Severe Neutropenia After HIPEC Using Mitomycin-C

Study Overview
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Brief Summary
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Mitomycin-C (MMC) is the most commonly used chemotherapeutic agent for hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) to treat colorectal cancer patients with peritoneal metastases. However, MMC has a side effect of myelosuppression. Particularly, severe neutropenia after CRS with HIPEC can be a life-threatening condition. Despite the postoperative risks of this side effect, the causes and risk factors for severe neutropenia after CRS followed by HIPEC is not identified so far. Therefore, in this study, we aimed to evaluate to evaluate clinical risk factors and pharmacologic properties after CRS with HIPEC using MMC in patients with colorectal cancer or appendiceal mucinous neoplasms with peritoneal metastases.

Detailed Description
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Evaluation parameters Preoperative period Obtaining informed consent Assessment of baseline clinical characteristics: vital sign, BMI, BSA, ASA classification, ECOG, CBC, CEA level Before 1 day of surgery, assessment of QoR-40 questionnaires Intra-operative period CRS / HIPEC Assessment for peritoneal cancer index, complete cytoreduction score HIPEC procedures: HIPEC was performed using MMC 35 mg/m2 at 41-43℃ for 90 min. Following the HIPEC triple method, MMC 35 mg/m2 was mixed with 3L of Physioneal PD-2 1.5% peritoneal dialysis solution and administered into the intraperitoneal cavity at 50% of the dose at the beginning of HIPEC, 25% of the dose at 30 min, and 25% of the dose at 60 min. Intraoperative samplings of blood and peritoneal fluids during HIPEC : Blood sampling of 5 ml at each time point (baseline, 0 (HIPEC starting point), 15, 30, 45, 60, 75, 90, 120 min) Peritoneal fluid sampling of 5 ml at each time point (baseline, 0 (HIPEC starting point), 15, 30, 45, 60, 75, 90 min) Postoperative period : Postoperative assessment until the discharge date or postoperative 14th days. Daily assessment before discharge : vital sign, transfusion, neutropenia occurrence, adverse events, hematologic blood test (CBC, absolute neutrophil count (ANC), postoperative complications, use of G-CSF, ICU admission (If severe neutropenia occurs in the postoperative period, the patient assigns in arm I.) CEA level: postoperative 5th day QoR-40 questionnaires: postoperative 4th and 7th days

Official Title
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A Phase II Trial to Analyze Clinical and Pharmacological Properties for Severe Neutropenia After Cytoreductive Surgery Followed by Hyperthermic Intraperitoneal Chemotherapy Using Mitomycin-C

Conditions
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Colorectal Cancer Metastatic, Cancer Metastatic to the Peritoneal Cavity, Appendiceal Neoplasm, Pseudomyxoma Peritonei

Intervention / Treatment
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* Procedure: Intraoperative blood and peritoneal fluid samplings during HIPEC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Joined the study voluntarily and signed informed consent form Patients who diagnosed colorectal cancer or appendiceal mucinous neoplasm with peritoneal metastases Patients who undergo CRS/HIPEC using MMC ECOG ≤ 1 Exclusion Criteria Patients who received synchronous operations for liver or lung metastatic sites during CRS/HIPEC Previous histories who underwent CRS/HIPEC Patients who received palliative 3rd line chemotherapy Patients who received chemotherapy within 1 year to treat other cancers Patients who had PCD cathethers for ascites control ECOG ≥2 Infectious status Age<19 years old Pregnant or breast-feeding women or people during the birth-period who refused to take contraceptives Drop-out criteria - Hospital stay > 30 days

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Arm I (Severe neutropnia group),<br>After CRS followed by HIPEC using MMC of 35mg/m2, patients who had absolute neutrophil count (ANC) < 1000/mm3 during the postoperative period are assigned as experimental group (Arm I, severe neutropnia group). | Procedure: Intraoperative blood and peritoneal fluid samplings during HIPEC<br>* - Intraoperative samplings of blood and peritoneal fluids during HIPEC : Blood sampling of 5ml at each time point (baseline, 0 (HIPEC starting point), 15, 30, 45, 60, 75, 90, 120 min) Peritoneal fluid sampline of 5ml at each time point (baseline, 0 (HIPEC starting point), 15, 30, 45, 60, 75, 90 min)<br>|
| Arm II (No severe neutropenia group)<br>After CRS followed by HIPEC using MMC of 35mg/m2, patients who had ANC ≥ 1000/mm3 during the postoperative period are assigned as the control group (Arm II: no severe neutropenia group). | Procedure: Intraoperative blood and peritoneal fluid samplings during HIPEC<br>* - Intraoperative samplings of blood and peritoneal fluids during HIPEC : Blood sampling of 5ml at each time point (baseline, 0 (HIPEC starting point), 15, 30, 45, 60, 75, 90, 120 min) Peritoneal fluid sampline of 5ml at each time point (baseline, 0 (HIPEC starting point), 15, 30, 45, 60, 75, 90 min)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Association between the concentration of intraoperative mitomycin-C absoprtion and severe neutropenia after CRS/HIPEC | Comparison of the pharmacologic association between occurrence of postoperative severe neutropenia, and blood absoprtion rates of MMC and the area-under-the curve (AUC) ratios during HIPEC | 2 weeks after the discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of severe neutropenia | Incidence (rates) | During 2 weeks after CRS/HIPEC | 
| Postoperative complications | Assessment from Clavien-Dindo classification | During 2 weeks after CRS/HIPEC | 
| Patterns of perioperative changes of WBC, Hemoglobin, platelet, lymphocyte, neutrophil counts | Records for serologic tests | During 2 weeks after CRS/HIPEC | 
| Frequency of postoperative uses for G-CSF | Numbers of G-CSF uses | During 2 weeks after CRS/HIPEC | 
| Changes of CEA level | ng/mL | During 2 weeks after CRS/HIPEC | 
| Quality of Life: QoR-40 questionnaire | Answer of questionnarie | During 2 weeks after CRS/HIPEC |