Rectal Cancer, Total Neoadjuvant Treatment, Neoadjuvant Therapy, Radiotherapy, Chemotherapy, Organ Preservation, Radiotherapy Side Effect, Chemotherapy Side Effects, Chemoradiotherapy, Low Anterior Resection Syndrome, Quality of Life
Conditions
Keywords
Rectal cancer, Total Neoadjuvant Treatment, Neoadjuvant therapy, Radiotherapy, Chemotherapy, Chemoradiotherapy, Organ Preservation, Radiotherapy Side Effect, Chemotherapy side effects, Quality of Lifte, Fatigue, Postoperative complications, Low Anterior Resection Syndrome
Brief summary
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.
Interventions
RADIATIONRadiation 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.
DRUGChemoradiotherapy
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.
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.
PROCEDURESurgery
Transabdominal Resection: Abdominoperineal resection, low anterior resection, or coloanal anastomosis using total mesorectal excision.
OTHERPart two
Standard treatment protocols and follow-up procedures are implemented in clinical practice.
OTHERAdjuvant treatment
If indicated, adjuvant therapy will be administered as usual in clinical practice.
Sponsors
Vilnius University
Tomas Poskus, Faculty of Medicine, Vilnius University
Vilnius University Hospital Santaros Klinikos
Research Council of Lithuania
National Cancer Center Affiliate of Vilnius University Hospital Santaros Klinikos
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Intervention model description
\*\*Part One:\*\* A prospective randomized study. Participants will be randomly divided into two groups: an experimental group and a control group. \*\*Part Two:\*\* A prospective cohort study. In the second part of the study, there is no planned allocation of groups.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Near-complete clinical response rate | 12 - 14 weeks after TNT | 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 |
| Postoperative complications | From the start of treatment until 3 months after surgery. | Assessed based on the Clavien Dindo classification. |
| TNT toxicity | From the start of treatment until 3 months after TNT. | 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). |
| Mortality rate | From the start of treatment until 3 months after treatment. | Mortality after TNT or surgery. |
| Quality of life | From the start of treatment until 3 years after treatment. | Quality of life Will be assessed using scoring manual of European Organisation For Research And Treatment Of Cancer of CR29 (Colorectal). |
| Low anterior resection syndrome rate. | From the start of treatment until 3 years after treatment. | Assessed based on the LARS questionnaire |
| Fatigue | From the start of treatment until 3 years after treatment | Fatigue will be assessed using scoring manual of the functional assessment of chronic illness therapy - fatigue (FACIT-F) questionnaire. |
| Complete clinical response rate | 12 - 14 weeks after TNT | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Local regrowth rate | 3 years after TNT | Percentage of participants with tumor regrowth after watch-and-wait when a complete or near-complete clinical response was achieved after TNT |
| Overall survival | 3 - 5 years. | The time between enrolment and death from any cause. |
| Disease-free survival | 3 - 5 years. | The time between enrolment and the first documented disease progression, i.e. local recurrence or metastasis, or death from any cause. |
| Local recurrence-free survival | 3 - 5 years. | Local recurrence rates in participants who underwent surgery. |
| Distant metastasis-free survival | 3 - 5 years. | Incidence of distant metastases |
| Stoma free survival | 3 - 5 years. | Stoma-free survival is defined as the period after treatment during which the patient does not develop a stoma. |
| Rectal preservation rate | 3 years after TNT | Percentage of participants achieving complete or near-complete clinical response and rectal preservation using a watch and wait approach. |
Countries
Lithuania
Contacts
Primary ContactErnestas Šileika, MD
Backup ContactAudrius Dulskas, PhD
Outcome results
None listed