Appropriate Timing of Surgery After Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer

Effect of Timing of Surgery After Neoadjuvant Chemoradiation on Histopathological Results, Complications, Recurrence and Survivals for Locally Advanced Rectal Cancer

This study aimed to compare the outcomes of early versus late surgical resection in patients who underwent curative total mesorectal excision after neoadjuvant chemoradiation. Half of the participants will undergo surgery before 8 weeks, while the other half will undergo surgery after 8 weeks.

Study Overview

• Status: Completed
• Conditions: Neoplasm, Rectum
• Intervention / Treatment: Procedure: Total mesorectal excision before 56 days (4-8 weeks); Procedure: Total mesorectal excision after 56 days (8-12 weeks)

• Study Type: Interventional
• Enrollment (Actual): 350
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Clinic stage II-III cancer ( T3- T4 tm or/and N(+) disease )
2. Patients with histologically confirmed adenocarcinoma of the rectum
3. Tumor distal border located within 15 cm. from anal verge (as measured by rigid rectoscopy)
4. Standardized total mesorectal excision surgery
5. Tumor must be clinically resectable with curative intent (R0 resection must be most likely)
6. Elective operation
7. The patient must consent to be in the study and the informed consent must be signed

Exclusion Criteria:

1. Clinic stage I and IV cancer disease
2. Patients with malignant disease of the rectum other than adenocarcinoma
3. Recurrent rectal cancer
4. Emergency cases (Mechanical bowel obstruction, perforation)
5. Other previous or concurrent malignancies
6. Any contraindication for radiochemotherapy
7. Previous chemotherapy or radiotherapy to the pelvis
8. Tumor has arisen from chronic inflammatory bowel disease or hereditary polyposis disease
9. American Society of Anesthesiologists Score >3 patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early surgery group; İn this arm patients will go under surgery before eight weeks, after neoadjuvant chemoradiation therapy.	Procedure: Total mesorectal excision before 56 days (4-8 weeks); Low anterior resection or abdominoperineal resection
Experimental: Late surgery group; İn this arm patients will go under surgery after eight weeks, after neoadjuvant chemoradiation therapy.	Procedure: Total mesorectal excision after 56 days (8-12 weeks); Low anterior resection or abdominoperineal resection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response Rate	Complete pathological response, defined as the absence of viable tumor cells, may develop after neoadjuvant treatment for rectal cancer. Prognostic factors affecting pathological complete response will be evaluated.	2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Completeness of the Mesorectal Dissection	Examination will be made in a fresh state for completeness of the mesorectal dissection and will be graded according to the criteria of Quirke as follows: Low: (Grade 1) Little bulk of the mesorectum with defects down into the muscularis propria and/or very irregular circumferential resection margin. Moderate: (Grade 2) Moderate bulk of the mesorectum but there is irregularity in the mesorectal surface. Moderate coning of the specimen toward the distal margin. At no site is the muscularis propria visible with exception of the insertion of the levator muscles. Moderate irregularity of the circumferential resection margin. High: (Grade 3) Intact mesorectum with smooth mesorectal surface. No defect deeper than 5 mm. No coning on the specimen. Smooth circumferential resection margins on slicing.	30 days after surgery
Tumour Regression Grade	All pathological examinations were undertaken by two experienced gastrointestinal pathologists. Pathological treatment response to neoadjuvant chemoradiotherapy was evaluated by a five-tiered system described by Mandard. Tumor regression grade groups were identified as: Grade 1: the absence of residual cancer Grade 2: the presence of residual cancer cells scattered throughout the fibrosis Grade 3: an increase in the number of residual cancer cells but fibrosis still predominant Grade 4: residual cancer outgrowing fibrosis Grade 5, the absence of regressive changes Grade 1 considered as complete response. Grade 2-4 considered as partial response and Grade 5 considered as no response.	30 days after surgery
Surgical Complications	Morbidity will be assessed according to the classification of Clavien-Dindo as follows: Grade 1: Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic, and radiological interventions. Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgetics, diuretics, electrolytes, and physiotherapy. This grade also includes wound infections opened at the bedside Grade 2: Requiring pharmacological treatment with drugs other than such allowed for grade I complications. Blood transfusions and total parenteral nutrition are also included. Grade 3: Requiring surgical, endoscopic or radiological intervention (Grade 3a: Intervention not under general anesthesia, Grade 3b: Intervention under general anesthesia) Grade 4: Life-threatening complication requiring Intensive Care Unit management (Grade 4a: Single organ dysfunction (including dialysis), Grade 4b: Multiorgan dysfunction) Grade 5 Death	90 days after surgery
Recurrence	Both pelvic recurrence and distant metastasis will be assessed.	5 years after surgery
Disease-free Survival	Recurrence free survival	5 years after surgery
Overall Survival	Total survival with or without disease	5 years after surgery

Collaborators and Investigators

• Sponsor: Ege University
• Investigators: Principal Investigator: Z.Erhan Akgun, Proffesor, Ege University

Publications and helpful links

General Publications

• Akgun E, Caliskan C, Bozbiyik O, Yoldas T, Doganavsargil B, Ozkok S, Kose T, Karabulut B, Elmas N, Ozutemiz O. Effect of interval between neoadjuvant chemoradiotherapy and surgery on disease recurrence and survival in rectal cancer: long-term results of a randomized clinical trial. BJS Open. 2022 Sep 2;6(5):zrac107. doi: 10.1093/bjsopen/zrac107.
• Akgun E, Caliskan C, Bozbiyik O, Yoldas T, Sezak M, Ozkok S, Kose T, Karabulut B, Harman M, Ozutemiz O. Randomized clinical trial of short or long interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg. 2018 Oct;105(11):1417-1425. doi: 10.1002/bjs.10984. Epub 2018 Aug 29.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2006
• Primary Completion (Actual): January 1, 2017
• Study Completion (Actual): January 1, 2022

Study Registration Dates

• First Submitted: September 13, 2017
• First Submitted That Met QC Criteria: September 17, 2017
• First Posted (Actual): September 19, 2017

Study Record Updates

• Last Update Posted (Actual): March 31, 2022
• Last Update Submitted That Met QC Criteria: March 22, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Locally advanced rectal cancer; Neoadjuvant chemoradiation
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms
• Other Study ID Numbers: 17-4.1/13

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No