Clinical trial NCT00002542: Tamoxifen in Treating Women With High-Risk Breast Cancer
Official title: Double-Blind Randomized Trial of Tamoxifen Versus Placebo in Patients With Node Positive or High Risk Node Negative Breast Cancer Who Have Completed CMF, CEF, or AC Adjuvant Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
First posted: 2004-07-29
Enrollment: 672
Sex: FEMALE
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

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.

Eligibility 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)

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

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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: St. John's
country: Canada
facility: Dr. H. Bliss Murphy Cancer Centre
state: Newfoundland and Labrador
city: Barrie
country: Canada
facility: The Royal Victoria Hospital
city: Brampton
country: Canada
facility: William Osler Health Centre, Brampton Memorial
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
city: Charlottetown
country: Canada
facility: PEI Cancer Treatment Centre,Queen Elizabeth Hospital
city: Edmonton
country: Canada
facility: Cross Cancer Institute
city: Halifax
country: Canada
facility: QEII Health Sciences Center
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
city: Joliette
country: Canada
facility: Centre Hospitalier Regional de Lanaudiere
city: Kingston
country: Canada
facility: Cancer Centre of Southeastern Ontario at Kingston
city: Levis
country: Canada
facility: L'Hotel-Dieu de Levis
city: London
country: Canada
facility: London Regional Cancer Program
city: Mississauga
country: Canada
facility: Credit Valley Hospital
city: Montreal
country: Canada
facility: CHUM - Hopital Notre-Dame
city: Montreal
country: Canada
facility: McGill University - Dept. Oncology
city: Montreal
country: Canada
facility: CHUM - Hotel Dieu du Montreal
city: Montreal
country: Canada
facility: CHUM - Pavillon Saint-Luc
city: Newmarket
country: Canada
facility: Stronach Regional Health Centre at Southlake
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa
city: Ottawa
country: Canada
facility: Ottawa Health Research Institute - General Division
city: Penticton
country: Canada
facility: Penticton Regional Hospital
city: Peterborough
country: Canada
facility: Peterborough Regional Health Centre
city: Quebec City
country: Canada
facility: CHUQ-Pavillon Hotel-Dieu de Quebec
city: Quebec City
country: Canada
facility: CHA-Hopital Du St-Sacrement
city: Quebec
country: Canada
facility: University Institute of Cardiology and
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
city: Saint John
country: Canada
facility: Atlantic Health Sciences Corporation
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
city: Sault Ste. Marie
country: Canada
facility: Algoma District Cancer Program
city: Sherbrooke
country: Canada
facility: Centre hospitalier universitaire de Sherbrooke
city: St. Catharines
country: Canada
facility: Niagara Health System
city: Sudbury
country: Canada
facility: Regional Cancer Program of the Hopital Regional
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Centre
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Science Centre
city: Toronto
country: Canada
facility: Toronto East General Hospital
city: Toronto
country: Canada
facility: Odette Cancer Centre
city: Toronto
country: Canada
facility: St. Michael's Hospital
city: Toronto
country: Canada
facility: Mount Sinai Hospital
city: Toronto
country: Canada
facility: Univ. Health Network-The Toronto General Hospital
city: Toronto
country: Canada
facility: Univ. Health Network-Princess Margaret Hospital
city: Toronto
country: Canada
facility: Women's College Hospital
city: Toronto
country: Canada
facility: St. Joseph's Health Centre
city: Toronto
country: Canada
facility: Trillium Health Centre - West Toronto
city: Toronto
country: Canada
facility: Humber River Regional Hospital
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
city: Victoria
country: Canada
facility: BCCA - Vancouver Island Cancer Centre
city: Windsor
country: Canada
facility: Windsor Regional Cancer Centre
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
Study officials:
affiliation: London Health Sciences Centre
name: Vivien HC Bramwell, MB, BS, PhD, FRCP
role: STUDY_CHAIR
References:
citation: Bramwell VHC, Pritchard KI, Tu D, et al.: How compliant are patients with oral hormonal therapies? Data from a randomized, placebo controlled study of tamoxifen after adjuvant chemotherapy in premenopausal women with early breast cancer (NCIC CTG MA.12). [Abstract] Breast Cancer Res Treat 106 (1): A-3055, 2007.
citation: Bramwell VH, Pritchard KI, Tu D, et al.: Tamoxifen (T) compared to placebo (P), after adjuvant chemotherapy (CT), in premenopausal women with early breast cancer (EBC): interim results of NCIC-CTG MA.12. [Abstract] J Clin Oncol 25 (Suppl 18): A-547, 2007.