SCARLET - Italian proSpeCtionAl obseRvationaL multicEntre Study on Treatment for recTal pT1 Cancer

Overview

The purpose of this prospective, observational, multicenter study is to evaluate the impact of adjuvant radiotherapy or chemoradiotherapy on disease-free survival (DFS) in patients with pathological T1 (pT1) rectal cancer presenting with at least one high-risk histological factor, such as deep submucosal invasion, poor differentiation, tumor budding, lymphovascular invasion, or positive resection margins, after local surgical or endoscopic excision, including Endoscopic Submucosal Dissection (ESD), Transanal Minimally Invasive Surgery (TAMIS), or Transanal Endoscopic Microsurgery (TEM). The study focuses on a specific patient population that has refused standard radical surgery with Total Mesorectal Excision (TME) because of its potential impact on quality of life and postoperative morbidity. The primary objective is to assess whether organ-preserving local treatment strategies can provide an effective alternative by evaluating long-term oncologic outcomes, quality of life, and colostomy-free survival.

Detailed description

Background To date, the therapeutic management of patients with pathological T1 (pT1) rectal cancer after local surgical or endoscopic excision remains a subject of ongoing debate. Although traditional radical surgery has demonstrated proven advantages, discussion persists regarding the adequacy of less invasive techniques for specific subgroups of patients, particularly those with a low risk of disease progression. In these cases, local excision options through endoscopic or surgical interventions, including Endoscopic Submucosal Dissection (ESD), Transanal Minimally Invasive Surgery (TAMIS), and Transanal Endoscopic Microsurgery (TEM), may represent a valid curative approach. These techniques, which generally carry a low risk of lymph node metastasis, offer important advantages in terms of organ preservation and reduction of postoperative complications, including anorectal, urinary, and sexual dysfunction, which may significantly impair quality of life.

Rationale The choice of a conservative approach must be carefully evaluated, especially when post-excision histopathological analysis reveals high-risk features. These include deep submucosal invasion greater than 1 mm, poor tumor differentiation, tumor budding, lymphovascular invasion, or positive or close resection margins. In these situations, radical surgery with Total Mesorectal Excision (TME) is considered the standard treatment strategy for reducing the risk of local and nodal recurrence, although available evidence is largely derived from retrospective studies. Because TME may substantially affect quality of life and functional outcomes, treatment decisions should be discussed within a multidisciplinary team. National and international guidelines suggest that patients with pT1 rectal cancer who present high-risk features and are either unwilling or unsuitable to undergo radical surgery may be considered for alternative organ-preserving strategies, including adjuvant radiotherapy or chemoradiotherapy.

Study Objective This prospective, observational, multicenter study aims to evaluate the impact of adjuvant radiotherapy or chemoradiotherapy on Disease-Free Survival (DFS) in patients with pT1 rectal cancer presenting at least one high-risk histopathological feature who have undergone local excision and declined treatment with TME. The study will also assess long-term oncologic outcomes, organ preservation, and quality of life in this patient population.

Primary outcome measures

• 3-year Disease-Free Survival (DFS) [Time frame: 3-years]

Secondary outcome measures (12)

• Disease-free survival at 1 year [Time frame: 1 year]
• Disease-free survival at 5 years [Time frame: 5 years]
• Local recurrence-free survival at 1 year [Time frame: 1 year]
• Local recurrence-free survival at 3 years [Time frame: 3 years]
• Local recurrence-free survival at 5 years [Time frame: 5 years]
• Overall survival at 1 year [Time frame: 1 year]
• Overall survival at 3 years [Time frame: 3 years]
• Overall survival at 5 years [Time frame: 5 years]
• Colostomy-free survival at 1 year [Time frame: 1 year]
• Colostomy-free survival at 3 years [Time frame: 3 years]
• Quality of life assessed by EORTC QLQ-C30 Global Health Status/Quality of Life score at 1 year [Time frame: 1 year]
• Colorectal cancer-specific quality of life assessed by EORTC QLQ-CR29 at 1 year [Time frame: 1 year]

Eligibility criteria

Inclusion criteria

• Age 18 years or older.
• Good performance status (Eastern Cooperative Oncology Group \[ECOG\] performance status 0 or 1).
• Primary tumor of the distal rectum (clinical T1) amenable to local endoscopic resection using Endoscopic Submucosal Dissection (ESD) or local surgical resection using Transanal Endoscopic Microsurgery (TEM) or Transanal Minimally Invasive Surgery (TAMIS).
• High-risk pathological T1 rectal cancer meeting at least one of the following conditions:

i) Poorly differentiated adenocarcinoma, mucinous adenocarcinoma, or signet ring cell carcinoma.

ii) Pathological submucosal invasion greater than 1000 micrometers. iii) Positive lymphatic invasion or positive venous invasion confirmed by immunohistochemistry.

iv) Tumor budding grade 2 or 3. v) Positive lateral or vertical resection margin (tumor within 1 mm of the surgical margin) or non-assessable resection margin.

• No lymph node or distant metastases confirmed by computed tomography of the chest, abdomen, and pelvis (clinical N0, M0 disease).
• Radiotherapy or chemoradiotherapy initiated within 12 weeks after local endoscopic or surgical resection.
• No previous rectal resection (other than local excision) or pelvic irradiation for any malignancy.
• Adequate organ function as assessed by the treating physician.
• The treating surgeons have explained to the patient that the current standard of care is Total Mesorectal Excision (TME) with D2 lymph node dissection and the patient has declined this treatment.
• Candidate for adjuvant chemoradiotherapy according to routine clinical practice.
• Written informed consent provided.

Exclusion criteria

• Synchronous or metachronous malignancy diagnosed within the previous 5 years.
• Infection requiring systemic treatment.
• Requirement for continuous systemic treatment with corticosteroids or immunosuppressive agents.
• Diagnosis of a hereditary colorectal cancer syndrome, including familial adenomatous polyposis or Lynch syndrome, or diagnosis of inflammatory bowel disease, including ulcerative colitis or Crohn disease.
• Squamous cell carcinoma, neuroendocrine neoplasm, or mixed neuroendocrine-non-neuroendocrine neoplasm histology.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Italy · 1 center

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS — Roma

Identifiers

NCT: NCT07695519 · 27321

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗