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	Completed	premenopausal	NCI	EST-5188 CLB-9192, SWOG-8851, INT-0101, E5188

Objectives

I.  Compare recurrence rates, disease-free intervals, and overall survival of 
premenopausal women with axillary node-positive, hormone receptor-positive 
adenocarcinoma of the breast randomly assigned to adjuvant therapy with CAF 
(cyclophosphamide/doxorubicin/fluorouracil) chemotherapy alone vs. CAF 
followed by 5 years of goserelin vs. CAF followed by 5 years of 
goserelin/tamoxifen.

II.  Compare the toxicities of these 3 regimens.

III.  Assess the effects of these 3 therapies on LH, FSH, and estradiol levels 
in these patients.

Entry Criteria

Disease Characteristics:

Histologically proven invasive adenocarcinoma of the breast

Tumor excised within previous 12 weeks

At least 1 positive lymph node after lower and middle
axillary node dissection (6 or more nodes examined)

No positive deep mastectomy margins

No clinical skin involvement
  (Focal microscopic dermal involvement and focal microscopic
  dermal lymphatic involvement acceptable)

Hormone receptor status:
  Estrogen and/or progesterone receptor positive (at least 10
  fmol protein/mg by biochemical assay or clearly positive
  immunocytochemical assay)

Primary tumor and nodal disease movable with respect to chest
wall

No evidence of metastatic disease or contralateral breast
cancer, determined by:
  Preoperative chest x-ray and mammogram (within 3 months
     prior or 12 weeks after surgery)
  Appropriate laboratory tests, including negative bone scan

None of the following:
  Peau d'orange skin changes
  Skin ulceration
  Inflammatory skin lesions
  Preoperative edema of the arm
  Bilateral breast cancer

Prior/Concurrent Therapy:

Biologic therapy:
  Not specified

Chemotherapy:
  None prior for breast cancer

Endocrine therapy:
  None prior for breast cancer except up to 14 days of
     tamoxifen
  Estrogen therapy should be discontinued at diagnosis

Radiotherapy:
  Required on protocol for those with less than total
     mastectomy
  May be given to those with total mastectomy

Surgery:
  Excision within previous 12 weeks
  Lower and middle axillary node dissection (at least 6 nodes)

  If less than total mastectomy:
     Tumor 5 cm or less in greatest dimension on mammogram
     No multiple suspicious calcifications on mammogram
     Negative inked margins of resection around primary

Patient Characteristics:

Age:
  Not specified

Sex:
  Women only

Menopausal status:
  Premenopausal, defined by one of the following:
     Within 4 months of LMP

     4-12 months since LMP with normal premenopausal FSH level

     60 years of age or less with a prior hysterectomy with 1
     or both ovaries left intact and normal premenopausal FSH

     55 years of age or less and on estrogen therapy for
     reasons other than surgical castration, with a
     premenopausal FSH 1-2 weeks after stopping estrogen

     (If on estrogen therapy following surgical castration
     prior to diagnosis, patient considered postmenopausal)

Performance status:
  Not specified

Hematopoietic:
  AGC at least 1,500
  Platelets at least 100,000

Hepatic:
  SGOT and alkaline phosphatase no more than 1.2 x normal
  Negative bone scan required if alkaline phosphatase abnormal

Renal:
  Serum creatinine no more than 1.2 x normal

Cardiovascular:
  No congestive heart failure
  No angina pectoris
  No cardiac arrhythmia
  No myocardial infarction within 12 months
  No poorly controlled hypertension

Pulmonary:
  No chronic obstructive pulmonary disease (COPD) that limits
     activity

Other:
  No brittle diabetes
  No major depression
  No other medical/neuropsychiatric problems difficult to
     manage
  No prior second malignancy within 5 years, except:
     Curatively treated nonmelanomatous skin cancer
     Carcinoma in situ of the cervix
  No pregnancy or lactation
  Nonhormonal, barrier contraception required during therapy

Expected Enrollment

1,500 patients will be entered over 4 years.

Outline

Randomized study.  Patients who have had less than total mastectomy receive 
radiotherapy on Regimen A beginning either prior to initiation of chemotherapy 
or within 4 weeks after completion of chemotherapy (those who have 
radiotherapy prior to chemotherapy must complete radiotherapy prior to 
randomization).  The interval between definitive surgery and initiation of 
adjuvant chemotherapy must not exceed 12 weeks (84 days).

Arm I:  3-Drug Combination Chemotherapy.  CAF:  Cyclophosphamide, CTX, 
NSC-26271; Doxorubicin, DOX, NSC-123127; Fluorouracil, 5-FU, NSC-19893.

Arm II:  3-Drug Combination Chemotherapy followed by Releasing Factor Agonist 
Therapy.  CAF; followed by Goserelin, ZDX, NSC-606864.

Arm III:  3-Drug Combination Chemotherapy followed by Releasing Factor Agonist 
Therapy plus Antiestrogen Therapy.  CAF; followed by ZDX; plus Tamoxifen, TMX, 
NSC-180973.

Regimen A:  Radiotherapy.  Irradiation of breast and supraclavicular and 
apical axillary nodes (entire axilla in patients with more than 4 positive 
nodes) using supervoltage equipment followed by a boost to the primary site 
using Iridium-192 implants or electron beams.

Davidson NE, O'Neill AM, Vukov AM, et al.: Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol 23 (25): 5973-82, 2005.[PUBMED Abstract]

Davidson NE, O'Neill A, Vukov A, et al.: Chemohormonal therapy in premenopausal node-positive, receptor-positive breast cancer: an Eastern Cooperative Oncology Group phase III intergroup trial (E5188,INT-0101). [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-15, 2003.

Davidson N, O'Neill A, Vukov A, et al.: Effect of chemohormonal therapy in premenopausal, node (+), receptor (+) breast cancer: an Eastern Cooperative Oncology Group phase III intergroup trial (E5188, INT-0101). [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-249, 67a, 1999.

Cuzick J, Ambroisine L, Davidson N, et al.: Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet 369 (9574): 1711-23, 2007.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

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

Southwest Oncology Group

C. Kent Osborne, MD, Protocol chair(Contact information may not be current)		Ph: 210-567-4777 Email: Kent_osborne@oncology.uthscsa.edu

Cancer and Leukemia Group B

Douglas White, MD, Protocol chair		Ph: 910-716-7973; 800-446-2255