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

Alternate Title

High-Dose Chemotherapy With Autologous Bone Marrow Transplantation Versus Standard Combination Chemotherapy in Treating Patients With High-Risk Breast Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Completed	over 18	NCI	CLB-9082 CAN-NCIC-MA13, SWOG-9114, INT-0163, MA13

Objectives

I.  Compare disease-free and overall survival of women with stage II/IIIA 
breast cancer randomized to receive high-dose 
cyclophosphamide/cisplatin/carmustine with autologous bone marrow/peripheral 
stem cell support plus chest wall irradiation vs. conventional doses of the 
same drugs plus chest wall irradiation, administered after 4 courses of 
adjuvant cyclophosphamide/doxorubicin/fluorouracil (CAF).

II.  Compare the toxic effects of these 2 regimens.

Entry Criteria

Disease Characteristics:

Histologically confirmed adenocarcinoma of the breast

Pathologically confirmed stage IIA, IIB, or IIIA (i.e., T1-3, N1-2, M0)

10 or more positive axillary nodes required

Absence of distant metastases, evidenced by:
  Negative bone scan
  Negative bilateral bone marrow aspirate/biopsy
  Negative CT of head, chest, abdomen, pelvis

Hormone receptor status:
  Any estrogen receptor (ER) or progesterone receptor (PR) status accepted,
     including unknown
  Knowledge of ER and PR status desired

No bilateral breast cancer

Prior/Concurrent Therapy:

Biologic therapy:
  Not specified

Chemotherapy:
  No prior chemotherapy

Endocrine therapy:
  Not specified

Radiotherapy:
  No prior radiotherapy

Surgery:
  Radical or modified radical mastectomy or lumpectomy with level I/II
  axillary dissection required
     Preferably within 2 weeks prior to initiating
        cyclophosphamide/doxorubicin/fluorouracil (CAF)
     Not more than 8 weeks prior to initiating CAF (10 weeks with permission
        of the study chairman)
     Negative resection margins required
     Lymphatic and vascular involvement permitted

Patient Characteristics:

Age:
  Over 18
  No upper limit, but over physiologic 50 expected to tolerate treatment less
     well

Sex:
  Women only

Menopausal status:
  Pre-, post-, or perimenopausal

Performance status:
  CALGB 0 or 1
  Karnofsky 80%-100%

Hematopoietic:
  ANC at least 1,800/mm3
  Platelet count at least 100,000/mm3
  Hemoglobin greater than 10 g/dL
  Bone marrow cellularity at least 30%

Hepatic:
  Bilirubin not more than 1.5 times normal
  AST not more than 1.5 times normal

Renal:
  Creatinine less than 1.8 mg/dL
  BUN not more than 1.5 times normal

Cardiovascular:
  Left ventricular ejection fraction (LVEF) on MUGA at least 45% at rest and
     at least 5% increase with exercise
        (exercise test not required if LVEF is at least 55%)
  EKG required within 90 days prior to entry
  No uncontrolled or significant cardiovascular disease, i.e.:
     No myocardial infarction within 1 year
     No congestive heart failure

Pulmonary:
  FVC at least 60% of predicted
  FEV1 at least 60% of predicted
  DLCO at least 60% of predicted

Other:
  No previous or concomitant second malignancy except:
     Curatively treated cervical cancer
     Nonmelanomatous skin cancer

  Negative viral titers, e.g.:
     HIV
     HBsAg
     Hepatitis C

  No serious medical/psychiatric condition that would:
     Preclude protocol therapy
     Prevent informed consent

Companion quality-of-life study (CLB-9066) must be offered

Expected Enrollment

At an anticipated accrual rate of 120 patients/year, 6.5-7 years will be 
necessary for accrual of 800 patients.

Outline

This is a randomized study.  Patients are stratified by participating 
institution, disease stage, hormone receptor status, and menopausal status.

All patients receive adjuvant chemotherapy with cyclophosphamide, doxorubicin, 
and fluorouracil (CAF) every 28 days for 4 courses.

One group of patients receives high-dose cyclophosphamide, cisplatin, and 
carmustine followed by autologous bone marrow and peripheral stem cell 
transplantation with growth factor support. 

The second group of patients receives standard-dose cyclophosphamide, 
cisplatin, and carmustine with growth factor support.

All patients receive radiotherapy to the chest wall and lymph nodes following 
chemotherapy.  In addition, patients with a hormone receptor status of 
positive or unknown receive oral tamoxifen daily for at least 5 years.

Patients are followed monthly for 6 months, every 6 months for 2 years, then 
annually.

Marks LB, Cirrincione C, Fitzgerald TJ, et al.: Impact of High-Dose Chemotherapy on the Ability to Deliver Subsequent Local-Regional Radiotherapy for Breast Cancer: Analysis of Cancer and Leukemia Group B Protocol 9082. Int J Radiat Oncol Biol Phys : , 2009.[PUBMED Abstract]

Peters WP, Rosner GL, Vredenburgh JJ, et al.: Prospective, randomized comparison of high-dose chemotherapy with stem-cell support versus intermediate-dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG 9114, and NCIC MA-13. J Clin Oncol 23 (10): 2191-200, 2005.[PUBMED Abstract]

Marks LB, Cirrincione C, Peterson B, et al.: The impact of local/regional radiotherapy (RT), and its timing, on survival following lumpectomy/mastectomy and systemic chemotherapy in patients with ≥10 positive axillary nodes: analysis of CALGB 9082. [Abstract] Int J Radiat Oncol Biol Phys 60 (1 Suppl 1): A-12, S136, 2004.

Peters WP, Rosner G, Vredenburgh J, et al.: Updated results of a prospective, randomized comparison of two doses of combination alkyating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): CALGB 9082/SWOG 9114/NCIC Ma-13. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-81, 21a, 2001.

Peters W, Rosner G, Vrendenburgh J, et al.: A prospective, randomized comparison of two doses of combination alkylating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13. [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-2, 1a, 1999.

Hurd DD, Peters WP: Randomized, comparative study of high-dose (with autologous bone marrow support) versus low-dose cyclophosphamide, cisplatin, and carmustine as consolidation to adjuvant cyclophosphamide, doxorubicin, and fluorouracil for patients with operable stage II or III breast cancer involving 10 or more axillary lymph nodes (CALGB Protocol 9082). Cancer and Leukemia Group B. J Natl Cancer Inst Monogr (19): 41-4, 1995.[PUBMED Abstract]

Day RS, Shackney SE, Peters WP: The analysis of relapse-free survival curves: implications for evaluating intensive systemic adjuvant treatment regimens for breast cancer. Br J Cancer 92 (1): 47-54, 2005.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

William Peters, MD, PhD, Protocol chair(Contact information may not be current)		Ph: 313-993-7777; 800-527-6266 Email: petersw@karmanos.org

Southwest Oncology Group

Elizabeth Shpall, MD, Protocol chair(Contact information may not be current)		Ph: 720-848-0300; 800-473-2288

NCIC-Clinical Trials Group

Michael Crump, MD, FRCPC, Protocol chair		Ph: 416-946-4567 Email: michael.crump@uhn.on.ca

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