Clinical trial NCT00754845: Letrozole in Breast Cancer Who Have Received 5 Years of Aromatase Inhibitor Therapy
Official title: A Double Blind Randomization to Letrozole or Placebo for Women Previously Diagnosed With Primary Breast Cancer Completing Five Years of Adjuvant Aromatase Inhibitor Either as Initial Therapy or After Tamoxifen (Including Those in The MA.17 Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: Eastern Cooperative Oncology Group
name: North Central Cancer Treatment Group
name: SWOG Cancer Research Network
name: Alliance for Clinical Trials in Oncology
First posted: 2008-09-18
Enrollment: 1918
Sex: FEMALE
Minimum age (years): 0
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 cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether letrozole is more effective than a placebo in treating in women with breast cancer who have already received 5 years of aromatase inhibitor therapy.

PURPOSE: This randomized phase III trial is studying letrozole to see how well it works compared with a placebo in treating women with primary breast cancer who have received 5 years of aromatase inhibitor therapy.

Detailed description: OBJECTIVES:

Primary

* To compare the disease-free survival of women with primary breast cancer treated with letrozole vs placebo after completing approximately 5 years (i.e., 4½ - 6 years) of aromatase inhibitor therapy (e.g., letrozole, anastrozole, or exemestane).

Secondary

* To compare the effect of these drugs on overall (all cause specific) mortality of these patients.
* To compare the incidence of contralateral breast cancer in patients treated with these drugs.
* To evaluate the long-term clinical and laboratory safety of aromatase inhibitor therapy, particularly cardiovascular morbidity and mortality (e.g., significant coronary artery disease, including myocardial infarction and angina requiring percutaneous transluminal coronary angioplasty or coronary artery bypass graft, fatal and nonfatal strokes, and all vascular deaths); incidence of all bone fractures (with particular emphasis on hip and wrist fractures as indicators of osteoporosis); changes in bone density; and common toxicities.
* To compare overall quality of life (QOL) and menopausal-specific QOL of patients treated with these drugs.

OUTLINE: This is a multicenter study. Patients are stratified according to lymph node status at diagnosis (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), interval between last dose of aromatase inhibitor therapy and study randomization (\< 6 months vs 6 months to 2 years), and duration of prior tamoxifen citrate use (0 vs \< 2 years vs 2 - 4½ years vs \> 4½ years). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive oral letrozole once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
* Arm II: Patients receive oral placebo once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.

Patients undergo bone mineral density measurement by DEXA scan at baseline (if not done within 12 months of study entry), at 24 and 48 months during study therapy, and at the completion of study therapy. Some patients also complete quality-of-life questionnaires at baseline and at 12, 24, 36, 48, and 60 months.

After completion of study therapy, patients are followed annually.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Previously diagnosed with primary breast cancer
* Must have received 4½ - 6 years of aromatase inhibitor therapy (e.g., letrozole, anastrozole, or exemestane), either as initial therapy or after prior tamoxifen citrate, including treatment received as part of clinical trial CAN-NCIC-MA17

  * Completed aromatase inhibitor therapy ≤ 2 years ago
* No metastatic or recurrent disease, contralateral breast cancer, or ductal carcinoma in situ in either breast, as determined by the following:

  * Clinical examination of the breast area, axillae, and neck within the past 60 days
  * Mammogram within the past 12 months\*
  * Chest x-ray within the past 60 days
  * Bone scan, if alkaline phosphatase \> 2 times normal and/or there are symptoms of metastatic disease AND confirmatory x-ray, if bone scan results are questionable, within the past 60 days
  * Abdominal ultrasound, liver scan, or CT scan of the abdomen within the past 60 days, if ALT, AST, or alkaline phosphatase \> 2 times normal NOTE: \*A baseline mammogram is not required for patients who have undergone bilateral complete mastectomy
* Hormone-receptor status:

  * Estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) primary tumor at the time of diagnosis, defined as a tumor receptor content of \> 10 fmol/mg protein or receptor positive by immunocytochemical assay (for patients not previously enrolled on clinical trial CAN-NCIC-MA17)
  * ER+ and/or PR+ primary tumor OR hormone receptor status of primary tumor unknown (for patients previously enrolled on clinical trial CAN-NCIC-MA17)

PATIENT CHARACTERISTICS:

* Menopausal status not specified
* ECOG performance status 0-2
* Life expectancy ≥ 5 years
* WBC \> 3.0 x 10\^9/L OR granulocyte count (polymorphs + bands) ≥ 1.5 times 10\^9/L
* Platelet count \> 100 x 10\^9/L
* AST and/or ALT \< 2 times upper limit of normal (ULN)\*
* Alkaline phosphatase \< 2 times ULN\*
* Able (i.e. sufficiently fluent) and willing to complete quality-of-life questionnaires in either English or French (NCIC CTG participating centers)

  * Inability to complete questionnaires due to illiteracy in English or French, loss of sight, or other equivalent reason allowed
* Accessible for treatment and follow-up
* No other prior or concurrent malignancy except adequately treated, superficial squamous cell or basal cell skin cancer, carcinoma in situ of the cervix, or other cancer treated \> 5 years ago that is presumed cured NOTE: \*Elevated levels allowed provided imaging examinations have ruled out metastatic disease

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No concurrent selective estrogen receptor modulator (e.g., raloxifene, idoxifene)
* No other concurrent anticancer therapy

Primary outcomes:
measure: Disease-free Survival (DFS)
timeFrame: Unitil the end of study with a median follow up of 75 months
Secondary outcomes:
measure: Incidence of Contralateral Breast Cancer
timeFrame: 10 years
measure: Overall Survival (OS)
timeFrame: Until the end of study with a median follow-up of 75 months
measure: Change From Baseline in Role Function- Physical Scale on SF(Short Form)-36 Health Survey
timeFrame: 8 years
Other outcomes:
Locations:
city: Kelowna
country: Canada
facility: BCCA - Cancer Centre for the Southern Interior
state: British Columbia
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Centre
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Victoria
country: Canada
facility: BCCA - Vancouver Island Cancer Centre
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Moncton
country: Canada
facility: The Moncton Hospital
state: New Brunswick
city: Moncton
country: Canada
facility: The Vitalite Health Network - Dr. Leon Richard
state: New Brunswick
city: Saint John
country: Canada
facility: Atlantic Health Sciences Corporation
state: New Brunswick
city: St. John's
country: Canada
facility: Dr. H. Bliss Murphy Cancer Centre
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: QEII Health Sciences Center
state: Nova Scotia
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Cancer Centre of Southeastern Ontario at Kingston
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Mississauga
country: Canada
facility: Credit Valley Hospital
state: Ontario
city: Newmarket
country: Canada
facility: Stronach Regional Health Centre at Southlake
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa
state: Ontario
city: Sault Ste. Marie
country: Canada
facility: Algoma District Cancer Program
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health System
state: Ontario
city: Sudbury
country: Canada
facility: Northeast Cancer Center Health Sciences
state: Ontario
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Science Centre
state: Ontario
city: Toronto
country: Canada
facility: North York General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto East General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Odette Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: Univ. Health Network-Princess Margaret Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Joseph's Health Centre
state: Ontario
city: Toronto
country: Canada
facility: Trillium Health Centre - West Toronto
state: Ontario
city: Toronto
country: Canada
facility: Humber River Regional Hospital
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Cancer Centre
state: Ontario
city: Charlottetown
country: Canada
facility: PEI Cancer Treatment Centre,Queen Elizabeth Hospital
state: Prince Edward Island
city: Gatineau
country: Canada
facility: Centre de Sante et de services sociaux de Gatineau
state: Quebec
city: Greenfield Park
country: Canada
facility: Hopital Charles LeMoyne
state: Quebec
city: Levis
country: Canada
facility: L'Hotel-Dieu de Levis
state: Quebec
city: Montreal
country: Canada
facility: Hopital Maisonneuve-Rosemont
state: Quebec
city: Montreal
country: Canada
facility: McGill University - Dept. Oncology
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Hotel Dieu du Montreal
state: Quebec
city: Montreal
country: Canada
facility: Hopital du Sacre-Coeur de Montreal
state: Quebec
city: Quebec City
country: Canada
facility: CHA-Hopital Du St-Sacrement
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre hospitalier universitaire de Sherbrooke
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
Study officials:
affiliation: Massachusetts General Hospital
name: Paul E. Goss, MD, PhD
role: STUDY_CHAIR
References:
citation: Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, Gelmon K, Whelan T, Strasser-Weippl K, Rubin S, Sturtz K, Wolff AC, Winer E, Hudis C, Stopeck A, Beck JT, Kaur JS, Whelan K, Tu D, Parulekar WR. Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. N Engl J Med. 2016 Jul 21;375(3):209-19. doi: 10.1056/NEJMoa1604700. Epub 2016 Jun 5.
citation: Li Y, Zheng X, Tu D, Ingle JN, Goss PE, Parulekar WR, Qin G. Predicting the clinical outcomes and benefit from letrozole after 5 years of treatment with aromatase inhibitors for early breast cancer: analysis from CCTG MA.17R. Breast Cancer Res Treat. 2022 Feb;191(3):523-533. doi: 10.1007/s10549-021-06448-5. Epub 2021 Nov 26.
citation: Ethier JL, Anderson GM, Austin PC, Clemons M, Parulekar W, Shepherd L, Summers Trasiewicz L, Tu D, Amir E. Influence of the competing risk of death on estimates of disease recurrence in trials of adjuvant endocrine therapy for early-stage breast cancer: A secondary analysis of MA.27, MA.17 and MA.17R. Eur J Cancer. 2021 May;149:117-127. doi: 10.1016/j.ejca.2021.02.034. Epub 2021 Apr 11.
citation: Lemieux J, Brundage MD, Parulekar WR, Goss PE, Ingle JN, Pritchard KI, Celano P, Muss H, Gralow J, Strasser-Weippl K, Whelan K, Tu D, Whelan TJ. Quality of Life From Canadian Cancer Trials Group MA.17R: A Randomized Trial of Extending Adjuvant Letrozole to 10 Years. J Clin Oncol. 2018 Feb 20;36(6):563-571. doi: 10.1200/JCO.2017.75.7500. Epub 2018 Jan 12.