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

• Sponsor: Ege University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03287843
• Collaborator: (none)
• Enrollment: 350
• Arms: 2
• Actual Duration (Months): 192

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Neoplasm, Rectum	Procedure: Total mesorectal excision before 56 days (4-8 weeks); Procedure: Total mesorectal excision after 56 days (8-12 weeks)	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 350 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effect of Timing of Surgery After Neoadjuvant Chemoradiation on Histopathological Results, Complications, Recurrence and Survivals for Locally Advanced Rectal Cancer
• Actual Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Jan 1, 2017
• Actual Study Completion Date: Jan 1, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Pathological Complete Response Rate [2 months]

   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.

Secondary Outcome Measures

1. Completeness of the Mesorectal Dissection [30 days after surgery]

   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.

2. Tumour Regression Grade [30 days after surgery]

   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.

3. Surgical Complications [90 days after surgery]

   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

4. Recurrence [5 years after surgery]

   Both pelvic recurrence and distant metastasis will be assessed.

5. Disease-free Survival [5 years after surgery]

   Recurrence free survival

6. Overall Survival [5 years after surgery]

   Total survival with or without disease

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Ege University

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Zekeriya Erhan Akgün, Professor of surgery, Ege University
• ClinicalTrials.gov Identifier: NCT03287843
• Other Study ID Numbers: 17-4.1/13
• First Posted: Sep 19, 2017
• Last Update Posted: Mar 31, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Zekeriya Erhan Akgün, Professor of surgery, Ege University: Locally advanced rectal cancer; Neoadjuvant chemoradiation
• Additional relevant MeSH terms: Rectal Neoplasms

Study Results

Participant Flow

Arm/Group Title	Classic Interval Group	Long Interval Group
Arm/Group Description	İn this arm patients will go under surgery before eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision before 56 days (4-8 weeks): Low anterior resection or abdominoperineal resection	İn this arm patients will go under surgery after eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision after 56 days (8-12 weeks): Low anterior resection or abdominoperineal resection
Period Title: Overall Study
STARTED	175	175
Excluded	12	8
Lost to Follow up	3	0
COMPLETED	160	167
NOT COMPLETED	15	8

Baseline Characteristics

Arm/Group Title	Classic Interval Group	Long Interval Group	Total
Arm/Group Description	İn this arm patients will go under surgery before eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision before 56 days (4-8 weeks): Low anterior resection or abdominoperineal resection	İn this arm patients will go under surgery after eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision after 56 days (8-12 weeks): Low anterior resection or abdominoperineal resection	Total of all reporting groups
Overall Participants	160	167	327
Age (years) [Mean (Inter-Quartile Range) ]
Mean (Inter-Quartile Range) [years]	60.4	61.7	61.0
Sex: Female, Male (Count of Participants)
Female	65 40.6%	71 42.5%	136 41.6%
Male	95 59.4%	96 57.5%	191 58.4%

Outcome Measures

1. Primary Outcome

Title	Pathological Complete Response Rate
Description	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.
Time Frame	2 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Classic Interval Group	Long Interval Group
Arm/Group Description	İn this arm patients will go under surgery before eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision before 56 days (4-8 weeks): Low anterior resection or abdominoperineal resection	İn this arm patients will go under surgery after eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision after 56 days (8-12 weeks): Low anterior resection or abdominoperineal resection
Measure Participants	160	167
Count of Participants [Participants]	16 10%	31 18.6%

2. Secondary Outcome

Title	Completeness of the Mesorectal Dissection
Description	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.
Time Frame	30 days after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Classic Interval Group	Long Interval Group
Arm/Group Description	İn this arm patients will go under surgery before eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision before 56 days (4-8 weeks): Low anterior resection or abdominoperineal resection	İn this arm patients will go under surgery after eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision after 56 days (8-12 weeks): Low anterior resection or abdominoperineal resection
Measure Participants	160	167
Low	5 3.1%	8 4.8%
Moderate	11 6.9%	10 6%
High	144 90%	149 89.2%

3. Secondary Outcome

Title	Tumour Regression Grade
Description	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.
Time Frame	30 days after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Classic Interval Group	Long Interval Group
Arm/Group Description	İn this arm patients will go under surgery before eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision before 56 days (4-8 weeks): Low anterior resection or abdominoperineal resection	İn this arm patients will go under surgery after eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision after 56 days (8-12 weeks): Low anterior resection or abdominoperineal resection
Measure Participants	160	167
Mandard Grade 1	16 10%	31 18.6%
Mandard Grade 2	37 23.1%	36 21.6%
Mandard Grade 3	73 45.6%	67 40.1%
Mandard Grade 4	31 19.4%	29 17.4%
Mandard Grade 5	3 1.9%	4 2.4%

4. Secondary Outcome

Title	Surgical Complications
Description	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
Time Frame	90 days after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Classic Interval Group	Long Interval Group
Arm/Group Description	İn this arm patients will go under surgery before eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision before 56 days (4-8 weeks): Low anterior resection or abdominoperineal resection	İn this arm patients will go under surgery after eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision after 56 days (8-12 weeks): Low anterior resection or abdominoperineal resection
Measure Participants	160	167
Clavien Dindo 1	4 2.5%	7 4.2%
Clavien Dindo 2	15 9.4%	14 8.4%
Clavien Dindo 3a	4 2.5%	3 1.8%
Clavien Dindo 3b	8 5%	2 1.2%
Clavien Dindo 4a	4 2.5%	2 1.2%
Clavien Dindo 4b	0 0%	1 0.6%
Clavien Dindo 5	1 0.6%	4 2.4%
No complication	124 77.5%	134 80.2%

5. Secondary Outcome

Title	Recurrence
Description	Both pelvic recurrence and distant metastasis will be assessed.
Time Frame	5 years after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Disease-free Survival
Description	Recurrence free survival
Time Frame	5 years after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Overall Survival
Description	Total survival with or without disease
Time Frame	5 years after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Classic Interval Group		Long Interval Group
Arm/Group Description	İn this arm patients will go under surgery before eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision before 56 days (4-8 weeks): Low anterior resection or abdominoperineal resection		İn this arm patients will go under surgery after eight weeks, after neoadjuvant chemoradiation therapy. Total mesorectal excision after 56 days (8-12 weeks): Low anterior resection or abdominoperineal resection
All Cause Mortality
	Classic Interval Group		Long Interval Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/160 (0.6%)		4/167 (2.4%)
Serious Adverse Events
	Classic Interval Group		Long Interval Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/160 (22.5%)		33/167 (19.8%)
Gastrointestinal disorders
Anastomotic leakage	4/160 (2.5%)		4/167 (2.4%)
Mechanical bowel obstruction	5/160 (3.1%)		4/167 (2.4%)
Infections and infestations
Pelvic abscess	1/160 (0.6%)		2/167 (1.2%)
Renal and urinary disorders
Urinary leakage	1/160 (0.6%)		0/167 (0%)
Urinary tract infectio	3/160 (1.9%)		2/167 (1.2%)
Prerenal insufficiency	5/160 (3.1%)		4/167 (2.4%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	2/160 (1.3%)		1/167 (0.6%)
Pneumonia	1/160 (0.6%)		3/167 (1.8%)
Surgical and medical procedures
Wound infection	6/160 (3.8%)		9/167 (5.4%)
Postoperative bleeding	2/160 (1.3%)		2/167 (1.2%)
Other	4/160 (2.5%)		0/167 (0%)
Vascular disorders
Deep vein thrombosis, pulmonary embolism	2/160 (1.3%)		2/167 (1.2%)
Other (Not Including Serious) Adverse Events
	Classic Interval Group		Long Interval Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/160 (0%)		0/167 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.