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

Phase 3
Open (Enrolling)
Breast Cancer

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Trial Information

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


- Determine the efficacy of adjuvant induction chemotherapy with or without
cyclophosphamide and methotrexate as maintenance chemotherapy in patients with stage I,
II, or III 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.

- Compare the quality of life of patients treated with these regimens.

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 (doxorubicin and cyclophosphamide vs other agents). Patients are randomized to
one of two treatment arms.

- Arm I: Patients receive one of the following approved adjuvant induction chemotherapy

- AC comprising doxorubicin and cyclophosphamide IV on day 1 every 21 days for 4
courses followed by paclitaxel IV or docetaxel IV on day 1 every 21 days for 4

- EC comprising epirubicin and cyclophosphamide IV on day 1 every 21 days for 4
courses followed by paclitaxel IV or docetaxel IV on day 1 every 21 days for 4

- FAC comprising cyclophosphamide, doxorubicin, and fluorouracil IV on days 1 every
21 days for 4 courses

- Doxorubicin every 21 days for 4 courses followed by CMF comprising
cyclophosphamide IV, methotrexate IV, and fluorouracil IV on days 1 and 8 every 28
days for 4 courses

- AC OR EC and paclitaxel IV with filgrastim (G-CSF) every 14 days for 4 courses

- FEC comprising cyclophosphamide IV, epirubicin IV and fluorouracil IV on day 1
every 21 days for 3 courses followed by docetaxel IV on day 1 every 21 days for 3

- TAC comprising docetaxel, doxorubicin, and cyclophosphamide IV on day 1 every 21
days for 6 courses

- AT comprising doxorubicin IV and docetaxel IV every 21 days for 3 courses followed
by CMF for 3 courses

- Arm II: Patients receive adjuvant induction chemotherapy as in arm I. Beginning within
56 days after the first day of the last course of induction chemotherapy, patients
receive CM (maintenance chemotherapy) comprising oral cyclophosphamide once daily and
oral methotrexate two times a day twice weekly for 1 year.

Patients with breast-conserving surgery receive radiotherapy following completion of
induction chemotherapy.

Patients with HER2-positive primary breast cancer may also receive trastuzumab (Herceptin)
during or following induction, and/or during and following CM.

Quality of life is assessed at baseline, at the beginning of each course of induction
chemotherapy, and at months 9, 12, 18, and 24.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: Approximately 900 patients will be accrued for this study within 5 years.

Inclusion Criteria


- 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

- Must have undergone prior total mastectomy OR breast-conserving procedure (e.g.,
lumpectomy, quadrantectomy, or partial mastectomy with negative margins)

- Patients must begin or have begun induction chemotherapy within 8 weeks after
definitive surgery

- Negative surgical margins

- Axillary clearance with at least 6 lymph nodes examined OR

- Negative sentinel node biopsy OR

- Positive lymph nodes and unsuitable for taxane-based chemotherapy

- 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



- Not specified


- 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


- WBC greater than 3,000/mm3

- Platelet count greater than 100,000/mm3


- 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


- Creatinine less than 1.2 mg/dL


- 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


Biologic therapy:

- Prior trastuzumab (Herceptin) allowed


- 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


- No prior radiotherapy for breast cancer except primary irradiation


- See Disease Characteristics


- No prior preventative therapy for breast cancer

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Disease-free survival

Outcome Time Frame:

Estimated 10 years after last patient in

Safety Issue:


Principal Investigator

Marco Colleoni, MD

Investigator Role:

Study Chair

Investigator Affiliation:

European Institute of Oncology


Switzerland: Swissmedic

Study ID:




Start Date:

November 2000

Completion Date:

Related Keywords:

  • Breast Cancer
  • 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
  • Breast Neoplasms