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

Alternate Title

Sequential Versus Concurrent Doxorubicin and Cyclophosphamide as Adjuvant Therapy for Breast Cancer at High Risk of Recurrence

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	adult	NCI	SWOG-9313 CLB-9394, E-S9313, NCCTG-933051, INT-0137

Objectives

I.  Compare the disease-free survival and overall survival of high-risk 
primary breast cancer patients with no more than 3 positive axillary lymph 
nodes treated with adjuvant high-dose chemotherapy with 
doxorubicin/cyclophosphamide (AC) vs. high-dose sequential chemotherapy with 
doxorubicin followed by cyclophosphamide (A-C).

II.  Compare the toxic effects of these two treatment regimens.

Entry Criteria

Disease Characteristics:

Primary invasive adenocarcinoma of the breast considered at high risk of
recurrence, i.e.:
  Estrogen-receptor and progesterone-receptor negative and greater than 1.0 cm
  in greatest diameter
                              OR
  Greater than 2.0 cm in greatest diameter regardless of hormone receptor
  status (including unknown)
                              OR
  Tumor involves 0-3 axillary lymph nodes
     Any node greater than 0.2 cm and all nodes less than 2.0 cm in greatest
     diameter

  AJCC/WHO pathologic stage T1-3, N0-1, M0 (selected stage I/II/III) required
     Nodal status confirmed by axillary lymph node dissection and examination
     of at least 6 nodes

     No ductal or lobular carcinoma in situ with negative nodes and
     microinvasive lesions only

No evidence of disease following mastectomy or breast-sparing surgery with
axillary dissection, including:
  No evidence of distant disease on chest x-ray or contralateral mammogram
  prior to registration (within 3 months prior to surgery)

  No gross or microscopically positive surgical margins

No pure tubular, mucinous, or papillary carcinoma

No sarcoma, lymphoma, or apocrine, adenocystic, or squamous cell cancer of the
breast
  Metaplastic carcinoma eligible as a variant form of adenocarcinoma

No locally advanced disease at diagnosis, e.g.:
  No fixed tumors or nodes
  No peau d'orange skin changes
  No skin ulcerations
  No inflammatory changes (T4 disease)
  No recurrent invasive carcinoma

Bilateral breast cancer allowed provided:
  Both breasts treated with curative intent
  Eligibility based on side with most adverse prognostic factors

Registration within 84 days of surgery required

Tumor tissue blocks must be submitted within 6 months of registration

Prior/Concurrent Therapy:

No systemic therapy of any type for a previous breast cancer

Biologic therapy:
  Not specified

Chemotherapy:
  No prior chemotherapy for this breast cancer

Endocrine therapy:
  Not specified

Radiotherapy:
  No prior external-beam radiotherapy (EBRT) for this breast cancer
  Brachytherapy at time of breast-sparing procedure allowed
     EBRT planned with brachytherapy must be delayed until after chemotherapy
  Radiotherapy following chemotherapy must be planned for patients whose most
     extensive surgery was a breast-sparing procedure

Surgery:
  Prior mastectomy or breast-conserving surgery with axillary dissection
  required

Patient Characteristics:

Age:
  Adult

Sex:
  Women only

Menopausal status:
  Any status

Performance status:
  Not specified

Life expectancy:
  Adequate health for long-term follow-up required

Hematopoietic:
  WBC at least 4,000/mm3
  ANC at least 1,500/mm3
  Platelet count normal

Hepatic:
  Bilirubin no greater than 1.5 times normal

Renal:
  Creatinine no greater than 1.5 times normal

Cardiovascular:
  Left ventricular ejection fraction normal

Other:
  No serious disease other than breast cancer
  No pregnant or nursing women
  Effective contraception required of fertile women during and for 2 months
     after completion of protocol therapy

Expected Enrollment

1,500 patients will be entered on each arm.  At an anticipated accrual rate of 
800 patients/year, accrual is expected to be completed in 3.75 years.

Outline

This is a randomized study.  Patients are stratified by participating 
institution.

The first group receives adjuvant chemotherapy with doxorubicin followed 
immediately by cyclophosphamide every 3 weeks for 6 courses.

The second group receives adjuvant chemotherapy with doxorubicin every 3 weeks 
for 4 courses, then cyclophosphamide every 2 weeks for 3 courses.

Granulocyte colony-stimulating factor is given for hematologic support with 
all chemotherapy courses.

Following chemotherapy, postmenopausal patients and premenopausal patients 
with hormone-receptor-positive disease receive oral tamoxifen daily for 5 
years.

Treatment is discontinued in patients who develop locoregional or metastatic 
disease or breast cancer in the opposite breast.  Patients are followed for 
disease-free and overall survival.

Rimm DL, Barlow WE, Harigopal M, et al.: Multiplexed AQUA-based assessment of SWOG 9313 shows prognostic value of continuous ER, PR and HER2 assessment. [Abstract] 31st Annual San Antonio Breast Cancer Symposium, December 10-14, 2008, San Antonio, Texas. A-704, 2008.

Linden HM, Haskell CM, Green SJ, et al.: Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313). J Clin Oncol 25 (6): 656-61, 2007.[PUBMED Abstract]

Porter PL, Barlow WE, Yeh IT, et al.: p27(Kip1) and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy. J Natl Cancer Inst 98 (23): 1723-31, 2006.[PUBMED Abstract]

Porter PL, Barlow W, Yeh IT, et al.: Prognostic value of cell cycle regulators p27 and cyclin E: tissue microarray analysis of 1753 women enrolled in SWOG breast cancer trial 9313. [Abstract] J Clin Oncol 23 (Suppl 16): A-507, 5s, 2005.

Haskell CM, Green SJ, Sledge GW, et al.: Phase III comparison of adjuvant high-dose doxorubicin plus cyclophosphamide (AC) versus sequential doxorubicin followed by cyclophosphamide (A->C) in breast cancer patients with 0-3 positive nodes (intergroup 0137). [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-142, 2002.

Trial Contact Information

Trial Lead Organizations

Southwest Oncology Group

Robert Figlin, MD, FACP, Protocol chair(Contact information may not be current)		Ph: 310-825-5268; 888-798-0719

North Central Cancer Treatment Group

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

Cancer and Leukemia Group B

Charles Shapiro, MD, Protocol chair		Ph: 614-293-6401 Email: charles.shapiro@osumc.edu

Eastern Cooperative Oncology Group

George Sledge, MD, Protocol chair		Ph: 317-554-0000 ext. 2416; 888-878-6889

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