Pressurized intraperitoneal aerosol chemotherapy: a review of the introduction of a new surgical technology using the IDEAL framework

Background The IDEAL (Idea, Development, Evaluation, Assessment, Long‐term study) framework is a scheme of investigation for innovative surgical therapeutic interventions. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a procedure based on laparoscopy to deliver intraperitoneal chemotherapy for peritoneal metastases, introduced in 2011. The aim of this article was to review literature on PIPAC and assess whether development of the technique has followed the IDEAL framework. Methods A search of MEDLINE and Embase was carried out to identify scientific reports on PIPAC published between January 2000 and February 2019. The studies were categorized according to the IDEAL stages. Results Eighty‐six original research papers on PIPAC were identified. There were 23 stage 0, 18 stage 1, 25 stage 2a and six stage 2b studies. Protocol papers for stage 1, 2b and 3 studies, and trial registrations for stage 2a studies, were also identified. The number of centres publishing reports and the number of publications has increased each year. Overall, there has been progression through the IDEAL stages; however, about 60 per cent of clinical reports published in 2018 were stage 1 Idea‐type studies. Conclusion Since its introduction, studies investigating PIPAC have progressed in line with the IDEAL framework. However, the majority of studies reported recently were stage 0 and 1 studies.


Introduction
In 2008, the Society of University Surgeons defined an innovative procedure as one that 'differs from currently accepted local practice, the outcomes of which have not been described, and which may entail risk to the patient' 1 . The IDEAL (Idea, Development, Evaluation, Assessment, Long-term study) framework is a scheme of investigation for innovative surgical therapeutic interventions proposed by the Balliol Collaboration in 2009 2 -5 as a strategy to address concerns regarding shortcomings of research in surgery, with particular reference to novel procedures and practices ( Table 1). The framework requires that surgical innovation should be carried out in a coordinated manner, with investigations progressing to a series of randomized trials. The results of the process should be audited using a clinical registry.
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for peritoneal metastases is a laparoscopic procedure used to assess the burden of the peritoneal disease, take biopsies, and deliver intraperitoneal chemotherapy as an aerosol, without increasing the intra-abdominal pressure 6 . Intraperitoneal administration of chemotherapy for peritoneal metastases from ovarian cancer was developed in the 1970s 7 and has subsequently been used for many different cancer types in the context of heated intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC) 8 . Experimental work 9 -11 suggests that both increased Table 1 Summary of the stages of surgical innovation according to the IDEAL paradigm (adapted from references 2 and 5), with description of the interpretation of these stages in this review relating to published work on pressurized intraperitoneal aerosol chemotherapy temperature and increased pressure can enhance the effect of chemotherapy. The concept of PIPAC was first described in 2000 12 , and was first performed in a patient in 2011 13 . The aim of this literature review was to assess whether the development and introduction of PIPAC has followed the IDEAL framework.

Methods
A literature search of the Ovid database was carried out using the terms 'PIPAC', 'ePIPAC', 'aerosol$ adj3 chemotherapy' and 'pressuri$ adj3 chemotherapy' on 28 February 2019. The first report describing the concept of a 'therapeutic capnoperitoneum' was published in 2000 12 , so the search was limited from 1 January 2000 to February 2019. In addition, the reference lists of identified papers were screened, and ResearchGate.net was searched for the term PIPAC to identify other publications.
Conference abstracts, review articles, articles associated with videos, and book chapters were excluded, as were errata to articles. Only articles in English were reviewed. The full text was then obtained, and the studies were graded according to the stages of innovation set out in the IDEAL paradigm. To obtain an up-to-date picture of research activity, ClinicalTrials.gov and the EU Clinical Trials Register (EudraCT) were searched to identify trials. The results were cross-referenced with the identified publications. Trials that had not yet been reported in the literature were included and assigned a stage as published protocols. Criteria used to assign the stages are described in Table 1.

PIPAC: a review of the literature in stages
The search strategy identified 287 articles after duplicates were removed (Fig. 1). Some 172 articles were excluded after review of the title and abstract, and a further 29 were excluded after reviewing the full text. This left 81 original research papers on PIPAC and/or related technology, and five trial registrations.

Stage 0 -Idea: preclinical work
The potential to deliver drugs by aerosolization into the pneumoperitoneum at laparoscopy was demonstrated initially in vivo in a pig model in 2000 12 . Two hypotheses were proposed 12 to support the technique. The first hypothesis was that intraperitoneal chemotherapy was superior to intravenous chemotherapy for the treatment of peritoneal metastases. The second was that delivery of intraperitoneal chemotherapy as an aerosolized solution to the pressurized pneumoperitoneum would confer pharmacological advantages over chemotherapy in the liquid phase, specifically better distribution around the abdominal cavity and improved penetration into the tissues.  I  I  I  I  I  I  I  I  D  D  D  E  D  E  D  D  E  A  0  0  Studies were identified using the search strategy described in Fig. 1. Included studies were then reviewed by a single author and assigned a stage of innovation according to the description of the stage and proposed method of investigation suggested by the IDEAL paradigm, as described in Table 1. The first studies 6,12 investigating the technique used methylene blue dye, allowing visual assessment of the distribution and penetration of the aerosol versus lavage in an in vivo pig model. Distribution of the dye was observed to be superior for aerosolization, although this was assessed by visual inspection. The second stage of preclinical testing involved an ex vivo tissue model to assess the penetration of a therapeutic substance, Dbait, into peritoneal tissue from a patient with metastatic endometrial cancer 14 . Dbait penetration was assessed using immunohistochemistry. Nodules treated with a pressurized aerosol had a more homogeneous drug uptake and deeper penetration than nodules treated by lavage.
Following these preclinical experiments, the same team progressed to human applications. Subsequent preclinical studies by other groups suggested that the first generation of PIPAC technology had limitations. Experiments using chemotherapeutic agents, where drug uptake can be measured objectively, found that drug distribution and penetration in ex vivo 18,20 and post-mortem animal 21 models was heterogeneous. Although drug was detected in tissue that had not been exposed directly to the aerosol jet, the greatest deposition of the aerosol was opposite to the nebulizer.
Analysis of the aerosol has shown that the droplet size is heterogeneous 23 . One group 24 has developed and brought to market a second device to enable PIPAC, but there is currently little information on the technical performance of this device, nor on its use outside Brazil.

Stage 1 -Idea: first human applications
The first human applications of PIPAC were carried out between 2011 and 2013, and the first reports were published in 2013 35 and 2014 13 . PIPAC was delivered as an off-label therapy to patients for whom 'no satisfactory alternative therapy was available' as a result of progression on systemic treatment or intolerance to systemic treatment. Patients were treated with doxorubicin 1⋅5 mg/m 2 in 50 ml 0⋅9 per cent saline, and cisplatin 7⋅5 mg/m 2 in 150 ml 0⋅9 per cent saline, the doses being set arbitrarily as 10 per cent of the HIPEC doses used at that institution. A formal dose escalation study was not done until 2018 48 . The drugs were administered using the nebulizer device (MicroPump™, Reger Medizintechnik, Rottweil, Germany, until 2015; then CapnoPen ® , Capnomed, Villingendorf, Germany, from 2015), and the pneumoperitoneum was then left in a steady state for 30 min. Regressive histological changes were observed in repeat biopsies from consecutive procedures, suggesting efficacy. Mild and moderate adverse events were reported, with patients experiencing fatigue, fever, pain and vomiting after surgery 80 . Pharmacokinetic data were collected; these determined that systemic absorption of the chemotherapy agents was low, although only doxorubicin was monitored 13 .
Data on the occupational health and safety aspects of the technique were collected, with no evidence of platinum contamination in the operating theatres 36,80 . As centres across Europe started performing the procedure, verification of its occupational health and safety was repeated 41,43 -45 . Similarly, as shown in Fig. 2, small case series describing the initial experiences of new centres have been published 40,46,47,49,51 .

Stage 2a -Development: larger case series
The PIPAC programme at the original centre in Ruhr University Bochum, Germany, continued and further case series were published, including patients with colorectal cancer 78,81 , primary peritoneal cancer 81 , gastric cancer 58,81 and malignant mesothelioma 81 . In gastrointestinal cancer 78 , oxaliplatin was used at a dose of 92 mg/m 2 . Again, this was an arbitrarily derived dose, and no formal dose-finding study has been published. A larger series of patients with ovarian cancer included one patient who sustained a life-threatening bowel perforation; however, this occurred when PIPAC was combined with cytoreductive surgery 74 .
A PIPAC training programme was developed, and sales of the device required to deliver PIPAC were limited to clinicians who had been certified. This programme is now overseen by the International Society for the Study of Pleura and Peritoneum 92 . In addition, clinicians were asked to agree to submit data from all cases to an international registry, managed independently by the University of Magdeburg (NCT03210298).

Stage 2b -Exploration: expanding the indications
As experience of PIPAC has increased, there has been evolution in the perioperative management of these patients, and in the indications for surgery. The duration of hospital stay has decreased, and in one centre selected patients undergo PIPAC as a day-case procedure 75 . Additional technology has been applied to the technique by some users. Electrostatic PIPAC (ePIPAC) involves the application of electrostatic precipitation to the abdominal cavity, with the aim of increasing drug deposition and adsorption. In preclinical testing, its use during PIPAC increased the penetration of drug 17 . The use of PIPAC in other scenarios, for example in combination with systemic chemotherapy, is under investigation 57,86 . Although the majority of procedures are still performed where disease has progressed despite conventional treatment, one centre 87 has proposed a randomized trial that will use PIPAC as adjuvant therapy after resection of high-risk colorectal cancer. The potential of PIPAC as a downstaging treatment to enable cytoreductive surgery was noted in some of the larger retrospective case series 82,93 , and will be evaluated further in an upcoming RCT 86 .
The future: Moving to stage 3 As documented in Fig. 2, there has been rapid expansion in the published literature since the first human report of PIPAC less than a decade ago, and an increasing number of centres are participating. PIPAC is now in widespread use worldwide. There are a number of RCTs proposed or ongoing 86,89 -91 , focusing in particular on survival and aiming to determine whether PIPAC could become part of standard care in the treatment of peritoneal disease.

Discussion
The introduction of PIPAC has, in principle, followed the pattern of investigation advocated by the IDEAL collaboration. However, this review of the development of PIPAC has highlighted some of the difficulties in research in surgical practice. Despite hundreds of reported cases in the literature, the true efficacy of the procedure is still unclear.
In many instances, PIPAC has been initiated outside of a trial. Although centres have published case series of prospectively collected data, there have been multiple publications of data from overlapping time periods, for example in 2014 and 2015 13,38,55,74 and 2016 40,73 . Formally registered programmes of research have also been conducted, usually consisting of small studies of safety and feasibility initially, followed by larger cohort studies. However, this pattern has been repeated several times across different centres in different countries. This may have been unnecessary in cases where the same drug doses and procedural steps were used, and may have delayed the progression to larger phase II/III studies.
The difficulty of overcoming the technical learning curve associated with a new procedure has been described as a potential barrier to effective research in surgery in the past 3,4 . In the case of PIPAC, there may also be issues relating to patient selection and perioperative care. Other reasons for the duplication of safety studies may relate to individual regulatory requirements in the different countries, or because studies were conceived before the results of earlier trials had been published.
The IDEAL framework recommends that trial protocols are registered publicly, and advocates the reporting of the results from new procedures on online registers available to all surgeons 2 . This recommendation has not been followed by all PIPAC centres. Although 67 clinical studies were published, only 23 of them were registered on ClinicalTrials.gov and EudraCT.
There is also the issue of the limited funds available for surgical studies. This can result in the duplication of smaller, less powerful, studies, without assessing the effect of the treatment on longer-term outcomes.
Ethical concerns have been raised in the past about surgical innovation 94 . Three systematic reviews 95 -97 have summarized the likelihood of adverse effects after PIPAC, although the lack of efficacy data resulting from controlled trials makes a risk versus benefit discussion challenging. There may also be rare complications not identified during early development of the technique, such as the cases of peritoneal sclerosis after PIPAC with oxaliplatin 65 and severe hypersensitivity reactions to platinum-based chemotherapy during PIPAC 69 . The IDEAL Collaboration suggest that clinicians use all available data from previous studies to counsel patients and disclose the possibility of unknown or unanticipated side-effects and complications 5 .
There may be ethical concerns relating to the involvement of the innovator or manufacturer of a new device in ongoing research. In the case of PIPAC, the sale of the MicroPump™/CapnoPen ® device was initially limited to clinicians who had been trained by the developer, and a contribution to an independently managed international registry (NCT03210298) was expected. An annual symposium was organized, and latterly this platform for sharing experience and update training has been formalized with the foundation of the International Society for the Study of Pleura and Peritoneum 92 , contributing to standardization of the technique 98 . This may prove useful for the conduct of multicentre trials in the future.

Disclosure
The authors declare no conflict of interest.