CHIPOFIL: A pilot study assessing the feasibility of HIPEC without extracorporeal circuit

Design of the study

The CHIPOFIL prospective study was a pilot study assessing for the first time the safety of Thermowire^® in humans. All patients undergoing HIPEC were eligible, except in case of known allergy to latex due to the use of an abdominal cavity expander [4]. To calculate the sample size, a Bayesian approach was performed. Based in a risk of thermal injury similar or higher than with other techniques of HIPEC (1% per patient according to the most “pessimistic” data) and a chance of obtaining hyperthermia close to other techniques of HIPEC (90% per procedure according to the most “pessimistic data”) [5, 6, 7], the number of patients needed to obtain either a thermal injury or the impossibility to achieve hyperthermia was established at 12. In order to have 12 patients with all data available, one more patient was added in case of missing data. Thus, 13 patients were to be included in the study. Patients were included between January 2015 and June 2016 after they provided a written informed consent.

Description of the device

The device consists of a disposable electric heating cable covered with silicone rubber insulation. This cable is connected to a 24-V transformer and regulator, which is connected to current electric outlet (Figure 1). Several lengths of cable are available for use in order to adapt to each patient’s anatomy (17 m, 13 m, 10 m, 7 m, 5 m and 3 m; references JB001 to 006, respectively). In the present study, two sets of 17 m Thermowire^® were used for each patient. The device undergoes sterilization with ethylene oxide by the current manufacturer (DistriClass Medical SA, Chaponnay, France). The heating cable (Thermowire^®) is not still CE certified, while the electric transformer is already certified by the manufacturer. According to the Directive 93/42/CEE, Thermowire^® is a “temporary, surgically invasive, therapeutically active, single use device type IIa”.

Figure 1:

View of the 2 units of 24-V transformer and regulator and the heating cable. Several lengths of cable are available although in the present study we always used 2 sets of 17 meters of length.

Surgical technique and follow-up

We used a large midline laparotomy to access the abdomen. After CRS was achieved in all patients, an open-abdomen closed-HIPEC technique was performed as previously described in detail elsewhere and currently performed in our department since 15 years [4]. Briefly, it consists of a latex abdominal cavity expander stapled to the cutaneous edges and suspended on a metallic frame held by a Thompson retractor (Landanger, France). A transparent methacrylate cover with a Gelport in its centre (Landanger, France) is placed over the metallic frame and the latex piece hermetically closing the abdominal cavity. Three temperature probes (one fixed with a stitch to the diaphragm, one close to the mesentery root and one into the pelvis) were passed through the latex sheet and connected to an integrated system of temperature control. The abdominal cavity was filled in with 2 L/m² of physiologic serum at 37 °C. Two sets of 17 m long Thermowire (JB001) were used for every patient, one in the supramesocolic and one in the inframesocolic area (Figure 2, Video in the Supplementary Material). The loops of the heating cable passed through the abdominal cavity expander and were uniformly distributed within the abdominal cavity, between bowel loops, in the infradiaphragmatic and infrahepatic areas, in the lesser sac, in both paracolic gutters and in the pelvis. We switched on both devices and the temperature progressively increased until 42 °C was reached. The target temperature was 42–43 °C, during 30, 60 or 90 min depending on the drug used (30 min for oxaliplatin, 60 min for mitomycin C and 90 min for all other protocols). In our department, viscera are constantly stirred, whatever the HIPEC technique. At the end of HIPEC, the device was dismantled and the whole abdominal cavity contents were carefully examined searching for any thermal injury.

Figure 2:

Overview of the system including the abdominal cavity expander with its cover (the « glove-box » system) and the heating wire. No pump, no circuit, no tubes are necessary anymore.

The postoperative surveillance was made according to the current protocols of each institution. For the purposes of the present study, the follow-up ended at 1 year of the procedure.

Ethics and safety issues

All adverse events within 1 year after HIPEC were recorded and evaluated by an independent committee of experts composed of one surgeon and two oncologists from non-participating institutions in order to determine any potential relationship with the use of Thermowire^®.

This protocol received approval from the French National Agency watching over the security of drugs and medical devices (ANSM), the Institutional Board Review and the Regional Ethics Committee (CPP Est 1: ID RCB N° 2012-A01509-34). The study was registered in clinicaltrials.gov (NCT02862899).

Description of the patients

Thirteen consecutive patients (nine women and four men; median age: 59 ± 9 years) underwent HIPEC using Thermowire^®. Their weight was 66 ± 13 kg and their body surface was 1.74 ± 0.2 m². The disease leading to HIPEC was colorectal cancer in eight patients, appendiceal cancer in two and gastric cancer, pseudomyxoma peritonei and peritoneal mesothelioma in each one of the three other patients. The peritoneal carcinomatosis index (PCI) ranged between 0 and 20 (median: 6). In five patients, HIPEC was prophylactic (PCI=0). In all other patients, a CRS (CC-0) was achieved. The drugs used were mitomycin-C in seven patients, oxaliplatin in four, cisplatin and doxorubicin in one and cisplatin and mitomycin-C in one. A homogenous and constant hyperthermia was obtained in all patients, with temperatures ranging between 42 °C and 43 °C in all three thermal probes during the scheduled time according to each protocol (30, 60 or 90 min).

Time to set up and dismantle the device

The median time to set up the device (abdominal cavity expander and Thermowire^®) was 23.7 ± 5.7 min. The target temperature was obtained in 10.3 ± 4.3 min and maintained along all the procedure homogeneously in the thermal probes. No peak or drop of temperature was registered during the desired hyperthermia period in any patient (Figure 3). The time to dismantle the device was 10.5 ± 4.2 min.

Figure 3:

Mean temperatures (with min and max temperature) recorded at the diaphragm (a) and Douglas (b) thermal probes along 1-hour procedures of HIPEC. The curves show the thermal homogeneity achieved with the device.

Morbidity

Two patients presented a colorectal anastomotic leak (one requiring reoperation), two had hemoperitoneum requiring reoperation (both in oxaliplatin patients), one evisceration and one prolonged gastroparesia (resolved spontaneously at 2 months). No other complications were registered. Namely, there was no thermal injury. No complication was related to the use of Thermowire^® according to the scientific committee and the independent committee of the study.