The Clinical Desire for Pressurized Intraperitoneal Aerosol Chemotherapy in South Korea: An Electronic Survey-based Study

Background/Aim: To evaluate the clinical desire for pressurized intraperitoneal aerosol chemotherapy (PIPAC) in South Korea. Patients and Methods: We performed an online survey on surgical oncologists between November and December 2019 using a questionnaire consisting of 20 questions. Results: A total of 164 respondents answered the questionnaire. Among those specialized in ovarian cancer, pseudomyxoma peritonei, and malignant mesothelioma 41.7-50% preferred PIPAC for the curative treatment of primary diseases, whereas 32.7-33.3% majoring in colorectal and hepatobiliary cancers chose it for the palliative treatment of recurrent diseases. Furthermore, 66.7-95.2% considered PIPAC appropriate for the cancers they specialized in, and 76-78.7% expected a treatment response of more than 50% and considered grade 1 or 2 complications acceptable. Most respondents answered the reasonable costs to purchase and implement PIPAC once at between 1,000,000-5,000,000 South Korean Won (KRW). Conclusion: Most Korean surgical oncologists expected relatively high tumor response rates with minor toxicities through the repeated implementation of PIPAC.

Peritoneal metastasis (PM) is commonly accompanied by a variety of solid tumors showing drug resistance to intravenous (IV) chemotherapy, which leads to a poor prognosis (1)(2)(3). To try to overcome the limitations of IV chemotherapy, the effects and safety of intraperitoneal (IP) chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) have been investigated in solid tumor patients with PM. However, the effects of these therapies are still controversial (4)(5)(6)(7), and renal and hepatic toxicities, a lack of relevant IP administration cycles, and the required one-time administration after cytoreductive surgery are considered as disadvantages in IP chemotherapy and HIPEC (8).
On the other hand, pressurized intraperitoneal aerosol chemotherapy (PIPAC) delivers chemotherapeutic agents as an aerosol formed by a high-pressure injector at room temperature. Chemotherapeutic agents equivalent to 10% of those used in IV chemotherapy are effectively spread diffusely throughout the abdominal cavity by PIPAC, but tissue concentration is maintained up to 200 times that of IV chemotherapy (9). Moreover, PIPAC can be conducted repeatedly with more diffuse distribution, deeper penetration, and fewer toxicities than IP chemotherapy and HIPEC (10,11). Nevertheless, PIPAC is currently considered primarily a  (12), and is only available in the limited areas including European countries and Singapore (13). A survey evaluating the clinical application and scope of PIPAC in countries where PIPAC has not been introduced is essential to establish the required medical foundation for future introduction. Thus, we performed a survey of surgical oncologists related to PIPAC to evaluate the clinical desire for PIPAC in South Korea.

Patients and Methods
Participation. This study was approved by the Institutional Review Board of Seoul National University Hospital in advance (No. 1907-054-104), granting an exemption from requiring written informed consent. We surveyed surgical oncologists from the following four societies between November and December 2019: the Korean Society of Gynecologic Oncology (14); the Korean Society of Surgical Oncology (15); the Korean Surgical Society  (Table I).
Statistical analysis. This survey was performed via the Elimnet Corporation (18), a commercially available web-based survey platform. All categorical variables were analyzed using the Chisquared or Fisher's exact test. For the statistical analyses, we used SPSS software version 21.0 (SPSS Inc., Chicago, IL, USA).
About 60% of the respondents had more than ten years of experience and worked at university hospitals. Moreover, about 40% of the respondents said they treated more than ten solid tumor patients with PM annually and undertook a multidisciplinary treatment approach. However, there were no differences in periods of experience, working hospitals, and numbers of patients treated annually among the various surgical oncologists. In terms of treatment approach, the respondents majoring in gastric cancer (41.8%), colorectal cancer (50%), pseudomyxoma peritonei (37.5%), and hepatobiliary cancer (33.3%) preferred the multidisciplinary approach. In contrast, those majoring in ovarian cancer (33.9%) and malignant mesothelioma (44.4%) chose to plan their treatment by themselves (Table II).
Procedure inquiry. In relation to the course of disease progression and the suitable point for PIPAC, 41.7-50% of respondents specialized in ovarian cancer, pseudomyxoma peritonei, and malignant mesothelioma preferred PIPAC as a curative treatment for primary diseases, whereas 32.7-33.3% of those majoring in colorectal and hepatobiliary cancers preferred PIPAC as a palliative treatment for recurrent diseases.
Moreover, 65.5% of respondents answered that advancedstage disease among primary diseases was suitable for applying PIPAC and 55.2% would consider neoadjuvant chemotherapy before PIPAC. In particular, 66.7-95.2% of respondents answered that the cancers they majored in were appropriate for PIPAC, and 87.2% considered the advantages of high concentration in tissues and lower toxicity as decisive factors for choosing PIPAC. However, 65.5% of respondents considered results from randomized trials prerequisite for introducing PIPAC. Approximately 70% of respondents stated that they expected a treatment response of more than 50% through repeated implementation of PIPAC, and that grade 1 or 2 minor surgical complications were acceptable. About 60% of respondents answered that the patient's general status was the most important factor hindering the effect of PIPAC, and that the current level of evidence for the therapeutic effects of PIPAC was low.
However, there were no differences in the extents of primary diseases considered suitable for PIPAC treatment, the potential need for neoadjuvant chemotherapy, the decisive factors for using PIPAC, the prerequisites for introducing PIPAC, types and severities of tolerable complications, acceptability for implementing PIPAC under general anesthesia, and the expected percentage of treatment response among the various surgical oncologists (Table III).
Cost inquiry. Most respondents answered that the reasonable cost to purchase and implement PIPAC once was between 1,000,000-5,000,000 South Korean Won (KRW). There were no differences in the reasonable expenses to purchase and implement PIPAC among the various surgical oncologists (Table IV).

Discussion
This study was conducted to evaluate the clinical desire for PIPAC in South Korea, one of the countries where PIPAC has not yet been introduced. Through our survey, we identified the potential availability and scope of PIPAC, the expected effects and toxicity, and the expected reasonable cost of PIPAC in South Korea.
Although PIPAC is readily used to treat PM in Europe, its use does not come without concerns. First, the relevant studies are heterogeneous concerning patients and clinical indications. Second, the assessments of treatment response differed considerably among the relevant studies. Third, the appropriate endpoints to evaluate the effect of PIPAC, such as survival, quality of life, and ascites control are ambiguous (12). In the absence of randomized controlled trials, the clinical desire for PIPAC is expected to differ according to the medical environment of each country.
We found that the availability and scope of PIPAC were different among different types of Korean surgical oncologists. Many respondents majoring in ovarian cancer, pseudomyxoma peritonei, and malignant mesothelioma preferred PIPAC for the curative treatment of primary diseases. In contrast, those majoring in colorectal and hepatobiliary cancers chose PIPAC for the palliative treatment of recurrent diseases. These findings are similar to the results from studies related to IP chemotherapy and HIPEC. In these studies, IP chemotherapy and HIPEC improved the prognosis of ovarian cancer (6, 7), pseudomyxoma peritonei (19,20), and malignant mesothelioma (21,22). In contrast, they did not show any definitive effects for treating colorectal and hepatobiliary cancers (4,23). This suggests that Korean surgical oncologists may consider applying PIPAC in conditions similar to those that warrant IP chemotherapy and HIPEC.
Despite these differences, 66.7-95.2% of respondents considered the cancers they majored in appropriate for PIPAC. Moreover, about 70% expected a treatment response of more than 50% through repeated implementation of PIPAC and considered grade 1 or 2 minor surgical complications acceptable. These findings are in line with data from previous studies where the rate of clinical response was 36-80% and grade 3 or 4 adverse events were observed in only 12-15% of procedures (12). These data suggest that the medical needs of Korean oncologists prior to the introduction of PIPAC are likely similar to those of their European counterparts.
Furthermore, what was considered a reasonable cost to purchase and implement PIPAC once was between 1,000,000-  All studies have limitations and ours is no exception. First, the number of specialists who could reply appropriately to this survey from each society could not be confirmed due to the Personal Information Protection Act. Considering the email was sent to all members including residents, general doctors, and specialists, we could not estimate the response rates of only specialists in this study. Second, this survey was Possible regardless of 6 (3.7) 0 (0) 3 (5.5) 2 (3.8) 2 (4.2) 1 (3.7) 0 (0) 0 (0) complications Impossible regardless of conducted exclusively on surgical oncologists. For more meaningful results, the survey should also be performed on medical oncologists who treat solid tumors with PM. Third, it may be unreasonable to consider these results similar to those from other countries where PIPAC has not been introduced because the medical environment may be very different. This is the first study to investigate the clinical desire for PIPAC in countries where PIPAC has not yet been introduced. Based on the results from this study, we believe that the introduction of PIPAC will help to further establish the availability, scope, and reasonable cost of PIPAC treatment.

Conflicts of Interest
All Authors have no conflicts of interest to declare in relation to this study.