Adjuvant HIPEC in High Risk Colon Cancer
Condition: Colorectal Neoplasms; Peritoneal Neoplasms
MeSH terms: Neoplasms; Colorectal Neoplasms; Peritoneal Neoplasms
Study type: Interventional
Phase: Phase 3

Summary: 
      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: 
      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.
    

Intervention name(s): Adjuvant HIPEC (open/laparoscopic); Standard adjuvant systemic chemotherapy; Diagnostic laparoscopy
Intervention type(s): Procedure; Drug; Procedure
Intervention description(s): 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.; 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.; 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.
Other intervention name(s): I.V. leucovorin 20 mg/m2 (maximum 40 mg); I.V. 5-fluorouracil 400 mg/m2 (maximum 800 mg); Intraperitoneal oxaliplatin 460 mg/m2 (maximum 920 mg); adjuvant capecitabine and oxaliplatin (CAPOX); adjuvant 5-FU and oxaliplatin (FOLFOX); Diagnostic laparoscopic surgery
Intervention MeSH terms: Leucovorin; Capecitabine; Fluorouracil; Oxaliplatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Chemotherapy, Adjuvant; Laparoscopy; Peritoneal Lavage; HIPEC