Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multinational, Randomized, Phase III Study of XELIRI With/Without Bevacizumab Versus FOLFIRI With/Without Bevacizumab As Second-line Therapy in Patients With Metastatic Colorectal Cancer
Brief Summary: The primary purpose of this study is to determine the non-inferiority of overall survival XELIRI with or without Bevacizumab compared with FOLFIRI with or without Bevacizumab as Second-line therapy in Patient with Metastatic Colorectal Cancer.


Options:
A: Inclusion Criteria:

1. Histologically-confirmed inoperable colorectal adenocarcinoma excluding vermiform appendix cancer and anal canal cancer.
2. Age ≥20 years at the time of informed consent
3. ECOG performance status (PS) of 0-2
4. Written informed consent prior to study-specific screening procedures
5. Life expectancy of at least 90 days
6. Withdrawal from first-line chemotherapy (regardless of containing molecular-targeted drugs) for metastatic colorectal cancer due to intolerable toxicity or progressive disease, or relapse within 180 days after the last dose of adjuvant chemotherapy.
7. Adequate organ function according to following laboratory values obtained within 14 days before enrolment (excluding patients who received blood transfusions or hematopoietic growth factors within 14 days before the laboratory test) Neutrophil count: ≥1500/mm3 Platelet count: ≥10.0 x 104/mm3 Hemoglobin: ≥9.0 g/dL Total bilirubin: ≤1.5 mg/dL AST, ALT: ≤100 IU/L (≤200 IU/I if liver metastases present) Serum creatinine: ≤1.5 mg/dL

Exclusion Criteria:

1. History of other malignancy with a disease-free interval \<5 years (other than curatively treated cutaneous basal cell carcinoma, curatively treated carcinoma in situ of the cervix, and gastroenterological cancer confirmed to be cured by endoscopic mucosal resection)
2. With massive pleural effusion or ascites requiring intervention
3. Radiological evidence of brain tumor or brain metastases
4. Active infection including hepatitis
5. Any of the following complication:

   i) Gastrointestinal bleeding or gastrointestinal obstruction (including paralytic ileus) ii) Symptomatic heart disease (including unstable angina, myocardial infarction, and heart failure) iii) Interstitial pneumonia or pulmonary fibrosis iv) Uncontrolled diabetes mellitus v) Uncontrolled diarrhea (that interferes with daily activities despite adequate therapy)
6. Any of the following medical history:

   Myocardial infarction: History of one episode within one year before enrollment or two or more lifetime episodes i) Serious hypersensitivity to any of the study drugs ii) History of adverse reaction to fluoropyrimidines suggesting dihydropyrimidine dehydrogenase (DPD) deficiency
7. Previous treatment with irinotecan hydrochloride
8. Current treatment with atazanavir sulfate
9. Previous treatment with tegafur, gimeracil, and oteracil potassium within seven days before enrollment
10. Pregnant or lactating females, and males and females unwilling to use contraception
11. Requires continuous treatment with systemic steroids
12. Psychiatric disability that would preclude study compliance
13. Otherwise determined by the investigator to be unsuitable for participation in the study
14. Concurrent gastrointestinal perforation or history of gastrointestinal perforation with 1 year before enrollment
15. History of pulmonary hemorrhage/hemoptysis ≥ Grade 2 (defined as bright red blood of at least 2.5mL) within 1 month prior to enrollment.
16. History of laparotomy, thoracotomy, or intestinal resection within 28 days before enrollment
17. Unhealed wound (except suture wounds from implantation of a central venous port), gastrointestinal ulcer, or traumatic fracture
18. Current or recent (within 1 year) thromboembolism or cerebrovascular disease
19. Currently receiving or requires anticoagulation therapy (\> 325 mg/day of aspirin)
20. Bleeding diathesis, coagulopathy, or coagulation factor abnormality (INR ≥1.5 within 14 days before enrollment)
21. Uncontrolled hypertension
22. Urine dipstick for proteinuria \>+2
B: DISEASE CHARACTERISTICS:

* Histologically confirmed resectable adenocarcinoma of the rectum

  * Any grade
  * Tumor macroscopically within 15 cm of anal margin on rigid rectoscopy
  * Tumor tethered or partially fixed on digital rectal exam and/or T3-4 on rectal ultrasound
* No acute or subacute bowel obstruction without colostomy diversion
* No chronic inflammatory disease of the ileum and/or colon
* No primary adenocarcinoma of the anal canal
* No distant metastasis

PATIENT CHARACTERISTICS:

Age:

* 80 and under

Performance status:

* WHO 0-1

Life expectancy:

* Not specified

Hematopoietic:

* Granulocyte count greater than 2,000/mm\^3
* Platelet count greater than 130,000/mm\^3

Hepatic:

* Not specified

Renal:

* Creatinine less than 1.36 mg/dL

Cardiovascular:

* No angina pectoris

Other:

* No other prior malignancy except basal cell skin cancer or carcinoma in situ of the uterine cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy

* No prior biologic therapy for adenocarcinoma of the rectum

Chemotherapy

* No prior chemotherapy for adenocarcinoma of the rectum

Endocrine therapy

* No prior endocrine therapy for adenocarcinoma of the rectum

Radiotherapy

* No prior radiotherapy for adenocarcinoma of the rectum

Surgery

* No prior surgery for adenocarcinoma of the rectum
C: Inclusion Criteria:

* Patients must consent to participate in the study and must have signed and dated an IRB-approved consent form conforming to federal and institutional guidelines.
* Patients must be \> 18 years of age.
* Patients must have a life expectancy of 5 years, excluding their diagnosis of cancer (as determined by the investigator), and must have an Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status of 0 or 1.
* Patients must have a diagnosis of adenocarcinoma of the rectum obtained by a biopsy technique which leaves the major portion of the tumor intact.
* The interval between the initial diagnosis of rectal adenocarcinoma and randomization must be no more than 42 days.
* Prior to randomization, the investigator must specify the intent for sphincter saving or non-sphincter saving surgery.
* The tumor must be either palpable by digital rectal exam or be accessible via a proctoscope or sigmoidoscope.
* Distal border of the tumor must be located \< 12 cm from the anal verge.
* The tumor must be considered by the surgeon to be amenable to curative resection. (Note that curative resection can include pelvic exenteration.)
* The tumor must be clinically Stage II (T3-4 N0 with N0 being defined as all imaged lymph nodes are \< 1.0 cm) or Stage III (T1-4 N1-2 with the definition of a clinically positive node being any node \> 1.0 cm). Stage of the primary tumor may be determined by ultrasound or Magnetic Resonance Imaging (MRI). Computed Tomography (CT) scan is acceptable provided there is evidence of T4 and/or N1-2 disease.
* At the time of randomization, all patients must have had the following within the previous 42 days: history and physical examination; if technically feasible, a complete colonoscopic examination; if not feasible, a proctoscopic or sigmoidoscopic exam; clinical staging of the tumor; CT or MRI of the abdomen and pelvis (combined PET/CT may be substituted), and a chest x-ray (PA and lateral) or CT scan of the chest to exclude patients with metastatic disease.
* At the time of randomization: Absolute neutrophil count (ANC) must be \> 1,200/mm3; Platelet count must be \> 100,000/mm3; There must be evidence of adequate hepatic function as follows: total bilirubin must be \< 1.5 x the upper limit of normal (ULN) for the lab; and alkaline phosphatase must be \< 2.5 x Upper Limit of Normal (ULN) for the lab; and the Aspartate Amino Transferase (AST) must be \< 2.5 x ULN for the lab; and If AST is \> ULN, serologic testing for Hepatitis B and C must be performed and results must be negative; Calculated creatinine clearance must be \> 50 mL/min.
* Patients with prior malignancies, including invasive colon cancer, are eligible if they have been disease-free for \> 5 years and are deemed by their physician to be at low risk for recurrence. Patients with squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum that have been effectively treated are eligible, even if these conditions were diagnosed within 5 years prior to randomization.

Exclusion Criteria:

* Findings of metastatic disease.
* On imaging, clear indication of involvement of the pelvic side wall(s).
* Rectal cancers other than adenocarcinoma, i.e., sarcoma, lymphoma, carcinoid, squamous cell carcinoma, cloacogenic carcinoma, etc.
* History of invasive rectal malignancy, regardless of disease-free interval.
* Pregnancy or lactation at the time of proposed randomization. Eligible patients of reproductive potential (both sexes) must agree to use adequate contraceptive methods.
* Any therapy for this cancer prior to randomization.
* Synchronous colon cancer.
* History of viral hepatitis or other chronic liver disease.
* Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude the patient from receiving any chemotherapy treatment option or would prevent required follow-up. Specifically excluded are patients with active ischemic heart disease (class III\* or class IV\*\* myocardial disease as described by the New York Heart Association), a recent history (within 6 months) of myocardial infarction, or symptomatic arrhythmia at the time of randomization. \*Class III: Patients with cardiac disease resulting in marked limitation of physical activity. Such patients are comfortable at rest. Less than ordinary physical activity that causes fatigue, palpitation, dyspnea, or anginal pain. \*\*Class IV: Patients with cardiac disease resulting in inability to perform any physical activity without discomfort. Symptoms of cardiac insufficiency or anginal syndrome may be present even at rest.
* Patients who, in the opinion of the investigator, have uncontrolled hypertension.
* Active inflammatory bowel disease (i.e., patients requiring current medical interventions or who are symptomatic).
* Prior pelvic radiation therapy for any reason.
* Known hypersensitivity to 5-fluorouracil, capecitabine, or oxaliplatin.
* Clinically significant peripheral neuropathy at the time of randomization (defined in the NCI Common Terminology Criteria for Adverse Events Version 3.0 \[CTCAE v3.0\] as grade 2 or greater neurosensory or neuromotor toxicity).
* Existing uncontrolled coagulopathy.
* Inability to take oral medications.
* Participation in any investigational drug study within 4 weeks prior to randomization.
* Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements.
D: Inclusion Criteria:

* Histologically documented colorectal adenocarcinoma
* Age over 18 years old
* Performance status (ECOG scale): 0-2
* Measurable or evaluable disease
* Patients can take food and drugs orally
* Adequate organ functions
* Life expectancy ≥ 3 months
* Patients should sign a written informed consent before study entry

Exclusion Criteria:

* Tumor type other than adenocarcinoma
* Second primary malignancy
* Prior systemic therapy (for instance, cytotoxic chemotherapy or active/passive immunotherapy) for advanced or metastatic colorectal cancer
* Adjuvant or neo-adjuvant treatment for non-metastatic (M0) disease has been completed within 6 months prior to initiation of study treatment.
* Prior radiotherapy was administered to target lesions selected for this study, or radiotherapy to the non-target lesions has been completed within 4 weeks before randomization.
* Presence of CNS metastasis
* Obvious peritoneal seeding or bowel obstruction disturbing oral intake
* Symptomatic peripheral neuropathy
* Major surgery within 4 weeks prior to study treatment start, or lack of complete recovery from the effects of major surgery. The patient received curative operation or RFA for metastatic disease.
* Serious illness or medical conditions
* Receiving a concomitant treatment with drugs interacting with S-1, capecitabine or oxaliplatin, as follows;flucytosine, a fluorinated pyrimidine antifungal agent phenytoin warfarin etc.
* Received any investigational drug or agent/procedure, i.e. participation in another trial within 4 weeks before beginning treatment with study drug.
* Pregnant or lactating woman
* Women of child bearing potential not using a contraceptive method
* Sexually active fertile men not using effective birth control during medication of study drug and up to 6 months after completion of study drug if their partners are women of child-bearing potential
* Any patients judged by the investigator to be unfit to participate in the study

Answer: A