Use of hyperthermia versus normothermia during intraperitoneal chemoperfusion with oxaliplatin for colorectal peritoneal carcinomatosis: A propensity score matched analysis

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Abstract

Background

Hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (OX) is increasingly used in the treatment of colorectal peritoneal carcinomatosis (PC). However, the additional benefit of hyperthermia remains clinically unproven, while it may aggravate postoperative morbidity. Here, we report the correlation of perfusion temperature with postoperative morbidity during clinical HIPEC with OX.

Patients and methods

Patients who underwent hyperthermic (41 °C, HT) or normothermic (37 °C, NT) chemoperfusion with OX for colorectal PC were identified from a prospectively kept database of HIPEC cases and matched for baseline characteristics using propensity score (PS) analysis. The groups were compared to assess the impact of perfusion temperature on morbidity. Morbidity was graded using the Clavien-Dindo (CD) classification and the Comprehensive Complication Index (CCI).

Results

Out of 612 patients, 146 patients met the inclusion criteria and from these patients, 45 HT patients were matched with 45 NT patients. Baseline variables were comparable between the PS matched groups. Overall mortality was 0.7% and major morbidity (CD ≥ 3) occurred in 35,6% of patients. There were no significant differences between the HT and NT cohorts in mortality, major morbidity (RR 1.33, 95% CI 0.71 to 2.49, p = 0.36), anastomotic leakage (13.8% versus 11.1%, p = 1.0), hemorrhagic complications, or systemic toxicity. A trend of increased wound infections was observed in the hyperthermia group (13.3% versus 4.4%, P = 0.27).

Conclusions

Compared to NT, the use of HT during HIPEC with OX does not aggravate postoperative mortality or morbidity in a high-volume center.

Introduction

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly used in peritoneal carcinomatosis (PC) from colorectal cancer (CRC) [1]. The randomized controlled trial by Verwaal et al. reported improved overall survival after a combined treatment of 5-FU based chemotherapy and CRS + HIPEC, compared to palliative chemotherapy alone [2,3]. However, the morbidity of the procedure is high (0–62%), with most authors reporting major morbidity in around 35% of cases [4,5]. This morbidity is likely to be attributed primarily to the long and extensive surgical procedure, the safe performance of which requires extensive experience and training [[6], [7], [8]]. Systemic toxicity from intraperitoneal (IP) chemotherapy is usually limited, since systemic drug exposure is typically limited compared to IP exposure. Over the last decade, oxaliplatin (OX) is increasingly used for HIPEC in CRC. Oxaliplatin has a favorable pharmacokinetic profile (AUC peritoneal/plasma is approximately 15–20). In vitro, hyperthermia enhances the cytotoxic activity of OX [9]. However, hyperthermia enhances systemic release of heat shock proteins (HSP), which are implicated in treatment resistance [10]. Also, in a murine model, hyperthermia did not significantly increase tissue OX concentrations [11]. In animal models, HIPEC adversely affects anastomotic healing [12]. Clinically, HIPEC elicits a generalized inflammatory response, as evidenced by sharply risen levels of, among other mediators, interleukin-6 and procalcitonin; high levels of postoperative IL-6 are known to correlate with postoperative complications after major abdominal surgery [13].

These findings prompted us, in an effort to minimize postoperative morbidity, to start performing HIPEC under normothermic conditions (target intra-abdominal temperature 37 °C) in patients perceived to be at higher risk of complications. Here, we report, for the first time, a comparison of postoperative complications between patients undergoing normo-versus hyperthermic intraperitoneal chemoperfusion (IPC) using OX. Patients were matched according to clinical and treatment variables using the propensity score method.

Section snippets

Methods

Patients were identified from a comprehensive prospectively kept database of all IPC patients that has been maintained at our institution since January 1999. Candidates for surgery were preoperatively assessed by the surgical team and each case discussed in a multidisciplinary conference. Selection criteria were the type of cancer (CRC) and type of intraperitoneal chemotherapy (Oxaliplatin). Exclusion criteria were concomitant liver resection, IPC without CRS, multiple IPC procedures, and

Patient selection and characteristics

From a total of 612 patients treated with CRS and IPC between 1999 and 2016, 146 met the selection criteria. All included patients were treated from 2005 to 2016. Half of these patients (73) patients were treated with hyperthermic IPC (mean T 40.74 °C; SD 1.219), while the other 73 were treated with normothermic IPC (mean T 37.60 °C; SD 0.427). Baseline characteristics in both groups are presented in Table 1. Normothermic IPC patients had a higher percentage of neo-adjuvant chemotherapy and

Discussion

Surgery and HIPEC are increasingly regarded as a rational option for patients with colorectal PC. Nevertheless, the efficacy of HIPEC compared to modern systemic therapy alone remains to be demonstrated. Also, although expert centers report major morbidity rates in the range of 30–35%, debulking and HIPEC is a formidable undertaking with potentially serious functional and quality of life consequences [19]. Anastomotic leakage is one of the most dreaded postoperative complications, and occurs in

Acknowledgments

Wim Ceelen is a Senior Clinical Investigator of the Fund for Scientific Research — Flanders (FWO).

The authors wish to thank Natacha Rosseel for updating the institutional HIPEC database.

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