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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	pre- and postmenopausal	NCI	SWOG-8897 CLB-8897, EST-2188, INT-0102

Objectives

I.  Compare, in a Phase III Intergroup setting, disease-free survival and 
overall survival of high-risk primary node-negative breast cancer patients 
randomly assigned to adjuvant chemotherapy with 6 courses of CAF 
(cyclophosphamide/adriamycin/5-fluorouracil) vs. 6 courses of CMF 
(cyclophosphamide/methotrexate/5-fluorouracil).

II.  Assess the value of 5 years of tamoxifen therapy vs. no tamoxifen therapy 
following completion of adjuvant chemotherapy.

III.  Compare the toxicities of these treatments.

IV.  Assess the prognostic significance of ploidy and % S phase as determined 
by DNA flow cytometry in patients with small, occult invasive breast cancer 
treated by surgery or surgery and radiotherapy only.

V.  Evaluate disease-free survival and overall survival of patients with 
low-risk invasive breast cancer (as characterized by receptor status, tumor 
size, and % S phase) who are treated with local therapy only.  (Accrual closed 
to low-risk patients as of 9/91).

Entry Criteria

Disease Characteristics:

Histologically documented invasive adenocarcinoma of the
breast with negative axillary nodes (pathologic stage T1-3a,
N0, M0)

  Apocrine, adenoidcystic, and squamous carcinomas and
  sarcomas specifically excluded

Patients must be within 12 weeks (15 weeks for patients
requiring a second registration) of definitive surgery and
must begin protocol therapy within 1 working day of
registration

  Radical, modified radical, or breast-sparing surgery and
  levels I and II axillary node dissection with analysis of
  at least 6 nodes required

  If margins are positive, re-excision permitted prior to
  entry

    Patients with positive deep mastectomy margins excluded

    Type of surgery, number of nodes examined, and tumor
    size (size of only largest tumor in patients with more
    than 1 discrete mass) must be reported

    Patients electing breast-sparing procedure (partial
    mastectomy or lumpectomy) must have had total excisional
    biopsy including a small rim of normal tissue and a
    level I and II axillary dissection; the tumor must be no
    greater than 5 cm in greatest diameter, and clinical and
    mammographic examination must demonstrate the absence of
    multicentric lesions

    Date of definitive surgery defined as day of axillary
    dissection in patients undergoing lumpectomy

Tumor must be movable in relation to chest wall

No peau d'orange skin changes, skin ulcerations, or
inflammatory changes allowed

No evidence of metastatic disease on chest x-ray,
contralateral mammogram, and any other indicated imaging
studies

  Prestudy chest x-ray and mammogram must be performed prior
  to registration and no earlier than 3 months prior to
  definitive surgery

No bilateral breast cancer

  Patients found to have ductal carcinoma in situ without
  invasion in the contralateral breast are eligible only if a
  contralateral mastectomy has been done

Hormone receptor status:

  Any ER or PgR status accepted

    ER and PgR status must be determined by biochemical
    methods or ELISA with monoclonal antibodies on the
    primary tumor (immunohistochemical assay not acceptable)

    Receptor assay may be done on intraductal tumor if there
    is insufficient infiltrating tumor available

Prior/Concurrent Therapy:

Biologic therapy:
  Not specified

Chemotherapy:
  No prior chemotherapy

Endocrine therapy:
  No prior hormonal therapy except up to 14 days of
  tamoxifen started by an outside physician and stopped
  prior to registration

Radiotherapy:
  All patients with breast-sparing surgery must receive
  radiotherapy on protocol as follows:
    High-risk patients are irradiated before or after
    adjuvant chemotherapy

    Uncertain-risk patients not irradiated before chemotherapy
    must be irradiated after chemotherapy if found to be
    high-risk or within 15 weeks of surgery if found to be
    low-risk

  Radiotherapy given before chemotherapy must be completed
  before registration

  No patients with a modified radical mastectomy may receive
  postoperative radiotherapy

Surgery:
  Radical, modified radical, or breast-sparing surgery and
  levels I and II axillary node dissection with analysis of
  at least 6 nodes required (as detailed above)

Other:
  Previous treatment with estrogen- or
  progesterone-containing preparations for reasons unrelated
  to breast cancer permitted, but such therapy must be
  discontinued prior to registration

Patient Characteristics:

Age:
  Not specified

Sex:
  Females only

Menopausal status:
  Pre- or postmenopausal

Performance status:
  Not specified

Hematopoietic:
  (within 2 weeks of registration)
  WBC at least 3,500
  Platelets at least 100,000

Hepatic:
  (within 2 weeks of registration)
  Bilirubin no greater than 1.2 x ULN
  SGOT or SGPT no greater than 1.2 x ULN
  Alkaline phosphatase no greater than 1.2 x ULN

Renal:
  (within 2 weeks of registration)
  Creatinine no greater than 1.5 mg/dl

Cardiovascular:
  No history of ischemic heart disease
  No history of CHF
  Normal ejection fraction by MUGA scan required if
  clinically indicated

Other:
  No pre-existing medical condition precluding protocol
  therapy, e.g.:
    No severe diabetes
    No active ulcer disease
    No uncontrolled hypertension
    No significant  psychiatric disease
  No active second malignancy within previous 5 years except:
    Nonmelanomatous skin cancer
    In situ carcinoma of the cervix
  No pregnant or lactating women
  Effective contraception required of fertile women

Expected Enrollment

1,300 patients will be required on each treatment arm, and it is anticipated 
that an additional 900 low-risk patients will be registered on the no 
treatment part of the trial.  Accrual should be complete in about 3 years, and 
4 additional years will be required for follow-up.

Outcomes

Disease-free survival
Overall survival
Value of tamoxifen therapy vs no tamoxifen therapy at 5 years
Toxicity
Prognostic significance of ploidy and % S phase as determined by DNA flow cytometry

Outline

Randomized study.  Patients with occult, small, or mammographically detected 
invasive tumors too small for biochemical ER assay are registered and observed 
without adjuvant therapy, as are those with ER-positive and/or PgR-positive 
tumors less than 2 cm in diameter and less than 4.4% S phase for diploid 
tumors or less than 7.0% S phase for aneuploid tumors or tumors 1 cm or less 
in size with unknown % S phase because of insufficient tumor (as of 9/91, 
entry is closed to low-risk patients).  All others (i.e., those with 
ER-negative and PgR-negative tumors; ER-positive and/or PgR-positive tumors at 
least 2 cm in size; ER-positive tumor less than 2 cm with at least 4.4% S 
phase for diploid tumors or at least 7.0% S phase for aneuploid tumors; tumors 
larger than 1 cm with unknown % S phase; and tumors with unknown % S phase for 
reasons other than insufficient tumor) are considered high-risk and are 
randomized on Arms I-IV.  Patients with multiclonal tumors are considered 
high-risk if any clone qualifies as high-risk.  All patients who had a 
breast-sparing surgical procedure receive radiotherapy on Regimen A, either 
prior to initiation or after completion of chemotherapy; radiotherapy given 
prior to chemotherapy must be completed before registration.

Arm I:  3-Drug Combination Chemotherapy.  CMF:  Cyclophosphamide, CTX, 
NSC-26271; Methotrexate, MTX, NSC-740; 5-Fluorouracil, 5-FU, NSC-19893.

Arm II:  3-Drug Combination Chemotherapy.  CAF:  CTX; Doxorubicin, Adriamycin, 
ADR, NSC-123127; 5-FU.

Arm III:  3-Drug Combination Chemotherapy followed by Antiestrogen Therapy.  
CMF; followed by Tamoxifen, TMX, NSC-180973.

Arm IV:  3-Drug Combination Chemotherapy followed by Antiestrogen Therapy.  
CAF; followed by TMX.

Regimen A:  Radiotherapy.  Irradiation of the breast and underlying chest wall 
using megavoltage equipment with photon energies of up to 6 MeV followed by an 
optional boost to the tumor bed using direct electrons or Iridium-192 implants.

Ganz PA, Hussey MA, Moinpour CM, et al.: Late cardiac effects of adjuvant chemotherapy in breast cancer survivors treated on Southwest Oncology Group protocol s8897. J Clin Oncol 26 (8): 1223-30, 2008.[PUBMED Abstract]

Ambrosone CB, Barlow W, Yeh I-T: Pharmacogenetics and breast cancer treatment outcomes: results on oxidative stress-related genotypes (MPO, MnSOD) from a Southwest Oncology Group intergroup trial (INT-0102). [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-37, S18, 2006.

Ambrosone CB, Choi JY, Barlow W, et al.: Pharmacogenetics and breast cancer treatment outcomes: results on oxidative stress related genotypes (MPO, MNSOD) from a Southwest Oncology Group trial (S8897). [Abstract] Int J Biol Markers 22 (1): 61-2, 2006.

Hutchins LF, Green SJ, Ravdin PM, et al.: 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. J Clin Oncol 23 (33): 8313-21, 2005.[PUBMED Abstract]

Pierce LJ, Hutchins LF, Green SR, et al.: Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer. J Clin Oncol 23 (1): 24-9, 2005.[PUBMED Abstract]

Pierce LJ, Hutchins L, Green SJ, et al.: Sequencing of tamoxifen (TAM) and radiotherapy (RT) with breast conservation (BCT) in early stage breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-39, 10, 2003.

Hutchins L, Green S, Ravdin P, et al.: CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node negative patients: first results of intergroup trial INT 0102. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A2, 1a, 1998.

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.

Goldhirsch A, Gelber RD, Yothers G, et al.: Adjuvant therapy for very young women with breast cancer: need for tailored treatments. J Natl Cancer Inst Monogr (30): 44-51, 2001.[PUBMED Abstract]

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

Laura Hutchins, MD, Protocol chair		Ph: 501-686-8511 Email: hutchinslauraf@uams.edu

Cancer and Leukemia Group B

Larry Norton, MD, Protocol chair		Ph: 212-639-5319; 800-525-2225

Eastern Cooperative Oncology Group

Douglass Tormey, MD, PhD, Protocol chair		Ph: 303-320-2121