RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using exemestane or tamoxifen may fight cancer by blocking the uptake of estrogen. PURPOSE: Randomized phase II/III trial to compare the effectiveness of exemestane with that of tamoxifen in treating postmenopausal women who have locally recurrent or metastatic breast cancer.

Condition	Treatment or Intervention	Phase
stage IV breast cancer recurrent breast cancer	Procedure: hormone therapy  Procedure: endocrine therapy  Procedure: antiestrogen therapy  Drug: aromatase inhibition  Drug: exemestane  Drug: tamoxifen	Phase III

Further Study Details: 

OBJECTIVES: I. Compare the efficacy of exemestane vs tamoxifen, in terms of progression-free survival, in postmenopausal women with locally recurrent or metastatic breast cancer. II. Determine the safety profile of exemestane in these patients. III. Compare the overall survival of these patients treated with these regimens.

PROTOCOL OUTLINE: This is a randomized, multicenter study. (Phase II of this study closed as of 6/14/00). Patients are stratified by participating center, prior adjuvant tamoxifen (yes vs no), prior chemotherapy for metastatic disease (yes vs no), and dominant site of metastasis (visceral with or without others vs bone only vs bone and soft tissue vs soft tissue only). Patients are randomized to receive either oral exemestane or oral tamoxifen daily. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 18 months and then at least every 6 months thereafter.

PROJECTED ACCRUAL: A total of 768 patients will be accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Female

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

Histologically or cytologically proven adenocarcinoma of the breast that is metastatic and progressive or locally recurrent and inoperable

At least one bidimensionally measurable or evaluable lesion

• Lytic bone lesions on x-ray/CT scan, surrounded by calcified bone, and at least 1 cm
• Bidimensionally measurable extraosseous disease required for patients on bisphosphonates
• The following are not considered evaluable: *Previously irradiated lesions *Lymphangitic spread *Ascites *Blastic bone lesions *Pleural effusions

No rapidly progressive disease for which hormonal therapy is not indicated

No massive visceral disease (i.e., more than one third of any organ)

No brain metastases

Hormone receptor status:

• Estrogen receptor positive or progesterone receptor positive, defined by 1 of the following: *At least 10 femtomoles H3-estrogen or at least 20 femtomoles *H3 progesterone binding per mg of cytosol protein by DCC or sucrose density method *At least 0.10 femtomoles H3-estrogen or at least 0.20 femtomoles *H3-progesterone binding per mg of DNA by IF/EIA technique *Positive immunohistochemistry noted on pathology report
• Unknown receptor status eligible provided: Disease-free interval of at least 2 years since adjuvant therapy or initial surgery (if no adjuvant therapy), including most recently treated tumor in bilateral breast cancer if status unknown in one primary tumor

--Prior/Concurrent Therapy--

Biologic therapy: No concurrent immunotherapy

Chemotherapy:

• See Disease Characteristics
• At least 3 weeks since chemotherapy for metastatic disease and recovered
• No more than 1 prior chemotherapy regimen for metastatic disease
• Prior adjuvant chemotherapy allowed if disease free for at least 6 months
• No concurrent chemotherapy

Endocrine therapy:

• No prior hormonal therapy for advanced disease (e.g., tamoxifen or LHRH agonists)
• Prior adjuvant tamoxifen allowed if disease free for at least 6 months
• No other concurrent hormonal therapy, including steroids

Radiotherapy:

• Recovered from toxic effects of prior radiotherapy
• Concurrent palliative radiotherapy, including whole brain irradiation, allowed

Surgery:

• See Disease Characteristics
• No prior ovariectomy for advanced disease

Other:

• No other concurrent investigational drugs
• Concurrent bisphosphonates allowed if short term (7 days) for hypercalcemia due to suspect tumor flare or if on prior bisphosphonates with bidimensionally measurable extraosseous lesion

--Patient Characteristics--

Age: 18 and over

Sex: Female

Menopausal status: Postmenopausal by 1 of the following:

• Natural menopause and more than 1 year since last menstrual period (LMP)
• Radiation-induced oophorectomy and more than 1 year since LMP
• Chemotherapy induced menopause if: *At least 1 year since LMP (+ 1 year post-tamoxifen) *Serum FSH and LH and plasma estradiol levels in postmenopausal range *LHRH-induced amenorrhea
• Surgical castration - Patients under age 56 with prior hysterectomy and 1 or both ovaries intact or tamoxifen-induced amenorrhea with at least 12 months since prior tamoxifen must have postmenopausal serum FSH and LH and plasma estradiol concentrations

Performance status: ECOG (WHO) 0-2

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm3
• Platelet count at least 100,000/mm3

Hepatic:

• Bilirubin less than 1.5 times upper limit of normal (ULN)
• SGOT/SGPT less than 2.5 times ULN (less than 5 times ULN with liver metastases)

Renal: Creatinine less than 1.5 times ULN

Cardiovascular: No deep venous thrombosis

Other:

• No mental incapacitation
• No severe concurrent disease
• No prior or concurrent malignancy except curatively treated carcinoma in situ of the cervix or basal cell or squamous cell skin cancer

Australia
      Bankstown - Lidcombe Hospital, Bankstown,  NSW 2200,  Australia
Australia, New South Wales
      Liverpool Hospital, Liverpool,  New South Wales,  2170,  Australia
Australia, Queensland
      Princess Alexandra Hospital, Brisbane,  Queensland,  4102,  Australia
Australia, Victoria
      Austin Hospital, Heidelberg,  Victoria,  3084,  Australia
Belgium
      Algemeen Ziekenhuis Middelheim, Antwerp,  2020,  Belgium
      Algemeen Ziekenhuis Sint-Augustinus, Wilrijk,  2610,  Belgium
      Centre Hospitalier Etterbeek Ixelles, Brussels (Bruxelles),  B-1050,  Belgium
      Centre Hospitalier Universitaire de Tivoli, La Louviere,  7100,  Belgium
      Clinique Sainte Elisabeth, Namur,  5000,  Belgium
      Hopital de Jolimont, Haine-Saint-Paul,  7100,  Belgium
      Institut Jules Bordet, Brussels (Bruxelles),  1000,  Belgium
      U.Z. Gasthuisberg, Leuven,  B-3000,  Belgium
France
      Centre de Lutte Contre le Cancer, Georges-Francois Leclerc, Dijon,  21079,  France
      Centre Eugene Marquis, Rennes,  35064,  France
      Centre Henri Becquerel, Rouen,  76038,  France
      Centre Jean Perrin, Clermont-Ferrand,  63011,  France
      Centre Leon Berard, Lyon,  69373,  France
      Centre Regional Francois Baclesse, Caen,  14076,  France
      Centre Rene Huguenin, Saint Cloud,  92211,  France
      Institut Bergonie, Bordeaux,  33076,  France
Malaysia
      University of Malaysia Medical Center, Kuala Lumpur,  59100,  Malaysia
Netherlands
      Academisch Ziekenhuis Maastricht, Maastricht,  6202 AZ,  Netherlands
      Antoni van Leeuwenhoekhuis, Amsterdam,  1066 CX,  Netherlands
      Catharina Ziekenhuis, Eindhoven,  5602 ZA,  Netherlands
      Diakonessenhuis Utrecht, Utrecht,  3508 TG,  Netherlands
      Leiden University Medical Center, Leiden,  2300 CA,  Netherlands
      Leyenburg Ziekenhuis, 's-Gravenhage (Den Haag, The Hague),  2545 CH,  Netherlands
      Maasland Hospital, Sittard,  6131 BK,  Netherlands
      Medisch Centrum Haaglanden Locatle Antoniushove, Leidschendam,  2262 BA,  Netherlands
      Onze Lieve Vrouwe Gasthuis, Amsterdam,  1091 HA,  Netherlands
      Rotterdam Cancer Institute, Rotterdam,  3075 EA,  Netherlands
      Saint Laurentius Ziekenhuis, Roermond,  6043 CV,  Netherlands
      Sint Joseph Ziekenhuis, Veldhoven,  5500 MB DB,  Netherlands
      St. Elisabeth Ziekenhuis, Tilburg,  5022 GC,  Netherlands
      University Medical Center Nijmegen, Nijmegen,  NL-6500 HB,  Netherlands
      Waterlandziekenhuis, Purmerend,  1440 AG,  Netherlands
      Ziekenhuis Eemland de Lichtenberg, Amersfont,  3016 CP,  Netherlands
Philippines
      Chong Hua Medical Arts Center, Cebu City,  6000,  Philippines
Poland
      Medical University of Gdansk, Gdansk,  80-211,  Poland
Russian Federation
      Petrov Research Institute of Oncology, Saint Petersburg,  197758,  Russian Federation
      Russian Academy of Medical Sciences Cancer Research Center, Moscow,  115478,  Russian Federation
Slovenia
      Institute of Oncology, Ljubljana, LJUBLJANA,  Sl-1000,  Slovenia
Taiwan, Province of China
      Tri-Service General Hospital, Taipei,  NEIHU- 114,  Taiwan, Province of China
Thailand
      Siriraj Hospital, Bangkok,  10700,  Thailand
United Kingdom, England
      Guy's and St. Thomas' Hospitals Trust, London,  England,  SE1 9RT,  United Kingdom
      South Tees Hospitals NHS Trust, Middlesbrough, Cleveland,  England,  TS4 3BW,  United Kingdom
      Weston Park Hospital, Sheffield,  England,  S1O 2SJ,  United Kingdom
United Kingdom, Scotland
      Western General Hospital, Edinburgh,  Scotland,  EH4 2XU,  United Kingdom

Study chairs or principal investigators

Robert Paridaens,  Study Chair,  EORTC Breast Cancer Cooperative Group   

Study ID Numbers:  CDR0000064764; EORTC-10951; PHARMACIA-EORTC-10951
Record last reviewed:  April 2003
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002777
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08