Clinical trial NCT00016432: Exemestane in Treating Postmenopausal Women With Resected Stage I, Stage II, or Stage IIIA Breast Cancer Who Have Completed 5 Years of Tamoxifen
Official title: A Randomized Trial Evaluating The Effect Of Exemestane In Clinical Stage T1-3 N0-1 M0 Postmenopausal Breast Cancer Patients Completing At Least Five Years Of Tamoxifen Therapy
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: NSABP Foundation Inc
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 1598
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using exemestane may fight breast cancer by reducing the production of estrogen by the tumor cells. It is not yet known whether exemestane is effective in preventing the recurrence of breast cancer.

PURPOSE: Randomized phase III trial to study the effectiveness of exemestane in preventing cancer recurrence in postmenopausal women who have resected stage I, stage II, or stage IIIA breast cancer and have completed 5 years of tamoxifen.

Detailed description: OBJECTIVES:

* Determine whether the administration of 5 years of exemestane after 5 years of tamoxifen therapy is more effective than 5 years of prior tamoxifen therapy alone in prolonging disease-free survival, overall survival, and time to treatment failure in postmenopausal women with resected stage I, II, or IIIA breast cancer.
* Determine the effect of tamoxifen withdrawal on bone, in terms of height, fractures, and total alkaline phosphatase in these patients and on bone mineral density and bone biochemical markers in a subset of patients.
* Determine the effect of exemestane on bone loss after tamoxifen withdrawal in these patients.
* Evaluate the quality of life of a subset of these patients.

OUTLINE: This is a randomized study. Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive oral exemestane daily for 5 years.
* Arm II (closed as of 10/15/03): Patients receive an oral placebo daily for 5 years.

Quality of life is assessed at baseline and then every 6 months for 5.5 years.

Patients are followed every 6 months for 6 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 3,000 patients will be accrued for this study within 3 years and 4 months.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed invasive adenocarcinoma of the breast at time of original diagnosis

  * Tumor confined to the breast and ipsilateral axilla on clinical exam (T1-3, N0-1, M0) (stage I-IIIA)
  * No ipsilateral lymph nodes clinically fixed to one another or to other structures (N2 disease) at time of original diagnosis
* Prior surgical resection, including 1 of the following:

  * Total mastectomy and axillary dissection (modified radical mastectomy) OR
  * Lumpectomy and axillary dissection

    * Prior post-lumpectomy breast radiotherapy required
  * Prior sentinel node biopsy allowed with the exception of the following:

    * If any sentinel node is histologically positive by hematoxylin and eosin (H \& E) OR histologically suspicious on H \& E and confirmed positive by immunohistochemistry then the patient must have a complete axillary dissection
  * Previously resected margins must be clear of invasive tumor and ductal carcinoma in situ
* Currently disease free
* Previously treated with tamoxifen for 57-66 months

  * Completed tamoxifen within the past 180 days
* No bilateral malignancy or mass in the opposite breast suspicious for malignancy unless biopsy proven negative
* No local, regional, or distant recurrence of disease or second primary breast malignancy (including contralateral breast cancer)
* No advanced disease at time of original diagnosis (e.g., ulceration, erythema, infiltration of the skin or underlying chest wall \[complete fixation\], peau d'orange, or skin edema of any magnitude)

  * Tethering or dimpling of the skin or nipple inversion allowed
* Current skeletal pain allowed if a bone scan and/or radiologic exam is negative for metastatic disease
* Hormone receptor status:

  * Primary tumor estrogen receptor (ER) positive AND/OR
  * Progesterone receptor positive
  * Borderline ER positive tumors allowed if previously treated with tamoxifen

PATIENT CHARACTERISTICS:

Age:

* Postmenopausal

Sex:

* Female

Menopausal status:

* Postmenopausal, defined as 1 of the following:

  * Prior bilateral oophorectomy
  * Absence of spontaneous menstrual cycle for more than 1 year
  * Follicle-stimulating hormone within the postmenopausal range if under 55 and had a prior hysterectomy without a bilateral oophorectomy

Performance status:

* Not specified

Life expectancy:

* At least 10 years

Hematopoietic:

* Absolute granulocyte count at least 1,500/mm\^3
* Platelet count at least 100,000/mm\^3
* Hemoglobin normal

Hepatic:

* Bilirubin less than 2 times upper limit of normal (ULN)
* SGOT or SGPT no greater than 2.5 times ULN
* Alkaline phosphatase less than 2 times ULN
* No systemic hepatic disease that would preclude study participation

Renal:

* Creatinine no greater than 1.5 times ULN
* No systemic renal disease that would preclude study participation

Cardiovascular:

* No systemic cardiovascular disease that would preclude study participation

Other:

* No other malignancy within the past 5 years except effectively treated squamous cell or basal cell skin cancer, surgically treated carcinoma in situ of the cervix, or surgically treated lobular carcinoma in situ of the ipsilateral or contralateral breast
* No nonmalignant systemic disease that would preclude study participation
* No psychiatric or addictive disorder that would preclude informed consent
* Not pregnant

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* Not specified

Chemotherapy:

* Prior adjuvant chemotherapy allowed if administered concurrently with or prior to tamoxifen

Endocrine therapy:

* See Disease Characteristics
* No concurrent estrogen, progesterone, clomiphene, testosterone, gonadotropin-releasing hormone, oral contraceptives, selective estrogen-receptor modulators, or dehydroepiandrosterone (DHEA)

  * Estring or estrogen vaginal cream at 0.3 mg or 1/8 of an applicator applied vaginally 3 times a week allowed
* No other concurrent systemic hormonal therapy (e.g., tamoxifen or raloxifene)

Radiotherapy:

* See Disease Characteristics
* Prior post-mastectomy loco-regional radiotherapy or post-lumpectomy regional radiotherapy allowed

Surgery:

* See Disease Characteristics

Other:

* Prior participation in other adjuvant NSABP study allowed if study was reported in peer-review publication or tamoxifen was not a study drug
* Concurrent bisphosphonates or calcitonin for prevention or treatment of osteoporosis allowed
* Concurrent statins (simvastatin, pravastatin, fluvastatin, atorvastatin, or lovastatin) or other drugs to control lipid levels allowed

Primary outcomes:
measure: Disease-free survival
timeFrame: Every 12 months until breast cancer recurrence, second primary cancer or death from any cause.
Secondary outcomes:
measure: Overall survival
timeFrame: Death from any cause
measure: Time to treatment failure
timeFrame: time from randomization to recurrence or contralateral second primary cancer
measure: Bone measure as measured by total alkaline phosphatase, fracture history, and height measurement
timeFrame: measurements taken at regular intervals from randomization through 6 years following randomiztion
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: Comprehensive Cancer Institute of Huntsville
state: Alabama
city: Phoenix
country: United States
facility: CCOP - Greater Phoenix
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Fresno
country: United States
facility: California Cancer Center
state: California
city: Greenbrae
country: United States
facility: Sutter Health Western Division Cancer Research Group
state: California
city: La Jolla
country: United States
facility: Scripps Cancer Center
state: California
city: La Jolla
country: United States
facility: Rebecca and John Moores UCSD Cancer Center
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Cancer Institute
state: California
city: Long Beach
country: United States
facility: Pacific Shores Medical Group
state: California
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center, UCLA
state: California
city: Orange
country: United States
facility: Chao Family Comprehensive Cancer Center
state: California
city: Palm Springs
country: United States
facility: Comprehensive Cancer Centers of the Desert
state: California
city: Sacramento
country: United States
facility: Sutter Cancer Center
state: California
city: San Diego
country: United States
facility: Kaiser Permanente Medical Center/Kaiser Foundation Hospital - San Diego
state: California
city: Santa Rosa
country: United States
facility: CCOP - Santa Rosa Memorial Hospital
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Vallejo
country: United States
facility: Kaiser Permanente Medical Center - Vallejo
state: California
city: Denver
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Denver
country: United States
facility: CCOP - Colorado Cancer Research Program, Incorporated
state: Colorado
city: Farmington
country: United States
facility: University of Connecticut
state: Connecticut
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Newark
country: United States
facility: CCOP - Christiana Care Health Services
state: Delaware
city: Washington
country: United States
facility: George Washington University Medical Center
state: District of Columbia
city: Clearwater
country: United States
facility: Morton Plant Hospital
state: Florida
city: Daytona Beach
country: United States
facility: Halifax Medical Center
state: Florida
city: Jacksonville
country: United States
facility: Baptist Regional Cancer Institute - Jacksonville
state: Florida
city: Miami Beach
country: United States
facility: CCOP - Mount Sinai Medical Center
state: Florida
city: Miami
country: United States
facility: Sylvester Cancer Center, University of Miami
state: Florida
city: Orlando
country: United States
facility: MD Anderson Cancer Center Orlando
state: Florida
city: Plantation
country: United States
facility: Cancer Research Network Inc.
state: Florida
city: Sarasota
country: United States
facility: Oncology Hematology Consultants
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Augusta
country: United States
facility: Medical College of Georgia
state: Georgia
city: Fort Gordon
country: United States
facility: Dwight David Eisenhower Army Medical Center
state: Georgia
city: Honolulu
country: United States
facility: Cancer Center of Hawaii
state: Hawaii
city: Coeur d'Alene
country: United States
facility: North Idaho Cancer Center
state: Idaho
city: Belleville
country: United States
facility: Illinois Oncology, Ltd.
state: Illinois
city: Chicago
country: United States
facility: Rush-Presbyterian-St. Luke's Medical Center
state: Illinois
city: Chicago
country: United States
facility: Illinois Masonic Medical Center
state: Illinois
city: Decatur
country: United States
facility: CCOP - Central Illinois
state: Illinois
city: Elk Grove Village
country: United States
facility: Alexian Brothers Medical Center
state: Illinois
city: Evanston
country: United States
facility: CCOP - Evanston
state: Illinois
city: Oak Park
country: United States
facility: West Suburban Hospital Medical Center
state: Illinois
city: Peoria
country: United States
facility: CCOP - Illinois Oncology Research Association
state: Illinois
city: Urbana
country: United States
facility: CCOP - Carle Cancer Center
state: Illinois
city: Indianapolis
country: United States
facility: Clarian Health Partners Inc.
state: Indiana
city: Indianapolis
country: United States
facility: St. Vincent Hospital and Health Care Center
state: Indiana
city: South Bend
country: United States
facility: CCOP - Northern Indiana CR Consortium
state: Indiana
city: Davenport
country: United States
facility: Genesis Medical Center
state: Iowa
city: Des Moines
country: United States
facility: CCOP - Iowa Oncology Research Association
state: Iowa
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center
state: Iowa
city: Wichita
country: United States
facility: CCOP - Wichita
state: Kansas
city: Lexington
country: United States
facility: Lucille Parker Markey Cancer Center, University of Kentucky
state: Kentucky
city: Louisville
country: United States
facility: Norton Healthcare System
state: Kentucky
city: Louisville
country: United States
facility: Consultants in Blood Disorders and Cancer
state: Kentucky
city: New Orleans
country: United States
facility: Louisiana State University Medical Center - New Orleans
state: Louisiana
city: New Orleans
country: United States
facility: Tulane University Medical Center
state: Louisiana
city: New Orleans
country: United States
facility: CCOP - Ochsner
state: Louisiana
city: Bangor
country: United States
facility: Eastern Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: Franklin Square Hospital Center
state: Maryland
city: Bethesda
country: United States
facility: National Naval Medical Center
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Clinic - Burlington
state: Massachusetts
city: Pittsfield
country: United States
facility: Berkshire Medical Center
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: CCOP - Michigan Cancer Research Consortium
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: East Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Grand Rapids
country: United States
facility: CCOP - Grand Rapids
state: Michigan
city: Kalamazoo
country: United States
facility: CCOP - Kalamazoo
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital
state: Michigan
city: Southfield
country: United States
facility: Providence Hospital - Southfield
state: Michigan
city: Duluth
country: United States
facility: CCOP - Duluth
state: Minnesota
city: Minneapolis
country: United States
facility: Abbott-Northwestern Hospital
state: Minnesota
city: Saint Louis Park
country: United States
facility: CCOP - Metro-Minnesota
state: Minnesota
city: Columbia
country: United States
facility: Ellis Fischel Cancer Center - Columbia
state: Missouri
city: Kansas City
country: United States
facility: CCOP - Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis University Health Sciences Center
state: Missouri
city: Saint Louis
country: United States
facility: CCOP - St. Louis-Cape Girardeau
state: Missouri
city: Springfield
country: United States
facility: CCOP - Cancer Research for the Ozarks
state: Missouri
city: Billings
country: United States
facility: CCOP - Montana Cancer Consortium
state: Montana
city: Omaha
country: United States
facility: CCOP - Missouri Valley Cancer Consortium
state: Nebraska
city: Omaha
country: United States
facility: Methodist Hospital Cancer Center - Omaha
state: Nebraska
city: Las Vegas
country: United States
facility: CCOP - Southern Nevada Cancer Research Foundation
state: Nevada
city: Hackensack
country: United States
facility: CCOP - Northern New Jersey
state: New Jersey
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey
state: New Jersey
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: MBCCOP - University of New Mexico HSC
state: New Mexico
city: Albany
country: United States
facility: New York Oncology Hematology, P.C.
state: New York
city: Bronx
country: United States
facility: Lincoln Medical and Mental Health Center
state: New York
city: Bronx
country: United States
facility: MBCCOP-Our Lady of Mercy Cancer Center
state: New York
city: Glens Falls
country: United States
facility: Glens Falls Hospital
state: New York
city: Staten Island
country: United States
facility: Staten Island University Hospital
state: New York
city: Syracuse
country: United States
facility: CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.
state: New York
city: Burlington
country: United States
facility: Alamance Cancer Center
state: North Carolina
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center, UNC
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University School of Medicine
state: North Carolina
city: Winston-Salem
country: United States
facility: CCOP - Southeast Cancer Control Consortium
state: North Carolina
city: Winston-Salem
country: United States
facility: Comprehensive Cancer Center at Wake Forest University
state: North Carolina
city: Fargo
country: United States
facility: CCOP - Merit Care Hospital
state: North Dakota
city: Akron
country: United States
facility: Akron City Hospital
state: Ohio
city: Canton
country: United States
facility: Aultman Cancer Center
state: Ohio
city: Cincinnati
country: United States
facility: Jewish Hospital of Cincinnati, Inc.
state: Ohio
city: Cincinnati
country: United States
facility: Barrett Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Ireland Cancer Center
state: Ohio
city: Columbus
country: United States
facility: CCOP - Columbus
state: Ohio
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital - Ohio State University
state: Ohio
city: Kettering
country: United States
facility: CCOP - Dayton
state: Ohio
city: Toledo
country: United States
facility: CCOP - Toledo Community Hospital
state: Ohio
city: Warrensville Heights
country: United States
facility: South Pointe Hospital - Cancer Care Center
state: Ohio
city: Tulsa
country: United States
facility: CCOP - Oklahoma
state: Oklahoma
city: Portland
country: United States
facility: CCOP - Columbia River Oncology Program
state: Oregon
city: Allentown
country: United States
facility: Lehigh Valley Hospital
state: Pennsylvania
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Kimmel Cancer Center of Thomas Jefferson University - Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Albert Einstein Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute
state: Pennsylvania
city: Reading
country: United States
facility: Reading Hospital and Medical Center
state: Pennsylvania
city: Scranton
country: United States
facility: Mercy Hospital Cancer Center - Scranton
state: Pennsylvania
city: Wynnewood
country: United States
facility: CCOP - MainLine Health
state: Pennsylvania
city: York
country: United States
facility: York Cancer Center
state: Pennsylvania
city: Greenville
country: United States
facility: CCOP - Greenville
state: South Carolina
city: Spartanburg
country: United States
facility: CCOP - Upstate Carolina
state: South Carolina
city: Sioux Falls
country: United States
facility: CCOP - Sioux Community Cancer Consortium
state: South Dakota
city: Knoxville
country: United States
facility: Thompson Cancer Survival Center
state: Tennessee
city: Dallas
country: United States
facility: Center for Oncology Research and Treatment, Medical City Hospital
state: Texas
city: Dallas
country: United States
facility: Simmons Cancer Center - Dallas
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Lubbock
country: United States
facility: Joe Arrington Cancer Research and Treatment Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Temple
country: United States
facility: CCOP - Scott and White Hospital
state: Texas
city: Provo
country: United States
facility: Utah Valley Regional Medical Center - Provo
state: Utah
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Bennington
country: United States
facility: Green Mountain Oncology Group
state: Vermont
city: Burlington
country: United States
facility: Vermont Cancer Center
state: Vermont
city: Newport News
country: United States
facility: Virginia Oncology Associates - Newport News
state: Virginia
city: Norfolk
country: United States
facility: Eastern Virginia Medical School
state: Virginia
city: Richmond
country: United States
facility: Massey Cancer Center
state: Virginia
city: Roanoke
country: United States
facility: Oncology and Hematology Associates of Southwest Virginia, Inc.
state: Virginia
city: Seattle
country: United States
facility: CCOP - Virginia Mason Research Center
state: Washington
city: Seattle
country: United States
facility: Puget Sound Oncology Consortium
state: Washington
city: Tacoma
country: United States
facility: CCOP - Northwest
state: Washington
city: Charleston
country: United States
facility: Camcare Health
state: West Virginia
city: Parkersburg
country: United States
facility: Camden-Clark Memorial Hospital
state: West Virginia
city: Green Bay
country: United States
facility: St. Vincent Hospital
state: Wisconsin
city: Marshfield
country: United States
facility: CCOP - Marshfield Medical Research and Education Foundation
state: Wisconsin
city: Milwaukee
country: United States
facility: St. Luke's Medical Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin Cancer Center
state: Wisconsin
city: Calgary
country: Canada
facility: Tom Baker Cancer Center - Calgary
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency
state: British Columbia
city: Mississauga
country: Canada
facility: Credit Valley Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto Sunnybrook Regional Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Montreal
country: Canada
facility: Royal Victoria Hospital - Montreal
state: Quebec
city: Montreal
country: Canada
facility: Montreal General Hospital
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital - Montreal
state: Quebec
city: Montreal
country: Canada
facility: St. Mary's Hospital Center
state: Quebec
city: Quebec City
country: Canada
facility: Hopital du Saint-Sacrement, Quebec
state: Quebec
city: San Juan
country: Puerto Rico
facility: MBCCOP - San Juan
Study officials:
affiliation: NSABP Foundation Inc
name: Norman Wolmark, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol. 2008 Apr 20;26(12):1965-71. doi: 10.1200/JCO.2007.14.0228. Epub 2008 Mar 10.
citation: Mamounas E, Jeong J-H, Wickerham L, et al.: Benefit from exemestane (EXE) as extended adjuvant therapy after 5 years of tamoxifen (TAM): intent-to-treat analysis of NSABP B-33. [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-49, S22, 2006.