Adjuvant hyperthermic intraperitoneal chemotherapy in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicenter trial.

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 colon
carcinoom patients in order to prevent the development of PC with treatment at
a subclinical stage.

The aim is to determine the effectiveness of adjuvant HIPEC using oxaliplatin
following a curative resection of a pT4 or intra-abdominally perforated colon
cancer in preventing the development of PC in comparison to the standard
adjuvant systemic treatment

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 standard adjuvant systemic chemotherapy alone in the
control arm. Adjuvant HIPEC will preferably be performed simultaneously with
primary tumour resection or within 10 days after resection, 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.

Adjuvant HIPEC procedure: re-laparoscopy or re-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, adding Oxaliplatin (460 mg/m2) after attaining at least 42 degrees,
30 minutes perfusion time. Before the beginning of HIPEC, fluorouracil 400
mg/m2 and leucovorin 20 mg/m2 will be administered intravenously to potentiate
oxaliplatin activity.
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, cytoreductive surgery with
HIPEC will be performed in patients with a maximum of 5 involved regions and
without evidence of systemic disease.

The burden for the patients in the experimental arm are adding HIPEC to the
primary tumour resection or undergoing relaparoscopy or relaparotomy with
HIPEC, A Dutch pilot study showed no morbidity and no mortality of staged
adjuvant laparoscopic HIPEC in 10 patients, with a postoperative stay between 1
and 3 days. Based on literature, adjuvant HIPEC is associated with a slightly
increased risk of wound infection, chemical peritonitis, bowel perforation,
abdominal pain, intraabdominal abscess, and ileus.