Peritoneal carcinomatosis is important because it is found in many patients with gastrointestinal or gynecological carcinoma. For example, in gastric cancer, peritoneal carcinomatosis is the most common type of first recurrence and the most common cause of death [1, 2]. In addition, there are many patients with gastric cancer who have risk factors for peritoneal carcinomatosis: serosa exposure, other organ invasion, cancer perforation, and positive peritoneal lavage cytology [3].

However, there are no definitive treatment guidelines for peritoneal carcinomatosis [4]. Many treatment methods have been tried in patients with peritoneal carcinomatosis, including cytoreductive surgery (CRS), radiotherapy, systemic chemotherapy, intraperitoneal chemotherapy (IPC), and combination therapy. However, no treatment method has significant superiority or effectiveness over the others.

Theoretically, IPC can achieve greater drug exposure in the peritoneal nodules compared with the plasma [5]. Therefore, various types of IPC have been introduced according to temperature or timing: normothermic IPC, hyperthermic IPC (HIPEC), early postoperative IPC, and delayed postoperative IPC [6]. HIPEC following CRS improved survival significantly in peritoneal carcinomatosis of colorectal and gastric origin [7, 8].

However, HIPEC has two significant pharmacokinetic problems: limited penetration into peritoneal nodules and limited intraperitoneal drug distribution [9]. To overcome these two limitations, Solass et al. [10, 11] developed pressurized intraperitoneal aerosol chemotherapy (PIPAC). PIPAC showed significantly improved distribution and penetration of methylene blue into the peritoneal cavity in a preclinical experiment [10]. After that, they showed the safety and utility of PIPAC in human patients: high local concentration and low systemic exposure [11–13].

However, PIPAC does not have the advantage of hyperthermia [6]. Hyperthermic aerosols might have the antitumor effect of hyperthermia, as in HIPEC. However, it is more difficult to make hyperthermic gas and maintain its temperature than to make hyperthermic liquid and maintain its temperature, because the temperature of gas, which has lower density, can change easily and rapidly.

We have developed a device for hyperthermic pressurized intraperitoneal aerosol chemotherapy (H-PAC), which uses the improved distribution and penetration of pressurized aerosol and the superior antitumor effect of hyperthermia. The aims of the present study were to develop a device that can make hyperthermic gas and maintain its temperature stably, and to evaluate the feasibility and safety of H-PAC in a porcine model. The present preclinical study is believed to be the first study of H-PAC in a porcine model.

Materials and methods

Development of new device

The H-PAC device consisted of a laparoscopic spray nebulizing aerosol and a heater to create hyperthermic capnoperitoneum. An aerosol containing chemotherapeutic agents was nebulized by a laparoscopic aerosol spray (Fig. 1). It used CO2 gas, which is commonly used in laparoscopic surgery. The apparatus for hyperthermic capnoperitoneum consisted of heating units that increased the temperature of CO2 gas, a CO2 gas delivery line covered with a heating line, and a temperature monitor unit (WooGun ENG, Gyenggi-do, Korea; Fig. 2A). The heating units consisted of four heaters that heated the water to 52 °C. CO2 gas gained heat by passing through this heated water, and its temperature increased to 37.5 °C. A CO2 gas delivery line covered with a heating line had the most important role because CO2 gas lost heat easily and rapidly during delivery from the device to the porcine model (Fig. 2B). It increased the temperature of the CO2 gas from 37.5 to 40 °C. A temperature-monitoring unit was located at the outflow pipe of the heating units where the CO2 gas delivery line connected to the heating units (Fig. 2C).

Fig. 1
figure 1

Laparoscopic aerosol spray

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Fig. 2
figure 2

A A heater to create hyperthermic capnoperitoneum, B a CO2 gas delivery line covered with a heating line, C a temperature-monitoring unit was located at the outflow pipe of the heating units where the CO2 gas delivery line connected to the heating units

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Animal

After receiving authorization of the Institutional Animal Care and Use Committee (IACUC; No. BA1408-159/044-01), we operated on five pigs for development of the new device and on another five pigs as a survival model, to evaluate the feasibility and safety of laparoscopy-assisted distal gastrectomy (LADG) followed by H-PAC. All pigs were female and weighed 35–40 kg.

In the survival model, a pilot experiment (Pig A) was performed to check the experimental protocol, which consisted of the operation, hyperthermic pressurized capnoperitoneum, postoperative care for 7 days, and autopsy. After the pilot experiment, the first-stage experiment was performed to evaluate the feasibility and safety of hyperthermic capnoperitoneum. A hyperthermic pressurized intraperitoneal aerosol of indocyanine green (ICG) was administered after insertion of three trocars (Pig B) and LADG (Pig C), without chemotherapeutic agents. After the success of the first-stage experiment, the second-stage experiment was performed to evaluate the feasibility and safety of hyperthermic chemotherapeutic agents. In the second-stage experiment, H-PAC with cisplatin was administered after insertion of three trocars (Pig D) and LADG (Pig E). Autopsies were performed on postoperative day 7.

Experimental protocol 1: in vivo test of new device

In the five pigs for device development, three trocars were inserted under pneumoperitoneum of 12 mmHg (Fig. 3A). The laparoscope was inserted through the first, 12-mm trocar located beneath the umbilicus. Hyperthermic CO2 gas was infused through the first trocar (Fig. 3B). After exploration of the intra-abdominal cavity, the laparoscope was moved to the second, 12-mm trocar located at the right upper abdomen. Circulating CO2 gas was extracted through the second trocar. A laparoscopic aerosol spray was administered through the first trocar to spray the entire intraperitoneal cavity because the trocar was located at the center of the abdomen (Fig. 3C). For the laparoscopic aerosol spray, we decided that the amount of solution (diluted ICG or cisplatin) was 150–250 mL, after reviewing previous studies [11, 12]. An esophageal temperature probe for monitoring the intraperitoneal temperature was inserted through the third, 5-mm trocar located at the left lower abdomen. The intraperitoneal pressure was controlled by the Stryker Laparoscopy System. Autopsies were performed immediately at the end of the experiment.

Fig. 3
figure 3

A Three trocars were inserted under pneumoperitoneum of 12 mmHg. B Hyperthermic CO2 gas was infused through the first, 12-mm trocar located beneath the umbilicus. C A laparoscopic aerosol spray was administered through the first trocar to spray the entire intraperitoneal cavity

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Experimental protocol 2: survival model

Three trocars were inserted without any operative procedures in two Pigs (B and D) to reduce the influence of LADG. LADG was performed in the same way as in humans in Pigs A, C, and E [14]. The range of the lymph node dissection was D1+. The type of anastomosis was gastroduodenostomy. The temperature of the intraperitoneal cavity reached 40 °C after 30-min infusion of hyperthermic CO2 gas. One vial of ICG (25 mg) was diluted in 150 mL normal saline (0.9 % NaCl). Cisplatin (25 mg, 50 mL) was diluted in 150 mL normal saline (0.9 % NaCl). Diluted ICG (Pigs A–C) or cisplatin (Pigs D and E) was nebulized under hyperthermic capnoperitoneum of 40 °C and intra-abdominal pressure of 12 mmHg. Hyperthermic pressurized capnoperitoneum (40 °C, 12 mmHg) was maintained for 1 h after infusion. The used ICG or cisplatin aerosol was disposed in a waste water bottle, comprising a closed system [15]. Autopsy was performed on postoperative day 7.

Results

Device development (Table 1)

Before the porcine model test, many ex vivo tests were performed successfully in the industrial laboratory of WooGun ENG.

Table 1 Summary of in vivo tests for new device development
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We failed to develop the laparoscopic aerosol spray in the first in vivo test because of low pressure of CO2. We successfully developed the laparoscopic aerosol spray in the second test after using a thicker CO2 line that maintained a high pressure of 40 mmHg. We found that a conventional laparoscopic CO2 line was suitable.

The first and second in vivo tests failed because the temperature of CO2 gas was not increased easily and rapidly. After adding two more heating units to the existing two units, the temperature of CO2 gas was increased satisfactorily in the third test. However, the CO2 gas lost heat easily during delivery from the device to the porcine model. In the fourth test, covering the CO2 gas delivery line with a heating line maintained the gas temperature. However, the heating line covering the CO2 gas delivery line was not cooled immediately. After the temperature controller was added to the heating line, the temperature of CO2 gas decreased immediately in the fifth test.

Survival model (Table 2)

In the pilot experiment, the time of anesthesia, LADG, and hyperthermic ICG aerosol infusion was 30, 110, and 90 min. The intraperitoneal temperature was 38.8–40.2 °C. Widespread staining with ICG was observed throughout the intraperitoneal cavity. This pig could drink water, eat food, sleep, and survive for 7 days. Autopsy showed that the wound, anastomosis site, and tissue ultrastructure were intact.

Table 2 Summary of survival model for evaluating the feasibility and safety of H-PAC
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Including the pilot experiment, the median operation time for LADG was 85 min (80–110 min). Hyperthermic gas was infused for 30 min before administration of the aerosol spray in all five survival model pigs. Aerosol spray time was <5 min. After administration of the aerosol spray, hyperthermic gas was infused for 1 h. The lowest temperature of the intraperitoneal cavity was 38.7 °C and the highest was 41.0 °C.

Including the pig in the pilot experiment, all five pigs were given water on postoperative days 1 and 2. They all could drink well from postoperative day 2. They all received normal feeding from postoperative day 3. Median weight loss was 0.2 kg (0–0.5 kg). They all slept well and survived for 7 days. Autopsies were performed on postoperative day 7. Their wound and anastomosis site were completely healed. No microscopic thermal injury or excessive inflammation was observed in tissues from the stomach, peritoneum, and jejunum.

Discussion

Peritoneal carcinomatosis is a fatal condition in all types of malignancies. Many patients have peritoneal carcinomatosis at the time of initial diagnosis or at diagnosis of recurrence after curative-intent surgery and chemotherapy [1, 2]. However, there are no standard treatment guidelines for peritoneal carcinomatosis [4]. Recently, HIPEC following CRS showed survival benefits [7, 8]. Theoretically, improved types of HIPEC might help to treat peritoneal carcinomatosis. The purpose of the present study was to develop improved methods of IPC. For this purpose, we developed a device that created hyperthermic capnoperitoneum and maintained a steady temperature for H-PAC, and evaluated the feasibility and safety of H-PAC in a porcine model.

Before the porcine model test, many ex vivo tests were performed in the industrial laboratory of WooGun ENG. However, we found that the environment of the industrial laboratory differed greatly from that of a hospital operating room or animal laboratory. For example, the electrical power of the industrial laboratory was stronger, and the temperature was higher than those in a hospital operating room or animal laboratory. Engineers of WooGun ENG made this device operate effectively under strong electrical power and high temperature. Therefore, we modified this device to operate effectively under the weaker hospital electrical power and lower temperature. Collaboration between engineers and doctors needs more consideration and discussion than the environment does.

During the development of the heating apparatus, the heating line covering the CO2 gas delivery line became the most important feature. When the CO2 gas delivery line was covered by a line that did not create heat, it was not possible to maintain the temperature of the CO2 gas. The heating line increased the temperature of the CO2 from 37.5 to 40 °C. After adopting the heating line, the four heating units caused overheating of the intraperitoneal cavity in the fourth in vivo experiment. If the heating line had been incorporated before adding two more heating units, the extra units would not have been needed.

The survival model showed that the heating apparatus created and maintained hyperthermic capnoperitoneum for 90 min at a steady temperature of 39.0–41.0 °C. In fact, this apparatus might be expected to maintain hyperthermic capnoperitoneum for >3 h because it was applied to two pigs consecutively on the same experimental day. The survival model also showed that surgical wound, anastomosis, postoperative status, and survival status were not affected significantly by hyperthermic pressurized capnoperitoneum and H-PAC.

IPC has theoretical benefits over systemic chemotherapy in treating peritoneal carcinomatosis: high local concentration of chemotherapeutic agents and few systemic side effects [5]. Combined CRS and HIPEC against peritoneal carcinomatosis of colorectal, gynecological, and gastric origin appear to be superior to other treatment methods [7, 8, 16]. Solass et al. developed PIPAC, which might be superior to HIPEC in theory. PIPAC was shown to be superior to HIPEC in terms of distribution and penetration into the peritoneal cavity in an animal model [10]. PIPAC showed high local concentration and low systemic exposure using 10 % of the usual systemic dose [11, 12]. We added the benefits of hyperthermia to the efficacy of PIPAC.

In addition, neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) was effective and well tolerated in patients with advanced gastric cancer and peritoneal carcinomatosis [17]. In this NIPS chemotherapy, H-PAC might be the best type of IPC because H-PAC used the improved distribution and penetration of pressurized aerosol of PIPAC and also the superior antitumor effect of hyperthermia of HIPEC. H-PAC could be used many times easily before or after surgery.

We tried to improve HIPEC and PIPAC. Similar to our effort to improve HIPEC, many surgeons have tried to improve CRS, which has low morbidity and high survival rates [18]. Shin et al. reported feasibility of complete mesocolic excision with D3 lymph node dissection in laparoscopic colectomy [19]. Kim et al. presented several cases of laparoscopic total gastrectomy with D3 lymph node dissection (10th International Gastric Cancer Congress). Minimally invasive CRS has been improved by using better laparoscopic instruments, high-resolution laparoscopes, and well-trained laparoscopic surgeons [20]. Therefore, laparoscopic CRS with H-PAC might be a better option than CRS with HIPEC. In addition, HIPEC should be applied after surgery in CRS with HIPEC. H-PAC can be used during laparoscopic CRS with H-PAC, which could save 90 min.

This study had several limitations. First, the heating apparatus was made by an engineer for evaluating hyperthermic capnoperitoneum, and it was large and rough. In addition, it was revised many times, which increased its size. It is difficult to adapt such a large piece of equipment to the operating room. This apparatus should be adapted to make it suitable for human application, using our experiences like the heating line for maintaining CO2 gas temperature. Second, we did not evaluate the better distribution and penetration of hyperthermic pressurized capnoperitoneum. We adapted the results of Solass et al. with PIPAC, which confirmed the superior distribution and penetration of PIPAC, because we should follow the 3R principles of animal experimentation, especially reduction. We decided that the results of Solass et al. [10] with PIPAC could be acceptable because they were comprehensive theoretically. Third, we could not apply our results to humans directly. After we revise the machine for sterilization and decide upon the indications for H-PAC and doses of chemotherapeutic agents, we need to receive the approval of the Korean Ministry of Food and Drug Safety for use as a medical device. Solass et al. [11] showed that low-dose doxorubicin had a high concentration in the aerosol compared with HIPEC. We should evaluate the dose of chemotherapeutic agents for humans.

Steady hyperthermic pressurized capnoperitoneum was created by the heating apparatus developed in this study. H-PAC was feasible and safe in the porcine survival model. This could represent significant progress in treating peritoneal carcinomatosis.