HIPEC Using High Intra-abdominal Pressure
Condition: Pseudomyxoma Peritonei; Colorectal Cancer
MeSH terms: Pseudomyxoma Peritonei
Study type: Interventional
Phase: Phase 2

Summary: 
      Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a
      promising therapy for peritoneal carcinomatosis (PC) of various origins. Rather than the
      pharmacokinetic advantage, the uptake of chemotherapy by tumor tissue has been proposed as
      the best pharmacologic endpoint to assure the efficacy of HIPEC.

      The primary endpoints of the present phase II randomized study are to test whether the
      increased intra abdominal pressure (IAP) during HIPEC could:

        -  enhance the penetration of cisplatin into the residual neoplastic and normal tissues;

        -  elicit changes on pharmacokinetic advantage of cisplatin.

      Secondary endpoints are to evaluate the:

        -  impact of high IAP on intraoperatory hemodynamic and respiratory parameters;

        -  impact on short-term surgical outcomes (in hospital stay, morbidity, mortality).

      Patients affected by PC from colorectal cancer or pseudomyxoma peritonei, submitted to
      complete cytoreduction (residual disease <2.5mm) would be eligible for the study. HIPEC will
      be performed using closed abdomen technique and cisplatin + mitomycin-C. Patients will be
      randomly assigned to HIPEC with low IAP (8-12 mmHg) or high IAP (18-22 mmHg). IAP will be
      measured using bladder catheter. High IAP will be obtained increasing the volume of
      perfusate.

      Thirty-eight patients (19 in each study groups) will be enrolled in 30 months. The randomized
      groups will be stratified according to tumor type.
    

Detailed description: 
      Patients affected by peritoneal metastasis from colorectal cancer or pseudomyxoma peritonei,
      submitted to complete cytoreduction (residual disease <2.5mm) would be eligible for the
      study. Residual and resectable tumour nodules of 0.5 to 1.0 cm will be left behind after the
      cytoreduction and they will be collected at the end of HIPEC for the purpose of this study.
      HIPEC will be performed using closed abdomen technique and cisplatin (42mg/L of perfusate) +
      mitomycin-C (3.3mg/m2/L of perfusate) for 60 minutes, at 42.5°C. Patients will be randomly
      assigned to HIPEC with low IAP (8-12 mmHg) or high IAP (18-22 mmHg). IAP will be measured
      using bladder catheter. Patients of high IAP group will be strictly monitored during the
      perfusion regarding hemodynamic/respiratory parameters. During the HIPEC, perfusate and blood
      samples will be collected every 10 minutes. Additional samples of arterial blood will be
      collected at 70, 90,120,180 and 240 minutes. After the completion of HIPEC residual tumor
      tissues, normal peritoneum and muscular fascia will be sampled for determination of cisplatin
      concentration.

      Blood samples will be immediately centrifuged to separate plasma. An aliquot of plasma will
      be stored at -30°C for total platinum determination. Another aliquot will be ultrafiltered by
      centrifugation through a membrane with a cut-off 5000 Da for ultrafilterable platinum
      determination. The ultrafiltrate will be stored at -30°C until analysis.

      Perfusate samples will follow the same procedure of blood samples. Tissues samples will be
      stored at -80°C until analysis. Platinum determination will be performed using an Inductive
      Coupled Plasma Mass Spectrometry (ICP-MS) system by Thermo Scientific after preparing
      calibration curves with atomic platinum. Fluid samples simply dilute before ICP-MS
      examination while tissues will be desiccated, digested with a mixture of nitric acid and
      oxygen water, and evaporated to dryness prior to determination.

      The investigators will compare the following outcomes between the study groups: tumor tissue
      concentration of cisplatin; the area under the curve (AUC) ratio of perfusate UF
      concentration of cisplatin times time to plasma UF concentration times time; in-hospital
      stay; systemic toxicity (NCI-CTCAE.v3), morbidity, and mortality.

      Thirty eight patients (19 in each group) would be needed to detect an increase cisplatin
      concentration of 20 ng/mg of tumor tissue if patients are submitted to high-IAP during HIPEC,
      assuming alfa=0.05 and power=0.90 and standard deviation of 15 ng. Accrual time will be 30
      months. The randomized groups will be stratified according to tumor type.
    

Intervention name(s): Cytoreductive surgery; Low Intra abdominal pressure HIPEC; High Intra abdominal pressure HIPEC
Intervention type(s): Procedure; Other; Other
Intervention description(s): Maximal surgical effort to obtain a minimal residual disease of less than 2.5 mm; Hyperthermic intraperitoneal chemotherapy using closed modality and intra abdominal pressure of 8-12 mmHg; Hyperthermic intraperitoneal chemotherapy using closed modality and intra abdominal pressure of 18-22 mmHg
Other intervention name(s): Peritonectomy procedures
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: cisplatin; HIPEC; Intra abdominal pressure; tissue drug concentration