Low-dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-negative Early Breast Cancer (22-00)

ETOP IBCSG Partners Foundation

Status and phase: Completed; Phase 3

Conditions: Breast Cancer

Treatments: Drug: Methotrexate; Drug: Cyclophosphamide

Study type: Interventional

Funder types: NETWORK

Identifiers

NCT00022516

2005-005666-36 (EudraCT Number)

CDR0000068827

EU-20119 (Registry Identifier)

IBCSG-22-00 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 1,086 patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,086 participants in 2 patient groups

No-CM

No Intervention group

Description:

No further chemotherapy following standard adjuvant chemotherapy.

CM-Maintenance

Experimental group

Description:

12-month CM-maintenance regimen (C, cyclophosphamide 50 mg/day orally continuously and M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week for 1 year)

Treatment:

Drug: Cyclophosphamide

Drug: Methotrexate