Pressurized Intraperitoneal Aerosol Chemotherapy Treatments Research Articles

Assessment of chemical stability of monoclonal antibody and antibody drug conjugate administered by pressurized intraperitoneal aerosol chemotherapy

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new therapeutic approach for patients with peritoneal cancer. So far, most published studies investigated the administration of established cytostatic agents through PIPAC. This study aimed to evaluate the effect of PIPAC on two breakthrough anti-cancer agents, specifically anti-PD1 pembrolizumab, and anti-HER2 antibody-drug conjugate (ADC) - trastuzumab-deruxtecan. We conducted systematic analyses on samples of pembrolizumab and trastuzumab-deruxtecan at clinically relevant concentrations before and after PIPAC administration using an experimental setup of a hermetic container system, mimicking the abdominal cavity and using identical features as in clinical use. We utilized a range of chromatographic and spectroscopic techniques to explore potential alterations in the primary, secondary, and tertiary structures of the drugs, focusing on post-translational modifications resulting from the aerosolization. Our findings indicate that PIPAC did not compromise the integrity of tested biopharmaceuticals. The size variants of both drugs, assessed by size exclusion chromatography (SEC), remained unchanged. Reversed-phase liquid chromatography (RPLC) and hydrophobic interaction chromatography (HIC) revealed no significant differences in hydrophobicity variants, the average drug-to-antibody ratio (DAR), or DAR distribution before and after PIPAC treatment. Circular dichroism (CD) spectroscopy confirmed that the secondary and tertiary structures were preserved. While pembrolizumab showed no change in charge variants post-PIPAC, trastuzumab-deruxtecan exhibited a non-negligible change in the quantity of charge variants on the monoclonal antibody itself, while the payload remained unchanged. This shift could possibly be related to the metallic composition of the CapnoPen® device (made of nickel and chromium) used in PIPAC and for these experiments. Together, our results suggest that PIPAC does not alter the structure of pembrolizumab and trastuzumab-deruxtecan, paving the way for future clinical trials.

Number of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Treatments is Associated with Longer Survival: Analysis of a Large Prospective Cohort of Patients With Unresectable Peritoneal Surface Malignancies.

To analyze the reasons for stopping pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivered for unresectable peritoneal surface malignancies (PSM) and to determine survival in a large patient cohort of an experienced PIPAC center. PIPAC alone or combined with systemic chemotherapy was developed to palliatively treat unresectable PSM. Safety, tolerance and promising survival results were already reported, but the reasons for stopping treatment remain unclear and the influence of the number of PIPAC procedures on prognosis has not been evaluated. A retrospective analysis of PIPAC procedures from a prospectively maintained single institution PSM database was conducted from January 2016 to January 2023. A total of 346 patients underwent 1200 PIPAC treatments in the defined time period. Two-thirds of the patients completed 3 or more PIPAC procedures, and 2 patients had more than 15 treatment procedures. Reasons for PIPAC cessation were disease progression or complication (56%), reorientation to a potential curative procedure (19%), surgical complications of the procedure (13%), death between procedures (8%) and patient request (3%). PSM origin and receiving 3 or more PIPAC treatments were independently correlated with better survival in the overall population, in the group of ultimately unresectable PSM and after propensity score weighting. The main reason for stopping PIPAC treatment in palliative management of PSM is disease progression. When 3 or more PIPAC procedures can be delivered in combination to systemic chemotherapy, survival is significantly improved. Its use should be validated by prospective studies.

Modified scoring system for the quantitative assessment of histological regression in peritoneal carcinomatosis after pressurized intraperitoneal aerosol chemotherapy: A pilot study.

Peritoneal carcinomatosis is one of the leading causes of death in patients with gastrointestinal cancer. Newer locoregional treatment concepts include pressurized intraperitoneal aerosol chemotherapy (PIPAC), the regional application of pressurized chemotherapeutic agents to the abdominal cavity, which is usually performed every 4 to 8 weeks. One of the main challenges of PIPAC therapy remains the objective assessment of treatment response. The present study describes a new scoring system to histologically assess the regression of peritoneal cancer following PIPAC therapy, quantitative assessment of histological regression in peritoneal carcinomatosis (QARP). Peritoneal biopsies from 27 patients with peritoneal metastases undergoing PIPAC were obtained and processed in a standardized fashion. Biopsies were scored according to the QARP grading system. The five-tiered system was graded as follows, Grade 0, no residual tumor cells with regressive changes present; grade 1, 1-25% viable tumor cells per tumor focus with regressive changes present; grade 2, 26-50% viable tumor cells per tumor focus with regressive changes present; grade 3, 51-75% viable tumor cells per tumor focus with few regressive changes; grade 4, >75% viable tumor cells per tumor focus with minimal or no regressive changes. Based on the new grading system, the study cohort was divided into QARP responders and QARP non-responders following PIPAC treatment. Higher QARP scores were significantly correlated with higher PCI scores (r=0.32; P=0.007). However, no difference in overall survival was detected between QARP responders and QARP non-responders. Further studies are required to ascertain the reproducibility and prognostic significance of QARP.

The role of cytology in patients undergoing pressurized intraperitoneal aerosol chemotherapy (PIPAC) treatment for peritoneal carcinomatosis.

Cytology of ascites or peritoneal washing is a routine part of staging of peritoneal metastases (PM). We aim to determine value of cytology in patients undergoing pressurized intraperitoneal aerosol chemotherapy (PIPAC). Single-center retrospective cohort study included consecutive patients having PIPAC for PM of different primary between January 2015 and January 2020. A total of 75 patients (median 63 years (IQR 51-70), 67 % female) underwent a total of 144 PIPAC. At PIPAC 1 59 % patients had positive and 41 % patients had negative cytology. Patients with negative and positive cytology only differed in terms of symptoms of ascites (16% vs. 39 % respectively, p=0.04), median ascites volume (100 vs. 0 mL, p=0.01) and median PCI (9 vs. 19, p<0.01). Among 20 patients who completed 3 PIPACs (per protocol), cytology changed in one from positive to negative, and in two from negative to positive. Median overall survival was 30.9months in the per protocol group and 12.9months in patients having <3 PIPACs (=0.519). Positive cytology under PIPAC treatment is more frequently encountered in patients with higher PCI and symptomatic ascites. Cytoversion was rarely observed and cytology status had no impact on treatment decisions in this cohort.

Pressurized intraperitoneal aerosol chemotherapy, reasons for interrupting treatment: a systematic review of the literature.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) gives encouraging results in the treatment of peritoneal metastasis (PM). The current recommendations require at least 3 sessions of PIPAC. However, some patients do not complete the full treatment course and stop after only 1 or 2 procedures, hence the limited benefit. A literature review was performed, with search terms including "PIPAC" and "pressurised intraperitoneal aerosol chemotherapy." Only articles describing the causes for premature termination of the PIPAC treatment were analysed. The systematic search identified 26 published clinical articles related to PIPAC and reporting causes for stopping PIPAC. The series range from 11 to 144 patients, with a total of 1352 patients treated with PIPAC for various tumours. A total of 3088 PIPAC treatments were performed. The median number of PIPAC treatments per patient was 2.1, the median PCI score at the time of the first PIPAC was 19 and the number of patients who did not complete the recommended 3 sessions of PIPAC was 714 (52.8%). Disease progression was the main reason for early termination of the PIPAC treatment (49.1%). The other causes were death, patients' wishes, adverse events, conversion to curative cytoreductive surgery and other medical reasons (embolism, pulmonary infection, etc…). Further investigations are necessary to better understand the causes for interrupting PIPAC treatment and also improving the selection of patients who are most likely to benefit from PIPAC.

Hospitalization cost of Pressurized Intraperitoneal Aerosol chemotherapy (PIPAC).

Pressurized Intraperitoneal Aerosol chemotherapy (PIPAC) is a new surgical technique for the treatment of unresectable peritoneal carcinomatosis. Very little data is available on the costs of this treatment in France as there is currently no code for PIPAC in the French Common Classification of Medical Acts (CCAM). Our objective was to estimate the mean cost of hospitalization for PIPAC in two French public teaching hospitals. The mean cost of hospitalization was estimated from the mean fixed-rate remuneration paid to the hospital and the mean additional costs of treatment paid by the hospital. At discharge a patient's hospitalization is classified into a diagnosis related group, which determines the fixed-rate remuneration paid to the hospital (obtained from the national hospitals database - PMSI). Costs of medical devices and drug treatments specific to PIPAC, not covered by the fixed-rate remuneration, were obtained from the hospital pharmacies. Between July 2016 and November 2021, 205 PIPAC procedures were performed on 79 patients (mean procedures per patient=2.6). Mean operating room occupancy was 165min. The mean fixed-rate remuneration received by the hospitals per PIPAC hospitalization was €4031. The actual mean cost per hospitalization was €6562 for a mean length-of-stay of 3.3 days. Thus, each PIPAC hospitalization cost the hospital €2531 on average. The current reimbursement of PIPAC treatment by the national health system is insufficient and represents only 61% of the real cost. The creation of a new fixed-rate remuneration for PIPAC taking into account this cost differential is necessary.

Is Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) Effective in Ovarian Cancer With Peritoneal Metastasis?

Ovarian cancer is one of the most common causes of mortality in women and is frequently diagnosed at an advanced stage. Ovarian cancer has a high recurrence rate, with most cases being peritoneal metastasis. The standard treatment of peritoneal metastasis is systemic chemotherapy, but naturally, the peritoneum is poorly vascularized, making this standard of treatment frequently ineffective. Hence, pressurized intraperitoneal aerosol chemotherapy (PIPAC) introduced a new type of intraperitoneal chemotherapy (IPC) in November 2011. Positive feedback on its feasibility, tolerance, and efficacy has encouraged medical communities worldwide to adopt PIPAC as a new drug delivery technique. This study's objective is to review previously conducted research on the efficacy of PIPAC treatment for peritoneal metastasis from ovarian cancer.

Current Medical Care Situation of Patients in Germany Undergoing Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

Simple SummaryThe treatment of peritoneal surface malignancies has evolved differently from other fields in surgical oncology in the past decades and modern approaches were introduced into daily-routine. Curative as well as palliative surgical treatment options redefined the fate of patients with this aggressive disease. Nowadays, patients with a limited peritoneal tumor spread of colonic origin have comparable survival rates compared with colorectal liver and pulmonary metastases. After the failure of systemic chemotherapy, the application of PIPAC revolutionized the palliative treatment for these patients and recent results show a high histological response rates, an improvement in quality-of-life and, furthermore, a cost-reduction compared to systemic chemotherapy. The application of PIPAC in other disease-settings (neoadjuvant/adjuvant) needs to be defined in further clinical trials.Objective: Tailored approaches in gastrointestinal oncology have been more frequently introduced in past years and for patients with peritoneal metastases. This article attempts to overview the current strategies in surgical gastrointestinal oncology, with a focus on gastrointestinal peritoneal metastases. Methods: In 2019, all patients undergoing PIPAC therapy in Germany were retrospectively analyzed regarding morbidity and in-hospital mortality rates. Furthermore, patients with chemotherapy-refractory peritoneal metastases from gastric cancer undergoing PIPAC-therapy at our institution were analyzed. Results: In 2019, 534 patients received PIPAC treatment in german hospitals. The in-hospital mortality rate was 0%. In total, 36 patients suffered from postoperative complications (8%). From April 2016 to September 2021, a total of 44 patients underwent 93 PIPAC applications at our institution. The non-access-rate was 0%. The median PRGS was two (range, 1–4). Eleven patients (44%) showed histologically stable disease, whereas six patients (24%) showed histological regression. Median survival, calculated from the date of the first PIPAC application, was 181 days (range, 43–636 days). Conclusions: PIPAC is a safe and feasible procedure with a low in-hospital morbidity and mortality. Furthermore, PIPAC in the palliative and chemorefractory setting and is an appealing approach for patient management in the future.

Consensus statement for treatment protocols in pressurized intraperitoneal aerosol chemotherapy (PIPAC).

ObjectivesSafe implementation and thorough evaluation of new treatments require prospective data monitoring and standardization of treatments. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a promising alternative for the treatment of patients with peritoneal disease with an increasing number of suggested drug regimens. The aim was to reach expert consensus on current PIPAC treatment protocols and to define the most important research topics.MethodsThe expert panel included the most active PIPAC centers, organizers of PIPAC courses and principal investigators of prospective studies on PIPAC. A comprehensive literature review served as base for a two-day hybrid consensus meeting which was accompanied by a modified three-round Delphi process. Consensus bar was set at 70% for combined (strong and weak) positive or negative votes according to GRADE. Research questions were prioritized from 0 to 10 (highest importance).ResultsTwenty-two out of 26 invited experts completed the entire consensus process. Consensus was reached for 10/10 final questions. The combination of doxorubicin (2.1 mg/m2) and cisplatin (10.5 mg/m2) was endorsed by 20/22 experts (90.9%). 16/22 (72.7%) supported oxaliplatin at 120 with potential reduction to 90 mg/m2 (frail patients), and 77.2% suggested PIPAC-Ox in combination with 5-FU. Mitomycin-C and Nab-paclitaxel were favoured as alternative regimens. The most important research questions concerned PIPAC conditions (n=3), standard (n=4) and alternative regimens (n=5) and efficacy of PIPAC treatment (n=2); 8/14 were given a priority of ≥8/10.ConclusionsThe current consensus should help to limit heterogeneity of treatment protocols but underlines the utmost importance of further research.

Pressurized intra-peritoneal aerosol chemotherapy (PIPAC): increased intraperitoneal pressure does not affect distribution patterns but leads to deeper penetration depth of doxorubicin in a sheep model

BackgroundPressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is an innovative treatment against peritoneal carcinomatosis. Doxorubicin is a common intra-venous chemotherapy used for peritoneal carcinomatosis and for PIPAC. This study evaluated the impact of increased PIPAC intraperitoneal pressure on the distribution and cell penetration of doxorubicin in a sheep model.MethodsDoxorubicin was aerosolized using PIPAC into the peritoneal cavity of 6 ewes (pre-alpes breed): N = 3 with 12 mmHg intraperitoneal pressure (“group 12”) and N = 3 with 20 mmHg (“group 20”). Samples from peritoneum (N = 6), ovarian (N = 1), omentum (N = 1) and caecum (N = 1) were collected for each ewe. The number of doxorubicin positive cells was determined using the ratio between doxorubicine fluorescence-positive cell nuclei (DOXO+) over total number of DAPI positive cell nuclei (DAPI+). Penetration depth (μm) was defined as the distance between the luminal surface and the location of the deepest DOXO+ nuclei over the total number of cell nuclei that were stained with DAPI. Penetration depth (μm) was defined as the distance between the luminal surface and the location of the deepest DOXO+ nuclei.ResultsDOXO+ nuclei were identified in 87% of samples. All omental samples, directly localized in front of the nebulizer head, had 100% DOXO+ nuclei whereas very few nuclei were DOXO+ for caecum. Distribution patterns were not different between the two groups but penetration depth in ovary and caecum samples was significantly deeper in group 20.ConclusionsThis study showed that applying a higher intra-peritoneal pressure during PIPAC treatment leads to a deeper penetration of doxorubicin in ovarian and caecum but does not affect distribution patterns.

Pressurized Intraperitoneal Aerosol Chemotherapy, a Palliative Treatment Approach for Patients With Peritoneal Carcinomatosis: Description of Method and Systematic Review of Literature.

Peritoneal metastases arise in patients with a variety of primary cancers, and are associated with a poor prognosis. Systemic chemotherapy is the mainstay of treatment; however, the morbidity is considerable and the survival benefit is modest. Cytoreductive surgery and heated intraperitoneal chemotherapy is a potentially curative treatment available to a minority of patients; however, most develop recurrent disease. A novel palliative treatment for peritoneal metastases, pressurized intraperitoneal aerosol chemotherapy, has recently been introduced. Pressurized intraperitoneal aerosol chemotherapy utilizes an aerosol of chemotherapy in carbon dioxide gas. It is instilled into the abdomen under pressure via laparoscopic ports. No cytoreduction is performed. Pressurized intraperitoneal aerosol chemotherapy can be repeated at 6-week intervals. Oxaliplatin or cis-platinum and doxorubicin have been used to date. This study aims to systematically review and evaluate the method, and the preclinical and early clinical results of pressurized intraperitoneal aerosol chemotherapy. Medline and the Cochrane Library were the data sources for the study. Peer-reviewed series of greater than 10 patients, with sufficient patient data, through April 2019, were selected. Patients with peritoneal metastases underwent pressurized intraperitoneal aerosol chemotherapy. Patient dropout, histologic tumor response, adverse events, and 30-day mortality were the primary outcomes measured. A total of 921 patients with peritoneal metastases were brought to the operating room for pressurized intraperitoneal aerosol chemotherapy. The number of pressurized intraperitoneal aerosol chemotherapy treatments administered was as follows: 1 treatment, 862 (94%); 2 treatments, 645 (70%); and 3 treatments, 390 patients (42%). Initial laparoscopic access was not possible in 59 patients (6.4%). Common Terminology Criteria for Adverse Events grade 3 or higher were noted in 13.7% of the patients who, collectively, underwent a total of 2116 treatments. The 30-day mortality was 2.4% (22/921). This study was limited by the heterogeneity of reported data and primary tumor types and by the lack of long-term survival data. Early clinical results are encouraging, but tumor-specific, prospective, randomized trials are needed to compare pressurized intraperitoneal aerosol chemotherapy to systemic chemotherapy. This method has yet to be introduced to the United States. It is another therapeutic option for patients with peritoneal metastases and will broaden the patient base for future clinical trials.

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.

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.

Overall clinical and trichoscopic analysis performed in patients who underwent pressurized intraperitoneal aerosol chemotherapy (PIPAC) treatment for peritoneal carcinomatosis - initial trial preliminary report.

IntroductionCutaneous adverse events are among the remaining problematic issues of current oncology. The term peritoneal carcinomatosis (PC) refers to the advanced cancer stage. The innovative treatment of PC includes the use of pressurized intraperitoneal aerosol chemotherapy (PIPAC).AimTo present a preliminary report from an initial trial aimed at an overall clinical and trichoscopic analysis performed in patients who underwent PIPAC treatment due to PC.Material and methodsFor all steps of this study we obtained the consent of the local bioethics commission #KB 196/2018. Three different hair assessment methods were used in our study: 1) general clinical and patient self-feeling assessment; 2) hair pull test; 3) and trichoscopic analysis.ResultsNo hair or scalp disorders were noted in the observation period. In the self-feeling test assessment the vast majority recognized their hair as being of comparable quality or even better in quality compared to previous forms of chemotherapy they had undergone. In all patients we observed a reduction of hair loss in the pull test in the hospitalization period. In trichoscopic analysis we found all determinants and signs of hair disorders in the assessed group.ConclusionsThe PIPAC is safe and is not a burdensome or aggressive form of therapy, especially according to the very important factors influencing the potential quality of hair and hair loss. The authors, however, realize that to obtain comprehensive results and evaluate this novel and promising method we need to perform more research without any limitations like those in our study.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) in pancreatic cancer patients with peritoneal metastasis

Introduction: The median survival in pancreatic cancer (PC) patients with synchronous peritoneal metastasis (PM) is six weeks, and the effect of palliative systemic chemotherapy is limited. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) has shown promising results in patients with PM of different origin, but data in patients with PM from PC are sparse. We present prospective data on PIPAC treatment in nine PC patients with PM. Methods: Between January 2016 and January 2018, PC patients with isolated PM were included. Objective response evaluation was based on the Peritoneal Regression Grading Score (PRGS) in repeated biopsies from PM. Survival data, prior chemotherapy, number and complications of PIPAC procedures were collected. Results: Nine patients (5M/4F, median age 62 years (range 46-72)) were included. Six patients had synchronous PM, whereas three patients developed PM after initial resection. Patients had received between 2 and 12 (median 9) cycles of systemic chemotherapy prior to inclusion. Twenty-four PIPAC procedures (median 2, range 1-5) were performed, without significant complications. The median survival was 11 months (range 8-25) after diagnosis of PM and 6 months (range 2-16) after the first PIPAC. Based on the PRGS score in six patients who received > 1 PIPAC, four patients responded and two had stable disease. One patient died before the second PIPAC (disease progression), two patients received no further PIPAC since PM could not be bioptically verified. Conclusions: PIPAC is safe in pancreatic cancer patients with peritoneal metastasis, and PIPAC may induce an objectively measureable treatment response.

Intraperitoneal aerosolization of albumin-stabilized paclitaxel nanoparticles (Abraxane™) for peritoneal carcinomatosis - a phase I first-in-human study.

BackgroundNanoparticles hold considerable promise for aerosol-based intraperitoneal delivery in patients with carcinomatosis. Recently, results from preclinical and early clinical trials suggested that albumin-bound paclitaxel (ABP, Abraxane™) may result in superior efficacy in the treatment of peritoneal metastases (PM) compared to the standard solvent-based paclitaxel formulation (Taxol™). Here, we propose a phase I study of pressurized intraperitoneal aerosol chemotherapy (PIPAC) using ABP in patients with upper Gastrointestinal, breast, or ovarian cancer.MethodsEligible patients with advanced, biopsy-proven PM from ovarian, breast, gastric, hepatobiliary, or pancreatic origin will undergo three PIPAC treatments using ABP with a 4-week interval. The dose of ABP will be escalated from 35 to 140 mg/m² using a Bayesian approach until the maximally tolerated dose is determined. The primary end point is dose-limiting toxicity. Secondary analyses include surgical morbidity, non-access rate, pharmacokinetic and pharmacodynamic analyses, quality of life, and exploratory circulating biomarker analyses.DiscussionABP holds considerable promise for intraperitoneal aerosol delivery. The aim of this study is to determine the dose level for future randomized phase II trials using ABP in PIPAC therapy.Trial registrationThis trial is registered as EudraCT: 2017-001688-20 and Clinicaltrials.gov: NCT03304210.

Peritoneal metastasis from pancreatic cancer treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC).

Patients with peritoneal metastasis (PM) from pancreatic cancer have a short life expectancy. Systemic combination chemotherapy leads to a median overall survival of 7-8 months. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a treatment alternative, where studies in patients with PM from ovarian, gastric and colorectal cancer show a high safety profile and interesting results. This case study report data on the PIPAC treatment in patients with PM from pancreatic cancer. In a standard laparoscopy, chemotherapeutics (cisplatin and doxorubicin) are nebulized within the peritoneal cavity. After 30min, the chemotherapeutics are evacuated through a closed system. The PIPAC procedure is repeated every 4-6 weeks. Five patients with PM from pancreatic cancer were treated with a total of 16 PIPAC procedures. All patients received >1 PIPAC and were eligible for evaluation of histological regression. Four patients demonstrated histological regression, and one patient had stable disease. Three patients are still alive, and the median overall survival is 14 months (range 10-20) since the diagnosis of PM. The histological regression and survival figures in this pilot study suggest activity of PIPAC with low-dose cisplatin and doxorubicin in pretreated peritoneal metastasis of pancreatic origin. This should now be evaluated in prospective studies.

Impact of Pressurized Intraperitoneal Aerosol Chemotherapy on Quality of Life and Symptoms in Patients with Peritoneal Carcinomatosis: A Retrospective Cohort Study.

Background. Peritoneal cancer treatment aims to prolong survival, but preserving Quality of Life (QoL) under treatment is also a priority. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a novel minimally invasive repeatable treatment modality. The aim of the present study was to assess QoL in our cohort of PIPAC patients. Methods. Analysis of all consecutive patients included from the start of PIPAC program (January 2015). QoL (0–100: optimal) and symptoms (no symptom: 0–100) were measured prospectively before and after every PIPAC procedure using EORTC QLQ-C30. Results. Forty-two patients (M : F = 8 : 34, median age 66 (59–73) years) had 91 PIPAC procedures in total (1 : 4x, 17 : 3x, 12 : 2x, and 12 : 1x). Before first PIPAC, baseline QoL was measured as median of 66 ± 2.64. Prominent complaints were fatigue (32 ± 4.3) and digestive symptoms as diarrhea (17 ± 3.75), constipation (17 ± 4.13), and nausea (7 ± 2.54). Overall Quality of Life was 64 ± 3.75 after PIPAC#1 (p = 0.57), 61 ± 4.76 after PIPAC#2 (p = 0.89), and 70 ± 6.67 after PIPAC#3 (p = 0.58). Fatigue symptom score was 44 ± 4.86 after PIPAC#1 and 47 ± 6.69 and 34 ± 7.85 after second and third applications, respectively (p = 0.40). Diarrhea (p = 0.31), constipation (p = 0.76), and nausea (p = 0.66) did not change significantly under PIPAC treatment. Conclusion. PIPAC treatment of peritoneal carcinomatosis had no negative impact on patients' overall QoL and its components or on main symptoms. This study was registered online on Research Registry (UIN: 1608).