Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy in Treating Patients With Breast Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	18 and over	NCI	CLB-9741 E-C9741, NCCTG-C9741, SWOG-C9741, NCT00003088, C9741

Objectives

I.   Compare the sequential chemotherapy with doxorubicin, paclitaxel and 
cyclophosphamide to combined doxorubicin and cyclophosphamide followed by 
paclitaxel for disease free and overall survival in women with node positive 
stage II or IIIA breast cancer.

II.  Determine whether increasing the dose density of adjuvant chemotherapy 
will improve disease free and overall survival.

III. Compare the toxicity in patients treated with these regimens.

Entry Criteria

Disease Characteristics:

Histologically diagnosed operable, stage II or IIIA adenocarcinoma of the
breast

One or more positive lymph nodes (T0-3, N1-2, and M0)

Metaplastic carcinoma allowed

Bilateral breast cancer allowed

No metastatic disease

Not locally advanced and no tumors fixed to the chest wall, peau d'orange skin
changes, skin ulcerations, or clinical inflammatory changes

Hormone receptor status:
 Not specified

Prior/Concurrent Therapy:

Biologic therapy:
 Not specified

Chemotherapy:
 No prior chemotherapy

Endocrine therapy:
 No greater than 4 weeks of prior tamoxifen therapy for malignancy
 No concurrent tamoxifen therapy

Radiotherapy:
 No prior radiation therapy for this malignancy

Surgery:
 No greater than 84 days since prior mastectomy or axillary dissection

Patient Characteristics:

Age:
 18 and over

Sex:
 Female

Menopausal status:
 Not specified

Performance status:
 Not specified

Life expectancy:
 Not specified

Hematopoietic:
 Granulocyte count at least 1000/mm3
 Platelet count at least 100,000/mm3

Hepatic:
 Bilirubin within upper limits of normal

Renal:
 Not specified

Cardiovascular:
 No uncontrolled or severe cardiovascular disease
 No myocardial infarction within 6 months
 No congestive heart failure

Other:
 No other serious medical illness
 No psychoses
 No active uncontrolled bacterial, viral, or fungal infection
 HIV negative
 Not pregnant

Expected Enrollment

A total of 2,000 patients will be accrued for this study within 22 months.

Outline

This is a randomized study.  Patients are randomized into one of four arms 
(sequential chemotherapy every 2 weeks vs every 3 weeks vs concurrent 
chemotherapy followed by paclitaxel every 2 weeks vs every 3 weeks).

All tumor should be removed by either a modified radical mastectomy or a 
segmental mastectomy plus axillary node dissection.

Adjuvant chemotherapy is started within 84 days following the last surgical 
procedure.

Arm I: Patients receive sequential chemotherapy every 3 weeks.  Doxorubicin IV 
is administered once every 3 weeks for 4 doses.  Paclitaxel IV is then 
administered over 3 hours once every 3 weeks for 4 doses.  Cyclophosphamide IV 
is administered once every 3 weeks for 4 doses following paclitaxel.

Arm II: Patients receive sequential chemotherapy every 2 weeks.  Doxorubicin 
IV is administered once every 2 weeks for 4 doses.  Paclitaxel IV is then 
administered over 3 hours once every 2 weeks for 4 doses.  Cyclophosphamide IV 
is administered once every 2 weeks for 4 doses following paclitaxel.  
Filgrastim (G-CSF) is administered by subcutaneous injection on days 3-10 
after each dose of doxorubicin, paclitaxel, and cyclophosphamide.

Arm III: Patients receive combination chemotherapy every 3 weeks.  Combination 
doxorubicin IV and cyclophosphamide IV is administered once every 3 weeks for 
4 doses.  Paclitaxel IV is administered over 3 hours once every 3 weeks for 4 
doses following combination chemotherapy.

Arm IV: Patients receive combination chemotherapy every 2 weeks.  Combination 
doxorubicin IV and cyclophosphamide IV is administered once every 2 weeks for 
4 doses.  Paclitaxel IV is administered over 3 hours once every 2 weeks for 4 
doses following combination chemotherapy.  G-CSF is administered by 
subcutaneous injection on days 3-10 after each dose of 
doxorubicin/cyclophophamide and after each dose of paclitaxel.

After completion of all chemotherapy, patients receive tamoxifen orally for 5 
years.

Patients undergo radiotherapy 4-6 weeks after the completion of chemotherapy.

Patients are followed every 6 months for 5 years, then annually until death.

Citron ML, Berry DA, Cirrincione C, et al.: Dose-dense (DD) AC followed by paclitaxel is associated with moderate, frequent anemia compared to sequential (S) and/or less DD treatment: update by CALGB on Breast Cancer Intergroup Trial C9741 with ECOG, SWOG, & NCCTG. [Abstract] J Clin Oncol 23 (Suppl 16): A-620, 33s, 2005.

Fornier M, Norton L: Dose-dense adjuvant chemotherapy for primary breast cancer. Breast Cancer Res 7 (2): 64-9, 2005.[PUBMED Abstract]

Hudis C, Citron M, Berry D, et al.: Five year follow-up of INT C9741: dose-dense (DD) chemotherapy (CRx) is safe and effective. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-41, 2005.

Schwartz J, Domchek SM, Hwang WT, et al.: Evaluation of anemia, neutropenia and skin toxicities in standard or dose-dense doxorubicin/cyclophosphamide (AC)-paclitaxel or docetaxel adjuvant chemotherapy in breast cancer. Ann Oncol 16 (2): 247-52, 2005.[PUBMED Abstract]

Citron ML, Berry DA, Cirrincione C, et al.: 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. J Clin Oncol 21 (8): 1431-9, 2003.[PUBMED Abstract]

Citron M, Berry D, Cirrincione C, et al.: Superiority of dose-dense (DD) over conventional scheduling (CS) and equivalence of sequential (SC) vs. combination adjuvant chemotherapy (CC) for node-positive breast cancer (CALGB 9741, INT C9741). [Abstract] Breast Cancer Res Treat 76 (Suppl 1): A-15, 2002.

Muss HB, Berry DA, Cirrincione C, et al.: Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: the Cancer and Leukemia Group B Experience. J Clin Oncol 25 (24): 3699-704, 2007.[PUBMED Abstract]

Berry DA, Cirrincione C, Henderson IC, et al.: Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295 (14): 1658-67, 2006.[PUBMED Abstract]

Muss H, Berry D, Cirrincione C, et al.: Toxicity of older and younger patients (pts) treated (Rx) with intensive adjuvant chemotherapy (Cx) for node-positive (N+) breast cancer (BC): the CALGB experience. [Abstract] J Clin Oncol 24 (Suppl 18): A-559, 2006.

Campone M, Fumoleau P, Bourbouloux E, et al.: Taxanes in adjuvant breast cancer setting: which standard in Europe? Crit Rev Oncol Hematol 55 (3): 167-75, 2005.[PUBMED Abstract]

Orzano JA, Swain SM: Concepts and clinical trials of dose-dense chemotherapy for breast cancer . Clin Breast Cancer 6 (5): 402-11, 2005.[PUBMED Abstract]

Berry DA, Cirrincione C, Henderson IC, et al.: Effects of improvements in chemotherapy on disease-free and overall survival of estrogen-receptor negative, node-positive breast cancer: 20-year experience of the CALGB U.S. Breast Intergroup. [Abstract] Breast Cancer Res Treat 88 (Suppl 1): A-29, 2004.

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Marc Citron, MD, Protocol chair		Ph: 516-622-6150

North Central Cancer Treatment Group

James Ingle, MD, Protocol chair		Ph: 507-284-3731 Email: ingle.james@mayo.edu

Eastern Cooperative Oncology Group

Nancy Davidson, MD, Protocol chair		Ph: 410-955-8489

Southwest Oncology Group

Silvana Martino, DO, Protocol chair(Contact information may not be current)		Ph: 818-787-9911

Registry Information
Official Title		A Randomized Phase III Trial of Sequential Chemotherapy Using Doxorubicin, Paclitaxel, and Cyclophosphamide or Concurrent Doxorubicin and Cyclophosphamide Followed by Paclitaxel at 14 or 21 Day Intervals in Women with Node Positive Stage II/IIIA Breast Cancer
Trial Start Date		1997-09-15
Registered in ClinicalTrials.gov		NCT00003088
Date Submitted to PDQ		1997-09-12
Information Last Verified		2007-09-24
NCI Grant/Contract Number		U10-CA31946