Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase III Study of SOX vs. COX in Patients With Advanced Colorectal Cancer
Brief Summary: Primary objective :

To compare the combination of S-1 and oxaliplatin(SOX) to the combination of capecitabine and oxaliplatin(COX) therapy for advanced or metastatic colorectal carcinoma.

Secondary objectives :

1. To evaluate and compare the efficacy (overall survival and response rate) in the two treatment groups.
2. To evaluate and compare the quality of life of the patients and safety profiles of the two treatment groups.


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: Inclusion Criteria

1. Signed written informed consent obtained prior to any study specific screening procedures.
2. Patient willing and able to comply with the protocol.
3. Age ≥ 18 years-of-age.
4. Histologically confirmed colon carcinoma, American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) Stage II or Stage III defined as a tumor location ≥ 15 cm from the anal verge by endoscopy or above the peritoneal reflection at surgery. The patient was not to be a candidate for (neo) adjuvant radiotherapy. Note: Stage II patients were to be considered as high-risk patients fulfilling one of the following criteria:

   * T4 tumours,
   * Patients presenting with bowel obstruction or perforation,
   * Histological signs of vascular invasion (i.e. blood and lymphatic vessels) or perineural invasion,
   * Patients aged less than 50 years,
   * Patients with sub-optimal surgery (less than 12 nodes analyzed).
5. Curative surgery not less than 4 and not more than 8 weeks prior to randomization.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
7. Life expectancy of ≥ 5 years.

Exclusion Criteria

1. Macroscopic or microscopic evidence of remaining tumour. Patients should never have had any evidence of metastatic disease (including presence of tumour cells in the ascites). The isolated finding of cytokeratin positive cells in bone marrow is not considered evidence of metastatic disease for purposes of this study.
2. Carcinoembryonic antigen \> 1.5 x upper limit of normal (ULN) after surgery (during screening period).
3. For patients with colostomy, unwilling to delay revision until at least 28 days after treatment completion.
4. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, not fully healed wounds, or anticipation of the need for major surgical procedure during the course of the study. Any central venous access device (CVAD) for chemotherapy administration must be inserted at least 2 days prior to treatment start.
5. Previous anti-angiogenic treatment for any malignancy; cytotoxic chemotherapy, radiotherapy or immunotherapy for colon cancer.
6. Other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix).
7. Females with a positive or no pregnancy test (within 7 days before treatment start) unless childbearing potential can be otherwise excluded (postmenopausal i.e. amenorrheic for at least 2 years, hysterectomy or oophorectomy).
8. Lactating women.
9. Fertile women (\< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception.
10. History or evidence upon physical examination of central nervous disease (CNS) disease (eg, primary brain tumour, seizure not controlled with standard medical therapy, any brain metastases).
11. History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for oral drug intake.
12. Clinically significant (ie, active) cardiovascular disease. This includes, but is not limited to, the following examples: cerebrovascular accidents (≤ 6 months prior to randomization), myocardial infarction (≤ 1 year prior to randomization), uncontrolled hypertension (\>150/100 mmHg) while receiving chronic medication, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, clinically significant electrocardiogram (ECG) findings (e.g. QTc ≥ 440 msecs \[male\] 460 msecs \[female\] or ≥ 2º atrioventricular block, etc.).

    Patients who suffer from serious cardiac arrhythmia requiring medication can enter the study only if they are considered to be in a stable condition regarding both the arrhythmia and their medication. Patients with pacemakers are allowed to enter the study only if they are considered as being in a stable condition. In case of doubt, the investigator should obtain a consultation with a local cardiologist.
13. Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication.
14. Interstitial pneumonia or extensive symptomatic fibrosis of the lungs.
15. Known peripheral neuropathy ≥ Common terminology criteria for adverse events (CTCAE) version 3.0 Grade 1. Absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible.
16. Organ allografts requiring immunosuppressive therapy.
17. Serious, non-healing wound, ulcer, or bone fracture.
18. Evidence of bleeding diathesis or coagulopathy.
19. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes.
20. Chronic, daily treatment with high-dose aspirin (\> 325 mg/day) or clopidogrel (\> 75 mg/day).
21. Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
22. Serious intercurrent infections (uncontrolled or requiring treatment).
23. Known dihydropyrimidine dehydrogenase deficiency.
24. Current or recent (within the 28 days prior to randomization) treatment with another investigational drug or participation in another investigational study.
25. Patients with known allergy to Chinese hamster ovary cell proteins or other recombinant human or humanized antibodies or to any excipients of bevacizumab formulation, platinum compounds or to any other components of the study drugs.
26. History or presence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or patient at high risk from treatment complications.
27. Presence of proteinuria at baseline as defined by:

    - Patients with \> 1 g of protein/24 hour by a 24-hour urine collection.
28. Any laboratory values at baseline are as follows:

Haematology:

* Absolute neutrophil count (ANC) \< 1.5 x 109/L
* Platelet count \< 100 x 10\^9/L
* Haemoglobin \< 9 g/dL (may be transfused to maintain or exceed this level)
* International normalized ratio (INR) \> 1.5
* Activated partial prothrombin time (APTT) ≥ 1.5 x ULN

Biochemistry:

* Total bilirubin \> 1.5 x ULN
* aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) \> 2.5 x ULN
* Alkaline phosphatase (ALP) \> 2.5 x ULN
* Serum creatinine \> 1.5 x ULN or creatinine clearance ≤ 50 mL/min (e.g. Cockcroft-Gault formula).
C: Inclusion Criteria:

* Adult patients, \>=18 years of age
* Metastatic colorectal cancer and disease progression
* Previously treated with first-line chemotherapy plus Avastin
* Eastern Cooperative Oncology Group (ECOG) performance status \<=2.

Exclusion Criteria:

* Diagnosis of progression of disease more than 3 months after last Avastin administration
* First-line patients with progression-free survival in first-line of \<3 months
* Patients receiving less than 3 consecutive months of Avastin in first-line therapy
* Past or current history (within the last 2 years prior to treatment start) of other malignancies, except for curatively treated basal and squamous cell cancer of the skin or in situ cancer of the cervix
* Clinically significant cardiovascular disease within 6 months prior to start of study treatment
* Known central nervous system (CNS) disease, except for treated CNS metastases as defined by protocol
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: D