Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase III Study Comparing Docetaxel Followed by Cyclophosphamide, Epirubicin and 5-FU to Docetaxel With Capecitabine Followed by Cyclophosphamide, Epirubicin and Capecitabine as Adjuvant Treatment for Early Breast Cancer
Brief Summary: This study compares two chemotherapy regimens as adjuvant treatment for breast cancer. The study participants are randomly allocated to receive either 3 cycles of docetaxel followed by 3 cycles of CEF (cyclophosphamide, epirubicin and 5-fluorouracil) or to receive 3 cycles of docetaxel plus capecitabine followed by 3 cycles of CEX (cyclophosphamide, epirubicin and capecitabine). The study participants are required to to have a medium to high risk for breast cancer recurrence. The primary aim of the study is to investigate whether addition of capecitabine to a standard taxane/anthracycline regimen will influence recurrence-free survival.


Options:
A: 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
B: Inclusion Criteria:

To be eligible for inclusion in the study, each patient must fulfill each of the criteria below.

* Have provided written informed consent prior to study-specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.
* Be female and 18 years of age or older.
* Have histologically confirmed invasive breast cancer.
* High risk of breast cancer recurrence (\> 25% within the first 5 years without adjuvant therapy, \> 35% within the first 10 years) with one of the following:

  * Regional node positive disease (pN+; tumor cells or tumor cell clusters \< 0.2 mm in diameter are not counted as metastases);
  * Pathological N0 and PgR- and tumor size \> 20 mm.

Exclusion Criteria:

Patients who fulfill any of the following criteria will be excluded:

* \> 65 years of age.
* "Special type" histology (mucinous, papillary, medullary, or tubular breast cancer), when pN0.
* ER, PgR and HER-2 status (via in situ hybridization or immunohistochemistry) not determined.
* Presence of distant metastases.
* Previous chemotherapy in the neoadjuvant setting.
* Non-ambulatory or WHO performance status \> 1.
* Pregnant or lactating women. Women of childbearing potential (menstruating within 6 months of study entry or with no hysterectomy and age \< 55) with either a positive or no pregnancy test at baseline.
* Women of childbearing potential unless using a reliable and appropriate contraceptive method. (Post-menopausal women must have been amenorrheic for at least 6 months to be considered of non-childbearing potential).
* More than 12 weeks between breast surgery and date of randomization.
* Organ allografts with immunosuppressive therapy required.
* Major surgery (except breast surgery) within 4 weeks prior to study treatment start, or lack of complete recovery from the effects of major surgery.
* Participation in any investigational drug study within 4 weeks preceding treatment start.
* Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant precluding informed consent or interfering with compliance for oral drug intake.
* History of another malignancy within the last five years except cured basal cell carcinoma of skin or carcinoma in situ of the uterine cervix.
* Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmia not well controlled with medication) or myocardial infarction within the last 12 months.
* Abnormal laboratory values:

  * Hemoglobin \< 10.0 g/dL, neutrophils \< 1.5 x 10\^9/L, platelet count \< 120 x 10\^9/L;
  * Serum creatinine \> 1.5 x Upper Limit of Normal (ULN);
  * Creatinine clearance (calculated per Cockroft and Gault) \< 50 mL/min;
  * Serum bilirubin \> ULN;
  * ALAT \> 1.5 x ULN;
  * Alkaline phosphatase \> 2.5 x ULN.
* Serious uncontrolled intercurrent infections or other serious uncontrolled concomitant disease.
* Lack of physical integrity of the upper gastrointestinal tract or those who have clinically significant malabsorption syndrome.
* Inability to swallow tablets.
* Life expectancy of less than 3 months.
* Unwilling or unable to comply with the protocol for the duration of the study.
* Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine.
C: Inclusion Criteria:

* Female patients with histologically proven, core-biopsied, invasive breast cancer of any clinical and/or radiological T-stage (except for T4d)
* Age 18-70 years
* WHO performance status ≤ 2
* No prior or current neoplasm except for curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix
* No distant disease / secondary carcinoma judged clinically and at least by chest X-ray, liver sonography, and bone scan upon randomization
* No medical and/or cardiologic contraindication to receive an anthracycline- and taxane-containing chemotherapy regimen. Normal cardiac function must be confirmed by LVEF (echocardiography or Muga scan). The result must be above 50% or above the institution's ULN
* Results of the following assessments at the time of randomization must be available:

  1. chest wall CT, abdomen CT, bilateral mammography: within 4 weeks before enrolment;
  2. laboratory requirements: within 2 weeks before enrolment
  3. hematology: neutrophils ≥ 4.0 x 109/l, platelets ≥ 150 x 109/l, haemoglobin ≥ 13 g/dl
  4. hepatic function: total bilirubin \< 1 x ULN, ASAT (SGOT) and ALAT (SGPT) \< 1x ULN, alkaline phosphatase \< 1 x ULN. In case of abnormal values, liver function tests have to be repeated within 3 days before study treatment.
  5. renal function: creatinine ≤ 1 x ULN,
  6. histology, grading, hormone receptor status, HER-2/neu status
* Signed and dated informed consent before the start of specific protocol procedures
* Negative pregnancy test in the presence of childbearing potential

Exclusion Criteria:

* Stage T4d / inflammatory breast cancer
* Pregnant or lactating patients; patients of childbearing potential must implement adequate contraceptive measures during study participation
* Pre-existing motor or sensory neurotoxicity of a severity ≥ WHO grade 2
* Preoperative local treatment for breast cancer (i.e. incomplete surgery, radiotherapy)
* Prior or concomitant systemic antitumor therapy
* Other serious illness or medical condition

  1. congestive heart failure or unstable angina pectoris, even if medically controlled.

     Previous history of myocardial infarction within 1 year from study entry, uncontrolled hypertension or high-risk uncontrolled arrythmias
  2. history of significant neurologic or psychiatric disorders, including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent
  3. active uncontrolled infection
  4. unstable peptic ulcer, unstable diabetes mellitus or other contraindication for the use of corticosteroids
* Concurrent treatment with corticosteroids except as use for the prophylactic regimen, inhalational use, treatment of acute hypersensitivity reactions, treatment of nausea/vomiting or chronic treatment (initiated \> 6 months prior to study entry) at low dose (≤ 20 mg methylprednisolone or equivalent)
* Known hypersensitivity against taxanes and/or epirubicin and/or fluorouracil/capecitabine
* Known dihydropyrimidine-dehydrogenase (DPD) deficit
* Treatment with an investigational drug within 30 days prior to study entry
* Legally incapacitated and/or other circumstances which make it unfeasible for the subject to understand the nature, meaning and consequences of the clinical study
* Concurrent psychiatric illness according to ICD (alcohol addiction) at the time of study entry
D: Inclusion Criteria:

* Written informed consent.
* Histological diagnosis of operable invasive adenocarcinoma of the breast (T1-T3). Tumours must be HER2 negative. Time window between surgery and study randomization must be less than 60 days.
* Surgery must consist of mastectomy or conservative surgery with axillary lymph node dissection. Margins free of disease and ductal carcinomas in situ (DCIS) are required. Lobular carcinoma is not considered a positive margin.
* Positive axillary lymph nodes defined as at least 1 out of 10 nodes with presence of disease. If sentinel node technique is used, sentinel node can be the only node affected. Patients belonging to the following classifications are eligible: TNM pathologic stage N1a, TNM pathologic stage N2a, TNM pathologic stage N3a.
* Status of hormone receptors in primary tumour. Results must be available before the end of adjuvant chemotherapy.
* Patients must not present evidence of metastatic disease. Status of HER2 in primary tumour, known before randomization. Patients with immune histochemistry (IHC) 0 or +1 are eligible. For patients with IHC 2+, fluorescence in situ hybridization (FISH) is mandatory and result must be negative.
* Age \>= 18 and \<= 70 years old.
* Performance status (Karnofsky index) \>= 80.
* Normal electrocardiogram (EKG) in the 12 weeks prior to randomization. If needed, normal cardiac function must be confirmed by left ventricular ejection fraction (LVEF).
* Laboratory results (within 14 days prior to randomization):

  * Hematology: neutrophils \>= 1.5 x 10\^9/l; platelets \>= 100 x 10\^9/l; hemoglobin \>= 10 mg/dl;
  * Hepatic function: total bilirubin \<= 1 upper normal limit (UNL); serum glutamic-oxaloacetic transaminase (SGOT) and Serum glutamic pyruvic transaminase (SGPT) \<= 2.5 UNL; alkaline phosphatase \<= 2.5 UNL. If values of SGOT and SGPT \> 1.5 UNL are associated to alkaline phosphatase \> 2.5 UNL, patient is not eligible;
  * Renal function: creatinine \<= 175 mmol/l (2 mg/dl); creatinine clearance \>= 60 ml/min;
  * Pharmacogenetics: one blood sample is needed for single nucleotide polymorphism (SNP) assessment.
* Complete stage workup during the 12 weeks prior to randomization (mammograms are allowed within a 20 week window). All patients must have a bilateral mammogram, thorax x-ray, abdominal echography and/or computed tomography (CT)-scan. If bone pain, and/or alkaline phosphatase elevation, a bone scintigraphy is mandatory. This test is recommended for all patients. Other tests: as clinically indicated.
* Patients able to comply with treatment and study follow-up.
* Negative pregnancy test done in the 14 prior days to randomization.

Exclusion Criteria:

* Prior systemic therapy for breast cancer.
* Prior therapy with anthracyclines or taxanes (paclitaxel or docetaxel) for any malignancy.
* Prior radiotherapy for breast cancer.
* Bilateral invasive breast cancer.
* Pregnant or lactating women. Adequate contraceptive methods must be used during chemotherapy and hormone therapy treatments.
* Any T4 or M1 tumour.
* Axillary lymph nodes: patients belonging to the following classifications are excluded: TNM pathologic stage N1b, TNM pathologic stage N1c, TNM pathologic stage N2b, TNM pathologic stage N3b, TNM pathologic stage N3c.
* HER2 positive breast cancer (IHC 3+ or positive FISH result).
* Pre-existing grade \>= 2 motor or sensorial neurotoxicity (National Cancer Institute Common Toxicity Criteria version 2.0 \[NCICTC v-2.0\]).
* Any other serious medical pathology, such as congestive heart failure; unstable angina; history of myocardial infarction during the previous year; uncontrolled hypertension or high risk arrhythmias.
* History of neurological or psychiatric disorders, which could preclude the patients from free informed consent.
* Active uncontrolled infection.
* Active peptic ulcer; unstable diabetes mellitus.
* Previous or current history of neoplasms different from breast cancer, except for skin carcinoma, cervical in situ carcinoma, or any other tumour curatively treated and without recurrence in the last 10 years; ductal in situ carcinoma in the same breast; lobular in situ carcinoma.
* Chronic treatment with corticosteroids.
* Contraindications for corticosteroid administration.
* Concomitant treatment with raloxifene, tamoxifen or other selective estrogen receptor modulators (SERMs), either for osteoporosis treatment or for prevention. These treatments must stop before randomisation.
* Concomitant treatment with other investigational products; participation in other clinical trials with a non-marketed drug in the 20 previous days before randomization.
* Concomitant treatment with another therapy for cancer.
* Males.

Answer: B