Active Surveillance vs Adjuvant Chemoradiotherapy for Locally Resected Intermediate-Risk T1 Rectal Cancer (T-REX)

Inclusion Criteria:

1. Pathologically confirmed rectal cancer located extraperitoneally.
2. Complete tumour resection (R0) by means of ESD or IMD (endoscopic or TAMIS).

3. Pathological report indicative of:

   - pT1 with at least 1 of the following features: poor histological differentiation (grade 3), vascular invasion, lymphatic invasion, high tumour budding (grade 2-3), sm2 or sm3 invasion.

4. Endoscopic images or video of the tumour before local excision.
5. Maximum cancer diameter ≤ 30 mm based on the pathological assessment.

6. cN0 stage based on pelvic MRI; lymph nodes smaller than 10 mm will be considered as benign, independent of morphologic features. Staging must be performed within 6 weeks before randomisation.

   - If enlarged lymph nodes are present on MRI performed after ESD/IMD (raising the possibility of reactive inflammatory change), fine needle aspiration (FNA) will be undertaken, and patients with negative FNA cytology will remain eligible.

7. Adequate distant staging (thoracic and abdominal CT) without signs of distant metastasis (cM0).

8. Have undergone a high-quality full colonoscopy:

   • Boston Bowel Preparation Scale score equal or greater than 2 in all colonic segments.
   • Documented caecal intubation.
   • All polyps ≥20 mm in diameter other than the index lesion must be completely removed and assessed pathologically.
9. Expected survival time of more than 12 months from randomisation.
10. At least 18 years old at the time of informed consent.
11. Eastern Cooperative Oncology Group performance status (ECOG PS) 0, 1 or 2.

12. Adequate hematologic function, based upon meeting the following laboratory criteria within 7 days before randomisation:

    • Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L.
    • Haemoglobin (Hb) ≥ 8.0 g/dL (red blood cell transfusions are allowed to reach the target level).
    • Platelet count ≥ 75 × 10^9/L.

13. Adequate liver function, based upon meeting the following criteria within 7 days before randomisation:

    • Serum albumin ≥ 3.0 g/dL.
    • Total bilirubin (in serum) ≤ 2.0 mg/dL.
    • Aspartate aminotransferase (AST) ≤ 3 × the upper limit of normal (ULN).
    • Alanine aminotransferase (ALT) ≤ 3× ULN.
    • Alkaline phosphatase (ALP) ≤ 3 × ULN.
14. Adequate coagulation defined by International Normalized Ratio (INR) ≤ 2.0 within 7 days before randomisation.

15. Adequate renal function, based upon meeting the following laboratory criteria within 7 days before randomisation:

    • Serum creatinine clearance ≥ 50 mL/min calculated using the Cockcroft-Gault formula.
    • Absence of significant proteinuria. If the subject is found to have dipstick test indicative of proteinuria equal or larger than 2+, or lab urinalysis for protein is greater than or equal to 1 g/L, the subject must demonstrate urine protein < 1 g/24 h to be eligible.
16. Recovery from prior treatment-related toxicities to < Grade 2 severity per CTCAE v6.0, unless the adverse events are clinically nonsignificant and/or stable on supportive therapy.
17. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the study treatment. This does not apply to postmenopausal women (amenorrhoeic for at least 12 consecutive months), women aged above 55, or surgically sterilized patients (men and women).

18. Female participants of childbearing potential must not be lactating or pregnant, with a negative beta-human chorionic gonadotropin (beta-hCG) test (blood or urine) at screening and before the first dose of the study treatment.

    Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e., females who have had any evidence of menses in the past 12 months, except for those who had prior hysterectomy). However, women who have been amenorrhoeic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antioestrogens, ovarian suppression, low body weight, or other reasons.

19. Written informed consent to participate in the study provided before randomisation.
20. Capability of understanding and complying with the protocol requirements.
21. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
22. Eligibility for thoracic, abdominal and pelvic CT and MRI.

Exclusion Criteria:

1. Suspicion of distant metastases on computed tomography of the abdomen or thorax or lymph node involvement (lymph nodes >9mm in short axis); In case of isolated enlarged nodes biopsy will be required before exclusion.
2. Mesorectal tumour involvement on pelvic MRI.
3. Synchronous colorectal cancer in screening colonoscopy.
4. Known genetic cancer syndrome, including, but not limited to adenomatous or serrated polyposis syndrome; Lynch or Lynch-like syndrome.
5. Known inflammatory bowel disease.
6. Previously identified allergy or hypersensitivity to 5-FU or capecitabine.
7. Known or suspected dihydropyridine dehydrogenase (DPD) deficiency.
8. Prior receipt of pelvic radiation.
9. Other contraindications to pelvic irradiation.
10. Serious illness other than cancer that would preclude safe participation in the study

11. Uncontrolled and significant condition, including, but not limited to, the following conditions:

    • Heart failure NYHA II or above.
    • Major cardiac arrhythmia.
    • Myocardial infarction within 6 months before randomisation.
    • Unstable angina pectoris.
    • Stroke (including transient ischemic attack, TIA) within 6 months before randomisation.
    • Thromboembolism within 3 months before randomisation.
    • History of hypertensive crisis.
12. Gastrointestinal disorders associated with a high risk of perforation or fistula formation.
13. Gastrointestinal bleeding event within 28 days of randomisation.
14. Major surgery performed within 4 weeks prior to randomisation or scheduled for surgery during the study period. Complete healing from major surgery must have occurred 1 month before randomisation. Complete healing from minor surgery must have occurred at least 7 days before randomisation.
15. Serious non-healing wound or bone fracture.
16. Malabsorption syndrome.
17. Pregnancy or lactation.
18. Mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H).