Next Generation STAR-TREC (NG-ST) - Organ Preservation in Early Rectal Cancer

Background and Rationale

Standard treatment for early-stage rectal cancer is total mesorectal excision (TME), which provides good oncologic control but may result in substantial functional morbidity. Even in early tumors, radical surgery can lead to bowel dysfunction (including low anterior resection syndrome), urinary and sexual dysfunction, and in some cases permanent stoma formation. While oncologic outcomes are generally favorable, the long-term impact on quality of life remains significant for many patients.

Neoadjuvant chemoradiotherapy (CRT) has been shown to induce tumor regression in rectal cancer, and in a subset of patients a clinical complete response (cCR) may be achieved. In such cases, surgery may potentially be deferred under strict surveillance protocols, a strategy often referred to as organ preservation or "watch and wait." Previous prospective and international studies, including STAR-TREC, have demonstrated promising rates of clinical complete response in selected patients with early rectal tumors.

Study Objectives

Primary Objective To determine whether mesorectal chemoradiotherapy (50 Gy in 25 fractions combined with capecitabine 825 mg/m² twice daily on radiotherapy days) can achieve a sustained clinical complete response at one year in patients with early rectal cancer, allowing surgery to be safely deferred.

Secondary Objectives

• To evaluate local recurrence and local regrowth rates
• To assess distant metastases and overall survival
• To evaluate organ preservation rates at 3 years
• To assess surgical morbidity (if surgery is performed)
• To evaluate patient-reported outcomes including quality of life, bowel function, urinary function, and sexual function
• To perform health economic evaluation

Study Design

NG-ST is a national, multicenter, prospective, non-randomized phase IV cohort study conducted under EU Regulation 536/2014 (CTR). The study is classified as a low-intervention clinical trial, as capecitabine is an authorized medicinal product used within its marketing authorization, albeit at an earlier tumor stage than standard routine.

Eligible patients have biopsy-confirmed rectal adenocarcinoma ≤12 cm from the anal verge and MRI-staged T1-T3b, N0/NX, M0 disease. Both TME surgery and chemoradiotherapy must be considered feasible treatment options by the multidisciplinary team (MDT).

Patients are offered a choice between standard upfront TME surgery and organ preservation with mesorectal chemoradiotherapy.

Interventions

Organ Preservation Arm Radiotherapy: 50 Gy delivered in 25 fractions (2 Gy per fraction), 5 days per week over 5 weeks.

Capecitabine: 825 mg/m² orally twice daily on radiotherapy days.

Structured response assessment is performed 6-8 weeks after completion of CRT using MRI, endoscopy, and clinical examination. Patients achieving clinical complete response enter a structured surveillance program. Patients without complete response proceed to TME surgery.

Standard Surgery Arm Patients undergo total mesorectal excision (TME) according to local standards. Surgical approach is at the discretion of the treating surgeon.

Definition of Clinical Complete Response

• No residual tumor or suspicious lymph nodes on MRI
• No visible tumor on endoscopy (scar or fibrosis permitted)
• No palpable tumor on digital rectal examination

Follow-Up

Patients are followed prospectively with structured surveillance including MRI, endoscopy, clinical examination, and quality-of-life questionnaires. Follow-up continues for at least three years, with longer-term survival assessment up to five years.

Safety Monitoring

Adverse events (AE), serious adverse events (SAE), and suspected unexpected serious adverse reactions (SUSAR) are recorded and reported according to EU CTR requirements. Annual Safety Reports are submitted via CTIS in accordance with Article 43 of Regulation (EU) 536/2014.

Significance

The NG-ST study aims to prospectively evaluate an organ-preserving strategy that may reduce the need for radical surgery and improve long-term functional outcomes without compromising oncologic safety in selected patients with early rectal cancer.

Inclusion criteria

• Age ≥ 18 years
• Written informed consent
• Biopsy-proven rectal adenocarcinoma
• Tumor located <12 cm from the anal verge
• MRI-staged T1-T3b tumor
• N0 or NX (no radiologic evidence of nodal metastases)
• M0 or MX (no radiological evidence of distant metastases)
• ECOG performance status 0-1
• Multidisciplinary team (MDT) assessment confirming that both total mesorectal excision (TME) and chemoradiotherapy are feasible treatment options

Exclusion criteria

• MRI-defined N1 or higher nodal disease
• Distant metastases (M1)
• MRI extramural vascular invasion (mriEMVI)
• Threatened mesorectal fascia (≤1 mm on MRI)
• Maximum tumor diameter > 40 mm
• MRI defined mucinous tumor
• No residual luminal tumor following prior endoscopic resection
• Recurrent rectal cancer
• Prior pelvic radiotherapy
• Uncontrolled significant cardiorespiratory comorbidity
• Known complete dihydropyrimidine dehydrogenase (DPYD) deficiency
• Known Gilbert's syndrome
• Pregnancy or breastfeeding
• Concomitant medication contraindicated with capecitabine that cannot be safely discontinued
• Age <18 years