Please select the eligibility criteria that correspond to the clinical trial below.
Title: Safety and Tolerability of Bevacizumab Plus Paclitaxel vs. Bevacizumab Plus Metronomic Cyclophosphamide and Capecitabine as First-Line Therapy in Patients With HER2-Negative Metastatic or Locally Recurrent Breast Cancer - A Multicenter, Randomized Phase III Trial.
Brief Summary: RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as paclitaxel, cyclophosphamide, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether bevacizumab is more effective when given together with paclitaxel or cyclophosphamide and capecitabine in treating patients with breast cancer.

PURPOSE: This randomized phase III trial is studying the side effects of giving bevacizumab together with paclitaxel and to see how well it works compared with giving bevacizumab together with cyclophosphamide and capecitabine as first-line therapy in treating women with locally advanced, recurrent, or metastatic breast cancer.


Options:
A: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed adenocarcinoma of the breast

  * Locally advanced, recurrent, or metastatic disease
* HER2-negative disease
* Measurable or evaluable disease
* Candidate for taxane-based chemotherapy
* No presence or history of CNS metastasis

  * Clinical suspicion of CNS metastasis must be confirmed by CT or MRI scan
* Hormone receptor status not specified

PATIENT CHARACTERISTICS:

* Menopausal status not specified
* WHO performance status 0-2
* Neutrophil count ≥ 1.5 x 10\^9/L
* Platelet count ≥ 100 x 10\^9/L
* Hemoglobin ≥ 80 g/L
* Bilirubin ≤ 1.5 times upper limit of normal (ULN)
* AST ≤ 5 times ULN
* Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in case of liver metastases or ≤ 10 times ULN in case of bone metastases)
* Serum creatinine ≤ 1.5 times ULN
* Urine protein \< 2+ by dipstick OR ≤ 1 g by 24-hour urine collection
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for 12 months after completion of study therapy
* Patients with INR \> 1.5 (or Quick ≤ 70%) OR aPTT \> 1.5 times ULN within 7 days prior to expected first trial treatment must be receiving anticoagulant medication

  * Patients receiving full-dose oral or parental anticoagulants may be included in the trial provided anticoagulant dosing has been stable for at least 2 weeks prior to trial entry and the appropriate coagulation monitoring tests are within local therapeutic limits
* Must be compliant and geographically proximal for staging and follow-up
* No previous malignancy within the past 5 years except for adequately treated carcinoma in situ of the cervix or localized nonmelanoma skin cancer
* No known hypersensitivity to trial drugs or its active compound (e.g., fluoropyrimidine), any other components of the trial drugs, or drugs formulated with cremophor EL including hypersensitivity to Chinese hamster ovary cell products or any other humanized recombinant antibodies
* No preexisting peripheral motor or sensory neuropathy \> NCI CTCAE grade 2 (i.e., moderate symptoms or limiting instrumental activities of daily living)
* No history or evidence of inherited bleeding diathesis, coagulopathy with the risk of bleeding, serious nonhealing wound, active peptic ulcer, nonhealing bone fracture, or bleeding metastases
* No history of abdominal fistula, grade 4 bowel obstruction, or gastrointestinal perforation or intra-abdominal abscess within the past 6 months
* No evidence of other medical conditions that would impair the ability of the patient to participate in the trial or might preclude therapy with trial drugs, including any of the following:

  * DPD deficiency
  * Severe respiratory, cardiac, hepatic, or renal disease
  * Active infection
  * Uncontrolled diabetes mellitus
  * Uncontrolled hypertension ≥ 140/100 mm Hg
  * Myocardial infarction within the past 12 months
  * Cerebrovascular accident or stroke within the past 6 months
  * History of hemorrhagic disorders
* No psychiatric disorder precluding understanding of information on trial-related topics, giving informed consent, filling out quality-of-life forms, or interfering with compliance for oral drug intake

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy for metastatic or locally recurrent breast cancer
* No prior radiotherapy for metastatic disease

  * Prior radiotherapy for the relief of metastatic bone pain allowed provided no more than 30% of marrow-bearing bone was irradiated
* At least 12 months since prior bevacizumab or other anti-VEGF therapy
* At least 12 months since prior capecitabine, continuous (\> 24 hours) fluorouracil infusion, or other oral fluoropyrimidine (e.g., eniluracil/fluorouracil, uracil/tegafur, S1, or emitefur)
* At least 12 months since prior taxane-based chemotherapy
* At least 6 months since other prior (neo)adjuvant chemotherapy
* At least 30 days since prior treatment in another clinical trial
* At least 24 hours since prior minor surgical procedures
* At least 28 days since prior and no concurrent major surgical procedures (including open biopsy) and no anticipation of the need for major surgery during the first course of this trial
* At least 10 days since prior hormone therapy for metastatic disease
* No continuous daily treatment with corticosteroid except for inhaled steroids
* No concurrent chronic daily aspirin \> 325 mg/day
* No concurrent chronic daily clopidogrel \> 75 mg/day
* No other concurrent anticancer treatments
* No other concurrent investigational treatments or experimental drugs
* No other concurrent drug therapy contraindicated for use with the trial drugs
B: DISEASE CHARACTERISTICS:

* Histologically confirmed unilateral or bilateral primary breast cancer

  * Meets 1 of the following staging criteria:

    * Clinical stage T4 or T3 disease
    * Clinical stage T1 and pathologic stage N+ by sentinel lymph node biopsy OR clinical stage T2, N+ disease AND estrogen receptor (ER) or progesterone receptor (PR) positive tumor
    * ER and PR negative tumor (T1-4, N0-3, M0)
* Disease confirmed by core biopsy

  * No fine-needle aspiration or incisional biopsy
* Bidimensionally measurable disease\*

  * Tumor lesion palpable and measures ≥ 2 cm OR tumor lesion ≥ 1 cm in maximum diameter by sonography

    * For inflammatory disease, extent of inflammation can be used as measurable lesion NOTE: \*In patients with multifocal or multicentric breast cancer, the largest lesion should be measured
* Candidate for adjuvant chemotherapy

  * No low- or moderate-risk patients who are doubtful candidates for adjuvant chemotherapy and do not fulfill the staging criteria
* Known HER-2/neu status by core biopsy

  * HER-2/neu positive tumor is defined as +3 by immunohistochemistry \[IHC\] OR positive by fluorescence in situ hybridization (FISH)
* No evidence of distant metastasis
* Hormone receptor status:

  * ER- or PR-positive tumor OR ER- and PR-negative tumor

PATIENT CHARACTERISTICS:

* No male patients
* Menopausal status not specified
* Karnofsky performance status 80-100%
* Life expectancy ≥ 10 years (disregarding diagnosis of cancer)
* Normal cardiac function confirmed by ECG
* LVEF ≥ 55% by cardiac ultrasound
* Neutrophil count ≥ 2,000/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Hemoglobin ≥ 10 g/dL
* Bilirubin normal
* AST and ALT ≤ 2.5 times upper limit of normal (ULN)
* Alkaline phosphatase (AP) ≤ 5 times ULN OR
* AP ≤ 2.5 times ULN AND AST and/or ALT ≤ 1.5 times ULN
* Creatinine ≤ 2 mg/dL
* Creatinine clearance ≥ 50 mL/min
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective nonhormonal contraception
* No motor or sensory neuropathy ≥ grade 2
* No other malignancy within the past 5 years except carcinoma in situ of the cervix or nonmelanoma skin cancer
* No New York Heart Association class II-IV congestive heart failure
* No coronary artery disease
* No history of myocardial infarction
* No uncontrolled arterial hypertension (i.e., blood pressure ≥ 160/90 mm Hg despite antihypertensive therapy)
* No rhythm abnormalities requiring permanent therapy
* No history of significant neurological or psychiatric disorders including psychotic disorders, dementia, or seizures that would preclude giving informed consent
* No active infection
* No active peptic ulcer
* No unstable diabetes mellitus or insulin-dependent type II diabetes mellitus
* No other serious illness or medical condition
* No known hypersensitivity reaction to investigational compounds or incorporated substances
* No definite contraindications for the use of corticosteroids
* No known dihydropyrimidine dehydrogenase deficiency
* Must be fit for anthracycline/taxane-containing chemotherapy

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy for any malignancy
* No prior radiation therapy for breast cancer
* No concurrent bisphosphonates during chemotherapy

  * Bisphosphonates allowed postoperatively
* No chronic treatment with corticosteroids unless it is initiated \> 6 months prior to study entry and is given at low doses (≤ 20 mg methylprednisolone or equivalent)
* No concurrent amifostine during chemotherapy
* No concurrent cardioprotectors (e.g., dexrazoxane) during chemotherapy
* No concurrent sex hormone therapy
* No concurrent virostatic agents (e.g., sorivudine or brivudine)
* No concurrent aminoglycosides
* No other concurrent experimental drugs or anticancer therapy
* At least 30 days since prior participation in another clinical trial with any investigational (not marketed) drug
C: Inclusion Criteria:

* Written informed consent must be obtained and documented according to the local regulatory requirements prior to beginning specific protocol procedures.
* Complete baseline documentation sent to SKM CRS.
* Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration is not sufficient. Incisional biopsy is not allowed. In case of bilateral cancer the investigator has to decide prospectively which side will be evaluated for the primary endpoint.
* Tumor lesion in the breast with a palpable size of \> 2 cm in maximum diameter. The leasion has to be measurable in two-dimensions by sonography. In case of inflammatory disease the extent of inflammation can be used as measurable lesion. The following tumor stages are eligible:

  * Palpable breast tumor size of \> 2 cm without involvement of the skin or muscle or evidence of inflammatory disease (T2-3). Clinical N0-2. (Study population I)
  * Primary tumor with clinical involvement of skin or muscle or clinically evidence of inflammatory breast cancer (T4 a-d) or clinical N3 including supraclavicular nodes. (Study population II). In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
* Age \> 18 years.
* Karnofsky Performance status index \> 80%.
* Normal cardiac function must be confirmed by LVEF or shortening fraction (echocardiography or MUGA scan respectively) within 3 months prior to registration. The result must be above the normal limit of the institution.
* Laboratory requirements (within 14 days prior to registration):

  * Hematology:

    * Neutrophils \> 2.0 x 109/L and
    * Platelets \> 100 x 109/L and
    * Hemoglobin \> 10 g/dL
  * Hepatic function:

    * Total bilirubin \< 1 x UNL and
    * ASAT (SGOT) and ALAT (SGPT) \< 2.5 x UNL and
    * Alkaline phosphatase \< 5 UNL. Patients with ASAT and/or ALAT \> 1.5 x UNL associated with alkaline phosphatase \> 2.5 x UNL are not eligible for the study.
  * Renal function:

    * Creatinine \< 175 µmol/L (2 mg/dL)
* Tissue block centrally available for further biological tests.
* Negative pregnancy test (urine or serum) within 14 days prior to registration for all women of childbearing potential.
* Complete staging work-up within 3 months prior to registration. All patients must have bilateral mammography, breast ultrasound, breast MRI (optional), chest X-ray (PA and lateral), abdominal ultrasound and/or CT scan, and bone scan. In case of positive bone scan, bone X-ray is mandatory. Other tests may be performed as clinically indicated.
* Patients must be available and compliant for treatment and follow-up. Patients registered on this trial must be treated and followed up at the participating center which can be the Principal or the Co- Investigator's site.

Exclusion Criteria:

* Early breast cancer with a tumor size of \< 2 cm measured by palpation.
* Patients with low or moderate risk. These patients are defined as having none of the following risk factors: Age \< 36 years, cT\> 5cm, ER and PR negative, cN+, or Grade III.
* Evidence of distant metastasis.
* Prior chemotherapy for any malignancy.
* Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures during study treatment.
* Pre-existing motor or sensory neuropathy of a severity \> grade 2 by NCI criteria.
* Other serious illness or medical condition:

  * previous malignant disease with a disease-free survival of less than 5 years (except CIS of the Cervix and non-melanomatous skin cancer.
  * congestive heart failure or unstable angina pectoris, previous history of myocardial infarction within 1 year prior to study entry, uncontrolled arterial hypertension or high-risk uncontrolled arrhythmias.
  * history of significant neurologic or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
  * active uncontrolled infection.
  * active peptic ulcer, unstable diabetes mellitus.
* Chronic treatment with corticosteroids unless initiated \> 6 months prior to study entry and at low dose (\</= 20 mg methylprednisolone or equivalent).
* Concurrent treatment with sex hormones. Prior treatment must be stopped before study entry.
* 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.
* Known hypersensitivity reaction to one of the investigational compounds or incorporated substances.
* Male patients.
D: Inclusion Criteria:

* adult patients, \>=18 years of age;
* HER2-negative metastatic breast cancer
* candidates for taxane-based chemotherapy;
* ECOG performance status of 0 or 1.

Exclusion Criteria:

* previous chemotherapy for metastatic breast cancer;
* prior adjuvant/neo-adjuvant chemotherapy within 6 months prior to study;
* prior radiotherapy for treatment of metastatic disease;
* chronic daily treatment with aspirin (325 mg/day) or clopidogrel(\>75mg/day).

Answer: A