Phase III Randomized Study of Adjuvant Anthracycline and Cyclophosphamide and Cyclophosphamide, Methotrexate, and Fluorouracil with vs without a 16-Week Treatment Free Interval Between Regimens and with vs without Subsequent Tamoxifen in Premenopausal Women with Node Positive Breast Cancer Unsuitable for Endocrine Therapy Alone

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Alternate Title

Combination Chemotherapy With or Without Hormone Therapy in Treating Premenopausal Women With Node-Positive Breast Cancer

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosedpremenopausalIBCSG-13-93
EU-93016, NCI-F93-0011


I.  Evaluate the importance of a 16-week gap vs. no treatment gap between two 
sequential adjuvant chemotherapy regimens (4 courses anthracycline and 
cyclophosphamide followed by 3 courses of cyclophosphamide, methotrexate, and 
fluorouracil) on overall survival and local and systemic disease free survival 
in premenopausal women with node positive breast cancer who are considered 
unsuitable for endocrine therapy alone.

II.  Evaluate these same endpoints in patients randomized to either schedule 
with vs without tamoxifen maintenance therapy.

III.  Compare the quality of life of patients treated on these regimens.

IV.  Compare the toxic effects of these regimens.

Entry Criteria

Disease Characteristics:

Histologically proven stage T1-3, pN1, M0 carcinoma of the breast considered
unsuitable for adjuvant treatment with endocrine therapy alone

Potentially curative resection within 6 weeks of entry by one of the
  Total mastectomy with negative margins
Breast-conserving procedure (lumpectomy or quadrantectomy) for tumors less
than 5 cm
 Adequate re-resection or mastectomy within 4 weeks of initial surgery
 required if margins are positive after initial surgery

Axillary clearance (not sampling) required at surgery, with at least 1 node
positive upon histopathologic examination of at least 8 nodes

Suspicious manifestations of metastatic disease (e.g., hot spots on bone scan,
skeletal pain of unknown cause) must be proven benign

No bilateral breast cancer
  Any mass in contralateral breast must be proven benign by biopsy

Hormone receptor status:
  Estrogen receptor (ER) positive or ER-negative on quantitative or
  qualitative assay

Prior/Concurrent Therapy:

No prior therapy for breast cancer other than potentially curative surgery
(see Disease Characteristics)

Patient Characteristics:

  See Menopausal status


Menopausal status:
  Premenopausal, i.e.:
     Normal menstrual period within 6 months prior to entry with no prior
     hysterectomy and no hormone replacement therapy (HRT)

     Prior hysterectomy and no HRT and either age less than 40 or age 40 or
     greater with premenopausal luteinizing hormone, follicle-stimulating
     hormone, and estradiol levels

     On HRT and age 49 or less with menstruation within 6 months prior to
     starting HRT

Performance status:
  Not specified

  WBC greater than 4,000/mm3
  Platelet count greater than 100,000/mm3

  Bilirubin less than 1.1 mg/dL 
  AST less than 60 IU/L

  Creatinine less than 1.3 mg/dL 

  No nonmalignant systemic disease that would preclude protocol therapy or
     prolonged follow-up
  No psychiatric or addictive disorder that would preclude informed consent
  No prior or concurrent second malignancy except:
     Nonmelanomatous skin cancer
     Adequately treated carcinoma in situ of the cervix
  Not pregnant or nursing (including those who have stopped nursing
   within the past 6 months)

Expected Enrollment

Up to 1225 patients will be accrued until mid 1999, with one additional year 
of follow-up.


This is a randomized, multicenter study.  Patients are stratified by center, 
type of primary therapy, and estrogen receptor status. Patients are randomized 
to one of four treatment arms. Therapy begins within 6 weeks after breast 

Arm I: Patients receive doxorubicin (or epirubicin) plus cyclophosphamide (AC) 
every 21 days for 4 courses, followed immediately by cyclophosphamide, 
methotrexate, and fluorouracil (CMF) every 28 days for 3 courses.

Arm II: Patients receive AC as in arm I, followed 16 weeks later by CMF as in 
arm I.

Arm III: Patients receive AC and CMF as in arm I, then oral tamoxifen daily 
until 5 years after randomization.

Arm IV: Patients receive AC and CMF as in arm II, then oral tamoxifen daily 
until 5 years after randomization.

Patients with less than total mastectomy may receive optional radiation 
therapy either upon completion of all therapy or concurrently with CMF.

Quality of life is assessed periodically.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, 
and yearly thereafter.  Patients who experience a recurrence in the 
ipsilateral conserved breast undergo either local re-excision or total 
mastectomy and continue on study.

Published Results

Colleoni M, Gelber S, Goldhirsch A, et al.: Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol 24 (9): 1332-41, 2006.[PUBMED Abstract]

Related Publications

Gianni L, Cole BF, Panzini I, et al.: Anemia during adjuvant non-taxane chemotherapy for early breast cancer: Incidence and risk factors from two trials of the International Breast Cancer Study Group. Support Care Cancer 16 (1): 67-74, 2008.[PUBMED Abstract]

Pestalozzi BC, Zahrieh D, Mallon E, et al.: Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol 26 (18): 3006-14, 2008.[PUBMED Abstract]

Colleoni M, Gelber S, Simoncini E, et al.: Effects of a treatment gap during adjuvant chemotherapy in node-positive breast cancer: results of International Breast Cancer Study Group (IBCSG) Trials 13-93 and 14-93. Ann Oncol 18 (7): 1177-84, 2007.[PUBMED Abstract]

Keshaviah A, Dellapasqua S, Rotmensz N, et al.: CA15-3 and alkaline phosphatase as predictors for breast cancer recurrence: a combined analysis of seven International Breast Cancer Study Group trials. Ann Oncol 18 (4): 701-8, 2007.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

International Breast Cancer Study Group

Marco Colleoni, MD, Protocol chair
Ph: 39-2-5748-9502

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.