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	Closed	pre/perimenopausal		CAN-NCIC-MA5 NCI-V90-0027, MA5

Objectives

I.  Compare, in a Phase III setting, the relapse-free survival and overall 
survival of premenopausal women with node-positive breast cancer who have 
undergone complete surgical resection of all known disease and are 
subsequently randomized to adjuvant chemotherapy consisting of intensive CEF 
(cyclophosphamide/epirubicin/fluorouracil) vs. standard CMF 
(cyclophosphamide/methotrexate/fluorouracil).

II.  Compare the toxicities of these two regimens when administered as 
adjuvant therapy in this patient population.

III.  Compare the quality of life among patients receiving these adjuvant 
chemotherapy regimens.

Entry Criteria

Disease Characteristics:

Breast adenocarcinoma with at least one histologically positive
axillary node that has been completely resected

Total or partial mastectomy with axillary node dissection
required
  If less than total mastectomy, breast irradiation on protocol
  following completion of adjuvant chemotherapy required

  Complete resection of bilateral breast cancer required but
  contralateral axillary dissection optional if axilla
  clinically negative at surgery

  No evidence of microscopic residual disease in axilla
  following either procedure or in resection margins following
  total mastectomy

  Further excision recommended for residual microscopic margins
  following partial mastectomy
     If further excision not undertaken, boost irradiation to
     tumor bed in addition to breast irradiation required
     following chemotherapy on protocol

Preoperative clinical Stage T1-3a, N0-2, M0 required
  Clinical Stage T4 excludes (chest wall extension; edema,
  including peau d'orange; skin ulceration; satellite skin
  nodules confined to homolateral breast; and inflammatory
  carcinoma)

Postoperative pathologic Stage T0-4, N1-2, M0 (only T4 with
dermal involvement on pathologic exam allowed)

No evidence of metastatic disease on appropriate studies (e.g.,
chest x-ray, bone scan/x-ray, abdominal ultrasound if LFTs
abnormal)

Randomization within 10 weeks of initial surgical histologic
diagnosis required

Hormone receptor status:
  Not specified

Prior/Concurrent Therapy:

No prior therapy for breast cancer

Biologic therapy:
  Not specified

Chemotherapy:
  No planned other cytotoxic chemotherapy

Endocrine therapy:
  No planned tamoxifen, long-term prednisone, or other hormones

Radiotherapy:
  No planned regional nodal or chest wall irradiation

Surgery:
  Prior partial or total mastectomy required (see Disease
  Characteristics)

Patient Characteristics:

Age:
  Not specified

Sex:
  Females only

Menopausal status:
  Pre- or perimenopausal, i.e., one of the following:
     Normal menstruation
     Biochemical evidence of ovarian function
     Amenorrheic for less than 1 year
     Amenorrheic for 1-3 years and under age 52
     Hysterectomized but with at least 1 ovary intact and under
        age 56

Performance status:
  Not specified

Hematopoietic:
  WBC at least 3,000
  ANC at least 1,500
  Platelets at least 100,000

Hepatic:
  Bilirubin within normal limits
  Alkaline phosphatase within normal limits
  SGOT/SGPT within normal limits

  If LFTs are elevated, metastasis must be ruled out by
  abdominal ultrasound

Renal:
  Creatinine no greater than 1.5 x normal

Cardiovascular:
  LVEF at least 45% by MUGA
  No history of angina
  No current CHF
  No documented MI

Other:
  No serious underlying medical illness or psychiatric or
     addictive disorder that might interfere with adequate drug
     delivery and follow-up
  No history of second malignancy except:
     Treated nonmelanomatous skin cancer
     Curatively treated cancer of the cervix, endometrium,
        colon, or thyroid with no evidence of active disease
        for at least 5 years

Expected Enrollment

600 patients will be enrolled over about 4 years.

Outline

Randomized study.  Patients who have undergone less than total mastectomy 
receive radiotherapy on Regimen A upon completion of adjuvant chemotherapy.

Arm I:  3-Drug Combination Chemotherapy.  CEF:  Cyclophosphamide, CTX, 
NSC-26271; Epirubicin, EPI, NSC-256942; Fluorouracil, 5-FU, NSC-19893.

Arm II:  3-Drug Combination Chemotherapy.  CMF:  CTX; Methotrexate, MTX, 
NSC-749; 5-FU.

Regimen A:  Radiotherapy.  Breast irradiation using Co60 equipment or a linear 
accelerator with energies of 4 MeV or greater and (in selected cases) boost 
irradiation of the tumor bed with Co60 or electrons.

O'Malley FP, Chia S, Tu D, et al.: Topoisomerase II alpha protein overexpression has predictive utility in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA.5). [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-38, S18, 2006.

Pritchard KI, Shepherd LE, O'Malley FP, et al.: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354 (20): 2103-11, 2006.[PUBMED Abstract]

Shepherd LE, Parulekar W, Pritchard KI, et al.: Left ventricular function following adjuvant chemotherapy for breast cancer: the NCIC CTG MA5 experience. [Abstract] J Clin Oncol 24 (Suppl 18): A-522, 2006.

Levine MN, Pritchard KI, Bramwell VH, et al.: Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol 23 (22): 5166-70, 2005.[PUBMED Abstract]

Parulekar WR, Day AG, Ottaway JA, et al.: Incidence and prognostic impact of amenorrhea during adjuvant therapy in high-risk premenopausal breast cancer: analysis of a National Cancer Institute of Canada Clinical Trials Group Study--NCIC CTG MA.5. J Clin Oncol 23 (25): 6002-8, 2005.[PUBMED Abstract]

Radice D, Redaelli A: Q-TWiST analysis of cyclophosphamide, epirubicin, fluorouracil versus cyclophosphamide, methotrexate, fluorouracil treatment for premenopausal women with node-positive breast cancer. Pharmacoeconomics 23 (1): 69-75, 2005.[PUBMED Abstract]

Pritchard KI, O'Malley FA, Andrulis I, et al.: Prognostic and predictive value of HER2/neu in a randomized trial comparing CMF to CEF in premenopausal women with axillary lymph node positive breast cancer (NCIC CTG MA.5). [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-165, 2002.

Levine MN, Bramwell VH, Pritchard KI, et al.: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16 (8): 2651-8, 1998.[PUBMED Abstract]

Levine M, Bramwell V, Bowman D, et al.: A clinical trial of intensive CEF versus CMF in premenopausal women with node positive breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 14: A-112, 103, 1995.

Gennari A, Sormani MP, Puntoni M, et al.: A pooled analysis on the interaction between HER-2 expression and responsiveness of breast cancer to adjuvant chemotherapy. [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-41, S19, 2006.

Findlay B, Myles J, Levine M, et al.: Using ideal vs. actual weights to calculate chemotherapy doses in premenopausal women with stage 2 breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-56, 63, 1994.

Trial Contact Information

Trial Lead Organizations

NCIC-Clinical Trials Group

Mark Levine, MD, Protocol chair(Contact information may not be current)		Ph: 905-527-4322 ext. 42176