Adjuvant HIPEC in High Risk Colon Cancer

Study Overview
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Brief Summary
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This study aims to determine the oncological effectiveness of adjuvant HIPEC, using intraperitoneal oxaliplatin with concomitant i.v. 5-FU/LV, following a curative resection of a T4 or intra-abdominally perforated Colon cancer in preventing the development of peritoneal carcinomatosis in addition to the standard adjuvant systemic treatment. Hypothesis: The hypothesis is that adjuvant HIPEC preceding routine adjuvant systemic therapy using i.p. oxaliplatin with concomitant i.v. 5-FU/LV following a curative resection of a T4 or intra-abdominally perforated colon cancer reduces the development of peritoneal carcinomatosis in comparison to standard adjuvant systemic treatment alone.

Detailed Description
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Background: The peritoneum is the second most common site of recurrence in patients with colon cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult and adjuvant systemic treatment does not seem to affect peritoneal dissemination in contrast to haematogenous dissemination in the liver or lungs. Of all patients eventually presenting with clinically apparent PC, only a quarter have potentially curable disease. The curative option is cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC), but the effectiveness depends highly on the extent of disease and is associated with a considerable complication rate. These clinical problems underline the need for effective adjuvant intraperitoneal therapy in high risk colon cancer patients in order to prevent the development of PC with treatment at a subclinical stage. Study design: This will be a multicentre study in which 176 eligible patients will be randomized to adjuvant HIPEC followed by adjuvant systemic chemotherapy in the experimental arm, or the standard adjuvant systemic chemotherapy alone in the control arm. Adjuvant HIPEC will be performed preferably simultaneously or within 10 days after resection of the primary tumour, either by laparoscopy or open approach, similar to the technique used for resection of the primary tumour. If adjuvant HIPEC cannot be performed within 10 days (i.e. complicated postoperative course), the procedure will be delayed until 5 to 8 weeks postoperatively. Subsequently, patients will receive routine adjuvant chemotherapy (CAPOX) within 3 weeks from HIPEC. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. If peritoneal carcinomatosis is found during staging laparoscopy, CR/ HIPEC will be performed in patients with a maximum of 5 involved regions and without evidence of systemic disease. Study population: Patients who underwent intentionally curative resection for a T4N0-2M0 or intra-abdominally perforated colon cancer. Intervention: 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 at a flow rate of 1-2l/min and an inflow temperature of 42-43˚C. Before the beginning of HIPEC, 5-fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 will be administered intravenously to potentiate oxaliplatin activity. Oxaliplatin (460 mg/m2) is added to the perfusate after attaining at least 42 degrees inflow temperature with a total of 30 minutes perfusion time. Outcomes: Primary endpoint is peritoneal recurrence-free survival at 18 months. Secondary endpoints are number of participants with adverse events as a measure of safety and tolerability, incidence of PC at end of follow-up with or without concomitant liver/lung metastases, percentage of false negative CT at 18 months (second look laparoscopy/laparotomy as gold standard), disease-free survival, overall survival, quality of life and costs.

Official Title
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Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Colon Cancer at High Risk of Peritoneal Carcinomatosis

Conditions
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Colorectal Neoplasms, Peritoneal Neoplasms

Intervention / Treatment
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* Procedure: Adjuvant HIPEC (open/laparoscopic)
* Drug: Standard adjuvant systemic chemotherapy
* Procedure: Diagnostic laparoscopy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age between 18 and 75 years Intention to start routine adjuvant systemic therapy adequate clinical condition to undergo simultaneous HIPEC or re- laparoscopy or re-laparotomy with HIPEC within either 10 days or between week 5-8 from --primary resection written informed consent white blood cell count of at least 3000/mm3, platelet count of at least 100.000/mm3 no bleeding diathesis or coagulopathy normal creatinine or creatinine clearance of at least 50 ml/min Exclusion Criteria: postoperative complications that interfere with adjuvant HIPEC within 8 weeks (i.e. persisting intra-abdominal abscess, significant fascial dehiscence, enteric fistula) no intention to start routine adjuvant systemic therapy liver and/or lung metastases pregnant or lactating women unstable or uncompensated respiratory or cardiac disease serious active infections other concurrent chemotherapy hypersensitivity to fluorouracil, folinic acid or another substance of leucovorin or oxaliplatin stomatitis, ulceration in the mouth or gastrointestinal tract. severe diarrhea severe hepatic and / or renal dysfunction. plasma bilirubin concentrations greater than 85 μmol/l. pernicious anemia or other anaemias due to vitamin B12 deficiency. peripheral sensory neuropathy with functional impairment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard adjuvant systemic chemotherapy<br>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. | Drug: Standard adjuvant systemic chemotherapy<br>* 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.<br>* Other names: adjuvant 5-FU and oxaliplatin (FOLFOX);Procedure: Diagnostic laparoscopy<br>* 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.<br>* Other names: Diagnostic laparoscopic surgery;|
| Experimental: Adjuvant HIPEC (open/laparoscopic)<br>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. | Procedure: Adjuvant HIPEC (open/laparoscopic)<br>* 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 at a flow rate of 1-2l/min and an inflow temperature of 42-43˚C. Before the beginning of HIPEC, 5-fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 will be administered intravenously to potentiate oxaliplatin activity. Oxaliplatin (460 mg/m2) is added to the perfusate after attaining at least 42 degrees inflow temperature with a total of 30 minutes perfusion time.<br>* Other names: Intraperitoneal oxaliplatin 460 mg/m2 (maximum 920 mg);Drug: Standard adjuvant systemic chemotherapy<br>* 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.<br>* Other names: adjuvant 5-FU and oxaliplatin (FOLFOX);Procedure: Diagnostic laparoscopy<br>* 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.<br>* Other names: Diagnostic laparoscopic surgery;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peritoneal Recurrence Free Survival at 18 Months | 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. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Related Toxicity of Adjuvant HIPEC | Toxicity directly related to adjuvant HIPEC included 30-day complication rate, re-intervention rate, and re-admission rate. | 30 days after adjuvant HIPEC | 
| Hospital Stay for Simultaneous and Staged HIPEC, Either Open or Laparoscopic | Hospital stay for simultaneous and staged HIPEC, either open or laparoscopic. | 10 weeks | 
| False-negative Rate of CT-scan for Peritoneal Metastases | 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. | 5 years | 
| Patterns of Dissemination (Peritoneal Plus or Minus Distant Metastases) | Patterns of dissemination (peritoneal plus or minus distant metastases). | 5 years | 
| Disease-free Survival | Disease-free survival. | 5 years | 
| Overall Survival | Overall survival. | 5 years | 
| Quality of Life Questionnaire Survey 5- Year Follow-up | Quality of life questionnaire survey 5- year follow-up. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIPEC, Chemotherapy, Adjuvant, Laparoscopy, Peritoneal Lavage