Pressurized Intraperitoneal Aerosol Chemotherapy Procedure Research Articles

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) for Gastric Cancer Peritoneal Metastases: Results from the Lithuanian PIPAC Program.

Peritoneal metastases (PM) of gastric cancer (GC) are considered a terminal condition, with reported median survival ranging from 2 to 9 months. Standard treatment typically involves systemic chemotherapy alone or combined with targeted therapy or immunotherapy, though efficacy is limited. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has emerged as a novel technique for treating GC PM, although it remains an experimental treatment under investigation. This study aimed to summarize the outcomes of GC PM treatment with PIPAC from the Lithuanian PIPAC program. All patients who underwent PIPAC for GC PM at Vilnius University Hospital Santaros Klinikos between 2015 and 2022 were included in this retrospective study. The safety of PIPAC was assessed by postoperative complications according to the Clavien-Dindo classification. Efficacy was evaluated based on the peritoneal carcinomatosis index (PCI), ascites dynamics throughout the treatment, and long-term outcomes. In total, 32 patients underwent 71 PIPAC procedures. Intraoperative and postoperative morbidity related to PIPAC occurred after three (4.2%) procedures. Following PIPAC, there was a tendency towards a decrease in median PCI from 10 (Q1 3; Q3 13) to 7 (Q1 2; Q3 12), p = 0.75, and a decrease in median ascites volume from 1300 mL (Q1 500; Q3 3600) at the first PIPAC to 700 mL (Q1 250; Q3 4750) at the last PIPAC, p = 0.56; however, these differences were not statistically significant. The median overall survival after PM diagnosis was 12.5 months (95% CI 10-17), and the median survival after the first PIPAC procedure was 5 months (95% CI 4-10). PIPAC is a safe and feasible treatment option for GC PM; however, well-designed prospective studies are needed to fully assess its efficacy.

10 Years of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC): A Systematic Review and Meta-Analysis.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel intraperitoneal drug delivery method of low-dose chemotherapy as a pressurized aerosol in patients affected by peritoneal cancer of primary or secondary origin. We performed a systematic review and meta-analysis with the aim of assessing the feasibility, safety, and efficacy of PIPAC. A systematic literature search was performed using Medline and Web of Science databases from 1 January 2011, to inception, to 31 December 2021. Data were independently extracted by two authors. The Newcastle-Ottawa Scale was used to assess the quality and risk of bias of studies. Meta-analysis was performed for pathological response, radiological response, PCI variation along treatment, and for patients undergoing three or more PIPAC. Pooled analyses were performed using the Freeman-Tukey double arcsine transformation, and 95% CIs were calculated using Clopper-Pearson exact CIs in all instances. A total of 414 papers on PIPAC were identified, and 53 studies considering 4719 PIPAC procedure in 1990 patients were included for analysis. The non-access rate or inability to perform PIPAC pooled rate was 4% of the procedures performed. The overall proportion of patients who completed 3 or more cycles of PIPAC was 39%. Severe toxicities considering CTCAE 3-4 were 4% (0% to 38.5%). In total, 50 studies evaluated deaths within the first 30 postoperative days. In the included 1936 patients were registered 26 deaths (1.3%). The pooled analysis of all the studies reporting a pathological response was 68% (95% CI 0.61-0.73), with an acceptable heterogeneity (I2 28.41%, p = 0.09). In total, 10 papers reported data regarding the radiological response, with high heterogeneity and a weighted means of 15% (0% to 77.8%). PCI variation along PIPAC cycles were reported in 14 studies. PCI diminished, increased, or remained stable in eight, one and five studies, respectively, with high heterogeneity at pooled analysis. Regarding survival, there was high heterogeneity. The 12-month estimated survival from first PIPAC for colorectal cancer, gastric cancer, gynecological cancer and hepatobiliary/pancreatic cancer were, respectively, 53%, 25%, 59% and 37%. PIPAC may be a useful treatment option for selected patients with PM, with acceptable grade 3 and 4 toxicity and promising survival benefit. Meta-analysis showed high heterogeneity of data among up-to-date available studies. In a subset analysis per primary tumor origin, pathological tumor regression was documented in 68% of the studies with acceptable heterogeneity. Pathological regression seems, therefore, a reliable outcome for PIPAC activity and a potential surrogate endpoint of treatment response. We recommend uniform selection criteria for patients entering a PIPAC program and highlight the urgent need to standardize items for PIPAC reports and datasets.

Strategy for Oligometastatic Recurrence of Cardia Adenocarcinoma: Liver Radiofrequency Ablation Associated with PIPAC Inducing Response Permitting Cytoreductive Surgery and HIPEC.

Management of oligometastatic disease (OMD) in esophagogastric junction cancer is complex due to anatomical location and adenocarcinoma pathway. Specific curative strategy is mandatory to increase survival. A multimodal approach combining surgery, systemic and peritoneal chemotherapy, radiotherapy, and radiofrequency could be envisaged. We report a strategy proposed for a 61-year-old male with cardia adenocarcinoma, initially treated with chemotherapy and superior polar esogastrectomy. He developed at later stage an OMD with peritoneal metastasis, single liver metastasis, and single lung metastasis. Considering that peritoneal metastases were unresectable at first, he was given multiple Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with oxaliplatin, associated with intravenous docetaxel. Percutaneous radiofrequency ablation was performed during the first PIPAC procedure. Peritoneal response allowed a secondary Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.

Oncological Outcomes After Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in the Treatment of Peritoneal Carcinomatosis.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique for the treatment of initially unresectable peritoneal carcinomatosis (PC). Our objective was to assess its oncological outcomes. Between July 2016 and September 2020, data from 100 PIPAC procedures with oxaliplatin or doxorubicin-cisplatin in 49 patients with PC (all etiologies) were analyzed. We studied the evolution of the peritoneal cancer index (PCI), the need for radical surgery (R0), and overall survival (OS). The patients' median age was 65 (59; 71) years, and 55.1% were women. Median PIPAC procedures per patient were 2 (1-3), and 28 (57.1%) underwent more than one PIPAC procedure. Median PCI at the first PIPAC was 19 (15-22). PCI decreased for 37%, remained stable for 29.6%, and increased for 33.4% patients. Four (8.3%) underwent radical R0 surgery after PIPAC. After a median follow-up of 16.1months (1.5-90.1), the median overall survival from PC diagnosis was 29.1months (14.8-34.3), with a median gastric and colorectal PC survival of 11.3 (7.2-34.3) and 29.1months (16.1-31) respectively. Overall survival after the first PIPAC session was 11.6months (6-17.3), with median survival after gastric and colorectal PCs being 6 (2.9-15.5) and 13.3months (5-17.6), respectively. Stratification of patients according to the number of lines of systemic chemotherapy, PIPAC procedures, and the chronology of PC onset did not result in a significant difference in survival. The OS was in line with the literature. PIPAC could delay oncological progression and improve survival. These encouraging results justify the ongoing and future evaluations of PIPAC by prospective randomized trials.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for unresectable PM from gastric cancer outstanding result from multicenter cohort study.

331 Background: PIPAC is a recent approach for intraperitoneal chemotherapy with promising results for patients with peritoneal metastasis (PM). It is a safe and well-tolerated treatment. Our aim was to report oncological outcomes after PIPAC for gastric PM. Methods: International retrospective cohort study of consecutive patients with gastric PM. Outcome measures were overall survival (OS), radiological response (RECIST), histological response by use of Peritoneal regression grading system (PRGS) and cytology, peritoneal cancer index (PCI) and symptoms. Results: 586 non-selected patients with a median age of 56 (47-64) years, 54% of them were female and underwent a total of 1566 PIPAC procedures. 37% of patients were treated with 2 or more lines of IV chemotherapy, median PCI at first PIPAC was 14 (7-24) and 63% of them were with signet ring adenocarcinoma. Grade III-IV morbidity was 5.1 % and 1.9% died within 30 days from PIPAC procedure. Median OS was 15.4 months from diagnosis and 20.1 months for patient with more than 3 PIPAC. 263/586 patients (44.9%) had ≥3 procedures ( pp: per protocol) with the following outcomes: RECIST: 4.3% complete response 11% partial remission, 44% stable; PRGS1 39% at PIPAC3 and negative cytology at PIPAC3 in 16% of patient. In multivariate analysis, 3 PIPAC or more HR 0.3 (95% CI 0.27-0.51), 2nd and 3rd line of chemotherapy HR 0.48 (95% CI 0.25-0.92) and CRS&HIPEC after PIPAC HR 0.3 (95% CI 0.18-0.51) were predictors for survival. Conclusions: Based on this large multicentre cohort study, PIPAC could be considered as an option for the treatment of PM from gastric cancer. More prospective study will validate this indication in the near future.

Non-resectable Malignant Peritoneal Mesothelioma Treated with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Plus Systemic Chemotherapy Could Lead to Secondary Complete Cytoreductive Surgery: A Cohort Study.

Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive primary peritoneal neoplasia. At diagnosis, few patients are eligible for a recommended cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Among neoadjuvant strategies, pressurized intraperitoneal aerosol chemotherapy (PIPAC) combined with systemic chemotherapy has been recently proposed. This study evaluated this strategy in a cohort of DMPM patients. Patients with DMPM and primary or recurrent non-resectable diseases who received at least one PIPAC procedure in alternation with systemic chemotherapy were included in this retrospective study to analyze oncologic outcomes. Overall, 26 DMPM patients were treated with at least one PIPAC, including 20 patients with no previous CRS. Of 22 patients (85%) who had symptoms, 9 had perceptible ascites. Overall, 79 PIPAC procedures were performed, with half of the patients receiving three PIPAC procedures or more. Among eight patients (31%), 10 adverse events (13% of procedures) were reported, including two severe complications, both corresponding to digestive perforations. Improvement of symptoms was reported for 32% of the patients, whereas control of ascites was noted in 46%. All but one procedure among 14 patients (54%) secondarily treated by CRS-HIPEC were considered complete resections. After a median follow-up period of 29.6 months (95% confidence interval [CI], 17.6-not reached [NR]), the median overall survival period was 12 months (95% CI 11.1-NR). The median progression-free survival (PFS) was significantly better among the patients who underwent resection than among those who did not (33.5 vs 7.4 months; hazard ratio [HR], 0.18; 95% CI 0.06-0.755; p < 0.001). For patients with initially non-resectable DMPM, PIPAC is feasible for treatment with neoadjuvant intent and could facilitate complete secondary resection.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for peritoneal malignancy: initial experience of the first program in the Baltic countries

BackgroundPeritoneal malignancies include primary and metastatic cancer of the peritoneal cavity. The most common origin for peritoneal metastasis is ovarian, gastric, and colorectal cancers. Irrespective of the origin, peritoneal metastases represent the advanced disease and are associated with poor long-term outcomes. The minimally invasive approach of pressurized intraperitoneal aerosol chemotherapy (PIPAC) allows repeated applications and objective assessment of tumor response by comparing histological samples. This study aimed to investigate the initial experience with PIPAC in the Baltic region.MethodsAll patients who underwent PIPAC at Vilnius University Hospital Santaros Klinikos between 2015 and 2020 were included in this retrospective study. The primary outcome of the study was overall survival (OS) in patients with peritoneal carcinomatosis treated by PIPAC. The secondary outcomes included postoperative morbidity; peritoneal carcinomatosis index (PCI) and ascites reduction after treatment by PIPAC.ResultsIn total, 15 patients underwent 34 PIPAC procedures. PIPAC-related intraoperative and postoperative morbidity occurred in 3 (8.8%) of 34 procedures. Following PIPAC, the median PCI decreased from 8 (4; 15) to 5 (1; 16) in GC patients, although, the difference failed for significance, p = 0.581. In OC patients, PCI after PIPAC remained stable. Median overall survival after PIPAC procedure was 25 (95% CI 5–44) months. Ovarian cancer patients (22; 95% CI 12–44 months) had significantly higher OS, compared to gastric cancer patients (8; 95% CI 4–16 months), p = 0.018.ConclusionsPIPAC is safe and feasible for patients with gastric and ovarian cancers peritoneal metastases.

A Phase I Dose Escalation Study of Oxaliplatin, Cisplatin and Doxorubicin Applied as PIPAC in Patients with Peritoneal Carcinomatosis.

Simple SummaryThis study is one of the very few phase I trials on intraperitoneal chemotherapy applied as PIPAC. Cisplatin and doxorubicin may be safely used as PIPAC at a dose of 30 mg/m2 and 6 mg/m2, respectively; oxaliplatin can be used at an intraperitoneal dose of 135 mg/m2. No serious adverse event was reported. The dosages achieved to date are the highest ever used in PIPAC. The results of these investigations should be the starting point for further clinical phase II trials regarding repeated PIPAC, possibly associated with systemic chemotherapy.Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an innovative laparoscopic intraperitoneal chemotherapy approach with the advantage of a deeper tissue penetration. Thus far, oxaliplatin has been administered at an arbitrary dose of 92 mg/m2, cisplatin at 7.5 mg/m2 and doxorubicin 1.5 mg/m2. This is a model-based approach phase I dose escalation study with the aim of identifying the maximum tolerable dose of the three different drugs. The starting dose of oxaliplatin was 100 mg/m2; cisplatin was used in association with doxorubicin: 15 mg/m2 and 3 mg/m2 were the respective starting doses. Safety was assessed according to Common Terminology Criteria for Adverse Events (CTCAE version 4.03). Thirteen patients were submitted to one PIPAC procedure. Seven patients were treated with cisplatin and doxorubicin and 6 patients with oxaliplatin; no dose limiting toxicities and major side effects were found. Common adverse events included postoperative abdominal pain and nausea. The maximum tolerable dose was not reached. The highest dose treated cohort (oxaliplatin 135 mg/m2; cisplatin 30 mg/m2 and doxorubicin 6 mg/m2) tolerated PIPAC well. Serological analyses revealed no trace of doxorubicin at any dose level. Serum levels of cis- and oxaliplatin reached a peak at 60–120 min after PIPAC and were still measurable in the circulation 24 h after the procedure. Cisplatin and doxorubicin may be safely used as PIPAC at a dose of 30 mg/m2 and 6 mg/m2, respectively; oxaliplatin can be used at an intraperitoneal dose of 135 mg/m2. The dosages achieved to date are the highest ever used in PIPAC.

Is pressurized intraperitoneal aerosol chemotherapy safe and effective in the treatment of peritoneal metastases from pancreatic adenocarcinoma?

Introduction and purpose: Pancreatic adenocarcinoma (PAC) is the third most common cancer of the gastrointestinal tract in the Western population. Peritoneal metastases (PM) affect 5-10% patients with PAC at the moment of diagnosis and 50% of patients who experience a recurrence after a successful resection. This review aims to evaluate the efficacy of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in the treatment of PM from PAC based on the literature available on PubMed websiteBrief description of the state of knowledge: PIPAC is a relatively new method of treatment and the number of studies investigating its application in the treatment of PM from PAC is scarce. Nevertheless, initial findings suggest that PIPAC is linked to 15,6 months of the median overall survival, while standard intravenous chemotherapy reaches only 7,6 months . Furthermore, PIPAC seems to be a fairly safe method, as no grade 3 or grade 4 complications (according to CTCAE v4.0) occurred. However, all of the studies involved an unrepresentative number of patients and they were not free from a selection bias. Moreover, due to the novelty of the PIPAC procedure, it still needs to be properly standardised. Conclusions: Available data concerning the application of PIPAC in the treatment of PM from PDAC is limited. Large prospective studies consisting of control groups are still lacking. Nevertheless, the results of accessible studies displaying a median OS of participants reaching 14-16,8 months, with no G3 and G4 complications, are encouraging and justify further research.

PRESSURIZED INTRAPERITONEAL AEROSOL CHEMOTHERAPY COMBINED WITH SYSTEM CHEMOTHERAPY – A NEW APPROACH TO TREATMENT OF GASTRIC CANCER PATIENTS WITH PERITONAL CARCINOMATOSIS

The aim of the study was to analyze the immediate and long-term outcomes of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in gastric cancer patients with peritoneal carcinomatosis (PC). Material and methods . The treatment protocol included diagnostic laparoscopy with PCI score assessment and peritoneal biopsy and 4 courses of systemic chemotherapy with XELOX or FOLFOX followed by PIPAC with cisplatin and doxorubicin at 6–8 week intervals. Between the PIPAC cycles patients received systemic chemotherapy according to previous regimen. Each PIPAC procedure included laparoscopy, evaluation of Peritoneal Carcinomatosis Index (PCI) and peritoneal biopsies. Results . 102 (80.3 %) patients had primary gastric cancer with PC and 25 (19.7 %) had peritoneal recurrence of gastric cancer. PCI 18 in 34 (26.7 %) patients. Diffuse type of cancer was diagnosed in 114 patients (89.7 %), intestinal type in 6 (4.7 %) patients and the mixed type in 7 (5.5 %) patients. 127 patients underwent 310 PIPAC procedures. No severe complications and were observed. Pathological response (PRGC score) was evaluated in 72 patients. Partial pathological response (PRGS 2) was achieved in 40 (55.6 %) cases and complete pathological response (PRGS 1) – in 10 (13.9 %). Survival was evaluated in 63 % (n=80) patients who received more than one PIPAC. The median survival was 16.0 months and one year survival rate was 77.9 %. Conclusion . A new approach to the treatment of gastric cancer with PC combining systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy is a simple and save method allowing improvement of survival of patients with peritoneal dissemination of gastric cancer.

Restricted access to innovative surgical technique related to a specific training, is it ethical? Example of the PIPAC procedure. A systematic review and an experts survey.

Using the example of Pressurized Intra Peritoneal Aerosol Chemotherapy (PIPAC), we analyse the development model of this procedure and provide an ethical analysis of the involvement of the industry in a new development. In the case of breakthrough innovation, medical training is essential for safe use of the new procedure. In some cases, pharmaceutical companies decide to organise this training. But when it becomes the only training opportunity to use the device, scientists and clinicians could be exposed to a conflict of interest? We performed a literature review of PIPAC publications using the STROBE criteria. Then, we conducted interviews with an expert panel to analyse the ethical impact of involvement of the industry in the development of the PIPAC procedure. The number of publications has increased every year since the first publication in Germany, where the technology was developed in 2013. The scientific production was of good quality, with a mean STROBE score of 18.2±2.4 out of 22 points. Ten of the 33 included studies declared a conflict of interest. From the interviews, the main axe concerning the implication of the industry was the training model. The company had decided that only trained and approval surgeon could perform the PIPAC procedure. All four interviewed practitioners agreed that it was initially a good way to implement the procedure safely, but later they felt uncomfortable about the control and validation by the industry. Based on the growing number of published papers from a growing number of international centres, the controlled training model is not limiting. However, the different levels of conflict of interest complicate transparency, and we postulated that this development model is limited to the beginning of the procedure diffusion. CLINICALTRIAL. NCT04341337.

Systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC): A bidirectional approach for gastric cancer peritoneal metastasis

BackgroundFew patients affected by gastric cancer peritoneal metastasis (GCPM) are offered locoregional treatment, despite several proof-of-efficacy trials. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has emerged in recent years as a promising tool to control peritoneal carcinomatosis. The combination of PIPAC with systemic chemotherapy may offer a greater clinical benefit than standard treatment alone. MethodsA single-center cohort of 28 consecutive patients affected by GCPM was scheduled for bidirectional treatment, comprising PIPAC and systemic chemotherapy, from September 2017 to September 2019. Data recorded included safety, efficacy and survival outcomes. Ascite volumes, the Peritoneal Cancer Index (PCI) and pathological response through the Peritoneal Regression Grading Score (PRGS) were compared in those patients who underwent more than one PIPAC procedure. ResultsForty-six PIPAC procedures were administered, with a mean of 1.7 PIPAC procedures per patient. The median time to resume systemic chemotherapy after PIPAC was 6 days (range 4–7). Concerning safety, two grade 3–4 CTCAE (Common Terminology Criteria for Adverse Events v4.0) toxicity events and one intraoperative complication were recorded. Thirteen patients repeated PIPAC. A pathological response was recorded in 61.5% of patients (one with complete and seven with partial regression). The median overall survival was 12.3 months in the overall population and 15.0 months in patients undergoing more than one PIPAC procedure. ConclusionsA bidirectional approach for GCPM was feasible and safe, as the PIPAC procedure integrates well with several systemic chemotherapy regimens. The pathological response demonstrated the antitumoral efficacy of PIPAC. The proposed bidirectional approach may be further investigated in the first-line treatment of metastatic gastric cancer.

Pressurized intra peritoneal aerosol chemotherapy (PIPAC) vs. intravenous chemotherapy to assess quality of life &amp; response rates in unresectable peritoneal metastases secondary to platinum resistant ovarian cancer: A comparative study.

e18091 Background: The primary objective of this study is to assess Qol &amp; response rates in platinum resistant ovarian cancer patients with peritoneal metastasis treated with PIPAC procedure in comparison with conventional systemic intravenous chemotherapy. Methods: Between October 2017 and December 2019, 31 PIPAC applications were done in 15 patients with cisplatin 10.5mg/m2 and doxorubicin 2.1mg/m2. During same period 20 patients received systemic chemotherapy with clinician’s choice of drug ((mono-therapy consisting of pegylated liposomal doxorubicin or topotecan or gemcitabine or paclitaxel weekly with or without bevacizumab).The response rate (With MRI &amp; Ca-125) &amp; quality of life assessment (QLQ C-30) of both the group was done periodically and recorded. Results: Overall 35 patients were analysed in this study. The results have been presented in Table. Conclusions: PIPAC in comparison to intravenous chemotherapy for platinum resistant ovarian cancer with peritoneal metastasis showed better response rates (66.6 vs. 22.4%) and improved quality of life score. PIPAC has shown promising results and should be in the arsenal of the clinicians managing patients with platinum resistant ovarian cancer. [Table: see text]

Safety and tolerability of oxaliplatin based pressurized intraperitoneal aerosol chemotherapy (PIPAC) for patients with peritoneal carcinomatosis: A phase I dose-finding study in Asian patients.

360 Background: PIPAC is a novel, laparoscopic intraperitoneal chemotherapy delivery technique which aims to improve on hyperthermic intraperitoneal chemotherapy (HIPEC), ameliorating drug distribution and tissue penetration. Thus far, PIPAC has been conducted with oxaliplatin chemotherapy in Europe, at an arbitrary dose of 92mg/m2; 150mg/m2 was found to be intolerable. We conducted a dose-escalation phase 1 study to establish the safety, tolerability and recommended phase 2 dose (RP2D) for PIPAC in Asian patients. Methods: This phase 1 study of oxaliplatin administered via PIPAC was designed as a traditional 3+3 dose escalation study for patients with predominant peritoneal metastasis from a gastrointestinal primary tumor, after failure of standard therapies. Dose levels were planned at 45, 60, 90 and 120mg/m2. Repeat doses of PIPAC were permitted, 6 weeks apart. Dose limiting toxicities (DLT) were defined as any clinically relevant grade 3 adverse events occurring within 28 days after PIPAC. Results: This study included 16 patients (25 PIPAC procedures; 8 gastric, 4 colorectal and 1 gallbladder, pancreas and appendix cancer each). Median age was 62 years, with a median peritoneal carcinomatosis index (PCI) score of 17 (range 1 - 39). Two patients developed pancreatitis (grade 2 and 3) on day 6 and day 9 after PIPAC administration at the dose cohort of 45mg/m2, necessitating cohort expansion to 6 patients. One patient was noted to have asymptomatic grade 3 hyperamylasemia (90mg/m2 cohort). There were no other DLTs and all 3 patients in the highest dose cohort (120mg/m2) tolerated PIPAC well. Nine patients who underwent a 2nd PIPAC procedure had a decrease in PCI score from 18.4 to 15.5; one patient at 120mg/m2 had an improvement in PCI from 30 to 12. Conclusions: The RP2D of PIPAC with oxaliplatin is 120mg/m2. Single agent PIPAC is well tolerated, and future studies with PIPAC must consider a bi-directional approach with the incorporation of systemic therapy, with either chemotherapy or immunotherapy to improve efficacy. Clinical trial information: NCT03172416.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) of peritoneal metastasis from gastric cancer: a descriptive cohort study.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) represents a novel approach to deliver intraperitoneal chemotherapy. We report our experience with PIPAC in patients with peritoneal metastasis (PM) from gastric cancer (GC). Data from GC patients (n = 20) included in the prospective PIPAC-OPC1 and PIPAC-OPC2 studies are reported. All patients had received prior systemic chemotherapy. The mean peritoneal cancer index (PCI) was 10.5 (range 0-39) and nine patients had diffuse GC. PIPAC with cisplatin 7.5mg/m2 and doxorubicin 1.5mg/m2 were administered at 4-6-week intervals. Outcome criteria were objective tumour response, survival and adverse events. Twenty patients had 52 PIPAC procedures with a median follow-up of 10.4months (3.3-26.5). Median survival from the time of PM diagnosis and after the first PIPAC procedure was 11.5months and 4.7months, respectively. Fourteen patients had repeated PIPAC (> 2), and the objective tumour response according to the histological peritoneal regression grading score (PRGS) was observed in 36%, whereas 36% had stable disease. Ten patients completed the three prescheduled sessions (per protocol group) and 40% of those displayed an objective tumour response, while 20% had stable disease. Only minor postoperative complications were noted, and none were considered causally related to the PIPAC treatment. PIPAC with low-dose cisplatin and doxorubicin can induce a quantifiable objective tumour response in selected patients with PM from GC. Survival data are encouraging and warrant further clinical studies.

Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in patients with peritoneal metastasized colorectal, appendiceal and small bowel cancer.

Patients with intestinal cancer (colorectal, appendiceal, and small bowel) with peritoneal metastases (PM) have a poor prognosis. We assessed whether pressurized intraperitoneal aerosol chemotherapy (PIPAC) together with systemic chemotherapy is an effective treatment option for these entities in palliative intent. Between November 2015 and February 2018, prospective data registry was performed (NCT03100708). Thirteen patients with intestinal cancer (median age 61 years [range 49-77]) underwent 26 PIPAC procedures with a median number of 2 interventions per patient (range 1-6). A chemoaerosol consisting of cisplatin/doxorubicin was administered during standard laparoscopy. The median peritoneal carcinomatosis index according to Sugarbaker before the first PIPAC was 14 (range 2-27), and the median ascites volume was 10 mL (range 0-6300 mL). Six patients who received 2 or more PIPAC procedures had decreased and stable ascites volumes, while only 1 patient displayed increased ascites. The median overall survival was 303 days (range 30-490) after the first PIPAC procedure. PIPAC offers a novel treatment option for patients with PM. Our data show that PIPAC is safe and well-tolerated. Ascites production can be controlled by PIPAC in patients with intestinal cancer. Further studies are required to document the significance of PIPAC within palliative therapy concepts. NCT03100708.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) might increase the risk of anastomotic leakage compared to HIPEC: an experimental study.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) and hyperthermic intraperitoneal chemotherapy (HIPEC) are technics proposed to treat patients with peritoneal carcinomatosis, in different settings. There is some concern about an over-risk of anastomotic leakage (AL) with PIPAC jeopardizing a combination with cytoreductive surgery. This study used a healthy swine model to compare the postoperative AL rate between PIPAC and HIPEC with digestive resection and to analyze macrocirculation and microcirculation parameters. Segmental colonic resection with a handsewn anastomosis was performed on 16 healthy pigs; 8 pigs had a PIPAC procedure with 7.5mg/m2 cisplatin (PIPAC group), and 8 pigs had a closed HIPEC procedure with 70mg/m2 cisplatin and 42°C as the target intraperitoneal temperature (HIPEC group). Pigs were kept alive for 8days, then sacrificed and autopsied to look for AL, which was defined as local abscess or digestive fluid leakage when pressure was applied to the anastomosis. Food intake, weight, and core temperature were monitored postoperatively. Macrocirculation (heart rate, systolic blood pressure) and microcirculation parameters (percentage of perfused vessels, perfused vessels density, DeBacker score) were evaluated intraoperatively at five timepoints. Results were compared between pigs with AL and those without. The HIPEC group had no AL, but 3 of 8 pigs (37.5%) had AL in the PIPAC group (p = 0.20). Heart rate and core temperature showed perioperative increases in the HIPEC group. Intraoperatively, heart rate was higher in the HIPEC group at the two last timepoints (123 vs. 93bpm, p = 0.031, and 110 vs. 85bpm, p = 0.010, at timepoints 3 and 4, respectively). Other macrocirculatory and microcirculatory parameters showed no significant differences. In this healthy swine model, PIPAC might have increased AL incidence compared to HIPEC. This potential over-risk did not seem to be related to changes in the microcirculation. PIPAC should probably not be used with digestive resection and should be avoided in cases of perioperative serosal injury.

Establishment of a rat ovarian peritoneal metastasis model to study pressurized intraperitoneal aerosol chemotherapy (PIPAC)

Backgroundpressurized intraperitoneal aerosol chemotherapy (PIPAC), with or without electrostatic precipitation (ePIPAC), was recently introduced in the treatment of peritoneal metastases (PM) from ovarian cancer (OC). Preliminary clinical data are promising, but several methodological issues as well the anticancer efficacy of PIPAC remain unaddressed. Here, we propose a rat ePIPAC model that allows to study these issues in a clinically relevant, reproducible, and high throughput model.Methodslaparoscopy and PIPAC were established in healthy Wistar rats. Aerosol properties were measured using laser diffraction spectrometry based granulometric analyses. Electrostatic precipitation was accomplished using a commercially available generator (Ultravision™). A xenograft model of ovarian PM was created in athymic rats using intraperitoneal (IP) injection of SKOV-3 luciferase positive cells. Tumor growth was monitored weekly by in vivo bioluminescence imaging.ResultsPIPAC and electrostatic precipitation were well tolerated using a capnoperitoneum of 8 mmHg. All rats survived the (e)PIPAC procedure and no gas or aerosol leakage was observed over the entire procedure. With an injection pressure of 20 bar, granulometry showed a mean droplet diameter (D(v,0.5)) of 47 μm with a flow rate of 0.5 mL/s, and a significantly lower diameter (30 μm) when a flow rate of 0.8 mL/s was used. Experiments using IP injection of SKOV-3 luciferase positive cells showed that after IP injection of 20 × 106 cells, miliary PM was observed in all animals. PIPAC was feasible and well supported in these tumor bearing animals.Conclusionswe propose a reproducible and efficient rodent model to study PIPAC and ePIPAC in OC xenografts with widespread PM. This model allows to characterize and optimize pharmacokinetic and biophysical parameters, and to evaluate the anti-cancer efficacy of (e)PIPAC treatment.

Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) as an outpatient procedure.

BackgroundPressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a drug-delivery method for patients with peritoneal metastasis (PM). The study objective was to investigate whether PIPAC is possible in an outpatient setting.MethodsData was extracted from the prospective PIPAC-OPC2 study (ClinicalTrials.gov NCT03287375). Patients with PM were treated by cisplatin and doxorubicin (PIPAC C/D), except patients with colorectal PM, who were treated by oxaliplatin (PIPAC OX). Patients were evaluated concerning the suitability for carrying out the PIPAC procedure in an out- patient setting. The preconditions for outpatient surgery were that the patient should be (1) freely mobilized, (2) adequately pain-relieved, (3) have untroubled urination and (4) without anxiety or discomfort caused by leaving the hospital.ResultsDuring the study period, 106 PIPAC procedures (79 PIPAC C/D, 27 PIPAC OX) were performed in 41 patients with gastrointestinal or ovarian PM. Ninety percent (37/41) of the patients were pretreated with systemic chemotherapy. Eight patients (20%) received bidirectional chemotherapy. Twenty-four percent (10/41) of the first PIPAC procedures were completed in an outpatient setting, which increased to 65% (13/20) in PIPAC no 3 (p=0.008). In the PIPAC C/D cohort, 28% and 80% of the PIPACs were performed in the outpatient setting at PIPAC 1 and 3 respectively, contrasting to only 11% and 20% in the PIPAC OX group. No readmissions after outpatient care. Postoperative morphine administration was more frequent in the PIPAC OX group.ConclusionsThe PIPAC procedure can be performed in an outpatient setting. The critical component for success is pain control.

Randomized control trial comparing quality of life of patients with end-stage peritoneal metastasis treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC) and intravenous chemotherapy.

BackgroundPeritoneal metastasis (PM) is a common occurrence in gynaecological and gastrointestinal cancers and is associated with poor survival. Patients typically present with ascites, abdominal pain, malnutrition, nausea, emesis, and bowel obstruction which significantly compromise the quality of life (QoL). The treatment remains a particular challenge, with palliative systemic chemotherapy being the standard of care. However, the efficacy of systemic chemotherapy is poor but with high potential for side effects and complications. QoL plays an important role in patients with PM and is deteriorating continuously until death. Thus, there is an obvious medical need for better therapeutic options in PM for prolonging survival and preserving QoL by reducing both disease-related symptoms and therapy side effects. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique for delivering pressurized normothermic chemotherapy into the abdominal cavity as an aerosol. 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.MethodsThe primary objective of this study is to assess QoL and symptoms in a consecutive cohort of patients with PM treated with PIPAC procedure in comparison with conventional systemic intravenous chemotherapy. QoL is assessed prospectively using European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30(Version 3.0) questionnaire. QLQ-C30 is a 30-question self-administered questionnaire inquiring about global health status, 9 individual symptoms, and 5 functional scales. Baseline QoL is measured using the global physical health functional score, and symptom scores derived from EORTC QLQ30 questionnaire before starting therapy, followed by at 60, 120, and 180 days after the first intervention. Calculated sample size is 119 and rounded to 120. For each treatment group, sample size of 60 will be enrolled; Intervention model: IV chemotherapy group (control group) and PIPAC group (experimental group); Study type: prospective randomized control intervention trialDiscussionAll consecutive patients diagnosed with advanced end-stage PM are randomized to be treated with PIPAC or IV chemotherapy. The primary objective of this study is to determine the QoL after three cycles of PIPAC in comparison with six cycles of systemic chemotherapy. The secondary outcome measures include morbidity and mortality. Analysis is by intention to treat.ResultsThe effect of systemic chemotherapy remains limited on the peritoneum due to poor vascularization and low penetration. Side effects after systemic chemotherapy for PM are relatively frequent. QoL plays an important role in these patients and is deteriorating continuously due to the disease or therapy related. Thus, there is need for better therapeutic options for prolonging survival and preserving QoL by reducing both disease-related symptoms and therapy side effects. PIPAC is a novel minimally invasive repeatable treatment modality which demonstrated potentially encouraging tumour response and only minimal toxicity in patients with PM of various origins. It can optimize local drug delivery and improve clinical outcome due to superior pharmacological properties as compared to systemic chemotherapy.Trial registrationREF/2018/08/021225 Registered on Clinical Trials Registry-India (CTRI); www.ctri.nic.in