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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	postmenopausal	NCI	SWOG-8814 CAN-NCIC-MA9, CLB-9194, EST-4188, NCCTG-883051, INT-0100, MA9

Objectives

I.  Compare disease-free survival and overall survival of postmenopausal women 
with node-positive, estrogen and/or progesterone receptor-positive 
adenocarcinoma of the breast randomly assigned to postoperative adjuvant 
treatment with long-term (5 years) tamoxifen vs. CAF 
(cyclophosphamide/doxorubicin/fluorouracil) plus concurrent and long-term 
tamoxifen vs. CAF followed by long-term tamoxifen.

II.  Compare the relative toxicities of these three regimens.

Entry Criteria

Disease Characteristics:

Histologically proven adenocarcinoma of the breast
  No apocrine, adenoidcystic, or squamous carcinomas or
  sarcomas

Pathologic Stage T1-3a, pathologic N1-2 (clinical N0-1), M0:

  Rendered free of gross tumor at surgery

  Primary tumor movable with respect to chest wall
  
  Axillary nodes movable with respect to chest wall and each
  other

  No preoperative edema of the arm, peau d'orange, skin
  ulceration, or inflammatory lesions

  One or more positive lymph nodes required

  No positive deep mastectomy margins or clinical skin
  involvement (focal microscopic dermal invasion or focal
  microscopic dermal lymphatic involvement allowed)

  No evidence of metastatic disease on pretherapy studies
  (including chest x-ray, bone scan, and mammogram)

No bilateral invasive tumors
  Patients who had noninvasive ductal carcinoma in situ of the
  opposite breast and underwent prophylactic contralateral
  mastectomy are eligible

Hormone receptor status:
  Positive for estrogen and/or progesterone receptors (at
  least 10 fmol/mg protein or unequivocally positive
  immunocytochemical assay for one or both)

Participation in SWOG-8854 (flow cytometry) recommended

Prior/Concurrent Therapy:

Biologic therapy:
  Not specified

Chemotherapy:
  No prior chemotherapy

Endocrine therapy:
  No prior hormonal therapy (except for up to 14 days of
  tamoxifen stopped prior to registration)

  Prior estrogen- and/or progesterone-containing hormone
  preparations for nononcologic therapy allowed, but must be
  discontinued prior to registration

  Postmenopausal estrogen therapy should be discontinued in
  all patients at the time of diagnosis of breast cancer

Radiotherapy:
  Postoperative chest wall and/or regional lymph node
  irradiation allowed for mastectomy patients (at discretion
  of the physician) either prior to registration or on
  protocol for any of the following:

     Tumor greater than 5 cm in diameter
     4 or more positive nodes
     Extranodal extension of tumor into the axillary fat

  No radiotherapy for any other reason in mastectomy patients

  Postoperative radiotherapy either prior to registration,
  during tamoxifen, or after completion of chemotherapy
  required for lumpectomy patients

  Radiotherapy must be completed (if it is to be given before
  chemotherapy) prior to registration

  No immediate radiotherapy after randomization to
  chemotherapy

Surgery:
  Radical, modified radical, or breast-sparing surgical
  procedure with at least a level I and II axillary
  dissection and analysis of at least 6 nodes required within
  12 weeks prior to registration

  Lumpectomy must include:

     Total excisional biopsy with rim of normal breast tissue
     Microscopically negative margins
     Level I and II axillary dissection
     Tumor no more than 5 cm in greatest diameter
     Clinical and mammographic examination demonstrating
        absence of multicentric lesions

  Type of surgery, number of nodes examined, number of
  positive nodes, and size of the primary tumor (size of the
  largest tumor if more than 1 mass) must be recorded

Patient Characteristics:

Age:
  Any age

Sex:
  Females only

Menopausal status:
  Postmenopausal as defined by 1 or more of the following:

     Bilateral oophorectomy at least 2 months prior to
     diagnosis of breast cancer (with or without estrogen
     therapy following surgery)

     Prior hysterectomy with at least 1 ovary remaining and
     either over 60 years old or with a postmenopausal FSH
     level

     Natural menopause (last menstrual period at least 1 year
     prior to registration or 4-12 months prior to
     registration with a postmenopausal FSH level)

     Treated with postmenopausal estrogen therapy and either
     over 55 years old or with a postmenopausal FSH level

Performance status:
  Not specified

Hematopoietic:
  WBC at least 3,500/mm3
  Platelet count at least 100,000/mm3

Hepatic:
  Bilirubin no more than 1.2 x normal
  Alkaline phosphatase no more than 1.2 x normal
  SGOT or SGPT no more than 1.2 x normal

Renal:
  Creatinine no more than 2.0 mg/dL

Cardiovascular:
  No uncontrolled hypertension
  No history of ischemic heart disease or CHF
  Normal ejection fraction by MUGA (required only if deemed
     clinically necessary for assessment)

Other:
  No medical condition that would preclude protocol therapy:
     No severe diabetes
     No active ulcer disease
     No significant psychiatric disease
  No second malignancy within 5 years except:
     Adequately treated nonmelanomatous skin cancer
     Curatively treated Stage I cervical carcinoma

Pretreatment mammogram and chest x-ray completed no more than
3 months preoperatively; blood/body fluid analyses to
determine eligibility completed within 14 days prior to
registration; prestudy bone scan completed within 12 weeks
prior to registration and/or within 4 weeks prior to surgery

Expected Enrollment

350 patients will be randomized to Arm I and 530 patients each will be 
randomized to Arms II and III.  Accrual should be completed in about 4 years, 
and 4 additional years will be required for follow-up.

Outline

Randomized study.  All patients are randomized on Arms I, II, and III.  
Lumpectomy patients must receive radiotherapy on Regimen A.  At the discretion 
of the physician, mastectomy patients may receive radiotherapy on Regimen B 
for a tumor greater than 5 cm in diameter, 4 or more positive nodes, or 
extranodal extension of the tumor into the axillary fat.  Patients randomized 
to Arm I who are to receive radiotherapy should begin as soon as feasible 
postoperatively; these patients may be irradiated while receiving tamoxifen.  
Patients on Arms II and III who are to receive radiotherapy are treated either 
postoperatively prior to registration or after completion of and recovery from 
6 courses of CAF.

Arm I:  Antiestrogen Therapy.  Tamoxifen, TMX, NSC-180973.

Arm II:  3-Drug Combination Chemotherapy followed by Antiestrogen Therapy.  
CAF:  Cyclophosphamide, CTX, NSC-26271; Doxorubicin, DOX, NSC-123127; 
Fluorouracil, 5-FU, NSC-19893; followed by TMX.

Arm III:  3-Drug Combination Chemotherapy plus Concurrent Antiestrogen 
Therapy.  CAF; plus concurrent TMX.

Regimen A:  Radiotherapy.  Irradiation of the breast and underlying chest wall 
and (optionally) of the supraclavicular area and, if indicated, the axilla, 
using megavoltage equipment with photon energies of up to 6 MV followed, if 
indicated, by a tumor bed boost using either electrons or iridium-192 (192-Ir) 
implants.

Regimen B:  Radiotherapy.  Irradiation of the chest wall using either 
megavoltage photons via a tangential field or electrons via a direct field 
plus (optional) photon irradiation of the supraclavicular area and, if 
indicated, the axilla.

Albain K, Barlow W, Shak S, et al.: Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal, node-positive, ER-positive breast cancer (S8814, INT0100). [Abstract] Breast Cancer Res Treat 106 (1): A-10, 2007.

Albain K, Barlow W, O'Malley F, et al.: Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal , node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: mature outcomes and new biologic correlates on phase III intergroup trial 0100 (SWOG-8814). [Abstract] Breast Cancer Res Treat 88 (Suppl 1): A-37, 2004.

Albain KS, Green SJ, Ravdin PM, et al.: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-143, 2002.

Albain K, Green S, Ravdin P, et al.: Overall survival after cyclophosphamide, adriamycin, 5-Fu, and tamoxifen (CAFT) is superior to T alone in postmenopausal, receptor(+), node(+) breast cancer: new findings from phase III Southwest Oncology Group intergroup trial S8814 (INT-0100). [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-94, 24a, 2001.

Ravdin P, Green S, Albain K, et al.: Initial report of the SWOG biological correlative study of c-erB-2 expression as a predictor of outcome in a trial comparing adjuvant CAF T with tamoxifen (T) alone. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A374, 97a, 1998.

Albain K, Green S, Osborne K, et al.: Tamoxifen (T) versus cyclophosphamide, adriamycin and 5-FU plus either concurrent or sequential T in postmenopausal, receptor(+), node(+) breast cancer: a Southwest Oncology Group phase III intergroup trial (SWOG-8814, INT-0100). [Abstract] Proceedings of the American Society of Clinical Oncology 16: A-450, 128a, 1997.

Hershman DL, Unger JM, Barlow WE, et al.: Treatment Quality and Outcomes of African American Versus White Breast Cancer Patients: Retrospective Analysis of Southwest Oncology Studies S8814/S8897. J Clin Oncol : , 2009.[PUBMED Abstract]

Hershman D, Unger J, Barlow W, et al.: Treatment quality and outcome of African American vs. European American breast cancer patients: retrospective analysis of Southwest Oncology Group studies S8814/S8897. [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-3049, S140-1, 2006.

Albain KS, Green SR, Lichter AS, et al.: Influence of patient characteristics, socioeconomic factors, geography, and systemic risk on the use of breast-sparing treatment in women enrolled in adjuvant breast cancer studies: an analysis of two intergroup trials. J Clin Oncol 14 (11): 3009-17, 1996.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Southwest Oncology Group

Kathy Albain, MD, Protocol chair		Ph: 708-327-3304 Email: kalbain@lumc.edu

Eastern Cooperative Oncology Group

Charles Cobau, MD, Protocol chair		Ph: 419-824-1952 Email: charles.cobaumd@promedia.org

North Central Cancer Treatment Group

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

Cancer and Leukemia Group B

Ellis Levine, MD, Protocol chair		Ph: 716-845-8547; 800-685-6825

NCIC-Clinical Trials Group

Kathleen Pritchard, MD, Protocol chair		Ph: 416-480-4616 Email: kathy.pritchard@sunnybrook.ca