Adjuvant HIPEC in High Risk Colon Cancer (COLOPEC)

• ClinicalTrials.gov Identifier: NCT02231086
• Recruitment Status: Completed
• First Posted: September 4, 2014
• Results First Posted: September 16, 2021
• Last Update Posted: September 16, 2021
• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Dutch Health Care Insurance Board
• Information provided by (Responsible Party): P.J. Tanis, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Conditions: Colorectal Neoplasms; Peritoneal Neoplasms
• Interventions: Procedure: Adjuvant HIPEC (open/laparoscopic); Drug: Standard adjuvant systemic chemotherapy; Procedure: Diagnostic laparoscopy
• Enrollment: 204

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Standard Adjuvant Systemic Chemotherapy	Adjuvant HIPEC (Open/Laparoscopic)
Arm/Group Description	Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively. Standard adjuvant systemic chemotherapy: Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months. Diagnostic laparoscopy: Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.	Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (<10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively. Adjuvant HIPEC (open/laparoscopic): Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis fluid
Period Title: Overall Study
Started	102	102
Completed	63	65
Not Completed	39	37

Baseline Characteristics

Arm/Group Title		Standard Adjuvant Systemic Chemotherapy	Adjuvant HIPEC (Open/Laparoscopic)	Total
Arm/Group Description		Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively. Standard adjuvant systemic chemotherapy: Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months. Diagnostic laparoscopy: Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.	Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (<10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively. Adjuvant HIPEC (open/laparoscopic): Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis flui	Total of all reporting groups
Overall Number of Baseline Participants		102	100	202
Baseline Analysis Population Description		Intention-to-treat Baseline population
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	102 participants	100 participants	202 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	67 65.7%	67 67.0%	134 66.3%
	>=65 years	35 34.3%	33 33.0%	68 33.7%
Age, Continuous; Median (Inter-Quartile Range); Unit of measure: Years
	Number Analyzed	102 participants	100 participants	202 participants
		61; (54 to 68)	61.5; (56 to 68)	61; (55 to 68)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	102 participants	100 participants	202 participants
	Female	50 49.0%	47 47.0%	97 48.0%
	Male	52 51.0%	53 53.0%	105 52.0%
Race and Ethnicity Not Collected [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	0 participants	0 participants	0 participants
				0
		[1] Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Region of Enrollment [1]; Measure Type: Count of Participants; Unit of measure: Participants
Netherlands	Number Analyzed	102 participants	100 participants	202 participants
		102 100.0%	100 100.0%	202 100.0%
		[1] Measure Description: Intention-to-treat Baseline population

Outcome Measures

1. Primary Outcome

Title	Peritoneal Recurrence Free Survival at 18 Months
Description	Peritoneal recurrence-free survival at 18 months determined by CT and CEA. If CEA was normal and CT did not show any signs of peritoneal metastase at 18 months, a diagnostic laparoscopy was performed in those patients who consented to this intervention. Complete peritoneal staging was performed during laparoscopy, and biopsies were taken from suspicious lesions. If no peritoneal lesions were seen or biopsies were negative, this indicated that the patient was free from peritoneal recurrence.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard Adjuvant Systemic Chemotherapy	Adjuvant HIPEC (Open/Laparoscopic)
Arm/Group Description:	Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively. Standard adjuvant systemic chemotherapy: Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months. Diagnostic laparoscopy: Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.	Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (<10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively. Adjuvant HIPEC (open/laparoscopic): Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis fluid
Overall Number of Participants Analyzed	102	100
Measure Type: Number; Unit of Measure: participants
	79	80

2. Secondary Outcome

Title	Treatment Related Toxicity of Adjuvant HIPEC
Description	Toxicity directly related to adjuvant HIPEC included 30-day complication rate, re-intervention rate, and re-admission rate.
Time Frame	30 days after adjuvant HIPEC

Outcome Measure Data

Analysis Population Description

Only measured in experimental group

Arm/Group Title	Standard Adjuvant Systemic Chemotherapy	Adjuvant HIPEC (Open/Laparoscopic)
Arm/Group Description:	Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively. Standard adjuvant systemic chemotherapy: Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months. Diagnostic laparoscopy: Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.	Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (<10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively. Adjuvant HIPEC (open/laparoscopic): Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis fluid
Overall Number of Participants Analyzed	0	87
Measure Type: Count of Participants; Unit of Measure: Participants
	0	0 0.0%

3. Secondary Outcome

Title	Hospital Stay for Simultaneous and Staged HIPEC, Either Open or Laparoscopic
Description	Hospital stay for simultaneous and staged HIPEC, either open or laparoscopic.
Time Frame	10 weeks

Outcome Measure Data Not Reported

4. Secondary Outcome

Title	False-negative Rate of CT-scan for Peritoneal Metastases
Description	The presence or absence of peritoneal metastasis on CT-scan will be compared to the findings during diagnostic laparoscopy, histological biopsy or fine needle aspiration cytology.
Time Frame	5 years

Outcome Measure Data Not Reported

5. Secondary Outcome

Title	Patterns of Dissemination (Peritoneal Plus or Minus Distant Metastases)
Description	Patterns of dissemination (peritoneal plus or minus distant metastases).
Time Frame	5 years

Outcome Measure Data Not Reported

6. Secondary Outcome

Title	Disease-free Survival
Description	Disease-free survival.
Time Frame	5 years

Outcome Measure Data Not Reported

7. Secondary Outcome

Title	Overall Survival
Description	Overall survival.
Time Frame	5 years

Outcome Measure Data Not Reported

8. Secondary Outcome

Title	Quality of Life Questionnaire Survey 5- Year Follow-up
Description	Quality of life questionnaire survey 5- year follow-up.
Time Frame	5 years

Outcome Measure Data Not Reported

Adverse Events

Time Frame	All postoperative complications after resection of the primary tumor and after adjuvant HIPEC, as well as adverse events occuring during adjuvant chemotherapy were collected, until 30 days after last trial related intervention, for an average of 2 years.
Adverse Event Reporting Description	We used standard definitions for AE and SAE
Arm/Group Title	Standard Adjuvant Systemic Chemotherapy	Adjuvant HIPEC (Open/Laparoscopic)
Arm/Group Description	Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively. Standard adjuvant systemic chemotherapy: Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months. Diagnostic laparoscopy: Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.	Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (<10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively. Adjuvant HIPEC (open/laparoscopic): Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis flui
All-Cause Mortality
	Standard Adjuvant Systemic Chemotherapy	Adjuvant HIPEC (Open/Laparoscopic)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/102 (0.00%)	0/100 (0.00%)
Serious Adverse Events
	Standard Adjuvant Systemic Chemotherapy	Adjuvant HIPEC (Open/Laparoscopic)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	46/102 (45.10%)	95/100 (95.00%)
Blood and lymphatic system disorders
venous thrombosis †	0/102 (0.00%)	1/100 (1.00%)
Cardiac disorders
atrial fibrillation †	0/102 (0.00%)	4/100 (4.00%)
cardiac †	1/102 (0.98%)	2/100 (2.00%)
Gastrointestinal disorders
Obstructive ileus †	1/102 (0.98%)	3/100 (3.00%)
Paralytic ileus †	4/102 (3.92%)	5/100 (5.00%)
Gastroparesis †	8/102 (7.84%)	15/100 (15.00%)
General disorders
cardiopulmonary resuscitation †	1/102 (0.98%)	0/100 (0.00%)
Infections and infestations
abscess †	1/102 (0.98%)	3/100 (3.00%)
line sepsis †	0/102 (0.00%)	1/100 (1.00%)
Injury, poisoning and procedural complications
chemical peritonitis †	1/102 (0.98%)	1/100 (1.00%)
encapsulating peritoneal sclerosis †	0/102 (0.00%)	1/100 (1.00%)
Metabolism and nutrition disorders
Electrolyte disorder †	6/102 (5.88%)	8/100 (8.00%)
parenteral feeding †	9/102 (8.82%)	22/100 (22.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
nodal metastasis †	1/102 (0.98%)	1/100 (1.00%)
Nervous system disorders
delirium †	1/102 (0.98%)	4/100 (4.00%)
Renal and urinary disorders
dehydration †	1/102 (0.98%)	1/100 (1.00%)
urologic †	2/102 (1.96%)	8/100 (8.00%)
Reproductive system and breast disorders
ovarian cyst †	1/102 (0.98%)	0/100 (0.00%)
Respiratory, thoracic and mediastinal disorders
pneumonia †	1/102 (0.98%)	3/100 (3.00%)
pulmonary embolism †	2/102 (1.96%)	2/100 (2.00%)
Surgical and medical procedures
Anastomotic leakage †	0/102 (0.00%)	2/100 (2.00%)
wound infection †	4/102 (3.92%)	7/100 (7.00%)
colonic stenosis †	0/102 (0.00%)	1/100 (1.00%)
gastric perforation †	1/102 (0.98%)	0/100 (0.00%)
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Standard Adjuvant Systemic Chemotherapy	Adjuvant HIPEC (Open/Laparoscopic)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	102/102 (100.00%)	100/100 (100.00%)
Gastrointestinal disorders
diarrhea †	73/102 (71.57%)	68/100 (68.00%)
vomiting †	24/102 (23.53%)	27/100 (27.00%)
mucositis †	20/102 (19.61%)	13/100 (13.00%)
General disorders
fatigue †	58/102 (56.86%)	58/100 (58.00%)
Metabolism and nutrition disorders
anorexia †	20/102 (19.61%)	13/100 (13.00%)
Nervous system disorders
peripheral sensible neuropathy †	73/102 (71.57%)	68/100 (68.00%)
† Indicates events were collected by systematic assessment

Limitations and 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.

Results Point of Contact

• Name/Title: Prof. dr. P.J. Tanis
• Organization: Amsterdam UMC
• Phone: +31-20-4444444
• EMail: p.j.tanis@amsterdamumc.nl

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Zwanenburg ES, Wisselink DD, Klaver CEL, van der Bilt JDW, Tanis PJ, Snaebjornsson P; COLOPEC trial collaborators. The measured distance between tumor cells and the peritoneal surface predicts the risk of peritoneal metastases and offers an objective means to differentiate between pT3 and pT4a colon cancer. Mod Pathol. 2022 Dec;35(12):1991-2001. doi: 10.1038/s41379-022-01154-z. Epub 2022 Sep 19.

Klaver CEL, Wisselink DD, Punt CJA, Snaebjornsson P, Crezee J, Aalbers AGJ, Brandt A, Bremers AJA, Burger JWA, Fabry HFJ, Ferenschild F, Festen S, van Grevenstein WMU, Hemmer PHJ, de Hingh IHJT, Kok NFM, Musters GD, Schoonderwoerd L, Tuynman JB, van de Ven AWH, van Westreenen HL, Wiezer MJ, Zimmerman DDE, van Zweeden AA, Dijkgraaf MGW, Tanis PJ; COLOPEC collaborators group. Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial. Lancet Gastroenterol Hepatol. 2019 Oct;4(10):761-770. doi: 10.1016/S2468-1253(19)30239-0. Epub 2019 Jul 29.

Klaver CE, Musters GD, Bemelman WA, Punt CJ, Verwaal VJ, Dijkgraaf MG, Aalbers AG, van der Bilt JD, Boerma D, Bremers AJ, Burger JW, Buskens CJ, Evers P, van Ginkel RJ, van Grevenstein WM, Hemmer PH, de Hingh IH, Lammers LA, van Leeuwen BL, Meijerink WJ, Nienhuijs SW, Pon J, Radema SA, van Ramshorst B, Snaebjornsson P, Tuynman JB, Te Velde EA, Wiezer MJ, de Wilt JH, Tanis PJ. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial. BMC Cancer. 2015 May 24;15:428. doi: 10.1186/s12885-015-1430-7.

• Responsible Party: P.J. Tanis, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• ClinicalTrials.gov Identifier: NCT02231086
• Other Study ID Numbers: NL49960.018.14; 2014-002794-11 ( EudraCT Number )
• First Submitted: August 22, 2014
• First Posted: September 4, 2014
• Results First Submitted: July 23, 2021
• Results First Posted: September 16, 2021
• Last Update Posted: September 16, 2021