Use of hyperthermia versus normothermia during intraperitoneal chemoperfusion with oxaliplatin for colorectal peritoneal carcinomatosis: A propensity score matched analysis☆
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.
References (29)
- et al.
Cytoreductive surgery with a hyperthermic intraperitoneal chemotherapy program: safe after 40 cases, but only controlled after 140 cases
Eur J Surg Oncol J. Eur Soc Surg Oncol Br Assoc Surg Oncol
(2015) - et al.
Cytoreduction and hyperthermic intraperitoneal chemotherapy: the learning curve reassessed
Eur J Surg Oncol J. Eur. Soc. Surg Oncol Br Assoc Surg Oncol
(2016) - et al.
Impact of hyperthermic intraperitoneal chemotherapy on Hsp27 protein expression in serum of patients with peritoneal carcinomatosis
Cell Stress & Chaperones
(2013) - et al.
Hyperthermic intra-peritoneal chemotherapy using Oxaliplatin as consolidation therapy for advanced epithelial ovarian carcinoma. Results of a phase II prospective multicentre trial. CHIPOVAC study
Ejso
(2010) - et al.
Organoids as preclinical models to improve intraperitoneal chemotherapy effectiveness for colorectal cancer patients with peritoneal metastases: preclinical models to improve HIPEC
Int J Pharm
(2017) - et al.
Prognostic factors of hemorrhagic complications after oxaliplatin-based hyperthermic intraperitoneal chemotherapy: toward routine preoperative dosage of Von Willebrand factor?
Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol
(2017) - et al.
Intraperitoneal cancer therapy : principles and practice
(2015) - et al.
Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer
J Clin Oncol Official J. Am. Soc. Clin. Oncol.
(2003) - et al.
8-year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer
Ann Surg Oncol
(2008) - et al.
Ninety-day post-operative morbidity and mortality using the National Cancer Institute's common terminology criteria for adverse events better describe post-operative outcome after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy
Int J Hyperther Official J. Eur. Soc. Hyperthermic Oncol.
(2017)
Cytoreduction and HIPEC in The Netherlands: nationwide long-term outcome following the Dutch protocol
Ann Surg Oncol
Institutional learning curve of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for peritoneal malignancies
Ann Surg Oncol
Thermal enhancement of melphalan and oxaliplatin cytotoxicity in vitro
Int J Hyperther Official J. Eur. Soc. Hyperthermic Oncol.
Pharmacokinetics of intraperitoneal oxaliplatin: experimental studies
J Surg Oncol
Cited by (11)
Surgical complications in colorectal cancer patients
2020, Annals of Medicine and SurgeryCitation Excerpt :Hot humified CO2 also results in the reduction of an inflammatory response and mesothelial cell injury [52]. Nonetheless, these techniques can lead to wound infection [53]. Anastomotic leak is also one of the frequently reported complications of colorectal surgery, that can cause mortality and various morbidities.
A Canadian single-centre experience with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for abdominal malignancies
2022, Canadian Journal of SurgeryCitation Excerpt :On the other hand, the American Society of Peritoneal Surface Malignancies (ASPSM) demonstrated that use of mitomycin C was associated with slightly better OS (a finding that was not statistically significant), but in subgroup analysis, the use of mitomycin C improved survival in patients with low burden disease who had complete resection.28 A propensity score matched analysis confirmed that hyperthermic oxaliplatin use during HIPEC did not increase morbidities or mortalities.29,30 Thus, the choice of intraperitoneal chemotherapy may vary according to several factors, including histology sub-types (grade of tumour and presence or absence of signet cells), disease burden and patients’ response to exposure to oxaliplatin in previous systemic therapy.
Chinese experts consensus on the prevention and treatment of complications caused by intraperitoneal perfusion chemotherapy for gastrointestinal tumors (2022 edition)
2022, Chinese Journal of Gastrointestinal Surgery / Zhonghua Wei Chang Wai Ke Za ZhiThe Role of Hyperthermia in the Treatment of Peritoneal Surface Malignancies
2022, Current Oncology ReportsTechnology development of hyperthermic pressurized intraperitoneal aerosol chemotherapy (hPIPAC)
2021, Surgical Endoscopy
- ☆
Poster presentation: Propensity Score Matched Analysis of Postoperative Outcome After Hyperthermic or Normothermic Intraperitoneal Chemoperfusion F. Gremonprez et al. Congress of the Society of Surgical Oncology 2016, Boston, USA.