Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information

Alternate Title

Standard Chemotherapy Compared With High-Dose Combination Chemotherapy and Stem Cell Transplantation in Treating Women With Stage II or Stage III Breast Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	15 to 60	NCI	EST-2190 CLB-9496, SWOG-9061, INT-0121, E2190

Objectives

I.  Compare sites and rates of recurrence, disease-free survival, overall 
survival, and toxicity of adjuvant chemotherapy with CAF (cyclophosphamide, 
doxorubicin, fluorouracil) vs. adjuvant CAF followed by marrow ablation with 
cyclophosphamide/thiotepa and autologous stem cell rescue in women with Stage 
II/III breast cancer and 10 or more positive lymph nodes.

II.  Evaluate prospectively the incidence and degree of occult marrow 
contamination with breast cancer cells at the time of study entry and 
following CAF chemotherapy by analyzing samples of marrow using a panel of 
monoclonal antibodies specific for breast cancer.

III.  Document the changes in psychosocial function that occur during 
treatment on either regimen, and compare post-treatment recovery of 
psychosocial function.

IV.  Establish a bank of paraffin-embedded tumor samples for future laboratory 
study.

Entry Criteria

Disease Characteristics:

Biopsy-proven epithelial carcinoma of the breast with at least 10 involved
lymph nodes

Stage II/III disease
 Synchronous bilateral breast cancer eligible provided primaries occurred
  within 6 weeks of each other

 Contralateral intraductal cancer eligible

The following conditions exclude:
 T4 disease
 Apocrine, adenoidcystic, or squamous carcinoma
 Inflammatory carcinoma of the breast
 Lesions fixed to skin or chest wall
 Peau d'orange skin changes
 Asynchronous bilateral infiltrating breast cancer

Radical or modified radical mastectomy or breast-sparing surgery with axillary
dissection required within 12 weeks of entry
 Negative surgical margins required

 Type of procedure, number of nodes examined, number of positive nodes, and
  tumor size must be reported

 Breast-sparing surgery must have included wide excision (i.e., removal of
  gross tumor plus normal breast tissue)

Bone marrow aspirate, bilateral core biopsy, and bone scan must be negative
for tumor
 Aspiration and biopsy not required for patients who received 1 or 2 courses
  of any doxorubicin-based chemotherapy prior to entry

Hormone receptor status:
 Estrogen and progesterone receptor status must be determined by either
  biochemical or immunohistochemical assays

Prior/Concurrent Therapy:

Biologic therapy:
 No prior therapy with colony stimulating factors for breast cancer

Chemotherapy:
 1 or 2 prior courses of any doxorubicin-based chemotherapy allowed provided
  documentation of treatment is available

Endocrine therapy:
 No prior hormonal therapy for breast cancer except up to 21 days of
  tamoxifen that is stopped prior to entry
 Prior postmenopausal estrogen therapy allowed but must be discontinued prior
  to entry

Radiotherapy:
 No prior radiotherapy
 Postoperative radiotherapy required on study

Surgery:
 Surgery completed no more than 12 weeks prior to entry
  Surgery completed no more than 12 weeks prior to start of chemotherapy in
   patients who receive one or two courses of doxorubicin-based chemotherapy
   prior to randomization

Patient Characteristics:

Age:
 15 to 60

Sex:
 Women only

Menopausal status:
 Pre- or postmenopausal

Performance status:
 ECOG 0 or 1

Hematopoietic:
 (obtained within 2 weeks prior to entry)
 WBC at least 4,000
 Platelet count at least 100,000

Hepatic:
 (obtained within 2 weeks prior to entry)
 Bilirubin no more than 1.2 times normal
 AST (or ALT) no more than 1.2 times normal
 Alkaline phosphatase no more than 1.2 times normal

Renal:
 Not specified

Cardiovascular:
 Left ventricular ejection fraction (by MUGA) at least 50% or equal to or
  greater than the lower limit of institutional normal
 No prior angina pectoris requiring nitrate therapy
 No myocardial infarction within 6 months
 No uncontrolled congestive heart failure
 No uncontrolled hypertension
 No major ventricular arrhythmia

Pulmonary:
 FEV1 at least 60% of predicted
 DLCO (corrected) at least 60% of predicted
 Lung volume at least 60%
  Lung volume not required if uncorrected FEV1 and DLCO greater than 80%
 No symptomatic obstructive or restrictive lung disease

Other:
 No symptomatic CNS disease of any etiology
 No insulin-dependent diabetes mellitus
 No uncompensated major thyroid dysfunction
 No uncompensated major adrenal dysfunction
 HIV negative
 No prior malignancy within 5 years except:
  In situ breast cancer (lobular or ductal)
  Inactive nonmelanomatous skin cancer
  In situ cervical cancer
 No pregnant or nursing women
 Assessment of insurance coverage required

Expected Enrollment

534 patients will be accrued over an estimated 6 years.

Outline

This is a randomized study.  Patients are stratified by participating 
institution, estrogen-receptor status, age, and menopausal status.  Patients 
begin treatment within 72 hours of randomization.

The first group receives conventional adjuvant chemotherapy with 
cyclophosphamide, doxorubicin, and fluorouracil (CAF) every 4 weeks for a 
total of 6 courses.  Bone marrow and/or peripheral blood stem cells (PBSC) are 
harvested and stored 4-8 weeks after the last dose of CAF. Cytokine priming is 
permitted.

The second group receives CAF and undergoes bone marrow harvest as in the 
first group.  Then, patients receive high-dose cyclophosphamide and thiotepa, 
followed by autologous bone marrow or PBSC rescue.  GM-CSF or G-CSF support is 
recommended.

Irradiation of the remaining breast tissue and/or chest wall and regional 
lymphatics begins within 4 weeks after chemotherapy in the first group and 
within 8 weeks after stem cell rescue in the second group.  All patients who 
are estrogen receptor or progesterone receptor positive also receive oral 
tamoxifen daily for 5 years.

Patients are followed for progression and survival.

Gor PP, Gray RJ, Horn M, et al.: Association of polymorphic drug metabolizing enzymes (DME) with outcomes in breast cancer patients treated on the ECOG 2190/Intergroup 0121 (E2190/Int0121) study. [Abstract] J Clin Oncol 25 (Suppl 18): A-596, 2007.

DeMichele A, Gray R, Horn M, et al.: Genetic polymorphisms in the IL-6 promoter region are associated with breast cancer outcomes in E2190/Intergroup 0121. [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-6026, S264-5, 2006.

Tallman M, Gray R, Robert N, et al.: Phase III study of conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem cell transplantation in patients with stage II and III breast cancer at high risk of recurrence (INT 0121). [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-19, 2003.

Tallman MS, Gray R, Robert NJ, et al.: Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 349 (1): 17-26, 2003.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

Martin Tallman, MD, Protocol chair		Ph: 312-695-0990

Southwest Oncology Group

Charles LeMaistre, MD, Protocol chair(Contact information may not be current)		Ph: 210-567-1956

Cancer and Leukemia Group B

William Vaughan, MD, Protocol chair		Ph: 205-934-1908 Email: wvaughan@uabmc.edu