; five were due to AML/MDS and two to cardiac causes.


As summarized by the investigators, “Our study demonstrates … that for women with relatively low-risk primary breast cancer, there is no evidence that extending chemotherapy of AC or single-agent paclitaxel regimens from four to six cycles improves clinical outcome. It should be noted that the 2×2 factorial design of this study combines the AC and paclitaxel groups in the four vs six analysis and, though there was no interaction with type of therapy, single-agent paclitaxel should not be considered a standard regimen for these patients, pending the results of the AC vs paclitaxel comparison…. It should also be noted that more than 90% of these patients had node-negative disease and 77% had HER2-negative disease. Taking these issues in context, patients can be spared longer and more toxic treatment with these regimens without fear of compromising breast cancer outcome.” ■

Disclosure: Among the JCO study authors, Dr. Donald A. Berry reported employment or a leadership position with Berry Consultants, and Dr. Eric P. Winer reported research funding from Genentech. All other coauthors reported no potential conflicts of interest.


1. Shulman LN, Cirrincione CT, Berry DA, et al: Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. July 23, 2012 (early release online).