Rectal Cancer CTC Trial

Impact of Neoadjuvant Chemoradiotherapy Versus Surgery Alone on Circulating Tumor Cells in Patients With Stage II-III Rectal Cancer and Negative Circumferential Resection Margin: a Multicenter Randomized Clinical Trial

This prospective, multi-centre, randomised clinical trial aims to compare the effect of neoadjuvant chemoradiotherapy versus primary surgery on circulating tumor cells (CTCs) in patients with stage II-III rectal cancer without circumferential resection mar-gin involvement. CTCs are considered a promising biomarker for disease dissemination and treatment response. Patients will be randomized to either primary surgical resection with total mesorectal excision or long-course neoadjuvant chemoradiotherapy followed by surgery. Serial blood samples will be collected at predefined time points to assess the presence and dynamics of CTCs. Secondary endpoints include perioperative morbidity and mortality, local recurrence rate, disease-free survival, and overall survival. The results of this study may provide new insights into the prognostic role of CTCs and contribute to optimising treatment strategies for rectal cancer.

Colorectal cancer remains one of the most common malignancies worldwide, and rectal cancer requires a multidisciplinary treatment approach. For patients with locally advanced rectal cancer, neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection has been widely used to reduce the risk of local recurrence. However, the indication for nCRT in patients without circumferential resection margin (CRM) involvement remains controversial. While some studies have suggested benefits of nCRT, others have shown comparable oncological outcomes with primary surgery when high-quality total mesorectal excision (TME) is performed.

Circulating tumor cells (CTCs) are malignant cells detectable in peripheral blood that have been associated with metastatic potential and poor prognosis in various cancers, including colorectal cancer. Monitoring the presence and dynamics of CTCs offers a minimally invasive "liquid biopsy" approach that may provide prognostic information and reflect treatment efficacy. Existing evidence suggests that changes in CTC levels after surgery or systemic therapy may correlate with recurrence risk and survival, but relevant data in rectal cancer patients undergoing multimodal treatment are limited.

This prospective, multi-centre, randomised clinical trial will enrol patients with stage II-III rectal cancer without evidence of CRM involvement on staging magnetic resonance imaging (MRI). Eligible patients will be randomized into two study arms:

1. Primary surgery arm: radical surgical resection with total mesorectal excision (TME).
2. Neoadjuvant therapy arm: long-course neoadjuvant chemoradiotherapy fol-lowed by delayed surgical resection.

Peripheral blood samples will be collected at predefined time points in both groups to determine the presence and quantity of CTCs. The primary objective is to compare the effect of neoadjuvant chemoradiotherapy versus surgery alone on CTC dynamics.

Secondary objectives include:

• Evaluation of short-term surgical outcomes (perioperative complications, 30-day morbidity and mortality).
• Assessment of long-term oncological outcomes (local recurrence, disease-free survival, and overall survival at 3 and 5 years).

By integrating CTC monitoring into a modern randomized clinical trial design, this study aims to clarify the prognostic value of CTCs in rectal cancer and determine whether specific treatment strategies are associated with more favourable biological and clinical outcomes. The findings may contribute to more individualised treatment planning and potentially reduce the risk of recurrence and mortality in rectal cancer patients.

Inclusion Criteria:

• Age ≥ 18 years
• Histologically confirmed rectal adenocarcinoma within 12 cm from anal verge
• Stage II (cT3-4 N0 M0) or stage III (cT1-4 N1-2, M0)
• Negative circumferential resection margin on staging MRI
• ASA physical status I-III
• Signed informed consent

Exclusion Criteria:

• Tumor infiltration beyond fascia recti propria on MRI
• Metastatic disease (stage IV)
• Recurrent rectal cancer
• Other concurrent malignancies
• Emergency surgery required
• Contraindication to surgery under general anesthesia