Total Neoadjuvant Therapy and Organ Preservation Versus Surgery for Rectal Cancer.

Total Neoadjuvant Therapy for Rectal Cancer - a New Standard of Care?

This study hypothesizes that approximately 50% of rectal cancer patients can preserve their rectum using a watch-and-wait strategy if they achieve a complete or near-complete clinical response to total neoadjuvant therapy (TNT). The objective is to determine whether the complications, quality of life, and survival rates of rectal cancer patients who have achieved a complete or near-complete clinical response to TNT, followed by a watch-and-wait approach, are comparable to those of patients who undergo surgery first. Additionally, the study aims to identify potential prognostic and predictive markers for rectal cancer and examine survival rates and factors influencing responses to chemoradiotherapy (CRT) or TNT.

The study is divided into two parts:

**Part One:** Participants with cT1N1, T2-T3 N0-1 rectal cancer, MRF-, and EMVI-, with surgery as one of the possible first-line treatment options, will be randomized into two groups. The experimental group will consist of participants receiving TNT, including CRT and consolidation chemotherapy (Ch). If these participants achieve a complete or near-complete clinical response, they will be observed using a watch-and-wait strategy, which is a non-operative approach. The control group will consist of participants who undergo surgical treatment initially.

**Part Two:** All participants with rectal cancer who have received CRT or TNT will be included. Additionally, participants diagnosed with rectal cancer who are scheduled for CRT or TNT but declined to participate in Part One or do not meet the inclusion criteria will also be included.

Study Overview

• Status: Recruiting
• Conditions: Quality of Life; Chemotherapy; Low Anterior Resection Syndrome; Rectal Cancer; Neoadjuvant Therapy; Radiotherapy Side Effect; Radiotherapy; Chemoradiotherapy; Chemotherapy Side Effects; Organ Preservation; Total Neoadjuvant Treatment
• Intervention / Treatment: Radiation: Radiation Therapy; Drug: Chemoradiotherapy; Drug: Consolidation Chemotherapy; Procedure: Surgery; Other: Adjuvant treatment; Other: Part two

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Audrius Dulskas, PhD; Phone Number: +370 675 20094; Email: audrius.dulskas@gmail.com
• Study Contact Backup: Name: Ernestas Šileika, MD; Phone Number: +37060950402; Email: ernestas.sileika@nvc.santa.lt

Study Locations

• Lithuania
  • Vilnius, Lithuania, 08660
    • Recruiting
    • Nacional Cancer Institute
    • Contact: Audrius Dulskas, PhD; Phone Number: +37067520094; Email: audrius.dulskas@gmail.com
    • Contact: Ernestas Šileika, MD; Phone Number: +37060950402; Email: ernestas.sileika@nvc.santa.lt
    • Principal Investigator: Tomas Poškus, PhD
    • Principal Investigator: Audrius Dulskas, PhD
    • Sub-Investigator: Ernestas Šileika, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Part One

Inclusion Criteria:

• Over 18 years of age.
• Participants who agreed to participate in the study signed an informed consent form.
• The Eastern Cooperative Oncology Group (ECOG) score ranges from 0 to 2.
• Pathologically confirmed rectal adenocarcinoma.
• Tumor up to 10 cm from the anus.
• Magnetic resonance imaging (MRI) of the pelvis and computed tomography (CT) of the thorax and abdomen were performed to confirm the diagnosis.
• cT1N1, T2-T3 N0 - 1, M0, MRF -, EMVI -.
• Normal bone marrow function: blood leucocytes > 3.5 × 10⁹/l, neutrophils > 1.5 × 10⁹/l, platelets > 100 × 10⁹/l.
• Normal renal function: creatinine within 1,5 × normal.
• Normal liver function: blood bilirubin levels within 1,5 times normal, AST, ALT levels within 2,5 times the upper limit.

Exclusion Criteria:

• Prior ST or Ch.
• Participants who are not eligible for pelvic MRI.
• Participants who have had a malignancy in the last 5 years, except for treatment for basal cell or squamous cell skin cancer or in situ cervical cancer.
• ECOG status ≥ 3.
• Distant metastases detected.
• Participants with uncontrolled therapeutic or psychiatric conditions.
• Infectious diseases requiring antibiotic treatment.

Part Two

Inclusion Criteria:

• Over 18 years of age.
• Participants who agreed to participate in the study signed an informed consent form.
• ECOG score between 0 and 2.
• Pathological confirmed rectal adenocarcinoma.
• Stage I to III rectal cancer confirmed.
• The tumor is localized up to 12 cm from the anus.
• Participants who refused to participate in the first part of the study or did not meet the inclusion criteria for the first part.
• Participants have received preoperative CRT or TNT or are in the planning stages of neoadjuvant treatment.

Exclusion Criteria:

• New cancer two years after CRT.
• Stage IV cancer before treatment.
• Participants refusing to participate in the study or unable to sign the informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part one. The first group: an experimental group - TNT, organ preservation.; Participants in the experimental group will be treated with TNT - CRT plus consolidating Ch. Consolidation Ch lasts 12 weeks. The response to TNT will be assessed 4 to 5 weeks after the last cycle of Ch. Response assessment will be performed through digital examination, pelvic MRI, rectoscopy, and biopsy. Participants will be actively followed up and not treated after a complete or near-complete response. In case of non-response, participants will undergo surgery. If the participant is diagnosed with a near-complete clinical response and wishes to avoid surgery, the response is reassessed after 8 weeks. If there is no response, i.e., near-complete clinical response persists, the participant is offered surgery. Participants in the experimental group do not receive adjuvant treatment after TNT and surgery.	Radiation: Radiation Therapy; Radiation therapy (RT) is administered at a dose of 2 Gy per day for a total dose of 50 Gy delivered to the pelvis. This is done throughout 5 to 6 weeks.; Drug: Chemoradiotherapy; Capecitabine: 825 mg/m² twice daily, prescribed 1-5 days per week, for 5 weeks during RT. Or Bolus 5-FU regimen: 5-fluorouracil (5-FU) 400 mg/m2/day intravenously, administered on days 1-4 and 33-35. Calcium folinate (folinic acid) 20 mg/m2/day intravenously on days 1-4 and 33-35.; Drug: Consolidation Chemotherapy; XELOX: Oxaliplatin 130 mg/m² (day 1) + capecitabine 1000 mg/m² (days 1-14), every 3 weeks for 4 cycles. Or FOLFOX: Oxaliplatin - 85 mg/m2 intravenously (2-hour infusion), drip for 1 day. Calcium folinate (folinic acid) - 400 mg/m2/d. intravenously (2-hour infusion), started on day 1. F(5-fluorouracil) - 400 mg/m2/d. intravenously (bolus), started on day 1. Repeat every 2 weeks for 6 times.; Procedure: Surgery; Transabdominal Resection: Abdominoperineal resection, low anterior resection, or coloanal anastomosis using total mesorectal excision.
Active Comparator: Part one. Second Group: a control Group - surgery; In the control group, treatment will start with surgery. Following surgical treatment, adjuvant therapy may be provided for control group participants according to standard clinical practice if indicated.	Procedure: Surgery; Transabdominal Resection: Abdominoperineal resection, low anterior resection, or coloanal anastomosis using total mesorectal excision.; Other: Adjuvant treatment; If indicated, adjuvant therapy will be administered as usual in clinical practice.
Other: Part two of the study; In the second part of the study, investigators will prospectively collect and analyze the personal medical records of participants who have already received treatment with CRT or TNT. No new diagnostic or therapeutic approaches will be implemented; routine clinical practices for long-term follow-up will continue. For participants who have not received specific treatment and do not meet the inclusion criteria for the first part of the study, as well as those who declined to participate in that part, investigators will follow the routine clinical practices for investigation, treatment, and follow-up as long as they meet the inclusion criteria for the second part of the study.	Other: Part two; Standard treatment protocols and follow-up procedures are implemented in clinical practice.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative complications	Assessed based on the Clavien Dindo classification.	From the start of treatment until 3 months after surgery.
TNT toxicity	Local and systemic toxicity and (or) side effects will be recorded according to the general terminology criteria for adverse events version 5.0 (CTCAE v5.0).	From the start of treatment until 3 months after TNT.
Mortality rate	Mortality after TNT or surgery.	From the start of treatment until 3 months after treatment.
Complete clinical response rate	Criteria for Complete Clinical Response DRE: Smooth, flat scar; No nodularity Endoscopy: Pale smooth scar with or without telangiectasia; No ulceration, nodularity, or mucosal irregularities; No stricture MRT: Fibrotic, linear scar with low signal intensity on T2-weighted images; No diffusion restriction; No suspicious lymph nodes All of the criteria must be satisfied to define a complete clinical response.	12 - 14 weeks after TNT
Near-complete clinical response rate	Near Complete Response DRE: - Smooth induration or superficial minor mucosal irregularity Endoscopic: Appearance with irregular small mucosal nodules, superficial ulceration, or mild persistent erythema MRI; Downstaging with or without residual fibrosis, small area of residual signal, and complete or partial regression of lymph nodes; Diffusion-weighted MRI with a small area of residual high signal intensity	12 - 14 weeks after TNT
Quality of life	Quality of life Will be assessed using scoring manual of European Organisation For Research And Treatment Of Cancer of CR29 (Colorectal).	From the start of treatment until 3 years after treatment.
Low anterior resection syndrome rate.	Assessed based on the LARS questionnaire	From the start of treatment until 3 years after treatment.
Fatigue	Fatigue will be assessed using scoring manual of the functional assessment of chronic illness therapy - fatigue (FACIT-F) questionnaire.	From the start of treatment until 3 years after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rectal preservation rate	Percentage of participants achieving complete or near-complete clinical response and rectal preservation using a "watch and wait" approach.	3 years after TNT
Local regrowth rate	Percentage of participants with tumor regrowth after watch-and-wait when a complete or near-complete clinical response was achieved after TNT	3 years after TNT
Overall survival	The time between enrolment and death from any cause.	3 - 5 years.
Disease-free survival	The time between enrolment and the first documented disease progression, i.e. local recurrence or metastasis, or death from any cause.	3 - 5 years.
Local recurrence-free survival	Local recurrence rates in participants who underwent surgery.	3 - 5 years.
Distant metastasis-free survival	Incidence of distant metastases	3 - 5 years.
Stoma free survival	Stoma-free survival is defined as the period after treatment during which the patient does not develop a stoma.	3 - 5 years.

Collaborators and Investigators

• Sponsor: National Cancer Center Affiliate of Vilnius University Hospital Santaros Klinikos
• Collaborators: Vilnius University; Vilnius University Hospital Santaros Klinikos; Tomas Poskus, Faculty of Medicine, Vilnius University; Research Council of Lithuania
• Investigators: Study Chair: Tomas Poškus, PhD, Translational Health Research Institute, Faculty of Medicine, Vilnius University Ciurlionio str. 21, LT-03101 Vilnius; Principal Investigator: Audrius Dulskas, PhD, General and Abdominal Surgery and Oncology Department, National Cancer Institute, Vilnius, Lithuania

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2025
• Primary Completion (Estimated): December 27, 2029
• Study Completion (Estimated): December 27, 2029

Study Registration Dates

• First Submitted: December 19, 2024
• First Submitted That Met QC Criteria: December 27, 2024
• First Posted (Actual): January 6, 2025

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 6, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Rectal cancer; Fatigue; Postoperative complications; Radiotherapy; Chemotherapy; Neoadjuvant therapy; Chemoradiotherapy; Radiotherapy Side Effect; Total Neoadjuvant Treatment; Low Anterior Resection Syndrome; Organ Preservation; Chemotherapy side effects; Quality of Lifte
• Additional Relevant MeSH Terms: Wounds and Injuries; Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Low Anterior Resection Syndrome; Rectal Neoplasms; Fatigue; Postoperative Complications; Radiation Injuries; Therapeutics; Drug Therapy; Combined Modality Therapy; Radiotherapy; Surgical Procedures, Operative; Chemoradiotherapy; Consolidation Chemotherapy
• Other Study ID Numbers: START

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No