Intraperitoneal chemotherapy hyperthermia (HIPEC) for peritoneal carcinomatosis of ovarian cancer origin by fluid and CO₂ recirculation using the closed abdomen technique (PRS-1.0 Combat): A clinical pilot study

Abstract

Background This paper reports a study of 21 patients with peritoneal carcinomatosis from ovarian cancer who underwent cytoreductive surgery and HIPEC by means of PRS-1.0 Combat®, a new model for closed abdomen HIPEC aimed at improving fluid distribution with assistance from a CO₂ recirculation system. This new technology has been previously shown to be successful in an experimental study (pig model) performed by our group, and has been approved for use in our hospital. Methods Twenty-one patients with peritoneal carcinomatosis of ovarian cancer origin were included in the study. Cytoreductive surgery and HIPEC were performed by a closed abdomen fluid and CO₂ recirculation technique using the PRS-1.0 Combat^® model. We analysed the intraoperative safety tolerance and post-operative morbidity and mortality during the first 30 days. Results Between November 2011 and March 2014 21 patients with epithelial ovarian cancer, International Federation of Gynecology and Obstetrics stage II–IV, were included in the study. During the procedure there were no significant haemodynamic or analytical disturbances. Complication rates were 38.1% and 57.14% for grade III/IV and minor (grade I/II) complications, respectively. Post-operative mortality was 4.76% (one patient). Complete cytoreductive surgery and intraperitoneal chemotherapy improved overall survival and disease-free survival in women with advanced ovarian cancer. The association of intra-abdominal hyperthermia with chemotherapy (HIPEC) increased the therapeutic benefit. Conclusions This study has shown that closed abdomen intraperitoneal chemohyperthermia by a fluid and CO₂ recirculation system (PRS-1.0 Combat^®) can be a safe and feasible model for the treatment of peritoneal carcinomatosis of ovarian cancer origin.

Keywords:

• Ovarian cancer
• closed abdomen HIPEC

Introduction

The development and improvement of locoregional treatment of peritoneal carcinomatosis by cytoreductive surgery and intraperitoneal chemotherapy has increased overall survival and disease-free survival for some tumour types, such as ovarian cancer or colon cancer [1]. Debulking techniques involve the surgical removal of all macroscopically visible tumour volume by visceral resections and peritonectomy. Intraperitoneal chemotherapy acts on microscopic residual disease with an enhanced intracavitary therapeutic dose, leading to less toxicity than an intravenous dose. The hyperthermic drug solution increases tumour apoptosis by its direct cytotoxic effect and improves chemotherapeutic toxicity against tumour cells [2,3].

The standard technique for intraperitoneal hyperthermia chemotherapy (HIPEC) is an open abdomen technique, or Coliseum technique, developed by Sugarbaker for the treatment of patients with peritoneal carcinomatosis. However, modifications to this approach have recently been developed to better control the hyperthermia and reduce the risk of contamination of medical personnel (e.g. semi-closed or closed techniques) [4].

In collaboration with industry, we have developed a model for closed abdomen HIPEC, with recirculation of CO₂ and fluids (PRS-1.0 Combat^®). The safety and effectiveness of this new technology was previously tested in an animal model [5]. Our experimental and initial study was approved by the Animal Ethics Committee of the University of Veterinary Medicine, Barcelona, Spain, following the specific laws of animal protection for experimentation and other specific regulations.

This new technology consisted of two roller pumps and a warm external reservoir for heating the perfusate solution, two inflow tubes, two outflow tubes and another tube used for CO₂ infusion. A gas exchanger was employed for CO₂ recirculation. The main advantages of this new device in the experimental study were the provision of homogeneous intra-abdominal temperature and good drug distribution (indicated by methylene blue staining) in the closed abdomen and CO₂ recirculation animal group, compared with the open and closed abdomen (no CO₂ recirculation) animal group. Another advantage of this new HIPEC system could be increased drug penetration through the peritoneal surface due to increased abdominal pressure, but this has not yet been demonstrated. Closed abdomen HIPEC with CO₂ recirculation had no deleterious impact on blood or haemodynamic parameters in the animal study.

Once the safety and feasibility of this new technique of HIPEC had been demonstrated we started a pilot study in patients with peritoneal carcinomatosis of ovarian cancer origin, who underwent cytoreductive surgery and HIPEC with this method. The new technique may be better than classical HIPEC methods in terms of the homogeneity of the intra-abdominal temperature and drug distribution in patients undergoing cytoreductive surgery and HIPEC, with no haemodynamic perturbation. Here we present a pilot study of patients with peritoneal carcinomatosis of ovarian cancer origin who underwent complete cytoreductive surgery and HIPEC by a closed abdomen technique and CO₂ recirculation using the recently developed PRS-1.0 Combat^® model.

This study was approved by the Ethics Committee of the University General Hospital of Ciudad Real. The clinical trial was approved by the Spanish Medicines Agency and Medical Devices.

Objectives

The aim was to report on a series of patients with peritoneal carcinomatosis from primary or recurrent ovarian cancer who underwent cytoreductive surgery with a new type of closed HIPEC and CO₂ recirculation system, using paclitaxel (175 mg/m²) for 60 min at 42 °C. We analysed the intraoperative safety as well as the post-operative safety, morbidity and mortality during the first 30 days.

Material and methods

Study population

We present the initial results of the first 21 patients included in the clinical trial EUDRACT (2011-006319-69). The main inclusion criteria for patients in this clinical trial were primary or recurrent ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) stage II, III or IV, with optimal cytoreductive surgery and no extra-abdominal metastasis. We present the first 21 patients in the HIPEC arm of the clinical trial. We performed complete cytoreductive surgery and intra-abdominal hyperthermic chemotherapy using paclitaxel (175 mg/m²) for 60 min at 42 °C. The closed abdominal HIPEC technique was used with fluid and CO₂ recirculation by means of a PRS-1.0 Combat^® system. Inclusion criteria were women aged 18–80 years with recurrent or primary epithelial ovarian cancer (stage II, III, or IV), performance status or functional status (according to the scale of the Eastern Cooperative Oncology Group) ≤ 2, CC0 cytoreduction rate CC1 (less than 0.25 cm), absence of extra-abdominal tumour disease; absence of cardiopulmonary, renal, or hepatic failure, provision for informed consent to participate in the study. Patients older than 80 years with a peritoneal carcinomatosis index (PCI) <10 and good performance status were assessed individually for inclusion in the study.

Perioperative management and anaesthesia

All patients received balanced general anaesthesia. In some cases an epidural catheter was used between the T7 and T8 levels for intraoperative and post-operative pain control. Invasive monitoring of blood pressure, cardiac output, and heart rate was performed by radial artery catheter pulse contour cardiac output (Pulsion^® Medical Systems, Munich, Germany). A peripheral vein, a central vein and a nasogastric tube were used. Thromboprophylaxis was performed 12 h before surgery and antibiotic prophylaxis 30 min before anaesthesia induction.

Surgical technique

A midline laparotomy was performed. We performed a hysterectomy, bilateral oophorectomy, peritonectomy, and pelvic-aortic lymphadenectomy to complete macroscopically visible peritoneal implant excision. Optimal cytoreductive surgery was performed. In some patients, intestinal resection, splenectomy, or hepatic metastasis resection was necessary to achieve complete cytoreduction (Table 1). Digestive anastomosis was performed after HIPEC.

Table 1. Surgical procedures.

	Patients
Surgical procedures	N	%
Pelvic lymphadenectomy	18	85.7
Aortic lymphadenectomy	18	85.7
Greater omentectomy	17	81.0
Hysterectomy	13	61.9
Bilateral oophorectomy	12	57.1
Apendicectomy	11	52.4
Small bowel resection	2	9.5
Large bowel resection	6	28.6
Right/left upper quadrant peritonectomy	7	33.3
Splenectomy	3	14.28
Gastrectomy	1	4.76
Liver resection	1	4.76
Bowel anastomosis	5

The closed abdomen HIPEC technique was performed using the PRS-1.0 Combat^® system. The efficiency of the distribution of fluids and the stability and homogeneity of the intra-abdominal temperature was demonstrated previously by our group in an experimental study using a pig model [5].Following cytoreductive surgery, inflow and outflow catheters and the gas exchanger were placed inside the abdominal cavity; we closed only the abdominal skin for the HIPEC procedure. The HIPEC device possessed four multi-perforated catheters, two placed in the upper abdomen (chemotherapy infusion) and two in the lower abdomen (fluid aspiration and CO₂ infusion), with two roller pumps and a gas exchanger at the top of abdominal cavity. Chemotherapy with the perfusion solution at 42 °C and CO₂ flowed into the abdominal cavity; turbulent flow was created to improve the drug distribution. The peritoneal dialysis solution contained 1.36% glucose and 25 mmol/L bicarbonate and 175 mg/m² paclitaxel. HIPEC was performed for 60 min. In the animal study by our group, the CO₂ infusion created turbulent flow inside the abdominal cavity, which separated all visceral faces and provided homogeneous drug distribution. In the pilot study we could not measure temperature by probe, and we only performed the same HIPEC procedure. In all cases, turbulent flow was created and there were no technological disruptions. After treatment the skin was opened and the abdominal cavity was washed and closed. All patients stayed in the intensive care unit (ICU) for the first 2–3 days.

The Sugarbaker score, i.e. the PCI, was used to define peritoneal carcinomatosis on the CT scan and during the surgical procedure. The completeness of cytoreduction (CCR-0) was defined as no macroscopic tumours. NCI-CTCAE version 4.0 was used to define the morbidity classification. The intra-abdominal temperature was evaluated using inflow and outflow temperature probes, as well as using a thermographic camera (FLIR E4,0BX, FLIR System, Kent, UK). Images were obtained during HIPEC; homogeneous colours in the thermographic images indicate a homogeneous intra-abdominal temperature. Blood samples, coagulation and arterial blood gases were taken at three time points: baseline, before HIPEC, and at the end of the procedure. The haemodynamic data were analysed at three time points during the HIPEC procedure: pre-HIPEC intra-HIPEC (at 30 min), and immediately post-HIPEC.

Statistical analysis was performed using SPSS for Windows software (version 19.0, IBM, Armonk, NY). Repeated measures analysis of variance was used to compare the means of quantitative variables taken over time from the same patient. The assumptions of normality, homoscedasticity and independence were checked, and the Friedman test was used for non-parametric data. For qualitative variables, the chi-square test was used. Differences were considered statistically significant when p < 0.05.

Results

Between November 2011 and March 2014, 21 patients with advanced epithelial ovarian cancer were included in the study. The mean age was 55.57 years (range 40–84 years). Hypertension was the most common co-morbidity (52.4% of cases, 11 patients), followed by diabetes (19% of cases, four patients). Six patients (28.6%) had previous abdominal surgery. Of the 21 patients included in the study, 16 cases (76.19%) were diagnosed with primary epithelial ovarian cancer, and five cases (23.8%) were diagnosed with recurrent ovarian epithelial cancer. FIGO stage III was the most common stage in the series (12 patients, 57.14%). Neoadjuvant chemotherapy was administered in five patients (23.8%) with carboplatin and Taxol in all cases. The PCI established by preoperative PET-CT showed considerable variability. The highest PCI was 17 (range 0–39). In 38.8% of cases the PCI by CT was greater than 10, and in 61.9% of patients the PCI by CT was less than 10. Patients with a PCI by CT lower than 10 had a higher PCI during surgery (PCI > 10). The mean time of surgery was 7 h (444.52 ± 70.74 min). The mean ICU stay was 3 days (± 1.6) and the mean hospital stay was 13.55 days (± 9.5). The analytical data collected during the procedure are shown in Table 2. There were statistically significant differences in all of the parameters studied (except for pCO₂) between baseline laboratory values (before surgery, basal) and the values before HIPEC (pre-HIPEC). Statistically significant differences in bicarbonate (HCO₃) and lactic acid values were found; this difference was observed between pre-HIPEC and post-HIPEC. Haemoglobin, haematocrit, prothrombin activity, pH, and pCO₂ did not change after HIPEC administration. Haemodynamic parameters showed a slight increase in cardiac output and decreased peripheral vascular resistance in relation to the hyperdynamic controlled situation (Table 3).

Table 2. Blood data collected during the procedure.

	Basal	Pre-HIPEC	p*	Post-HIPEC	p**
Haemoglobin (mg/dL)	12.014 ± 0.363	9.257 ± 0.423	<0.001	9.848 ± 0.380	0.356
Haematocrit (%)	35.79 ± 1.009	28.69 ± 1.327	<0.001	30.043 ± 1.128	0.492
Prothrombin activity (%)	94.85 ± 2.017	75.695 ± 3.376	<0.001	74.30 ± 2.874	0.605
pH	7.413 ± 0.007	7.333 ± 0.13	<0.001	7.299 ± 0.15	0.107
HCO3 (mmol/L)	23.671 ± 0.432	20.633 ± 0.599	<0.001	18.100 ± 0.555	<0.001
pCO2 (mmHg)	36.810 ± 0.709	37.619 ± 0.866	0.424	39.571 ± 1.273	0.202
Lactic acid (mg/dL)	11.952 ± 1.328	16.714 ± 2.298	0.022	32 ± 3.345	<0.001

Basal, basal line (before surgery); Pre-HIPEC, at the end of cytoreductive surgery, and before HIPEC administration; Post-HIPEC, at the end of HIPEC administration.

Mean and standard variations are shown.

*p-value between basal and pre-HIPEC data.

**p-value between pre-HIPEC and post-HIPEC data.

Table 3. Haemodynamic data collected during the procedure.

	Pre-HIPEC	Intra-HIPEC	p*	Post-HIPEC	p**
SVV, %	14.137 ± 1.191	14.842 ± 0.794	0.603	14.368 ± 1.05	0.698
GEVI, mL/m^2	646.737 ± 31.745	643.158 ± 25.21	0.787	653.263 ± 25.25	0.714
CPI, L.min^−2	4.13 ± 0.033	4.26 ± 0.035	0.653	5.50 ± 0.04	0.013
Cardiac index, L.min^−1.m ^−2	3.4 ± 0.7	2.8 ± 0.5	0.03	3.2 ± 0.8	0.21
ELWI, mL/kg	9.126 ± 0.509	8.505 ± 0.382	0.078	9.874 ± 0.809	0.101
ITBI, mL/m^2	1207.9 ± 73.823	1157.8 ± 38.278	0.412	1556.9 ± 69.027	0.985
SVRI, dyn/cm^−5/m^2	2098.471 ± 225.013	1909.94 ± 139.79	0.430	1572.765 ± 116.251	0.02
Heart rate, bpm	74.4 ± 4.28	81.1 ± 4.89	0.079	86.6 ± 4.78	0.412
Blood temperature, °C	34.863 ± 0.227	37.437 ± 0.259	<0.001	36.332 ± 0.34	0.011
Oesophageal temperature, °C	34.6 ± 1.1	37.4 ± 0.5	0.001	35.9 ± 1.1	0.001

SVV, stroke volume variation; GEVI, global end-diastolic volume index; CPI, cardiac performance index; ELWI, extravascular lung water index; ITBI, intrathoracic total blood index; SVRI, systemic vascular resistances index; Pre-HIPEC, at the end of cytoreductive surgery, and before HIPEC administration; Intra-HIPEC, at 30 min of HIPEC administration; Post-HIPEC, at the end of HIPEC administration.

Mean and standard variations are shown.

*p-value between basal and intra-HIPEC data.

**p-value between intra-HIPEC and post-HIPEC data.

Grade III/IV complications occurred in 38.1% and grade I/II complications occurred in 57.14% of patients (Table 4). The most frequent complications were infectious (27.27%, four cases of wound infection, a case of intra-abdominal collection treated with percutaneous drainage and one case of pneumonia) and haematological complications (22.7%) (anaemia and neutropenia). Respiratory complications occurred in 18.18% of cases; two patients had pleural effusion (thoracic drainage was necessary in one case), and one patient had an upper respiratory infection. Urological complications were observed in 18.18% of cases (pre-renal failure and urinary tract infection). Finally, 13.6% of patients had some gastrointestinal complications (post-operative ileus, nausea, or vomiting). Post-operative mortality was 4.76% (one case) due to acute respiratory distress caused by a pulmonary embolism on post-operative day 9.

Table 4. Serie morbidity.

	Grade (NCI-CTCAE 4.0)
Systems	I	II	III	IV	Total
Haematological					5
Anaemia	1	2
Leucopenia			1
Intra-abdominal bleeding			1
Infection					6
Wound infection	1		3
Intra-abdominal infection			1
Pneumonia			1
Gastrointestinal					3
Ileus			1
Nausea/vomiting		2
Genito-urinary					4
Acute renal failure	2
Urinary bleeding	1
Acute renal infection			1
Pulmonary					4
Upper respiratory infection		1
Pleural effusion	1
Endothoracic drain			1
Respiratory distress				1
Total	6	5	10	1	22

Discussion

Intraperitoneal (IP) chemotherapy given after complete cytoreductive surgery provides increased overall survival and disease-free survival in patients with advanced or recurrent primary ovarian cancer (FIGO stages III/IV), compared with systemic chemotherapy [1,6,7). There are many different IP treatment regimens for ovarian cancer, not only in the selection of patients, but also in cytotoxic agent (cisplatin, paclitaxel, etoposide, or carboplatin). Several studies have investigated paclitaxel-IP under normothermia. In 2013, Landrum et al. [8] published the main results of prognosis factors regarding overall survival (OS) and progression-free survival (PFS) compared IP chemotherapy vs. IV chemotherapy for ovarian cancer. The median OS for IP chemotherapy patients was 61.8 months vs. 50.9 months for IV chemotherapy patients (p = 0.046). The median PFS for IP chemotherapy patients was 24.9 months vs. 20.2 months for IV chemotherapy patients (p = 0.018) [8].

The most significant difference was shown by the GOG-172 (Gynecologic Oncology Group), published in 2006 by Armstrong et al. [9], who compared long-term survival in peritoneal carcinomatosis from epithelial ovarian cancer (EOC) inpatients treated with intravenous (IV) therapy (paclitaxel 175 mg/m² and cisplatin 35 mg/m²) and IV + IP therapy (paclitaxel 135 mg/m² IV + paclitaxel 60 mg/m² IP + cisplatin 100 mg/m² IP). A significant survival improvement was found in the IV + IP patients compared to IV patients (overall survival of 65.6 months vs. 49.7 months, OR 0.75, p = 0.008). In the IP group, treatment was completed in only 42%, due to intra-abdominal catheter complications and chemotherapy toxicity (high dose cisplatin).

The benefit of hyperthermia in intraperitoneal chemotherapy is due to a cytotoxic effect in tumour cells. Intra-abdominal temperatures between 41–43 °C can induce apoptosis and direct DNA damage in tumour cells. Hyperthermia also enhances the cytotoxic effect of the chemotherapy agent. In ovarian cancer, paclitaxel has been used in intraperitoneal and intravenous chemotherapy by many groups, and this is the ideal cytotoxic agent in ovarian cancer, along with platinum agents. The taxane group (paclitaxel and docetaxel) have the highest molecular weight of all of chemotherapy agents (853.9 and 861.9 Daltons, respectively), and a good area under the curve ratio, so they are one of the best agents to be used in intraperitoneal chemotherapy. Paclitaxel has been used under hyperthermic conditions by some groups [10–14). In those studies, the authors have shown the efficacy and safety of intraperitoneal hyperthermia with paclitaxel. There are some studies that have used paclitaxel in normothermia, but there are no studies comparing both (paclitaxel hyperthermia vs. normothermia). We think that both the hyperthermia effect and the intraperitoneal paclitaxel, could improve the efficacy of oncological treatment.

The porcine model study by our group [5] showed significant heat loss with the open abdomen technique. This situation could decrease the oncological efficacy of hyperthermia. A closed abdomen technique using the PRS-1.0 Combat^® fluid and CO₂ recirculation system showed intra-abdominal thermal homogeneity and an optimal solution distribution. Turbulent flow generates an internal agitation that achieves a homogeneous drug distribution between the visceral surfaces and recesses of the abdominal cavity, due to both the catheter distribution (on the hepatic surfaces, from right to left diaphragm) and turbulent flow. In our pig model study we demonstrated heterogeneous fluid distribution into the abdominal cavity without manual agitation. The most important point in the HIPEC technique to achieve homogeneous thermal and fluid distribution is a closed cavity, a closed circuit, and optimal agitation. With our model, we did not need to manipulate the fluid, and we obtained internal agitation and an optimal fluid distribution with no staff risk and with homogeneous intra-abdominal temperatures. In a study published in the Annals of Surgical Oncology in 2010 [15], a semi-closed HIPEC technique was described in four pigs. The author obtained homogeneous intra-abdominal temperatures due to manual fluid agitation during the HIPEC process. In comparison with our experimental study, we did not need this manual agitation in the closed abdominal HIPEC group, because the turbulent flow improved solution distribution throughout the abdominal cavity. Also, in this study, despite thermal intestinal injury due to the technology used, no morbidity was observed.

This novel closed HIPEC technique, as developed in the pilot phase, could overcome the two current principal HIPEC management techniques (open or Coliseum, and closed), achieving thermal uniformity and even distribution of the drug, with little or no emission of toxic vapours.

Haemodynamic analysis

Haemodynamic alterations in patients undergoing cytoreductive surgery and HIPEC are characterised by a hyperdynamic state, determined by an increase in heart rate and cardiac output [16]. Increased body temperature or possible alterations in intra-abdominal pressure during closed HIPEC might also cause haemodynamic changes [17]. The PICCO^® [18] system used in our study offers haemodynamic monitoring by a peripheral arterial catheter and a central venous catheter. The advantages of this technology include the total volume and interstitial water measurements. Our results are similar to those of other series (the hyperdynamic state and cardiac output increases, while peripheral resistance decrease at the end of HIPEC) (Table 3).

Control of intra-abdominal pressure

With the closed HIPEC technique, some groups perform a visual abdominal filling control or use palpation of the abdominal wall to assess abdominal distension [19–21]. A novel and original device has been developed by our group to control abdominal filling during HIPEC. This gas exchanger allows us to direct pressure to control intra-abdominal filling. Additionally, the intra-abdominal turbulent flow created by the solution and CO₂ infusion can be visualised using this transparent device. This represents a safe and new procedure because it allows us to visualise any increase in intra-abdominal pressure (fluid level would rise on the Gas exchanger). Indirect methods to control intra-abdominal pressure include PICCO analysis and assessment of the cardiac volume at the end of diastole (GEDI) or cardiac preload values [22]. No statistically significant differences in cardiac preload between the three time points analysed were observed in our series (pre-HIPEC, intra-HIPEC, and post-HIPEC, Table 3). The increase in intra-abdominal pressure due to closed CO₂ HIPEC did not affect the haemodynamic function of the patient, and we could control any haemodynamic alterations if they happened to arise [23].

One factor that can improve drug penetration into the tumour is intra-abdominal pressure. An experimental animal study was performed by Gesson-Paute et al. [24] comparing two groups of animals (adult pigs). In the first group HIPEC was administered by hand-assisted laparoscopic surgery, while in the other group open abdomen HIPEC was performed. Oxaliplatin absorption was higher in the laparoscopy group compared to the open surgery group. The authors concluded that the higher intra-abdominal pressure during laparoscopy increased drug penetration into the peritoneum. Also, there is a novel HIPEC treatment, pressurized intraperitoneal aerosol chemotherapy (PIPAC), which has been used in humans recently. The PIPAC method applies aerosol chemotherapy into the abdomen for 30 min at a pressure of 12 mmHg and a temperature of 37 °C [25]. We used a CO₂ pressure of 12 mmHg as well, but at 42 °C for 60 min. We applied a controlled high pressure, similar to the pressures used during conventional laparoscopic abdominal surgery. Both methods may improve tissue chemotherapy due to the high pressure, but in a closed HIPEC and CO₂ recirculation system homogenous and optimal hyperthermia is applied, adding to the oncological thermal effect. Although we have not analysed the depth of penetration of the drug into the peritoneum, this could be a line of future research that could provide important data to this model.

The use of CO₂ can be beneficial and add an oncological effect. An experimental study by Zhou et al. [26] demonstrated that adding a CO₂ pneumoperitoneum at 15 mmHg and 42–44° for 2–4 h induced a cytotoxic effect on gastric cancer cells induced by Bax protein, causing apoptosis. Ma et al. [27] also observed a decrease in adhesion molecule expression (E-cadherin, ICAM 1, CD44 and E-selectin) in colon cancer cells after an infusion with CO₂ at a pressure of 15 mmHg, both in vitro and in vivo.

Analysis of analytical variables

Anaemia and coagulopathy are the most significant haematological abnormalities during HIPEC [28–30] (Table 4). We found significant differences between the basal and post-cytoreductive surgery values; however, no significant differences were found after the HIPEC procedure. Moderate metabolic acidosis and high lactic acid levels are two of the most frequent blood alterations after HIPEC. Heat-induced fluid losses, intravenous electrolyte infusion, and hyperdynamic hyperthermia may produce a hypermetabolic state, with increased oxygen consumption and changes in tissue perfusion [28,31]. We observed stable arterial blood pCO₂ values. This new closed HIPEC model can be applied to standard laparoscopic surgeries [32], but with a lower CO₂ volume infusion during HIPEC. Therefore, closed HIPEC with CO₂ and management technique is a reliable and safe method in gasometric terms, compared with other HIPEC techniques.

Morbidity and mortality

Major complications in our study (grade III/IV) were found in eight patients (38.1%), and minor complications (grade I/II) in 12 patients (57.14%). These results are similar to those of other studies (Table 5). Two reviews on morbidity and mortality in the treatment of peritoneal carcinomatosis of ovarian cancer origin show data from 19 and 14 studies, respectively [33,34]. The morbidity rates reported in these reviews were 0% and 40%, respectively, and the mean mortality rate of these studies was 3% (range 0 to 10%) [37]. The results of our study show inpatients where bowel resection was performed (right or left hemicolectomy), a higher frequency of paralytic ileus (p = 0.041) and wound infection (p = 0.042). Unlike other studies, there were no cases of intestinal fistula or anastomosis dehiscence in our series. We identified no other variables that might be related to a higher rate of post-operative complications.

Figure 1. Schema device of PRS-1.0 Combat^® system for closed abdomen HIPEC showing the flow direction during the procedure. A and B, roller pumps; D, gas exchanger to CO₂ recirculation and visual control of filling abdominal cavity; blue keg, abdominal cavity; green line, solution and drug inflow and outflow tubes; yellow line, CO₂ recirculation tube; black line, CO₂ inflow tube.

Figure 2. PRS-1.0 Combat^® system for closed abdomen HIPEC administration.

Table 5. Frequency of perioperative morbidity.

				Morbidity (%)a
Reference (patients)	H (hours)	HS (days)	Mortality (%)	I	II	III	IV
Pavlov et al. 2009 (N = 25) [35]	5	14	2	5	11	0	2
Fagotti et al. 2009 (N = 25) [36]	5	13	0	0	36	8	8
Bae et al. 2007 (N = 67) [12]	–	–	0	14	13	0	0
Cotte et al. 2007 (N = 81) [19]	4	17	3	6	1	5	2
Helm et al. 2007 (N = 18) [37]	10	12	6	11	50	40	13
Rufián et al. 2006 (N = 33) [14]	5	11	0	12	10	10	6
Sánchez-García et al. 2014 (N = 21) actual series	7	13	4.76	27	22	45	4

H, surgical hours; HS, hospital stay.

a Common Terminology Criteria for Adverse Events (CTCAE) classification.

One limitation of the study was the absence of a control group in the clinical phase, where haemodynamic and laboratory data are compared between the open and closed HIPEC systems, as was conducted at the experimental stage in animals [5]. Although the two phases (experimental porcine model and clinical patients) are not methodologically comparable, the animal model provided considerable information on the fluid distribution in a closed recirculating CO₂-filled cavity. Despite this, the comparison between open and closed techniques in patients could represent a new line of research to corroborate our findings.

In summary, HIPEC by a closed abdomen technique with recirculation of CO₂ for the treatment of advanced ovarian cancer (primary or recurrent) does not increase the number of post-operative complications compared with other studies. Together with the results of the experimental stage, we propose that this novel approach is the most appropriate technique for maintaining thermal uniformity in the peritoneal cavity and improving the distribution of the drug through the peritoneal surfaces. The oncological effectiveness of the technique was shown by an increase in overall survival or progression-free survival in these patients. This hypothesis was assessed after completion of the clinical trial EUDRACT 2011-006319-69, currently in development at our hospital.

Acknowledgements

Special acknowledgements go to the surgical staff who made this trial possible.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.