Journal Article
. 2012 Jul;30(33).
doi: 10.1200/JCO.2011.40.6405.

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

Lawrence N Shulman 1 Constance T Cirrincione  Donald A Berry  Heather P Becker  Edith A Perez  Ruth O'Regan  Silvana Martino  James N Atkins  Erica Mayer  Charles J Schneider  Gretchen Kimmick  Larry Norton  Hyman Muss  Eric P Winer  Clifford Hudis  
Affiliations
  • PMID: 22826271
  •     13 References
  •     30 citations

Abstract

Purpose: The ideal duration of adjuvant chemotherapy for patients with lower risk primary breast cancer is not known. Cancer and Leukemia Group B trial 40101 was conducted using a phase III factorial design to define whether six cycles of a chemotherapy regimen are superior to four cycles. We also sought to determine whether paclitaxel (T) is as efficacious as doxorubicin/cyclophosphamide (AC), but with reduced toxicity.

Patients And Methods: Between 2002 and 2008, the study enrolled women with operable breast cancer and zero to three positive nodes. Patients were randomly assigned to either four or six cycles of either AC or T. Study stratifiers were estrogen receptor/progesterone receptor (ER/PgR), human epidermal growth factor receptor 2 (HER2), and menopausal status. After 2003, all treatment was administered in dose-dense fashion. The primary efficacy end point was relapse-free survival (RFS).

Results: A total of 3,171 patients were enrolled; 94% were node-negative and 6% had one to three positive nodes. At a median follow-up of 5.3 years, the 4-year RFS was 90.9% and 91.8% for six and four cycles, respectively. The adjusted hazard ratio (HR) of six to four cycles regarding RFS was 1.03 (95% CI, 0.84 to 1.28; P=.77). The 4-year OS was 95.3% and 96.3% for six and four cycles, respectively, with an HR of six to four cycles of 1.12 (95% CI, 0.84 to 1.49; P=.44). There was no interaction between treatment duration and chemotherapy regimen, ER/PgR, or HER2 status on RFS or OS.

Conclusion: For women with resected primary breast cancer and zero to three positive nodes, we found no evidence that extending chemotherapy regimens of AC or single-agent T from four to six cycles improves clinical outcome.

Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study.
P Therasse, L Mauriac, +8 authors, EORTC.
J Clin Oncol, 2003 Mar 01; 21(5). PMID: 12610183
Review.
Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer.
I Craig Henderson, Donald A Berry, +16 authors, Larry Norton.
J Clin Oncol, 2003 Mar 15; 21(6). PMID: 12637460
Highly Cited.
Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741.
Marc L Citron, Donald A Berry, +18 authors, Larry Norton.
J Clin Oncol, 2003 Apr 02; 21(8). PMID: 12668651
Highly Cited.
Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15.
B Fisher, A M Brown, +7 authors, C G Kardinal.
J Clin Oncol, 1990 Sep 01; 8(9). PMID: 2202791
Highly Cited.
HER2 and responsiveness of breast cancer to adjuvant chemotherapy.
Kathleen I Pritchard, Lois E Shepherd, +5 authors, National Cancer Institute of Canada Clinical Trials Group.
N Engl J Med, 2006 May 19; 354(20). PMID: 16707747
Highly Cited.
Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system.
Clifford A Hudis, William E Barlow, +8 authors, Jo Anne Zujewski.
J Clin Oncol, 2007 May 22; 25(15). PMID: 17513820
Highly Cited.
Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102.
Laura F Hutchins, Stephanie J Green, +7 authors, C Kent Osborne.
J Clin Oncol, 2005 Nov 19; 23(33). PMID: 16293862
Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735.
Stephen Jones, Frankie Ann Holmes, +17 authors, Michael A Savin.
J Clin Oncol, 2009 Feb 11; 27(8). PMID: 19204201
Highly Cited.
Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer.
Sandra M Swain, Jong-Hyeon Jeong, +14 authors, Norman Wolmark.
N Engl J Med, 2010 Jun 04; 362(22). PMID: 20519679    Free PMC article.
Adjuvant docetaxel for high-risk, node-negative breast cancer.
Miguel Martín, Miguel A Seguí, +29 authors, GEICAM 9805 Investigators.
N Engl J Med, 2010 Dec 03; 363(23). PMID: 21121833
Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group.
M N Levine, V H Bramwell, +15 authors, D Tu.
J Clin Oncol, 1998 Aug 15; 16(8). PMID: 9704715
Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28.
Eleftherios P Mamounas, John Bryant, +7 authors, Norman Wolmark.
J Clin Oncol, 2005 May 18; 23(16). PMID: 15897552
Highly Cited.
Concurrent doxorubicin plus docetaxel is not more effective than concurrent doxorubicin plus cyclophosphamide in operable breast cancer with 0 to 3 positive axillary nodes: North American Breast Cancer Intergroup Trial E 2197.
Lori J Goldstein, Anne O'Neill, +4 authors, Nancy E Davidson.
J Clin Oncol, 2008 Aug 06; 26(25). PMID: 18678836    Free PMC article.
A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101.
R Michael Baldwin, Kouros Owzar, +16 authors, Deanna L Kroetz.
Clin Cancer Res, 2012 Jul 31; 18(18). PMID: 22843789    Free PMC article.
Breast cancer: Fewer therapy cycles is better.
Lisa Hutchinson.
Nat Rev Clin Oncol, 2012 Aug 08; 9(9). PMID: 22869331
Integration of cell line and clinical trial genome-wide analyses supports a polygenic architecture of Paclitaxel-induced sensory peripheral neuropathy.
Heather E Wheeler, Eric R Gamazon, +18 authors, Mary Eileen Dolan.
Clin Cancer Res, 2012 Dec 04; 19(2). PMID: 23204130    Free PMC article.
Drug rechallenge and treatment beyond progression--implications for drug resistance.
Elizabeth A Kuczynski, Daniel J Sargent, Axel Grothey, Robert S Kerbel.
Nat Rev Clin Oncol, 2013 Sep 04; 10(10). PMID: 23999218    Free PMC article.
Review.
The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration: Prospective Combined Analysis of Phase III Trials Investigating Duration of Adjuvant Therapy with the FOLFOX (FOLFOX4 or Modified FOLFOX6) or XELOX (3 versus 6 months) Regimen for Patients with Stage III Colon Cancer: Trial Design and Current Status.
Thierry André, Timothy Iveson, +11 authors, for the IDEA Steering Committee.
Curr Colorectal Cancer Rep, 2013 Sep 14; 9. PMID: 24032000    Free PMC article.
Review.
Optimal duration of fluorouracil-based adjuvant chemotherapy for patients with resectable gastric cancer.
Jing-lei Qu, Xin Li, +8 authors, Yun-peng Liu.
PLoS One, 2014 Jan 05; 8(12). PMID: 24386161    Free PMC article.
Breast cancer follow-up strategies in randomized phase III adjuvant clinical trials: a systematic review.
Isabella Sperduti, Patrizia Vici, +6 authors, Clara Natoli.
J Exp Clin Cancer Res, 2014 Jan 21; 32. PMID: 24438135    Free PMC article.
Systematic Review.
Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).
A Chhibber, J Mefford, +16 authors, D L Kroetz.
Pharmacogenomics J, 2014 Feb 12; 14(4). PMID: 24513692    Free PMC article.
Two cases of mastectomy after Paclitaxel + bevacizumab therapy for locally advanced breast cancer.
Chika Shinoda, Ryutaro Mori, Yasuko Nagao.
Case Rep Oncol, 2014 Jun 17; 7(2). PMID: 24932175    Free PMC article.
Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance).
Lawrence N Shulman, Donald A Berry, +12 authors, Eric P Winer.
J Clin Oncol, 2014 Jun 18; 32(22). PMID: 24934787    Free PMC article.
How transferable are recommendations of the era of treating conventionally defined breast cancer for the era of molecularly characterised breast cancer?
Robert Königsberg, Christian Dittrich.
Gland Surg, 2012 Nov 01; 1(3). PMID: 25083440    Free PMC article.
Adjuvant chemotherapy in breast cancer: To use or not to use, the anthracyclines.
Jennifer A Crozier, Abhisek Swaika, Alvaro Moreno-Aspitia.
World J Clin Oncol, 2014 Aug 13; 5(3). PMID: 25114866    Free PMC article.
Review.
Chemotherapy in early breast cancer: when, how and which one?
Marcus Schmidt.
Breast Care (Basel), 2014 Sep 02; 9(3). PMID: 25177256    Free PMC article.
Review.
Update on adjuvant chemotherapy for early breast cancer.
Murtuza M Rampurwala, Gabrielle B Rocque, Mark E Burkard.
Breast Cancer (Auckl), 2014 Oct 23; 8. PMID: 25336961    Free PMC article.
Review.
SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer.
George T Budd, William E Barlow, +17 authors, Gabriel N Hortobagyi.
J Clin Oncol, 2014 Nov 26; 33(1). PMID: 25422488    Free PMC article.
Adjuvant chemotherapy for early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.
S Gandhi, G G Fletcher, +4 authors, M E Trudeau.
Curr Oncol, 2015 Apr 08; 22(Suppl 1). PMID: 25848343    Free PMC article.
Review.
Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015.
A S Coates, E P Winer, +6 authors, Panel Members.
Ann Oncol, 2015 May 06; 26(8). PMID: 25939896    Free PMC article.
Highly Cited.
Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances CoCl2 -induced doxorubicin resistance in breast cancer cells.
Zheqi Li, Qi Zhu, +3 authors, Dawei Li.
Cancer Sci, 2015 Jun 17; 106(8). PMID: 26079208    Free PMC article.
The Globalization of Cooperative Groups.
Manuel Valdivieso, Benjamin W Corn, +8 authors, Charles D Blanke.
Semin Oncol, 2015 Oct 05; 42(5). PMID: 26433551    Free PMC article.
Review.
Evaluation of the Survival Benefit of Different Chemotherapy Regimens in Patients with T1-2N0 Triple-Negative Breast Cancer.
Hyun-Ah Kim, Min-Ki Seong, +6 authors, Korea Breast Cancer Society.
J Breast Cancer, 2015 Oct 17; 18(3). PMID: 26472978    Free PMC article.
Comparison of toxicity profile and tolerability between two standard of care paclitaxel-based adjuvant chemotherapy regimens in breast cancer.
Mohamed Alsharedi, Todd Gress, +2 authors, Maria Tria Tirona.
Med Oncol, 2016 Feb 18; 33(3). PMID: 26883934
Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy.
Daniel L Hertz, Kouros Owzar, +29 authors, Howard L McLeod.
Clin Cancer Res, 2016 May 05; 22(19). PMID: 27143689    Free PMC article.
High Risk Stage 2 and Stage 3 Colon Cancer, Predictors of Recurrence and Effect of Adjuvant Therapy in a Nonselected Population.
Elmer E van Eeghen, Sandra D Bakker, Aart van Bochove, Ruud J L F Loffeld.
Int Sch Res Notices, 2015 Jan 01; 2015. PMID: 27347548    Free PMC article.
Accrual of Older Patients With Breast Cancer to Alliance Systemic Therapy Trials Over Time: Protocol A151527.
Rachel A Freedman, Jared C Foster, +13 authors, Arti Hurria.
J Clin Oncol, 2016 Dec 20; 35(4). PMID: 27992272    Free PMC article.
Highlights from the 15th St Gallen International Breast Cancer Conference 15-18 March, 2017, Vienna: tailored treatments for patients with early breast cancer.
Consuelo Morigi.
Ecancermedicalscience, 2017 May 12; 11. PMID: 28491135    Free PMC article.
A search for the "Goldilocks zone" with regard to the optimal duration of adjuvant temozolomide in patients with glioblastoma.
Stuart A Grossman, Lawrence Kleinberg.
Neuro Oncol, 2017 Sep 01; 19(8). PMID: 28854621    Free PMC article.
Adjuvant Anthracyclines in Breast Cancer: What Is Their Role?
Ami N Shah, William J Gradishar.
Oncologist, 2018 Aug 19; 23(10). PMID: 30120159    Free PMC article.
Review.
Taxanes for adjuvant treatment of early breast cancer.
Melina L Willson, Lucinda Burke, +3 authors, Nicholas Wilcken.
Cochrane Database Syst Rev, 2019 Sep 03; 9. PMID: 31476253    Free PMC article.
Systematic Review.
Age and the Risk of Paclitaxel-Induced Neuropathy in Women with Early-Stage Breast Cancer (Alliance A151411): Results from 1,881 Patients from Cancer and Leukemia Group B (CALGB) 40101.
Myra Barginear, Amylou C Dueck, +14 authors, Aminah Jatoi.
Oncologist, 2018 Nov 10; 24(5). PMID: 30409792    Free PMC article.
Older-Patient-Specific Cancer Trials: A Pooled Analysis of 2,277 Patients (A151715).
Dyda Dao, Tyler Zemla, +13 authors, Jennifer G Le-Rademacher.
Oncologist, 2019 Apr 13; 24(6). PMID: 30975921    Free PMC article.