Intra Peritoneal Chemo Hyperthermia (IPCH) : Cellular and Metabolic Consequences (CHIP)

Intra Peritoneal Chemo Hyperthermia (IPCH) is a recently validated option for the treatment of peritoneal carcinomatosis from colorectal or ovarian origin. This therapeutic program demonstrated a significant improvement of the late stages (i.e. carcinomatosis) of the disease. From a clinical point of view, within the first 24 hours after IPCH, patients undergo a systemic inflammatory response syndrome, and therefore require to be monitored in an intensive care unit. From a metabolic perspective, preliminary data have been shown a significant "anaerobic style" disturbance of energetic metabolism, suggesting a deep cellular energetic deficit throughout IPCH process. Putative contradictory effects of IPCH, like the increase of chemotherapy-related cellular toxicity due to heat and on the other hand the initiation of a stress protein response (heat shock response) which helps to reduce the cell injuries, leads to conduct a research project on the underlying mechanisms: consequences, in terms of patient's care and follow-up, are of high relevance. The primary goal is a multimodal assessment of the IPCH-related cell modifications: signaling pathways, apoptosis and antitumoral immune response. The assessment criteria include Heat shock protein expression (blood/cell ratio) compared to baseline values, apoptosis and immune response before/after IPCH. The scheduled sample size is 30 patients having an IPCH and 30 patients contraindicated per surgery.

Intra Peritoneal Chemo Hyperthermia (IPCH) is a recently validated option for the treatment of peritoneal carcinomatosis from colorectal or ovarian origin. This therapeutic program demonstrated a significant improvement of the late stages (i.e. carcinomatosis) of the disease (survival median > 33 months). IPCH induces morbidity as high as 20% and mortality less than 4%. From a clinical point of view, within the first 24 hours after IPCH, patients undergo a systemic inflammatory response syndrome, and therefore require to be monitored in an intensive care unit. From a metabolic perspective, preliminary data have been shown a significant "anaerobic style" disturbance of energetic metabolism, suggesting a deep cellular energetic deficit throughout IPCH process. Putative contradictory effects of IPCH, like the increase of chemotherapy-related cellular toxicity due to heat and on the other hand the initiation of a stress protein response (heat shock response) which helps to reduce the cell injuries, leads to conduct a research project on the underlying mechanisms: consequences, in terms of patient's care and follow-up, are of high relevance. Heat shock protein expression (stress protein response markers) and apoptosis are the main chosen tools to evaluate IPCH-related cellular consequences. Goals of the study Primary goal Multimodal assessment of the IPCH-related cell modifications: signaling pathways, apoptosis and antitumoral immune response. Secondary goal Comparative study of Heat shock protein expression, whether IPCH is done or the patient is recused for the surgery due to intraoperative contraindication. Method Prospective cohort follow up Procedure Besides the usual care (surgical debulking and extensive tumoral resection after laparotomy under general anesthesia), the research protocol includes : 7 blood samples over 72 hours (meaning less than 40 ml), including 4 samples under general anesthesia throughout surgery and 3 samples during the 3 following days (at 24th, 48th and 72th hours). 6 tissue biopsies, i.e. 2 from peritoneum disease-free and 2 from invaded peritoneum , each representing a volume less than 1 cm3 and 2 biopsies from healthy colonic tissue for the colon-related cancer and 4 biopsies (peritoneum n=2, tumoral tissue n=2) for ovarian-related cancer. All biopsies are done during the surgery under general anesthesia, and each biopsy per site before/after IPCH. Assessment criteria main criteria : Heat shock protein expression (blood/cell ratio) compared to baseline values. associate criteria : apoptosis and immune response before/after IPCH Statistical method/Sample size/Study's lenght Scheduled sample size is 30 patients having an IPCH and 30 patients contraindicated per surgery. The normal distribution is verified using the d'Agostino-Pearson test. For intragroup comparisons, the repeated measures ANOVA is done. For intergroup comparisons, an univariate analysis is done, using the Student t-test and the Fisher exact test. Taking into account the planned sample size and the annual number of IPCH, the scheduled length of the study is 18 months.

surgical debulking and extensive tumoral resection after laparotomy under general anesthesia 7 blood samples over 72 hours, including 4 samples under general anesthesia throughout surgery and 3 samples during the 3 following days (at 24th, 48th and 72th hours). 6 tissue biopsies, i.e. 2 from peritoneum disease-free and 2 from invaded peritoneum , each representing a volume less than 1 cm3 and 2 biopsies from healthy colonic tissue for the colon-related cancer and 4 biopsies (peritoneum n=2, tumoral tissue n=2) for ovarian-related cancer. All biopsies are done during the surgery under general anesthesia, and each biopsy per site before/after IPCH

The patients is opened and recused during the surgery because of extended carcinosis and closed without resection neither IPCH. 7 blood samples over 72 hours, including 4 samples under general anesthesia throughout surgery (2 hours before IPCH, 1.5hours after IPCH, 4 hours after IPCH) and 3 samples during the 3 following days (at 24th, 48th and 72th hours). 6 tissue biopsies, i.e. 2 from peritoneum disease-free and 2 from invaded peritoneum, each representing a volume less than 1 cm3 and 2 biopsies from healthy colonic tissue for the colon-related cancer and 4 biopsies (peritoneum n=2, tumoral tissue n=2) for ovarian-related cancer. All biopsies are done during the surgery under general anesthesia, and each biopsy per site before/after IPCH

7 blood samples over 72 hours (meaning less than 40 ml), including 4 samples under general anesthesia throughout surgery and 3 samples during the 3 following days (at 24th, 48th and 72th hours). 6 tissue biopsies, i.e. 2 from peritoneum disease-free and 2 from invaded peritoneum , each representing a volume less than 1 cm3 and 2 biopsies from healthy colonic tissue for the colon-related cancer and 4 biopsies (peritoneum n=2, tumoral tissue n=2) for ovarian-related cancer. All biopsies are done during the surgery under general anesthesia, and each biopsy per site before/after IPCH.

samples taken under general anesthesia throughout surgery and during the 3 following days (24h, 48h,72h)

Inclusion Criteria: adult patient eligible for IPCH with a social security number having a signed an informed consent Exclusion Criteria: study refusal parturiants psychiatric disorders