Active Surveillance vs Adjuvant Chemoradiotherapy for Locally Resected Intermediate-Risk T1 Rectal Cancer

Medical University of Gdansk480 enrolled

Overview

The goal of this clinical trial is to learn if close follow-up alone (active surveillance) works as well as radiation combined with chemotherapy (chemoradiotherapy) after removing early rectal cancer in adults. The main questions it aims to answer are: 1. Does active surveillance cause fewer serious adverse events than chemoradiotherapy within 3 years? Serious adverse events include a permanent or temporary ostomy (a surgical opening in the belly to pass stool), major bowel problems, or severe treatment-related complications. 2. Is active surveillance as safe as chemoradiotherapy in preventing cancer from coming back or spreading within 3 years? Researchers will compare active surveillance to chemoradiotherapy to see if surveillance causes fewer serious adverse events while keeping cancer outcomes comparable. To join this study, participants must be adults who had an early-stage rectal cancer (T1) removed by an endoscopic procedure, and whose removed tumor showed certain features that raise the risk of cancer cells remaining nearby. Participants will be randomly placed in one of two groups: 1. Active surveillance group: Participants will have regular checkups, blood tests, flexible camera exams of the bowel (rectoscopy), scans of the pelvis and abdomen, and colonoscopy on a set schedule for 5 years. If cancer comes back, doctors will propose further treatment options. 2. Chemoradiotherapy group: Participants will receive radiation to the pelvis along with a chemotherapy pill (capecitabine) or an intravenous (IV) chemotherapy drug (5-FU) for about 5 weeks. After treatment, they will have regular checkups and scans for 5 years.

The current standard treatment for T1 rectal cancer (T1N0M0) is local excision by endoscopic submucosal dissection (ESD) or intermuscular dissection (IMD) performed endoscopically or via transanal minimally invasive surgery (TAMIS). More than half of the patients treated with ESD or IMD require secondary treatment due to unfavourable histopathological features in the resected specimen. Lesions can be classified as intermediate-risk if the specimen presents at least one of the following features: poor differentiation (grade 3), lymphovascular invasion, high-grade tumour budding (grade 2-3), or deep submucosal invasion (sm2-sm3). Secondary treatment can be performed either by total mesorectal excision (TME) or adjuvant chemoradiotherapy. The latest evidence suggests that chemoradiotherapy may offer a superior risk-benefit ratio compared to completion TME. Still, chemoradiotherapy remains associated with a substantial risk of major low anterior resection syndrome (LARS); the risk is reduced but still reported at approximately 25-33%. Given a 15-20% risk of lymph node involvement in the intermediate-risk group, chemoradiotherapy might be overtreatment for the majority of these patients. Active surveillance can reduce treatment-related morbidity, but it is associated with higher local recurrence rates. Available cohort data suggest that most recurrences are detected early during structured surveillance and are salvageable with curative-intent surgery, resulting in oncological outcomes similar to those achieved with adjuvant chemoradiotherapy. However, no randomised trial has directly compared these two strategies in this population.

Interventions

Active surveillanceOTHER

Active surveillance includes physical examination, and carcinoembryonic antigen (CEA) testing every 3 months during years 1-2 and every 6 months during years 3-5. Rectoscopy is performed every 3 months during years 1-2 and every 6 months during years 3-5. Pelvic MRI is performed every 6 months for 5 years. Thoracic and abdominal CT scans are performed annually for 5 years. Colonoscopy is performed at 1 year after local excision and subsequently according to findings. Recurrences are managed according to multidisciplinary team recommendations.

Adjuvant chemoradiotherapyRADIATION

Adjuvant long-course pelvic chemoradiotherapy will be initiated within 12 weeks after local excision. Radiotherapy consists of 45 Gy delivered in 25 fractions of 1.8 Gy once daily, 5 days per week, over approximately 5 weeks. Concurrent chemotherapy consists of either oral capecitabine 825 mg/m² twice daily on radiotherapy days or continuous intravenous 5-fluorouracil 225 mg/m²/day throughout radiotherapy. After treatment, follow-up includes history, physical examination, CEA testing, and flexible sigmoidoscopy every 6 months for 5 years; pelvic MRI every 6 months during the first 3 years; annual thoracic and abdominal CT for 5 years; pelvic CT after discontinuation of MRI surveillance; and colonoscopy at 1 year and thereafter according to findings.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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).

Outcomes

Primary Outcomes

Disease-related treatment failure

Time from randomisation to the first occurrence of: 1. Cancer specific death. 2. Non-salvageable locoregional recurrence. 3. Distant metastases.

Time frame: 3 years from randomisation

Composite severe treatment-related adverse event

Occurrence of any of the following: 1. Stoma (permanent or temporary). 2. Major LARS (score ≥30). 3. CTCAE grade ≥3 toxicity. 4. Clavien-Dindo ≥3b complications.

Time frame: 3 years from randomisation

Secondary Outcomes

Disease-free survival

Time from randomisation to first event: death (any cause), distant metastases, or locoregional recurrence

Time frame: 3 and 5 years after randomization

Overall Survival

Time from randomization to death from any cause.

Time frame: 3 and 5 years after randomization

Stoma formation rate

Proportion of patients with a colostomy or ileostomy (permanent or temporary) present at assessment. Stoma rates will be evaluated at predefined follow-up intervals.

Time frame: 12 months, 3 years, and 5 years after randomization

Incidence of Major Low Anterior Resection Syndrome (LARS)

Proportion of patients with a LARS Questionnaire score of 30 points or greater, indicating major low anterior resection syndrome.

Time frame: 12 months, 3 years, and 5 years after treatment

Grade 3 or Higher Treatment-Related Toxicity

Incidence of adverse events of grade 3 or higher according to Common Terminology Criteria for Adverse Events (CTCAE) version 6.0 occurring during treatment and follow-up.

Time frame: From treatment initiation through 12 months after completion of chemoradiotherapy.

Locoregional Recurrence Rate

Proportion of patients with radiologically or histologically confirmed recurrence within the pelvis or mesorectum.

Time frame: 5 years after randomization.

Salvageability of Locoregional Recurrence

Proportion of detected locoregional recurrences amenable to curative-intent salvage therapy.

Time frame: At the time of recurrence detection, up to 5 years after randomization

Duration of Hospital Stay After Primary Treatment

Total cumulative length of hospitalization following the randomized treatment strategy, measured in calendar days.

Time frame: From the day of randomization untill 5 years from randomization.

Distant Recurrence Rate

Proportion of patients with radiologically or histologically confirmed distant metastatic disease outside the locoregional area.

Time frame: 3 years and 5 years after randomization.

Health-Related Quality of Life (EORTC QLQ-C30)

Health-related quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30).

Time frame: Baseline, 12 months, 3 years, and 5 years after randomization

Healthcare Resource Utilization Costs per Patient

Direct healthcare resource utilization costs including treatment, procedures, imaging, hospitalization, surveillance, and management of recurrence and complications measured as a total per patient in euro (€).

Time frame: Up to 5 years after randomization.

Cost-Effectiveness

Incremental cost-effectiveness expressed as cost per quality-adjusted life-year (QALY) gained and cost per disease-free survival year gained.

Time frame: 3 years and 5 years after randomization

Ostomy-Free Survival

Time from randomization to permanent ostomy formation or death, with estimation of the proportion of patients alive without a permanent ostomy.

Time frame: 3 years and 5 years after randomization.

Health-Related Quality of Life (EORTC QLQ-CR29)

Health-related quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Colorectal Cancer Module (EORTC QLQ-CR29).

Time frame: Baseline, 12 months, 3 years, and 5 years after randomization.