Practice patterns, attitudes, and knowledge among clinicians regarding hyperthermic intraperitoneal chemotherapy and pressurized intraperitoneal aerosol chemotherapy: a national survey by Indian society of peritoneal surface malignancies (ISPSM)

Abstract Objectives Perception of cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and pressurized intraperitoneal aerosol chemotherapy (PIPAC) for treating peritoneal surface malignancies (PSM) differ widely among physicians. Methods This on-site survey performed during a major oncology congress in 2019 evaluated the current opinion, perceptions, knowledge and practice of HIPEC and PIPAC among oncologists in India. Results There were 147 respondents (gynecologists (30%), surgical oncologists and gastrointestinal surgeons (64%), and medical oncologists (6%)). Whereas most respondents considered CRS and HIPEC an appropriate therapeutic option, 25% would not recommend CRS and HIPEC. The main barriers to referral to an expert center were inaccessibility to such a center (37.8%), non-inclusion of CRS and HIPEC in clinical practice guidelines (32.4%), and a high morbidity/mortality (21.6%). Variations were found in the various practice patterns of CRS/HIPEC like eligibility criteria, HIPEC protocols and safety measures. Although PIPAC awareness as a novel therapeutic option was high, only a limited number of centers offered PIPAC, mainly because of non-access to technology and missing training opportunities (76.2%). Conclusions Lack of widespread acceptance, poor accessibility and low utilization presents a significant challenge for HIPEC and PIPAC in India. There is a need to raise the awareness of curative and palliative therapeutic options for PSM. This might be achieved by the creation of expert centers, specialized training curricula and of a new sub-speciality in oncology.


Introduction
Peritoneal surface malignancies (PSM) represents a special locoregional disease pattern limited to the abdominal cavity and has traditionally been considered a death sentence by the medical fraternity due to the very poor prognosis and dismal survival of 6-12 months [1,2].
The multimodality treatment of cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) combines radical surgery with circulation of heated chemotherapy in the peritoneal cavity. This is a therapeutic option showing improved outcomes and quality of life compared to standard systemic chemotherapy for appropriately selected patients with PSM. It has been proposed as a treatment option in patients with peritoneal metastasis of colorectal, ovarian, gastric cancers and sarcomas and as a standard treatment for pseudomyxoma peritonei and peritoneal mesothelioma [3][4][5][6][7][8].
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique delivering normothermic chemotherapy into the abdominal cavity by laparoscopy as an aerosol under pressure. This concept seems to enhance the effectiveness of intraperitoneal chemotherapy by taking advantage of the physical properties of gas and pressure by generating an artificial pressure gradient and enhancing tissue uptake and distributing drugs homogeneously within the closed and expanded peritoneal cavity. Recommendations of operative technique, safety checklist and treatment protocols are well established [9][10][11][12].
Although the number of specialist centers for PSM in India is increasing, there seems to be two main challenges. Some clinicians still have nihilistic attitude to this disease and still adopt palliative treatment. While in others, who are aware of curative options there exist a lack of acceptance, utilization and a wide variability in management. It is imperative to evaluate the perceptions and opinions of this complex disease among the oncological fraternity. [7,8,13].
The aim of this survey-based study was to evaluate factors influencing referral choices, utilization of CRS and HIPEC, assess current practices and knowledge of the specialists that influence treatment for PSM [14,15].

Materials and methods
The survey was submitted to the attendees of the International conference of European Society of Surgical Oncology (ESSO) and Indian Society of Peritoneal Surface Malignancy (ISPSM) at TATA memorial cancer center, Mumbai on April 19th-21st, 2019. There were 228 delegates who attended the annual conference out of which 147 participated in the survey. The participants of the survey were super specialists involved in treating PSM regularly. The survey consisted of an independently developed 33 multiple choice questionnaires. The questionnaire was pilot-tested among the oncologists within our institution for assessment and changes were made based on feedback. It was divided into four parts. The first part had six items to characterize respondents; second part had six items to assess patient presentation, perioperative staging, patient selection and referral patterns. The third part had 12 questions to evaluate the patient eligibility, knowledge, surgical practice, HIPEC practices and safety measures during CRS and HIPEC. The 4th part evaluated the PIPAC related characteristics and responses.
A descriptive statistical analysis was carried out and described quantitative and qualitative data according to means (± standard deviation), medians (range) and percentages. The percentages were calculated over all the responses received for each question.

Results
We compiled and analyzed the results from 147 participants (Figures 1 and 2).
Demographic characteristics of survey respondents regarding PSM are shown in Table 1. Majority of doctors practiced in a medical college (32.6%) or private teaching institute (25.8%). Awareness regarding HIPEC treatment modality was learnt from peers or colleagues in practice (38.1%) or from scientific academic meetings (36%). More than half the doctors (53.7%) had not been involving any PSM specific treatment at the time of survey while 30.6% were working in the department which offered CRS/HIPEC. 25.9% of the respondents were actively involved in offering CRS/HIPEC to their patients and 8.2% also offered PIPAC. Close to 75% of the participants had personally never performed the procedure and only 17.4% of them had access to a surgeon with expertise in CRS and HIPEC.
Responses to questions regarding presentation characteristics, referral and practice patterns regarding CRS and HIPEC are summarized in Table 2. The most common presentation encountered by Indian physicians in clinical practice is peritoneal carcinomatosis secondary to ovarian cancer (63.2%). 58.5% diagnosed fewer than 10 patients with PSM annually. The diagnostic imaging of choice at presentation was abdominal CT scan (71.4%). Approximately 86% of respondents considered CRS/HIPEC as an appropriate therapeutic option for appendicular cancer (pseudomyxoma peritonei) and 51, 46.2, 66.7% considered it appropriate for ovarian cancer, colon cancer and peritoneal mesothelioma respectively. Interestingly 25% of the doctors surveyed indicated they would not recommend CRS/HIPEC. The most common reason was inaccessibility to an HIPEC expert (37.8%). Other factors impacting the decision not to offer the therapy was lack of level 1 evidence (27%), non-inclusion in National Comprehensive Cancer Network (NCCN) guidelines (32.4%) and associated high morbidity/mortality (21.6%). Table 3 summarizes the responses to the knowledge and safety based questions answered by experts who have performed CRS/HIPEC. Thirty-eight of our respondents had performed CRS/HIPEC and were familiar with the procedure. Most of them had started to perform the procedure recently and completed less than 10 procedures, 60.5% had received formal hands on training at a center of excellence. Poor Eastern Cooperative Oncology Group (ECOG) performance status and mesenteric invasion was an absolute contra indication. The other indications included multi organ involvement (92.1%) and frozen pelvis (78.9%). More than 80% found financial implications as an important factor for offering the procedure to the patient. More than 90% of surgeons had access to FDA approved HIPEC machine at their institution. 39.5% of the surgeons equally preferred coliseum and closed method for performing HIPEC. Some of them, 21% used the semi open method too. Most of the surgeons (73.7%) place abdominal drains routinely after HIPEC. Table 4 deals with the responses of the surgeons regarding PIPAC. Out of 147 respondents, only 12 had been trained in performing PIPAC. The most common reason for not performing PIPAC was lack of availability of capnopen and training in India (76.2%). Time interval between each PIPAC procedure was 6 weeks for 91.6% and only one center preferred eight weekly. One fourth of them combined PIPAC with concomitant systemic chemotherapy.
Regarding chemotherapy agents, the dosage varied for ovarian cancer, where two centres used the lower dosage of 7.5 mg/m 2 and 1.5 mg/m 2 , respectively.

Discussion
The ISPSM consists of over 250 members from various parts of India involved with treatment of peritoneal cancer with focus

Current scenario
There is differing approaches to PSM in India at present. Limited adoption and access of CRS/HIPEC for patients underlines the scepticism among the clinicians about its role and efficacy despite mounting evidence. Poor knowledge of procedure and benefit is one of the most important reasons for underutilization [13,16,17]. This procedure is technically challenging with high morbidity and mortality, needing an institutional setup with well-equipped OT, anaesthetic and intensive care departments. Numerous studies have demonstrated a consistent relationship between high volume centres and improved long term survival after cancer surgery [18,19]. At present in India, management of peritoneal carcinomatosis is restricted to selected specialized centres [20]. Most responders preferred abdominal CT scan as preferred method of preoperative staging. Despite its widespread use internationally, CRS with HIPEC continues to be perceived by the oncologists in India as experimental despite good evidence [3-7, 21, 22].

Acceptance and barriers
Overall, 75% of respondents regarded CRS + HIPEC as therapeutically effective, 25% responded that they are not fully convinced and may not refer or offer their patients this option. The main barriers influencing treatment choices ranged from lack of inclusion in clinical practice guidelines, high morbidity/mortality to lack of training and inaccessibility to an HIPEC expert. Interestingly, many respondents indicated that a change of NCCN guidelines may influence their decision to consider it as standard of care. Studies showed lack of familiarity with the results of CRS/HIPEC, both in terms of survival, for various pathologies and morbidity and mortality, would be one of the reasons for poor adoption. These gaps in knowledge and lack of awareness needs to urgently bridged [17,23,24]. Few international guidelines have been created to optimize the benefits and minimize the adverse events for patients with colorectal cancer. Similar protocols or guidelines are needed for other pathologies and for specific populations [25][26][27][28][29].

Treatment and safety practices
Our study indicated that diffuse mesenteric invasion and poor ECOG score are the most crucial factors impacting the treatment decision for PSM. More than three fourth of the respondents also indicated multi organ involvement and frozen pelvis as the second and third factors, respectively, for eligibility against the use of CRS with HIPEC. Studies have reported that surgeons practicing in high-volume hospitals produce favourable oncologic outcomes and reduced adverse events [29][30][31]. As this procedure is technically challenging with high morbidity and mortality, clinical practices for perioperative management has been developed [32,33]. Inconsistencies were found in the various technical practice patterns of HIPEC like method of HIPEC, selection of cytostatic agents, infusion temperature and safety measures applied which may significantly impact the clinical outcomes. Similar observation was made by other studies too and concluded need for standardization of procedures [34,35]. The current practices regarding usage of drains, ICU stay, hospital stay and time for starting adjuvant chemotherapy also varied. The use of specialized protective equipment and safety protocols are common but widely variable among the centers. Some practices were widespread, such as long-sleeve double gloving, covering floor for cytostatic spillage, shoe covers and high-power filtration masks while laminar flow equipped OT, some evacuators and ocular protection was uncommon [36,37].

Scenario of PIPAC
The application of PIPAC as new treatment approach is performed only at a handful of centers in India. More than 75% of the participants stated the reason for not performing PIPAC was lack of training in India. A well-structured certification training course in India would help to increase the number patients undergoing this novel procedure. The survey on PIPAC indicates that indications, technical aspects and treatment regimens are uniform. This is probably explained by a standardized training by International Society for the Study of Pleura and Peritoneum (ISSPP) to become a PIPAC surgeon. Evaluation of new modalities like intraperitoneal immunotherapy or pressurized intraperitoneal chemotherapy as neoadjuvant therapy or as curative is underway in order to expand the patient selection and improved outcomes [38][39][40]. The limitations of this study include moderate sample size and heterogeneity of participants that may not represent the "real-life" picture. Higher rate of "expert" responders might lead to selection bias. Also, PSM encompasses different origins of PSM requiring different treatment approaches and grouping them together may be over simplification of a complex disease.

Conclusions
The study demonstrates three main findings.  First, research is needed develop new treatment options for patients with co morbidities and poor performance status, border line indications and palliative patients.
Second, patient referral to HIPEC centers is underutilized due to lack of acceptance, adoption and awareness among the medical fraternity. This presents a significant challenge for CRS/HIPEC and strategies are needed to educate and provide also familiarize the clinicians with the procedure by providing surgical training to consultants/ residents. Standardization of HIPEC protocols is necessary among the specialists who are already performing the procedure to improve oncological outcomes while decreasing morbidity and mortality.
Third, PIPAC had a high awareness as a novel therapeutic option but the main reason for underutilization of PIPAC in huge country like India was lack of certified training which can easily be solved by setting up centres of excellence with regular structured training courses.
Our study emphasizes a need to raise the awareness of PSM as a specialized branch in oncology, to encourage prospective multicentric studies and to publish protocols for patients based on the best available evidence and consensus among the experts.
Research funding: None declared. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. Competing interests: Authors state no conflict of interest. Ethical approval: Institutional ethical Board approval obtained.