Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer
Condition: Breast Neoplasms
MeSH terms: Breast Neoplasms
Intervention: Doxorubicin; Cyclophosphamide; Docetaxel; Herceptin; Carboplatin
Intervention MeSH terms: Cyclophosphamide; Carboplatin; Docetaxel; Doxorubicin; Trastuzumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 3222.0
Sex: Female
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      Primary objective:

        -  Compare disease-free survival in women with human epidermal growth factor receptor 2
           (HER2)-neu-expressing node-positive or high-risk node-negative operable breast cancer
           treated with adjuvant doxorubicin, cyclophosphamide, and docetaxel with or without
           trastuzumab (Herceptin) vs trastuzumab, docetaxel, and carboplatin.

      Secondary objective:

        -  Compare overall survival of participants treated with these regimens.

        -  Compare the toxic effects (including cardiac) of these regimens in these participants.

        -  Compare quality of life of participants treated with these regimens.

        -  Compare pathologic and molecular markers for predicting efficacy of these regimens in
           these participants.

        -  For substudy: Compare peripheral levels of shed HER2-neu extracellular domain with
           fluorescence in situ hybridization in predicting outcome in participants treated with
           these regimens.
    

Eligibility criteria:

        Inclusion criteria:

          -  Written informed consent prior to beginning specific protocol procedures, including
             expected cooperation of the participants for treatment and follow-up.

          -  Accessible for treatment and follow-up at participating centers.

          -  Histologically proven breast cancer with an interval between definitive surgery that
             included axillary lymph node involvement assessment and registration of less than or
             equal to 60 days. A central pathology review might be performed post randomization for
             confirmation of diagnosis and molecular studies. The same block used for HER2neu
             determination prior to randomization might be used for the central pathology review.

          -  Definitive surgical treatment must be either mastectomy with axillary lymph node
             involvement assessment, or breast conserving surgery with axillary lymph node
             involvement assessment for operable breast cancer (T1-3, Clinical N0-1, M0). Margins
             of resected specimen from definitive surgery must be histologically free of invasive
             adenocarcinoma and/or ductal carcinoma in situ (DCIS).

          -  Participants must be either lymph node positive or high risk node negative. Lymph node
             positive participants were to be defined as participants having invasive
             adenocarcinoma with at least one axillary lymph node (pN1) showing evidence of tumor
             among a minimum of six resected lymph nodes. High risk lymph node negative
             participants were to be defined as participants having invasive adenocarcinoma with
             either 0 (pNo) among a minimum of 6 resected lymph nodes or negative sentinel node
             biopsy (pNo) and at least one of the following factors: tumor size > 2 cm, estrogen
             receptor (ER) and/or progesteron receptor (PR) status was negative, histologic and/or
             nuclear grade 2-3, or age < 35 years.

          -  Tumor must show the presence of the HER2neu gene amplification by Fluorescence In-Situ
             Hybridization (FISH analysis) by a designated central laboratory.

          -  Estrogen and/or progesterone receptor analysis performed on the primary tumor prior to
             randomization. Results must be known at the time of randomization.

          -  Karnofsky Performance status index ≥ 80%.

          -  Normal cardiac function must be confirmed by left ventricular ejection fraction (LVEF)
             (multiple-gated acquisition [MUGA] scan) and electrocardiogram (ECG) within 3 months
             prior to registration. The result of the MUGA must be equal to or above the lower
             limit of normal for the institution.

          -  Laboratory requirements: (within 14 days prior to registration)

             a) Hematology: i) Neutrophils ≥ 2.0 109/L ii) Platelets ≥ 100 109/L iii) Hemoglobin ≥
             10 g/Dl

             b) Hepatic function: i) Total bilirubin ≤ 1 UNL ii) Aspartate aminotransferase (ASAT)
             (Serum glutamic oxaloacetic transaminase [SGOT]) and alanine amino transferase (ALAT)
             (Serum glutamic-pyruvic transaminase [SGPT]) ≤ 2.5 UNL iii) Alkaline phosphatase ≤ 5
             UNL iv) Participants with ASAT and/or ALAT > 1.5 x UNL associated with alkaline
             phosphatase > 2.5 x UNL are not eligible for the study.

             c) Renal function: i) Creatinine ≤ 175 µmol/L (2 mg/dL) ii) If creatinine was 140 -
             175 μmol/L, the calculated creatinine clearance should be ≥ 60 mL/min.

          -  Complete staging work-up within 3 months prior to registration. All participants had
             bilateral mammography, chest X-ray (posterioanterior [PA] and lateral) and/or
             computerized tomography (CT) and/or magnetic resonance imaging (MRI), abdominal
             ultrasound and/or CT scan and/or MRI, and bone scan. In cases of positive bone scans,
             bone X-ray evaluation was mandatory to rule out the possibility of metastatic bone
             scan positivity. Other tests may be performed as clinically indicated.

          -  Negative pregnancy test (urine or serum) within 7 days prior to registration for all
             women of childbearing potential.

          -  An audiology assessment with normal results was to be performed within 4 weeks of
             registration. This was only for those centers who had selected cisplatin as their
             platinum salt of choice for the BCIRG 006 study.

        Exclusion criteria:

          -  Prior systemic anticancer therapy for breast cancer (immunotherapy, hormonotherapy,
             chemotherapy).

          -  Prior anthracycline therapy, taxoids (paclitaxel, docetaxel) or platinum salts for any
             malignancy.

          -  Prior radiation therapy for breast cancer.

          -  Bilateral invasive breast cancer.

          -  Pregnant, or lactating participants. Participants of childbearing potential must
             implement adequate non-hormonal contraceptive measures during study treatment
             (chemotherapy and tamoxifen therapy) and must had negative urine or serum pregnancy
             test within 7 days prior to registration.

          -  Any T4 or N2 or known N3 or M1 breast cancer.

          -  Pre-existing motor or sensory neurotoxicity of a severity ≥ grade 2 by National Cancer
             Institute (NCI) criteria.

          -  Cardiac disease that would preclude the use of doxorubicin, docetaxel and Herceptin:

               1. any documented myocardial infarction

               2. angina pectoris that required the use of antianginal medication

               3. any history of documented congestive heart failure

               4. Grade 3 or Grade 4 cardiac arrhythmia (NCI Common Terminology Criteria [CTC],
                  version 2.0)

               5. clinically significant valvular heart disease

               6. participants with cardiomegaly on chest x-ray or ventricular hypertrophy on ECG,
                  unless they demonstrate by MUGA scan within the past 3 months that the LVEF was ≥
                  the lower limit of normal for the radiology facility;

               7. participants with poorly controlled hypertension i.e. diastolic greater than 100
                  mm/Hg. (Participants who were well controlled on medication were eligible for
                  entry)

               8. participants who currently received medications (digitalis, beta-blockers,
                  calcium channel-blockers, etc) that altered cardiac conduction, if these
                  medications were administered for cardiac arrhythmia, angina or congestive heart
                  failure. If these medications were administered for other reasons (ie
                  hypertension), the participant was eligible.

          -  Other serious illness or medical condition:

               1. history of significant neurologic or psychiatric disorders including psychotic
                  disorders, dementia or seizures that would prohibit the understanding and giving
                  of informed consent

               2. active uncontrolled infection

               3. active peptic ulcer, unstable diabetes mellitus

               4. impaired hearing (only for those participants treated at centers who had selected
                  cisplatin as their platinum salt of choice)

          -  Past or current history of neoplasm other than breast carcinoma, except for:

               1. curatively treated non-melanoma skin cancer

               2. in situ carcinoma of the cervix

               3. other cancer curatively treated and with no evidence of disease for at least 10
                  years

               4. ipsilateral DCIS of the breast

               5. lobular carcinoma in-situ (LCIS) of the breast

          -  Current therapy with any hormonal agent such as raloxifene, tamoxifen, or other
             selective estrogen receptor modulators (SERMs), either for osteoporosis or prevention.
             Participants must had discontinued these agents prior to randomization.

          -  Chronic treatment with corticosteroids unless initiated > 6 months prior to study
             entry and at low dose (≤ 20 mg methylprednisolone or equivalent).

          -  Concurrent treatment with ovarian hormonal replacement therapy. Prior treatment must
             be stopped prior to randomization.

          -  Definite contraindications for the use of corticosteroids.

          -  Concurrent treatment with other experimental drugs. Participation in another clinical
             trial with any investigational not marketed drug within 30 days prior to study entry.

          -  Concurrent treatment with any other anti-cancer therapy.

        The above information is not intended to contain all considerations relevant to a
        participant's potential participation in a clinical trial.