Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma: Canadian practices and outcomes.

INTRODUCTION: Peritoneal mesothelioma (PM) is a rare malignancy originating from the peritoneal lining. Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is the standard-of-care for patients with isolated PM. Due to a paucity of prospective data there are several different HIPEC protocols. The aims of this study are to describe the CRS and HIPEC protocols for PM and patient outcomes across Canada. METHODS: A multicenter retrospective study was performed on patients diagnosed and treated for PM with CRS and HIPEC in four major peritoneal disease centers in Canada between 2000 and 2021. Data on patient characteristics, treatment patterns, postoperative morbidity, recurrence, and survival were collected. RESULTS: A total of 72 patients were identified. Mean age was 52 years (17-75) and 37.5% were male. Epithelioid (70.1%) and multicystic (13%) mesothelioma were the most common subtypes. Twenty-one patients (30%) were treated with neoadjuvant chemotherapy. CRS and HIPEC was performed in 64 patients (91.4%). Of these, the mean PCI was 22 (2-39) and cisplatin+doxorubicin was the most common HIPEC regimen (n = 33, 51.6%). A semi-closed coliseum technique was used in 68.8% of HIPECs and the mean duration of surgery was 486 min (90-1052). Clavien-Dindo III or IV complications occurred in 12 patients (16.9%). With a median follow-up of 24 months (0.2-104.4), we found a 5-year overall survival of 61% and a 5-year recurrence-free survival of 35%. CONCLUSION: CRS and HIPEC is a safe and effective treatment modality for well-selected patients with PM, with some achieving prolonged survival.

Predictors of Small Bowel Obstruction Post-Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for peritoneal malignancies carries considerable morbidity; however, the significance of postoperative small bowel obstruction (SBO) is not well defined. We aim to identify predictors for post-CRS/HIPEC SBO and their oncologic associations. METHODS: A retrospective review was conducted of all CRS/HIPEC cases performed at a surgical oncology center (2013-2018). Patient demographics, tumor characteristics, perioperative factors, and province-wide hospital readmissions were analyzed. Descriptive statistics were used for baseline characteristics, multivariate logistic regression for predictors of SBO at 1 year, and Kaplan-Meier method with log-rank test for survival analysis. RESULTS: A total of n = 97 CRS/HIPEC procedures were performed for diagnoses of low-grade appendiceal mucinous neoplasm (44%), high-grade appendiceal adenocarcinoma (8%), colorectal adenocarcinoma (34%), and mesothelioma (9%). The median peritoneal carcinomatosis index (PCI) score was 16. Cumulative incidence of post-CRS/HIPEC SBO readmission was 24% at 1 year and 38% at 2 and 3 years. Of 29 patients readmitted with SBO, 14 (48%) had more than one readmission for SBO, and nine surgeries were performed for obstruction. Multivariate regression identified significant independent predictors of SBO within 1-year post-CRS/HIPEC as high-grade appendiceal or colorectal primaries (odds ratio [OR] 4.58, p = 0.02) and PCI ≥ 20 (OR 3.27, p = 0.05). Overall survival (OS) was worse in patients readmitted with SBO within 1 year compared to those without (3-year OS 58% vs. 75%, p = 0.017). CONCLUSION: SBO is the most common readmission diagnosis post-CRS/HIPEC and is associated with worse survival. High-grade appendiceal and colorectal primary tumors and PCI ≥ 20 are predictors for SBO.

Cost-Effectiveness Analysis of Cytoreductive Surgery and HIPEC Compared With Systemic Chemotherapy in Isolated Peritoneal Carcinomatosis From Metastatic Colorectal Cancer.

BACKGROUND: Cost-effectiveness evaluations of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis (PC) from metastatic colorectal cancer (mCRC) in the United States are lacking. METHODS: The authors developed a Markov model to evaluate the cost-effectiveness of CRS/HIPEC compared with systemic chemotherapy for isolated PC from mCRC from a societal perspective in the United States. The systemic treatment regimens consisted of FOLFOX, FOLFIRI, bevacizumab, cetuximab, and pantitumumab. The model inputs including costs, probabilities, survival, progression, and utilities were taken from the literature. The cycle length for the model was 2 weeks, and the time horizon was 7 years. A discount rate of 3% was applied. The model was tested for internal and external validation, and robustness was established with univariate sensitivity and probabilistic sensitivity analyses (PSA). The primary outcomes were total costs, quality-adjusted life-years (QALYs), life-years (LYs), and incremental cost-effectiveness ratio (ICER). A willingness-to-pay (WTP) threshold of $100,000 per QALY was assumed. RESULTS: The ICER for treatment with CRS/HIPEC compared with systemic chemotherapy was $91,034 per QALY gained ($74,098 per LY gained). The univariate sensitivity analysis showed that the total costs for treatment with CRS/HIPEC had the largest effect on the calculated ICER. The CRS/HIPEC treatment was a cost-effective strategy during the majority of simulations in the PSA. The average ICER for 100,000 simulations in the PSA was $70,807 per QALY gained. The likelihood of CRS/HIPEC being a cost-effective strategy at the WTP threshold was 87%. CONCLUSIONS: The CRS/HIPEC procedure is a cost-effective treatment for isolated PC from mCRC in the United States.

Impact of Major Complications on Patients' Quality of Life After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

INTRODUCTION: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment for selected patients with peritoneal surface malignancies (PSM). Although it can have significant morbidity, perioperative mortality is low. Little is known about whether major complications after CRS/HIPEC have a lasting impact on patients' quality of life (QOL). METHODS: We retrospectively reviewed data from a prospectively collected database on patients treated with CRS/HIPEC for PSM (2011-2014). Patients with CRS/HIPEC and 6-month QOL evaluation were included. Major perioperative complications (Clavien-Dindo grade 3/4) were the primary independent variable. QOL was evaluated using the validated EORTC QLQ-C30 score. The primary outcome was 6-month global health score. Secondary outcomes were individual functional and symptom domains. RESULTS: Forty-two patients were analyzed. Median age was 57.5; 64 % were female. Origin of PSM was appendix (55 %), colorectal (38 %), mesothelioma (5 %), and small bowel (2 %). Fourteen patients (33 %) had major (grade 3/4) complications. Median length of stay was 16 days; patients experiencing major complications had significantly increased length of stay (35.5 vs. 13 days, p < 0.01). Major complications included intra-abdominal abscess (9.5 %), bleeding (9.5 %), symptomatic pleural effusion (7.1 %), anastomotic leaks (7.1 %), and renal failure (2.4 %). The average global health score at 6 months was 68.1. The worst-rated symptom scores at 6 months were diarrhea (39.8) and fatigue (35.4). There were no significant differences in 6-month QOL scores between patients with and without major complications, globally or in specific domains. CONCLUSIONS: Although major complications are common after CRS/HIPEC, QOL at 6 months recovers and is similar to those without major complications.

A novel method of drug administration to multiple zebrafish (Danio rerio) and the quantification of withdrawal.

Anxiety testing in zebrafish is often studied in combination with the application of pharmacological substances. In these studies, fish are routinely netted and transported between home aquaria and dosing tanks. In order to enhance the ease of compound administration, a novel method for transferring fish between tanks for drug administration was developed. Inserts that are designed for spawning were used to transfer groups of fish into the drug solution, allowing accurate dosing of all fish in the group. This increases the precision and efficiency of dosing, which becomes very important in long schedules of repeated drug administration. We implemented this procedure for use in a study examining the behavior of zebrafish in the light/dark test after administering ethanol with differing 21 day schedules. In fish exposed to daily-moderate amounts of alcohol there was a significant difference in location preference after 2 days of withdrawal when compared to the control group. However, a significant difference in location preference in a group exposed to weekly-binge administration was not observed. This protocol can be generalized for use with all types of compounds that are water-soluble and may be used in any situation when the behavior of fish during or after long schedules of drug administration is being examined. The light/dark test is also a valuable method of assessing withdrawal-induced changes in anxiety.