TNT of SCRT+CAPOX vs SCRT+CAPOXIRI for Locally Advanced Rectal Cancer

This trial is a multicenter randomized Phase III study to verify the superiority of short-course preoperative radiation (SCRT) and CAPOXIRI over SCRT and CAPOX as preoperative treatments for locally advanced rectal cancer.

Total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) has the promise, which means non-operative management (NOM) enable more patients (pts) with a complete clinical response (cCR) or near-complete clinical responses (nCR) after TNT to avoid subsequent radical surgery, with potentially maintaining anorectal function and quality of life (QoL). Recently, PRODIGE-23 trial demonstrated that triplet regimen (Irinotecan, oxaliplatin and fluoropyrimidine) before preoperative chemoradiotherapy (CRT) significantly improved outcomes compared with CRT. However, there has been no prospective study comparing consolidation triplet with doublet regimens following short course radiotherapy (SCRT). The aim of this randomized phase III trial is to test superiority of consolidation irinotecan, capecitabine and oxaliplatin (CAPOXIRI) vs. capecitabine and oxaliplatin (CAPOX) following SCRT as TNT in pts with LARC.

Pts in both groups will be re-staged after completing TNT before radical surgery according to the Memorial Sloan Kettering Regression Schema; pts with incomplete response (iCR) will undergo total mesorectal excision (TME), cCR pts will receive NOM, and nCR pts will undergo TME or NOM by a physician discretion under the recommendation of blind assessment by the designated NOM central committee. Pts will be followed by CT, MRI, colonoscopy and liquid biopsy every 4 months for 2 years, and every 6 months thereafter up to 5 years.

To detect a decrease in 3-year cumulative probability of organ preservation-adapted Disease free survival (DFS) from 75.0% to 81.7%, corresponding to a target hazard ratio of 0·70, a total of 608 pts (196 events) would achieve 70% power at a two-sided α significance level of 0.05.

Eligibility Criteria:
Inclusion Criteria:

1. The content of this research was fully explained, and written informed consent was obtained from the subject.
2. Histologically confirmed rectal adenocarcinoma.
3. Radical resection is clinically possible without any distant metastases on imaging studies.
4. Age of 18 years or older on the date of consent acquisition.
5. Eastern Cooperative Oncology Group (ECOG) PS 0-1 (PS 0 if aged 70 years or older on consent acquisition date).
6. Inferior margin of the tumor is within 12 cm of the AV.
7. No prior tumor treatment.
8. No history of radiation therapy to the pelvis, including treatment for other cancer types.
9. Cases with cT3-4N0M0\*or T1-4N1-2M0 based on Union Internationale Contre le Cancer (UICC) 8th edition.

   (\*5 cm\< AV ≤ 10 cm, T3a/bN0M0, extramural venous invasion (EMVI) -, mesorectal fascia (MRF) clear and 10 cm \< AV ≤ 12 cm, T3a/bN0-1M0, EMVI-, MRF clear are eligible only for those who refused surgery)
10. UGT1A1 is wild-type or single heterozygous.
11. Criteria for major organ function within 28 days prior to enrollment. If there are multiple test results within this period, the most recent one will be used, and blood transfusions and hematopoietic factor preparations will not be administered within 14 days before the test date for measurements before registration.

    1. Neutrophil count: ≥1,500/mm3
    2. Platelet count: ≥10.0×10 4/mm3
    3. Hemoglobin concentration: ≥9.0 g/dL
    4. Total bilirubin: ≤2.0 mg/dL
    5. Aspartate transaminase (AST): ≤100 IU/L or less
    6. Alanine transaminase (ALT): ≤100 IU/L or less
    7. Serum creatinine: Creatinine clearance ≥30 mL/min (by Cockcroft \& Gault formula)

Exclusion Criteria:

1. Extensive surgery (excluding colostomy and central venous port construction) within 4 weeks before starting protocol treatment.
2. Complications or history of severe lung disease (such as interstitial pneumonia, pulmonary fibrosis, and severe emphysema).
3. Colonic stent in place.
4. Contraindications for MRI such as cardiac pacemakers.
5. Serious comorbidities (such as heart failure, renal failure, liver failure, intestinal paralysis, intestinal obstruction, uncontrolled diabetes, and active inflammatory bowel disease).
6. Patients with multiple active cancers (simultaneous multiple cancers or metachronous multiple cancers with a disease-free interval of 5 years or less). However, carcinoma in situ or lesions equivalent to intramucosal carcinoma, which can be cured by local treatment, are not treated as active multiple cancers.
7. Pregnant women, lactating women, positive pregnancy test, or unwillingness to use contraception.
8. Hepatitis B surface (HBs) antigen positive or hepatitis C virus (HCV) antibody-positive. However, HCV-RNA-negative can be registered.
9. Have human immunodeficiency virus (HIV) infection.
10. MSI-high (MSI-H) or defective mismatch repair (dMMR) is known.
11. Unwilling to donate specimens for "Research on gene profiling and clinical significance using clinical specimens from cancer patients" for whole-genome analysis based on the "Action Plan for Whole-Genome Analysis, etc." (CONDUCTOR study).
12. Any other patients the principal investigator or co-investigator deems inappropriate for study participation.