Table 1 Patient inclusion and exclusion criteria
Inclusion criteria | |
|---|---|
1. Personal written informed consent is obtained after the study has been fully explained | |
2. Histologically confirmed colon or rectal adenocarcinoma (excluding appendix cancer and anal canal cancer) | |
3. Clinically unresectable tumor | |
4. ≥ 20 years of age at enrollment | |
5. The ECOG performance status (PS) score of 0 or 1 (≥ 71 years of age: PS score of 0) | |
6. Measurable lesion in accordance with RECIST ver. 1.1 criteria on contrast-enhanced chest, abdominal, or pelvic (trunk) CT (required within 28 days of enrollment) | |
7. No previous chemotherapy for colon or rectal cancer (patients with confirmed relapse ≥24 weeks after completing post-operative adjuvant chemotherapy can be enrolled) | |
8. RAS/BRAF mutation analysis at enrollment identifies RAS/BRAF status as either the wild-type or mutant type | |
9. Vital organ functions meet the following criteria within 14 days before enrollment. If multiple test results are available in that period, the results closest to enrollment will be used. No blood transfusions or hematopoietic factor administration will be permitted within 2 weeks before the date on which measurements are taken. a. Neutrophil count: ≥ 1500/mm3 b. Platelet count: ≥ 10.0 × 104/mm3 c. Hemoglobin concentration: ≥ 9.0 g/dL d. Total bilirubin: ≤ 1.5-fold the upper limit of normal (ULN) e. AST, ALT, ALP: ≤ 2.5-fold the ULN (≤ 5-fold the ULN for liver metastases) f. Serum creatinine: ≤ 1.5-fold the ULN, or creatinine clearance: ≥ 30 mL/min g. Urine protein: ≤ 2+ (if ≥3+, urine protein/creatinine ratio: < 2.0) | |
10. UGT1A1 polymorphism is wild-type or single heterozygous type | |
Exclusion criteria | |
1. Previous radiation therapy in which ≥20% bone marrow was exposed to the radiation field | |
2. Untreated brain metastases, spinal cord compression, or primary brain tumor | |
3. History of central nervous system disease (excluding asymptomatic lacunar infarction) | |
4. Continuous systemic corticosteroid treatment is required | |
5. Oral or parenteral (such as low molecular weight heparin) anticoagulant dose is not consistently (≥ 14 days) controlled (oral anticoagulants: conditions at high risk for bleeding, such as PT-INR ≥ 3, clinically significant active bleeding [within 14 days of enrollment]) | |
6. Arterial thrombosis or arterial thromboembolism such as myocardial infarction, transient ischemic attack, or cerebrovascular attack in the last year prior to enrollment | |
7. Previous treatment with an investigational drug within 28 days before enrollment, or participation in a study of an unapproved drug | |
8. Any of the following comorbidities: a. Uncontrolled hypertension b. Uncontrolled diabetes mellitus c. Uncontrolled diarrhea d. Peripheral sensory neuropathy (≥ Grade 1) e. Active peptic ulcer f. Unhealed wound (except for suturing associated with implanted port placement) g. Evidence of cardiovascular disease, cerebrovascular disorder (within 24 weeks), myocardial infarction (within 24 weeks), unstable angina pectoris, New York Heart Association classification ≥ Grade 2 congestive heart failure, serious arrhythmias requiring drug therapy h. Uncontrolled venous thromboembolism (unless clinically stable, asymptomatic, or appropriately treated with an anticoagulant) i. Systemic treatment required for, or evidence of, infections j. Other clinically significant diseases (such as interstitial pneumonia or renal impairment) | |
9. Major surgical procedure within 28 days before study treatment initiation | |
10. Physical defects of the upper gastrointestinal tract; malabsorption syndrome or difficulty taking oral medication | |
11. Pregnant, breastfeeding, positive pregnancy test (women who have menstruated in the last year will be tested), or patients who are unwilling to use contraception during the study | |
12. Active hepatitis B or C, or evidence of HIV infection | |
13. Previous chemotherapy for other malignancies (excluding hormone therapy for breast cancer). | |
14. Other active malignancies (excluding malignancies that are expected to be completely cured, such as intramucosal carcinoma and carcinoma in situ) | |
15. Diseases such as intestinal paralysis, intestinal obstruction, or gastrointestinal perforation within 1 year prior to enrollment | |
16. Pleural effusion, ascites, or pericardial effusion requiring drainage | |
17. History of hypersensitivity to fluorouracil, levofolinate, oxaliplatin, irinotecan, bevacizumab, and their excipients or Chinese hamster ovary cell proteins | |
18. History of adverse reactions to fluoropyrimidine drugs indicative of dihydropyrimidine dehydrogenase (DPD) deficiency | |
19. Endoluminal stenting | |
20. Otherwise unsuitable for the study in the opinion of the investigators |