Low-dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-negative Early Breast Cancer

Study Overview
=================
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.

Official Title
-----------------
Low-dose Cytotoxics as Anti-angiogenesis Treatment Following Adjuvant Induction Chemotherapy for Patients With ER-negative and PgR-negative Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide
* Drug: Methotrexate


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No-CM<br>No further chemotherapy following standard adjuvant chemotherapy. | |
| Experimental: CM-Maintenance<br>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) | Drug: Cyclophosphamide<br>* 50 mg/day orally continuously for 1 year<br>* Other names: Cytoxan;Drug: Methotrexate<br>* 2.5 mg twice/day orally days 1 and 2 of every week for 1 year<br>* Other names: Trexall;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival | Estimated percentage of patients alive and disease-free at 5 years from randomization, where disease-free survival is defined as the time from randomization to the first appearance of one of the following: invasive breast cancer recurrence at local, regional, or distant site, invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without cancer event; or censored at date of last follow-up. | 5-year estimates, reported at a median follow-up of 6.9 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Estimated percentage of patients alive and disease-free at 5 years from randomization, where overall survival is defined as the time from randomization to death from any cause; or censored at date last known alive. | 5-year estimates, reported at a median follow-up of 6.9 years | 
| Distant Recurrence-free Interval | Estimated percentage of patients alive and disease-free at 5 years from randomization, where distant recurrence-free Interval is defined as the time from randomization to invasive breast cancer recurrence at distant site, or invasive contralateral breast cancer; or censored at date of last follow up. | 5-year estimates, reported at a median follow-up of 6.9 years | 
| Breast Cancer-free Interval | Estimated percentage of patients alive and disease-free at 5 years from randomization, where breast cancer-free interval is defined as the time from randomization to invasive breast cancer recurrence at local, regional, or distant site, or invasive contralateral breast cancer; or censored at date of last follow up. | 5-year estimates, reported at a median follow-up of 6.9 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
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