Phase III Randomized Comparison of Adjuvant Therapies in Premenopausal Women with Resected Node-Positive Hormone Receptor-Positive Adenocarcinoma of the Breast: CAF (CTX/DOX/5-FU) vs CAF Followed by ZDX vs CAF Followed by ZDX/TMX

  • Resize font
  • Print
  • Email
  • Facebook
  • Twitter
  • Google+
  • Pinterest

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentCompletedpremenopausalNCIEST-5188
CLB-9192, SWOG-8851, INT-0101, E5188


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 

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

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

  None prior for breast cancer

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

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

  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:

  Not specified

  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

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

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

  Serum creatinine no more than 1.2 x normal

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

  No chronic obstructive pulmonary disease (COPD) that limits

  No brittle diabetes
  No major depression
  No other medical/neuropsychiatric problems difficult to
  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.


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, 

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.

Published Results

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.

Related Publications

Sparano JA, Wang M, Zhao F, et al.: Obesity at diagnosis is associated with inferior outcomes in hormone receptor-positive operable breast cancer. Cancer 118 (23): 5937-46, 2012.[PUBMED Abstract]

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

Cancer and Leukemia Group B

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

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.