Clinical trial NCT00022516: Low-dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-negative Early Breast Cancer
Official title: Low-dose Cytotoxics as "Anti-angiogenesis Treatment" Following Adjuvant Induction Chemotherapy for Patients With ER-negative and PgR-negative Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: stage IA breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IB breast cancer
estrogen receptor-negative breast cancer
progesterone receptor-negative breast cancer
triple-negative breast cancer
low-dose maintenance chemotherapy
stroma
angiogenesis
Lead sponsor: ETOP IBCSG Partners Foundation
Sponsor class: NETWORK
First posted: 2003-01-27
Enrollment: 1086
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized, phase III trial was designed to test the efficacy of a low-dose chemotherapy-maintenance regimen, hypothesized to have anti-angiogenic activity, administered following standard chemotherapy in patients with early breast cancer whose tumors are hormone receptor negative.

Detailed description: PURPOSE:

* Evaluate a low-dose cyclophosphamide and methotrexate chemotherapy-maintenance regimen in early breast cancer.
* Compare the disease-free survival, overall survival, and systemic disease-free survival of patients treated with these regimens.
* Compare the toxic effects of these regimens in these patients.

OUTLINE:

This is a randomized, open-label, multicenter study. Patients are stratified according to participating center, menopausal status (pre vs post), and approved induction chemotherapy (anthracycline and cyclophosphamide vs other agents). Treatment duration is 12 months of low-dose chemotherapy-maintenance regimen (CM-maintenance) vs no chemotherapy-maintenance regimen (no-CM) following standard adjuvant chemotherapy. Patients are randomized to one of two treatment arms. Patients are followed every 6 months for 5 years, and yearly follow-up thereafter.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed stage I, II, or III breast cancer

  * T1-3, N0-2, M0

    * Patients with sentinel node biopsy positive disease must have undergone axillary dissection
    * Tumor must be confined to the breast without detected metastases elsewhere
  * T4 disease with minimal dermal invasion allowed
  * No T4 disease with ulceration of skin, infiltration of skin (except pathologically minimal dermal involvement), peau d'orange, or inflammatory breast cancer
* No bilateral breast cancer (except in situ carcinoma) or suspicious mass in opposite breast that has not been proven benign
* No distant metastases

  * No skeletal pain of unknown cause, elevated alkaline phosphatase, or bone scan showing hot spots that cannot be ruled out as metastases by x-ray, MRI, and/or CT
* Must have undergone prior total mastectomy OR breast-conserving procedure (e.g., lumpectomy, quadrantectomy, or partial mastectomy with negative margins) with radiotherapy planned

  * Patients must begin or have begun an approved induction chemotherapy regimen within 8 weeks after definitive surgery
* Negative surgical margins
* Axillary clearance with at least 6 lymph nodes examined OR negative sentinel node biopsy
* Known HER2 status by immunohistochemistry or fluorescence in situ hybridization
* Hormone receptor status:

  * Estrogen and progesterone receptor negative

    * Less than 10% positive tumor cells by immunohistochemistry

PATIENT CHARACTERISTICS:

Age:

* Not specified

Sex:

* Not specified

Menopausal status:

* Premenopausal, defined as less than 6 months since last menstrual period (LMP) AND no prior bilateral ovariectomy AND not on estrogen replacement (OR under age 50) OR
* Postmenopausal, defined as prior bilateral ovariectomy OR more than 12 months since LMP without prior hysterectomy (OR age 50 and over)

Performance status:

* Not specified

Life expectancy:

* Not specified

Hematopoietic:

* WBC greater than 3,000/mm3
* Platelet count greater than 100,000/mm3

Hepatic:

* See Disease Characteristics
* Bilirubin less than 2.0 mg/dL
* ALT less than 1.5 times upper limit of normal OR AST less than 60 IU/L

Renal:

* Creatinine less than 1.2 mg/dL

Other:

* Not pregnant or lactating within the past 6 months
* Fertile patients must use effective barrier contraception
* No other prior or concurrent malignancy except adequately treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or contralateral or ipsilateral in situ breast carcinoma
* No psychiatric or addictive disorders that would preclude study
* No non-malignant systemic disease that would preclude study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* Prior trastuzumab (Herceptin) allowed

Chemotherapy:

* See Disease Characteristics
* No prior adjuvant or neoadjuvant chemotherapy for breast cancer

Endocrine therapy:

* No prior endocrine therapy for breast cancer or prevention
* No prior tamoxifen or raloxifene for breast cancer

Radiotherapy:

* No prior radiotherapy for breast cancer except primary irradiation

Surgery:

* See Disease Characteristics

Other:

* No prior preventative therapy for breast cancer

Primary outcomes:
measure: Disease-free Survival
timeFrame: 5-year estimates, reported at a median follow-up of 6.9 years
Secondary outcomes:
measure: Overall Survival
timeFrame: 5-year estimates, reported at a median follow-up of 6.9 years
measure: Distant Recurrence-free Interval
timeFrame: 5-year estimates, reported at a median follow-up of 6.9 years
measure: Breast Cancer-free Interval
timeFrame: 5-year estimates, reported at a median follow-up of 6.9 years
Other outcomes:
Locations:
city: Tweed Heads
country: Australia
facility: Tweed Heads Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Queen Elizabeth Hospital
state: South Australia
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: East Ringwood
country: Australia
facility: Maroondah Hospital
state: Victoria
city: Wodonga
country: Australia
facility: Murray Valley Private Hospital and Cancer Treatment Centre
state: Victoria
city: Christchurch
country: Australia
facility: Christchurch Hospital
city: Liege
country: Belgium
facility: CHU Liege - Domaine Universitaire du Sart Tilman
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
state: Rio Grande do Sul
city: Santiago
country: Chile
facility: Fundacion Arturo Lopez Perez
city: Santiago
country: Chile
facility: Centro de Estudios Oncologicos Santiago
city: Santiago
country: Chile
facility: Hospital Clinico San Borja Arriaran
city: Santiago
country: Chile
facility: Hospital Clinico Universidad de Chile
city: Valparaiso
country: Chile
facility: Hospital Carlos Van Buren
city: Budapest
country: Hungary
facility: National Institute of Oncology - Budapest
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo
city: Biella
country: Italy
facility: Ospedale degli Infermi - ASL 12
city: Carpi
country: Italy
facility: Ospedale Civile Ramazzini
city: Lecco
country: Italy
facility: Ospedale Alessandro Manzoni
city: Milano
country: Italy
facility: European Institute of Oncology
city: Milan
country: Italy
facility: Ospedale San Paolo
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Rimini
country: Italy
facility: Ospedale Civile Rimini
city: Rome
country: Italy
facility: Ospedale Sant' Eugenio
city: Udine
country: Italy
facility: Policlinico Universitario Udine
city: Ibadan
country: Nigeria
facility: University of Ibadan Health Center
city: Lima
country: Peru
facility: Instituto Nacional de Enfermedades Neoplasicas
city: Cluj-Napoca
country: Romania
facility: Institutul Oncologic - Universitatea de Medicina
city: Johannesburg
country: South Africa
facility: Sandton Oncology Centre
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico della Svizzera Italiana - Ospedale San Giovanni
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden
city: Rheinfelden
country: Switzerland
facility: FMH Onkologie/Haematologie
city: St. Gallen
country: Switzerland
facility: Kantonsspital - St. Gallen
city: Thun
country: Switzerland
facility: Regionalspital
city: Zurich
country: Switzerland
facility: UniversitaetsSpital Zuerich
Study officials:
affiliation: European Institute of Oncology
name: Marco Colleoni, MD
role: STUDY_CHAIR
References:
citation: Colleoni M, Gray KP, Gelber S, Lang I, Thurlimann B, Gianni L, Abdi EA, Gomez HL, Linderholm BK, Puglisi F, Tondini C, Kralidis E, Eniu A, Cagossi K, Rauch D, Chirgwin J, Gelber RD, Regan MM, Coates AS, Price KN, Viale G, Goldhirsch A. Low-Dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-Negative Early Breast Cancer: International Breast Cancer Study Group Trial 22-00. J Clin Oncol. 2016 Oct 1;34(28):3400-8. doi: 10.1200/JCO.2015.65.6595. Epub 2016 Jun 20.
citation: Pruneri G, Gray KP, Vingiani A, Viale G, Curigliano G, Criscitiello C, Lang I, Ruhstaller T, Gianni L, Goldhirsch A, Kammler R, Price KN, Cancello G, Munzone E, Gelber RD, Regan MM, Colleoni M. Tumor-infiltrating lymphocytes (TILs) are a powerful prognostic marker in patients with triple-negative breast cancer enrolled in the IBCSG phase III randomized clinical trial 22-00. Breast Cancer Res Treat. 2016 Jul;158(2):323-31. doi: 10.1007/s10549-016-3863-3. Epub 2016 Jul 2.