RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking the uptake of estrogen. Chemotherapy uses different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: Phase III trial to study the effectiveness of tamoxifen following surgery and chemotherapy in treating women who have stage I breast cancer at high risk of recurrence or stage II or stage III breast cancer.

Condition	Treatment or Intervention	Phase
stage I breast cancer stage II breast cancer stage IIIA breast cancer	Drug: cyclophosphamide  Drug: doxorubicin  Drug: epirubicin  Drug: fluorouracil  Drug: methotrexate  Drug: tamoxifen	Phase III

Further Study Details: 

OBJECTIVES: I. Compare the duration of overall survival and disease-free survival in premenopausal women with operable, high risk node negative or axillary node-positive breast cancer who have undergone complete surgical resection of all known disease by means of total or partial mastectomy, and have received standard adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF), cyclophosphamide, epirubicin, and fluorouracil (CEF), or doxorubicin and cyclophosphamide (AC) followed by either daily tamoxifen for 5 years or placebo.

II. Compare the short- and long-term toxicity in patients receiving tamoxifen versus placebo.

III. Monitor follicle-stimulating hormone, luteinizing hormone, and estradiol levels, and determine whether overall survival and disease-free survival are affected by hormonal or menopausal status during or at completion of adjuvant chemotherapy or during or after tamoxifen or placebo treatment in these patients.

PROTOCOL OUTLINE: This is a randomized, double blind study. Patients are stratified by adjuvant chemotherapy regimen (cyclophosphamide, epirubicin, and fluorouracil vs cyclophosphamide, methotrexate, and fluorouracil vs cyclophosphamide and doxorubicin), hormone receptor status (ER and/or PR positive vs ER and PR negative), number of positive nodes (1-3 vs 4-9 vs 10 or more), and participating institution.

Patients receive one of three regimens of adjuvant chemotherapy at the discretion of the investigator.

Regimen A: Patients receive oral cyclophosphamide on days 1-14 and epirubicin IV and fluorouracil IV on days 1 and 8. Courses repeat every 28 days for a total of 6 courses. Following chemotherapy, lumpectomy patients receive local radiotherapy daily for 5 weeks.

Regimen B: Patients receive oral cyclophosphamide on days 1-14 or cyclophosphamide IV on day 1 and 8, methotrexate on days 1 and 8, and fluorouracil IV on days 1 and 8. Courses repeat every 28 days for a total of 6 courses. Concurrent with or following chemotherapy, lumpectomy patients receive local radiotherapy daily for 5 weeks.

Regimen C: Patients receive doxorubicin IV and cyclophosphamide IV every 21 days for a total of 4 courses. Following chemotherapy, lumpectomy patients receive local radiotherapy daily for 5 weeks.

Patients are then randomized to receive either oral tamoxifen or a placebo once daily for 5 years, beginning within 6 weeks of completion of chemotherapy.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 800 patients will be accrued for this study over 4 years.

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Adenocarcinoma of the breast with 1 or more histologically proven positive axillary nodes OR Adenocarcinoma of the breast with negative axillary nodes or adverse prognostic factors such that the patient is at high risk for recurrence and node negative lesion is characterized by the following features: Tumor at least 1 cm; Poorly differentiated, SBR grade III, or MSBR grade V and/or lymphatic/vascular invasion; Pathologic review by experienced breast pathologist recommended if grade is unspecified and lymphatic/vascular invasion is absent
• Disease considered potentially curable and treated by 1 of the following: Complete surgical removal of the breast plus axillary node dissection; Partial surgical removal of the breast plus axillary node dissection, with the intention of giving breast irradiation following completion of an adjuvant chemotherapy regimen; Regional nodal or chest wall irradiation not prohibited but strongly discouraged
• No evidence of residual tumor in the axilla following dissection
• No microscopic evidence of residual tumor at the resection margins following total mastectomy
• Further excision highly recommended if there is microscopic residual disease present at partial mastectomy margins; If further excision is not undertaken, a radiotherapy boost to the tumor bed is required in addition to breast irradiation given following protocol chemotherapy
• Disease clinically staged prior to surgery as T1-T3a, N0-2, M0; No clinical T4 disease, i.e.: No extension to the chest wall; No edema (including peau d'orange); No skin ulceration; No satellite skin nodules confined to the same breast; No inflammatory carcinoma
• Disease pathologically staged following surgery as TNM stage I, II, or III (T0-4; N0-2; M0); T4 allowed only with dermal involvement on pathology assessment
• No evidence of metastatic disease beyond the homolateral axillary nodes on pre-chemotherapy chest x-ray, bone scan (with radiographs of suspicious areas), and abdominal ultrasound (required only if bilirubin, alkaline phosphatase, or AST/ALT are elevated)
• Simultaneous bilateral breast carcinoma allowed; Complete tumor resection on both breasts required; Axillary dissection on both sides must meet criteria as above if both sides are clinically node-positive; Axillary dissection on the second side optional if the axilla is clinically negative at the time of surgery and the other side is node-positive; Adjuvant chemotherapy must begin within 14 weeks of initial pathologic diagnosis
• Hormone receptor status: Any receptor level allowed (values must be available if biochemical method used; immunocytochemical assay permitted)

--Prior/Concurrent Therapy--

• Biologic therapy: Colony-stimulating factors allowed (use must be documented)
• Chemotherapy: No prior chemotherapy; No concurrent other cytotoxic therapy
• Endocrine therapy: Adjuvant tamoxifen (20 mg po daily) allowed up to 2 weeks before or during adjuvant chemotherapy provided drug is discontinued at randomization; No long-term prednisone or other hormones
• Radiotherapy: See Disease Characteristics
• Surgery: See Disease Characteristics

--Patient Characteristics--

• Age: Not specified
• Sex: Female
• Menopausal status: Pre- or perimenopausal, i.e., meeting at least 1 of the following criteria: Normal menstruation; Amenorrhea for less than 1 year (up to 3 years in patients under age 52); Biochemical evidence of ovarian function; Hysterectomy without bilateral oophorectomy in patients under age 56; Premenopausal women no greater than age 50 who were started on replacement hormone therapy before amenorrhea are eligible
• Performance status: ECOG 0-2 prior to chemotherapy
• Hematopoietic: WBC at least 3,000/mm3; Polymorphs and bands at least 1,500/mm3; Platelet count at least 100,000/mm3
• Hepatic: (unless abdominal ultrasound indicates liver metastasis); Alkaline phosphatase no greater than 2 times normal; AST and/or ALT no greater than 2 times normal
• Renal: Not specified
• Other: No history of serious underlying medical illness or psychiatric or addictive disorder; No second malignancy within 5 years except: Curatively treated nonmelanomatous skin cancer; Curatively treated endometrium, colon, or thyroid cancer or carcinoma in situ of the cervix; No plan for pregnancy during the 5-year study period; Fertile women must use effective contraception (other than oral contraception); Accessible for treatment and follow-up

Minnesota
      Duluth Clinic, Duluth,  Minnesota,  55805,  United States
Canada, Alberta
      Cross Cancer Institute, Edmonton,  Alberta,  T6G 1Z2,  Canada
Canada, British Columbia
      BC Cancer Agency, Vancouver,  British Columbia,  V5Z 4E6,  Canada
      British Columbia Cancer Agency - Fraser Valley Cancer Centre, Surrey,  British Columbia,  V3V 1Z2,  Canada
      British Columbia Cancer Agency - Vancouver Island Cancer Centre, Victoria,  British Columbia,  V8R 1J8,  Canada
      Penticton Regional Hospital, Penticton,  British Columbia,  V2A 3G6,  Canada
Canada, Manitoba
      CancerCare Manitoba, Winnipeg,  Manitoba,  R3E 0V9,  Canada
Canada, New Brunswick
      Saint John Regional Hospital, Saint John,  New Brunswick,  E2L 4L2,  Canada
Canada, Newfoundland and Labrador
      Dr. H. Bliss Murphy Cancer Centre, St. Johns,  Newfoundland and Labrador,  A1B 3V6,  Canada
Canada, Nova Scotia
      Nova Scotia Cancer Centre, Halifax,  Nova Scotia,  B3H 1V7,  Canada
Canada, Ontario
      Algoma District Medical Group, Sault Sainte Marie,  Ontario,  P6B 1Y5,  Canada
      Cancer Care Ontario - Windsor Regional Cancer Centre, Windsor,  Ontario,  N8W 2X3,  Canada
      Cancer Care Ontario-Hamilton Regional Cancer Centre, Hamilton,  Ontario,  L8V 5C2,  Canada
      Cancer Care Ontario-London Regional Cancer Centre, London,  Ontario,  N6A 4L6,  Canada
      Credit Valley Hospital, Mississauga,  Ontario,  L5M 2N1,  Canada
      Hotel Dieu Hospital - St. Catharines, St. Catharines,  Ontario,  L2R 5K3,  Canada
      Kingston Regional Cancer Centre, Kingston,  Ontario,  K7L 5P9,  Canada
      Lakeridge Health Oshawa, Oshawa,  Ontario,  L1G 2B9,  Canada
      Mount Sinai Hospital - Toronto, Toronto,  Ontario,  M5G 1X5,  Canada
      North York General Hospital, Ontario, North York,  Ontario,  M2E 1K1,  Canada
      Northeastern Ontario Regional Cancer Centre, Sudbury, Sudbury,  Ontario,  P3E 5J1,  Canada
      Northwestern Ontario Regional Cancer Centre, Thunder Bay, Thunder Bay,  Ontario,  P7A 7T1,  Canada
      Ottawa Regional Cancer Center - General Division, Ottawa,  Ontario,  K1H 8L6,  Canada
      Ottawa Regional Cancer Centre - Civic Campus, Ottawa,  Ontario,  K1Y 4K7,  Canada
      Peel Memorial Hospital, Brampton,  Ontario,  L6W 2Z8,  Canada
      Peterborough Oncology Clinic, Peterborough,  Ontario,  K9H 7B6,  Canada
      Princess Margaret Hospital, Toronto,  Ontario,  M5G 2M9,  Canada
      Royal Victoria Hospital, Barrie, Barrie,  Ontario,  L4M 6M2,  Canada
      Toronto East General Hospital, Toronto,  Ontario,  M4C 3E9,  Canada
      Toronto General Hospital, Toronto,  Ontario,  M5G 2C4,  Canada
      Toronto Sunnybrook Regional Cancer Centre, Toronto,  Ontario,  M4N 3M5,  Canada
      Trillium Health Centre, Mississauga,  Ontario,  L5B 1B8,  Canada
      Women's College Campus, Sunnybrook and Women's College Health Science Center, Toronto,  Ontario,  M5S 1B6,  Canada
Canada, Prince Edward Island
      Queen Elizabeth Hospital, PEI, Charlottetown,  Prince Edward Island,  C1A 8T5,  Canada
Canada, Quebec
      Centre Hospitalier de l'Universite de Montreal, Montreal,  Quebec,  H2W-W1T8,  Canada
      Centre Hospitalier Regional de Lanaudiere, Joliette,  Quebec,  J6E 6J2,  Canada
      Centre Hospitalier Universitaire de Quebec, Pavillion de Quebec, Quebec City,  Quebec,  G1R 2J6,  Canada
      Centre Universitaire de Sante de l'Estrie, Fleurimont,  Quebec,  J1H 5N4,  Canada
      Hopital du Saint-Sacrament, Quebec, Quebec City,  Quebec,  G1S 4L8,  Canada
      McGill University Department of Oncology, Montreal,  Quebec,  H2W 1S6,  Canada
Canada, Saskatchewan
      Allan Blair Cancer Centre, Regina,  Saskatchewan,  S4T 7T1,  Canada
      Saskatoon Cancer Centre, Saskatoon,  Saskatchewan,  S7N 4H4,  Canada

Study chairs or principal investigators

Vivien H.C. Bramwell,  Study Chair,  National Cancer Institute of Canada   

Study ID Numbers:  CDR0000063224; CAN-NCIC-MA12; NCI-V93-0323
Record last reviewed:  July 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002542
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08