Clinical trial NCT02949791: HIPEC Using High Intra-abdominal Pressure
Official title: Effects of High Intra-abdominal Pressure on Tissue Diffusion and Pharmacokinetics of Cisplatin During HIPEC
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pseudomyxoma Peritonei
Colorectal Cancer
Keywords: cisplatin
HIPEC
Intra abdominal pressure
tissue drug concentration
Lead sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Sponsor class: OTHER
Collaborators: name: Associazione Italiana per la Ricerca sul Cancro
First posted: 2016-10-31
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

1. Histological diagnosis of primary peritoneal carcinomatosis from colorectal origin or pseudomyxoma peritonei
2. Patients submitted to complete cytoreduction with residual tumor \<2.5 mm
3. Patients at the end of cytoreduction should present the laboratorial and hemodynamic parameters set as followings:

   * Mean arterial pressure \> 65 mmHg
   * Heart rate: \< 100 bpm
   * Central venous pressure \> 4 mmHg
   * Cardiac index \> 2.2
   * Central venous oxygen saturation (ScvO2) \> 72%, and
   * Haemoglobin \> 8.0 gr/dl.
4. Informed consent signed from the patient before the procedure.

Exclusion Criteria:

* Severe hemodynamic and/or respiratory instability after the cytoreduction that precludes HIPEC.

Primary outcomes:
measure: Tumor tissue concentration of cisplatin
timeFrame: collected within 15 minutes after the completion of HIPEC
measure: Normal tissue concentration of cisplatin
timeFrame: collected within 15 minutes after the completion of HIPEC
Secondary outcomes:
measure: Pharmacokinetic advantage
timeFrame: During the HIPEC up to 1 hour from the completion of perfusion
measure: Pharmacokinetic advantage 2
timeFrame: During the HIPEC up to 1 hour from the completion of perfusion
measure: Impact of high intra-abdominal pressure on anesthesiologic parameters 1
timeFrame: Intraoperative phase
measure: Impact of high intra-abdominal pressure on anesthesiologic parameters 2
timeFrame: Intraoperative phase
measure: Impact of high intra-abdominal pressure on anesthesiologic parameters 3
timeFrame: Intraoperative phase
measure: Impact of high intra-abdominal pressure on anesthesiologic parameters 4
timeFrame: Intraoperative phase
measure: Impact of high intra-abdominal pressure on anesthesiologic parameters 5
timeFrame: Intraoperative phase
measure: Impact of high intra-abdominal pressure on anesthesiologic parameters 6
timeFrame: Intraoperative phase
measure: Impact of intraoperative high intra-abdominal pressure on short-term surgical outcomes 1
timeFrame: within 30 days after surgery
measure: Impact of intraoperative high intra-abdominal pressure on short-term surgical outcomes 2
timeFrame: within 30 days after surgery
measure: Impact of intraoperative high intra-abdominal pressure on short-term surgical outcomes 3
timeFrame: within 30 days after surgery
Other outcomes:
Locations:
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
state: MI
Study officials:
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
name: Shigeki Kusamura, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Kusamura S, Azmi N, Fumagalli L, Baratti D, Guaglio M, Cavalleri A, Garrone G, Battaglia L, Barretta F, Deraco M. Phase II randomized study on tissue distribution and pharmacokinetics of cisplatin according to different levels of intra-abdominal pressure (IAP) during HIPEC (NCT02949791). Eur J Surg Oncol. 2021 Jan;47(1):82-88. doi: 10.1016/j.ejso.2019.06.022. Epub 2019 Jun 21.