Clinical trials in peritoneal metastases @ro

Adjuvant HIPEC in patients with high-risk colon cancer

The COLOPEC trial

Country: The Netherlands

vlag NL

Background:

The peritoneum is the second most common site of recurrence in patients with colorectal cancer (CRC). 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 CRC patients in order to prevent the development of PC with treatment at a subclinical stage.

Objectives:
The aim is to determine the effectiveness of 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 in preventing the development of PC in comparison to standard adjuvant systemic treatment alone.

Study design:

This will be a multicentre study in which 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 treatment related toxicity, incidence of PC, sensitivity of imaging to detect PC during follow-up, differences in patterns of dissemination (peritoneal plus or minus distant metastases), disease-free survival, overall survival, quality of life and costs.

Sample size:

Based on the currently available literature, approximately 25% of colon cancer patients with a pT4 or perforated primary tumour will develop PC. Adjuvant HIPEC is expected to result in a 60% relative risk reduction. To detect a 15% difference in PC rate at 18 months, a total number of 176 patients (88 in each arm) are needed (alpha=0.05, power of 80%, drop-out 5%).

Time schedule:

Accrual of 176 patients in nine centres in the Netherlands is planned between January 2015 and January 2017 with data analysis at the end of 2019. About 750 patients present each year with a pT4 and/or perforated colon cancer in the Netherlands yearly. Because the participating centres are all tertiary referral centres for PC with several referring hospitals each, timely accrual of 88 patients per year should be achievable.

Trial register: Clinicaltrial.gov

EudraCT number: 2014-002794-11

More information:  www.colopec.nl

Information in Dutch:

De COLOPEC-trial

Bij patiënten met kanker van de dikke darm kunnen er tumorcellen losraken en zich in de buikholte verspreiden. De kans hierop is verhoogd indien de tumor door de darmwand is gegroeid, in een nabijgelegen orgaan is gegroeid (bijvoorbeeld buikwand, blaas, dunne darm), of een perforatie heeft veroorzaakt. De losgelaten tumorcellen kunnen dan uiteindelijk in de buikholte uitgroeien. In dit stadium van de ziekte is behandeling gericht op genezing vaak niet meer mogelijk. Als echter alleen maar sprake is van (beperkte) uitzaaiingen in de buikholte, is er de mogelijkheid van een intensieve operatie. Daarbij wordt zoveel mogelijk tumorweefsel verwijderd (cytoreductie) waarna de buik wordt gespoeld met verwarmde chemotherapie (HIPEC), de zogenaamde cytoreductie met HIPEC procedure. Na het herstel van deze operatie worden dan nog aanvullende chemokuren gegeven.

Doordat buikvliesuitzaaiingen vaak (te) laat wordt ontdekt en vaak een intensieve behandeling vereist, zouden wij het ontstaan van deze uitzaaiingen willen voorkómen. Het blijkt dat bij patiënten met een verhoogd risico op deze buikvliesuitzaaiingen de standaard aanvullende chemotherapie via de bloedbaan niet in staat is om het uitgroeien van tumorcellen in de buikholte afdoende tegen te gaan. Preventieve buikspoeling met verwarmde chemotherapie (HIPEC) voorafgaande aan de standaard chemotherapie via de bloedbaan zou mogelijk de kans op verspreiding en uitgroei van tumorcellen in de buikholte kunnen verminderen. Deze HIPEC behandeling is een relatief weinig belastende operatie in vergelijking tot de gecombineerde cytoreductie met HIPEC behandeling. Omdat er geen zichtbare buikvliesuitzaaiingen zijn is er geen cytoreductie nodig, waardoor de kans op complicaties na deze HIPEC behandeling kleiner is en het herstel aanzienlijk sneller. De buikspoeling vindt dan tijdens of kort na de darmkankeroperatie plaats. In een aantal kleine studies lijkt deze behandeling effectief. Echter is er tot op heden nog onvoldoende wetenschappelijk bewijs om deze behandeling standaard toe te passen.

Doel van het onderzoek:
Het doel van deze studie is te onderzoeken of door spoeling van de buik met verwarmde chemotherapie uitzaaiing van darmkanker in de buikholte kan worden voorkomen.

Meer informatie: www.COLOPEC.nl