Breast Cancer
Conditions
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
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.
Interventions
DRUGCyclophosphamide
50 mg/day orally continuously for 1 year
DRUGMethotrexate
2.5 mg twice/day orally days 1 and 2 of every week for 1 year
Sponsors
ETOP IBCSG Partners Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival | 5-year estimates, reported at a median follow-up of 6.9 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 5-year estimates, reported at a median follow-up of 6.9 years | 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. |
| Distant Recurrence-free Interval | 5-year estimates, reported at a median follow-up of 6.9 years | 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. |
| Breast Cancer-free Interval | 5-year estimates, reported at a median follow-up of 6.9 years | 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. |
Countries
Australia, Belgium, Brazil, Chile, Hungary, Italy, Nigeria, Peru, Romania, South Africa, Switzerland
Participant flow
Recruitment details
1086 patients were randomized between November 2000 and December 2012.
Participants by arm
| Arm | Count |
|---|---|
| No-CM No further chemotherapy following standard adjuvant chemotherapy. | 542 |
| CM-Maintenance 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)
Cyclophosphamide: 50 mg/day orally continuously for 1 year
Methotrexate: 2.5 mg twice/day orally days 1 and 2 of every week for 1 year | 544 |
| Total | 1,086 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 59 |
| Overall Study | Incomplete documentation | 0 | 27 |
| Overall Study | Lack of Efficacy | 0 | 27 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 113 |
Baseline characteristics
| Characteristic | No-CM | CM-Maintenance | Total |
|---|---|---|---|
| Age, Continuous | 52 years | 52 years | 52 years |
| Sex: Female, Male Female | 542 Participants | 544 Participants | 1086 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 58 / 473 |
| serious Total, serious adverse events | 0 / 0 | 11 / 473 |
Outcome results
Primary
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.
Time frame: 5-year estimates, reported at a median follow-up of 6.9 years
Population: Intention to treat (N=1081 patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No-CM | Disease-free Survival | 74.7 percentage of participants |
| CM-Maintenance | Disease-free Survival | 78.1 percentage of participants |
p-value: 0.1495% CI: [0.6, 1.06]Log Rank
Secondary
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.
Time frame: 5-year estimates, reported at a median follow-up of 6.9 years
Population: Intention-to-treat (N=1081 patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No-CM | Breast Cancer-free Interval | 77.3 percentage of participants |
| CM-Maintenance | Breast Cancer-free Interval | 81.0 percentage of participants |
p-value: 0.0695% CI: [0.6, 1.01]Log Rank
Secondary
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.
Time frame: 5-year estimates, reported at a median follow-up of 6.9 years
Population: Intention-to-treat (N=1081 patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No-CM | Distant Recurrence-free Interval | 83.5 percentage of participants |
| CM-Maintenance | Distant Recurrence-free Interval | 85.5 percentage of participants |
p-value: 0.317895% CI: [0.62, 1.17]Log Rank
Secondary
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.
Time frame: 5-year estimates, reported at a median follow-up of 6.9 years
Population: Intention to treat (N=1081 patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No-CM | Overall Survival | 85.0 percentage of participants |
| CM-Maintenance | Overall Survival | 85 percentage of participants |
p-value: 0.35795% CI: [0.65, 1.17]Log Rank