Pressurized Intraperitoneal Aerosol Chemotherapy Research Articles

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in the Treatment of Gastric Cancer: Feasibility, Efficacy and Safety-A Systematic Review and Meta-Analysis.

Background: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an emerging technique for delivering chemotherapy directly to the peritoneum via a pressurized aerosol. Its growing attention stems from its effectiveness in treating peritoneal carcinomatosis (PC) originating from various primary tumors, with gastric cancer (GC) being among the most prevalent. This study aimed to systematically investigate PIPAC's therapeutic role in gastric cancer peritoneal metastasis (GCPM). Methods: The systematic review and meta-analysis followed the PRISMA 2020 guidelines, searching Pubmed, Web of Science, and SCOPUS databases. The meta-analysis of relative risks and mean differences compared patients undergoing one or two PIPAC sessions with those completing three or more, assessing various outcomes. Results: Eighteen studies underwent qualitative analysis, and four underwent quantitative analysis. Patients with three or more PIPAC procedures had shorter hospital stays (MD = -1.2; 95%CI (-1.9; -0.5); p < 0.001), higher rates of histopathological response (RR = 1.77, 95%CI 1.08; 2.90; p = 0.023), and significantly improved overall survival (MD = 6.0; 95%CI 4.2; 7.8; p < 0.001). Other outcomes showed no significant differences. Conclusions: PIPAC demonstrated efficacy in carefully selected patients, enhancing histopathologic response rates and overall survival without prolonging hospital stays. This study underscores the necessity for randomized controlled trials and precise selection criteria to refine PIPAC's implementation in clinical practice.

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.

Intraperitoneal chemotherapy for peritoneal metastases of gastric origin: a systematic review and meta-analysis.

Gastric cancer with peritoneal metastases is associated with a dismal prognosis. Normothermic catheter-based intraperitoneal chemotherapy and normothermic pressurized intraperitoneal aerosol chemotherapy (PIPAC) are methods to deliver chemotherapy intraperitoneally leading to higher intraperitoneal concentrations of cytotoxic drugs compared to intravenous administration. We reviewed the effectiveness and safety of different methods of palliative intraperitoneal chemotherapy. Embase, MEDLINE, Web of Science and Cochrane were searched for articles studying the use of repeated administration of palliative intraperitoneal chemotherapy in patients with gastric cancer and peritoneal metastases, published up to January 2024. The primary outcome was overall survival. Twenty-three studies were included, representing a total of 999 patients. The pooled median overall survival was 14.5 months. The pooled hazard ratio of the two RCTs using intraperitoneal paclitaxel and docetaxel favoured the intraperitoneal chemotherapy arm. The median overall survival of intraperitoneal paclitaxel, intraperitoneal docetaxel and PIPAC with cisplatin and doxorubicin were respectively 18.4 months, 13.2 months and 9.0 months. All treatment methods had a relatively safe toxicity profile. Conversion surgery after completion of intraperitoneal therapy was performed in 16% of the patients. Repeated intraperitoneal chemotherapy, regardless of method of administration, is safe for patients with gastric cancer and peritoneal metastases. Conversion surgery after completion of the intraperitoneal chemotherapy is possible in a subset of patients.

Performance of different nebulizers in clinical use for Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

Technical ex-vivo comparison of commercial nebulizer nozzles used for Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC). The performance of four different commercial nebulizer nozzles (Nebulizer; HurriChemTM; MCR-4 TOPOL®; QuattroJet) was analysed concerning: i) technical design and principle of operation, ii) operational pressure as function of the liquid flow rate, iii) droplet size distribution via laser diffraction spectrometry, iv) spray cone angle, spray cone form as well as horizontal drug deposition by image-metric analyses and v) chemical resistance via exposing to a cytostatic solution and chemical composition by means of spark optical emission spectral analysis. The Nebulizer shows quasi an identical technical design and thus also a similar performance (e.g., mass median droplet size of 29 μm) as the original PIPAC nozzles (MIP/ CapnoPen). All other nozzles show more or less a performance deviation to the original PIPAC nozzles. The HurriChemTM has a similar design and principle of operation as the Nebulizer, but provides a finer aerosol (22 μm). The principle of operation of MCR-4 TOPOL® and QuattroJet differ significantly from that of the original PIPAC nozzle technology. The MCR-4 TOPOL® offers a hollow spray cone with significantly larger droplets (50 μm) than the original PIPAC nozzles. The QuattroJet generates an aerosol (22 μm) similar to that of the HurriChemTM but with improved spatial drug distribution. The availability of new PIPAC nozzles is encouraging but can also have a negative impact if their performance and efficacy is unknown. It is recommended that PIPAC nozzles that deviate from the current standard should be subject to bioequivalence testing and implementation in accordance with the IDEAL-D framework prior to routine clinical use.

The role of cytoreductive surgery and HIPEC for the treatment of primary and secondary peritoneal malignancies-experience from a tertiary care center in Germany.

Peritoneal surface malignancies (PSM) are commonly known to have a dismal prognosis. Over the past decades, novel techniques such as cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and pressurized intraperitoneal aerosol chemotherapy (PIPAC) have been introduced for the treatment of PSM which could improve the overall survival and quality of life of patients with PSM. The decision to proceed with CRS and HIPEC is often challenging due the complexity of the disease, the extent of the procedure, associated side effects, and potential risks. Here, we present our experience with CRS and HIPEC to add to the ongoing discussion about eligibility criteria, technical approach, and expected outcomes and contribute to the evolution of this powerful and promising tool in the multidisciplinary treatment of patients with primary and secondary PSM. A single-center retrospective chart review was conducted and included a total of 40 patients treated with CRS and HIPEC from April 2020 to September 2022 at the University Hospital Münster Department of Surgery. All patients had histologically confirmed primary or secondary peritoneal malignancies of various primary origins. Our study included 22 patients with peritoneal metastases from gastric cancer (55%), 8 with pseudomyxoma peritonei (20%), 4 with mesothelioma of the peritoneum (10%), and 6 patients with PSM originating from other primary tumor locations. Median PCI at time of cytoreduction was 4 (0-25). Completeness of cytoreduction score was 0 in 37 patients (92.5%), 1 in two patients (5%), and 2 in one patient (2.5%). Median overall survival across all patients was 3.69years. Complete cytoreduction during CRS and HIPEC can be achieved for patients with low PCI, for patients with high PCI in low-grade malignancies, and even for patients with initially high PCI in high-grade malignancies following a significant reduction of cancer burden due to extensive preoperative treatment with PIPAC and systemic chemotherapy.

Hyperthermic pressurized intraperitoneal aerosol drug delivery system in a large animal model: a feasibility and safety study.

We developed a novel drug delivery system called hyperthermic pressurized intraperitoneal aerosol chemotherapy (HPIPAC) that hybridized Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). The present study aims to assess the feasibility and safety of HPIPAC system in a large animal survival model. Eleven pigs (eight non-survival models and three survival models) were used in the experiment. The heat module in the HPIPAC controller circulates hyperthermic CO2 in a closed-loop circuit and creates gas-based dry intraperitoneal hyperthermia. Three 12mm trocars were placed on the abdomen. The afferent CO2 tube wound with heat generating coil was inserted into a trocar, and the efferent tube was inserted into another trocar. Heated CO2 was insufflated and circulated in a closed circuit until the intra-abdominal and peritoneal surface temperature reached 42°C. 100ml of 5% dextrose in water was nebulized for 5min and the closed-loop circulation was resumed for 60min at 42°C. Tissue biopsies were taken from several sites from the pigs in the survival model. The average change in core temperature of the pigs was 2.5 ± 0.08°C. All three pigs displayed no signs of distress, and their vital signs remained stable, with no changes in their diet. In autopsy, inflammatory and fibrotic responses at the biopsy sites were observed without serious pathologic findings. We successfully proved the feasibility and safety of our novel HPIPAC system in an in-vivo swine survival model.

Safety assessment of preventive pressurized intraperitoneal aerosol chemotherapy in combined treatment of gastric cancer: preliminary results

Purpose of the study. Preventive pressurised intraperitoneal aerosol chemotherapy (PIPAC) safety assessment in the combined treatment of gastric cancer (GC).Patients and methods. The study included 48 patients with morphologically confirmed resectable GC and cardio esophageal transition, having at least one criterion that is a predictor of the development of peritoneal carcinomatosis, e. g. tumor spread to the serous layer (≥ T4a), diffuse tumor type, affected regional lymph nodes, large tumor, young age (up to 45 years), subtotally and totally affected stomach. 36 out of those patients received treatment according to the protocol. All patients received 4 cycles of neoadjuvant chemotherapy according to the FLOT scheme, radical surgical treatment in combination with a PIPAC session, 4 cycles of adjuvant chemotherapy according to the FLOT scheme. The safety assessment was carried out according to the classification of surgical complications according to Clavien-D indo and the international scale for toxicity scaling NCI–CTCAE v5.0.Results. Postoperative complications were diagnosed in 25 %, &gt;III grade complications were revealed in 11 % of cases according to the Clavien-D indo classification. The postoperative mortality rate was 0 %.Conclusion. Preventive PIPAC of locally advanced GC and CET in combined treatment is a reproducible and safe method, which is characterized by the absence of an increase in the number of postoperative complications and mortality rate.

Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) Applied to Platinum-Resistant Recurrence of Ovarian Tumor: A Single-Institution Experience (ID: PARROT Trial)

BackgroundWe aimed to investigate the therapeutic efficacy and safety of Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in platinum-resistant recurrence of ovarian cancer and peritoneal carcinomatosis, while our secondary endpoint was to establish any changes in quality of life estimated via the EORTC QLQ-30 and QLQ-OV28 questionnaires.MethodsIn this monocentric, single-arm, phase II trial, women were prospectively recruited and every 28–42 days underwent courses of PIPAC with doxorubicin 2.1 mg/m2 followed by cisplatin 10.5 mg/m2 via sequential laparoscopy.ResultsOverall, 98 PIPAC procedures were performed on 43 women from January 2016 to January 2020; three procedures were aborted due to extensive intra-abdominal adhesions. The clinical benefit rate (CBR) was reached in 82% of women. Three cycles of PIPAC were completed in 18 women (45%), and 13 (32.5%) and 9 (22.5%) patients were subjected to one and two cycles, respectively. During two PIPAC procedures, patients experienced an intraoperative intestinal perforation. There were no treatment-related deaths. Nineteen patients showed no response according to the Peritoneal Regression Grading Score (PRGS) and 8 patients showed minor response according to the PRGS. Median time from ovarian cancer relapse to disease progression was 12 months (95% confidence interval [CI] 6.483–17.517), while the median overall survival was 27 months (95% CI 20.337–33.663). The EORTC QLQ-28 and EORTC QLQ-30 scores did not worsen during therapy.ConclusionsPIPAC seems a feasible approach for the treatment of this subset of patients, without any impact on their quality of life. Since this study had a small sample size and a single-center design, future research is mandatory, such as its application in addition to systemic chemotherapy.

What is long-term survival in patients with peritoneal metastasis from gastric, pancreatic, or colorectal cancer? A study of patients treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC).

A definition of long-term survival (LTS) in patients with peritoneal metastasis (PM) from gastric cancer (GC), pancreatic cancer (PC) or colorectal cancer (CRC) treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC) is lacking. We aimed to define LTS and investigate characteristics and treatment response in patients who reached LTS in data from two prospective trials. Retrospective study of patients with GC-, PC-, or CRC-PM from the prospective PIPAC-OPC1 and PIPAC-OPC2 studies. The definition of LTS was based on published systematic reviews and randomized controlled trials. LTS was defined at the time point where 25 % of the patients were alive in these studies. Histology based response was evaluated by the mean Peritoneal Regression Grading Score (PRGS) using biopsies obtained prior to PIPAC 3, and defined by a mean PRGS of≤2.0 or a decrease of mean PRGS of≥1, compared to baseline. LTS was defined at 21 (GC), 15 (PC), and 24 (CRC) months. Fifty-one (47.2 %) patients (nine GC, 17 PC, 25 CRC) reached LTS calculated from the date of PM diagnosis. All but one received palliative chemotherapy before PIPAC, and 37 % received bidirectional treatment. More than 90 % of the LTS patients had response according to PRGS. The mOS from PIPAC 1 was 23.3, 12.4, and 28.5months for GC, PC, and CRC LTS patients. Patients with PM from GC, PC, and CRC treated with systemic chemotherapy and PIPAC can reach LTS and most show histological response. Causality must be further investigated.

Massive neoplastic ascites

Peritoneal metastases frequently occur in primary or recurrent abdominal malignancy and are often associated with massive ascites, which determines severe abdominal bloating, respiratory distress, and poor quality of life in patients with few months of life. After the failure of traditional medical therapies, simple drainage is effective in providing temporary symptom relief but does not provide a durable solution. Several treatment options are available, but no standard treatment strategy has been established, and none of the treatments consistently showed the ability to extend life expectancy. This review focuses on outcomes and adverse events of simple drainage, catheter placement, intraperitoneal therapy, peritoneovenous shunting, hyperthermic intraperitoneal chemotherapy, early postoperative intraperitoneal chemotherapy, pressurized intraperitoneal aerosol chemotherapy, and cell-free and concentrated ascites reinfusion therapy. The choice between the available options for durable symptom management requires both care and caution in weighing risks and benefits according to the patient’s life expectancy.

Comparing patient reported abdominal pain between patients treated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) and primary colorectal cancer surgery

Oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) is an emerging palliative treatment for patients with unresectable colorectal peritoneal metastases. Previously, our study group reported that patients experienced abdominal pain for several weeks after PIPAC-OX. However, it is unknown how this compares to abdominal pain after regular colorectal cancer surgery. To provide some perspective, this study compared the presence of abdominal pain after PIPAC-OX to the presence of abdominal pain after primary tumor surgery. Patient reported abdominal pain scores (EORTC QLQ-CR-29), from two prospective, Dutch cohorts were used in this study. Scores ranged from 0 to 100, a higher score represents more abdominal pain. Abdominal pain at baseline and at four weeks after treatment were compared between the two groups. Twenty patients who underwent PIPAC-OX and 322 patients who underwent primary tumor surgery were included in the analysis. At baseline, there were no differences in abdominal pain between both groups (mean 20 vs. 18, respectively; p = 0.688). Four weeks after treatment, abdominal pain was significantly worse in the PIPAC group (39 vs 15, respectively; p < 0.001; Cohen’s d = 0.99). The differential effect over time for abdominal pain differed significantly between both groups (mean difference: 19 vs − 3, respectively; p = 0.004; Cohen’s d = 0.88). PIPAC-OX resulted in significantly worse postoperative abdominal pain than primary tumor surgery. These results can be used for patient counseling and stress the need for adequate analgesia during and after PIPAC-OX. Further research is required to prevent or reduce abdominal pain after PIPAC-OX.Trial registration CRC-PIPAC: Clinicaltrails.gov NCT03246321 (01-10-2017)

Gastric cancer with peritoneal metastases: a single center outline and comparison of different surgical and intraperitoneal treatments.

Gastric cancer with peritoneal metastasis (GCPM) has an unfavourable prognosis. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are promising treatment options that have been shown to improve survival. The aim of this study was to assess the impact of different treatments such as systemic chemotherapy, systemic chemotherapy + PIPAC, and CRS + HIPEC in patients with GCPM. This single-centre retrospective study included 82 patients with GCPM treated between January 2016 and June 2021. After first-line chemotherapy, depending on disease response and burden, the patients were divided into three treatment groups: chemotherapy alone, chemotherapy + PIPAC, and CRS + HIPEC. The primary outcome was overall survival (OS) from diagnosis, which was compared among the treatment groups. Thirty-seven (45.1%) patients were administered systemic chemotherapy alone, 25 (30.4%) received chemotherapy + PIPAC, and 20 (24.4%) underwent CRS + HIPEC. The CRS + HIPEC group had better OS (median 24 months) than the PIPAC group (15 months, p = 0.01) and chemotherapy group (5 months, p = 0.0001). Following CRS + HIPEC, the postoperative grade 3-4 complication rate was 25%, and no postoperative in-hospital deaths occurred. The median disease-free survival (DFS) was 12 months. Multivariate analysis identified peritoneal carcinomatosis index (PCI) > 7 as an independent predictor of worse DFS. No independent predictors of OS were identified. Among patients with GCPM, we identified a highly selected population with oligometastatic disease. In this group, CRS + HIPEC provided a significant survival advantage with an acceptable major complication rate compared with other available therapies (systemic chemotherapy alone or in combination with PIPAC).

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) with cisplatin and doxorubicin in combination with FOLFOX chemotherapy as a first-line treatment for gastric cancer patients with peritoneal metastases: single-arm phase II study

BackgroundGastric cancer (GC) remains among the most common and most lethal cancers worldwide. Peritoneum is the most common site for distant dissemination. Standard treatment for GC peritoneal metastases (PM) is a systemic therapy, but treatment outcomes remain very poor, with median overall survival ranging between 3-9 months. Thus, novel treatment methods are necessary. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is the most novel technique for intraperitoneal chemotherapy. Some preliminary data suggest PIPAC can achieve improved long-term outcomes in patients with GC PM, especially when used in combination with systemic chemotherapy. However, there is a lack of data from well-design prospective studies that would confirm the efficacy of PIPAC and systemic therapy combination for first-line treatment.MethodsThis study is an investigator-initiated single-arm, phase II trial to investigate the efficacy of PIPAC combined with systemic FOLFOX (5-fluorouracil, oxaliplatin, leucovorin) as a first-line treatment for GC PM. The study is conducted in 2 specialized GC treatment centers in Lithuania. It enrolls GC patients with histologically confirmed PM without prior treatment. The treatment protocol consists of PIPAC with cisplatin (10.5 mg/m2 body surface in 150 mL NaCl 0.9%) and doxorubicin (2.1 mg/m2 in 50 mL NaCl 0.9%) followed by 2 cycles of FOLFOX every 6–7 weeks. In total 3 PIPACs and 6 cycles of FOLFOX will be utilized. The primary outcome of the study is the objective response rate (ORR) according to RECIST v. 1.1 criteria (Eisenhauer et al., Eur J Cancer 45:228–47) in a CT scan performed 7 days after the 4th cycle of FOLFOX. Secondary outcomes include ORR after all experimental treatment, PIPAC characteristics, postoperative morbidity, histological and biochemical response, ascites volume, quality of life, overall survival, and toxicity.DiscussionThis study aims to assess PIPAC and FOLFOX combination efficacy for previously untreated GC patients with PM.Trial registrationNCT05644249. Registered on December 9, 2022.

CO2-Driven Nebulization of pH-Sensitive Supramolecular Polymers for Intraperitoneal Hydrogel Formation and the Treatment of Peritoneal Metastasis.

Because peritoneal metastasis (PM) from ovarian cancer is characterized by non-specific symptoms, it is often diagnosed at advanced stages. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) can be considered a promising drug delivery method for unresectable PM. Currently, the efficacy of intraperitoneal (IP) drug delivery is limited by the off-label use of IV chemotherapeutic solutions, which are rapidly cleared from the IP cavity. Hence, this research aimed to improve PM treatment by evaluating a nanoparticle-loaded, pH-switchable supramolecular polymer hydrogel as a controlled release drug delivery system that can be IP nebulized. Moreover, a multidirectional nozzle was developed to allow nebulization of viscous materials such as hydrogels and to reach an even IP gel deposition. We demonstrated that acidification of the nebulized hydrogelator solution by carbon dioxide, used to inflate the IP cavity during laparoscopic surgery, stimulated the in situ gelation, which prolonged the IP hydrogel retention. In vitro experiments indicated that paclitaxel nanocrystals were gradually released from the hydrogel depot formed, which sustained the cytotoxicity of the formulation for 10 days. Finally, after aerosolization of this material in a xenograft model of PM, tumor progression could successfully be delayed, while the overall survival time was significantly increased compared to non-treated animals.

PRELIMINARY RESULTS OF PRESSURIZED INTRAPERITONEAL AEROSOL CHEMOTHERAPY (PIPAC) FOR OVARIAN CANCER WITH PERITONEAL METASTASES IN TAJIKISTAN

Relevance: Ovarian cancer is the most aggressive form among all nosologies of the female reproductive system. More than 75% of women are diagnosed at advanced stages, and about 60% have metastases to other organs at diagnosis. Systemic chemotherapy has a limited effect on the peritoneum and a high incidence of side effects. There is a need for more effective approaches to prolong survival and preserve quality of life by reducing disease symptoms and treatment side effects, especially in countries with limited health resources.&#x0D; The study aimed to evaluate the preliminary results of using pressurized intraperitoneal aerosol chemotherapy (PIPAC) in patients with ovarian cancer with peritoneal metastases.&#x0D; Methods: 18 women with disease stage T3a-cN0M0 treated at the Republican Cancer Research Center for 2022-2023 were studied. The first group included six patients who underwent cytoreduction + PIPAC at the 1st stage, and the second group (12 women) underwent exploratory laparotomy + biopsy + PIPAC at the 1st stage. Patients in both groups received two courses of chemotherapy followed by a repeat of PIPAC. Taxanes + platinum-containing drugs were used in the PIPAC process — cisplatin or carboplatin with doxorubicin. Each patient received 2 PIPAC sessions and 4 to 6 chemotherapy courses with cytoreductive surgery. All patients underwent laparoscopic control with a reassessment of the Peritoneal Carcinomatosis Index (PCI) by Sugarbaker (2010) and repeated biopsy of the peritoneum.&#x0D; Results: The use of cytoreductive surgery + PIPAC at the first stage made it possible to level the symptoms of peritoneal carcinomatosis, to achieve a complete radiological response in 12 (67%) cases, a complete morphological response in the form of complete regression in 44%, a moderate response in 39% of cases&#x0D; Conclusion: The use of PIPAC with a cytoreductive component at the first stage of combined treatment of ovarian cancer with peritoneal metastases improves immediate results and patient’s quality of life and reduces the hospital stay. The research is ongoing.

Descriptive review of current practices and prognostic factors in patients with ovarian cancer treated by pressurized intraperitoneal aerosol chemotherapy (PIPAC): a multicentric, retrospective, cohort of 234 patients.

Ovarian cancer (OC) is the primary cause of mortality in women diagnosed with gynecological cancer. Our study assessed pressurized intraperitoneal aerosol chemotherapy (PIPAC) as treatment for peritoneal surface metastases (PSM) from recurrent or progressive OC and conducted survival analyses to identify prognostic factors. This retrospective cohort study, conducted across 18 international centers, analyzed the clinical practices of patients receiving palliative treatment for PSM from OC who underwent PIPAC. All patients were initially treated appropriately outside any clinical trial setting. Feasibility, safety, and morbidity were evaluated along with objective endpoints of oncological response. Multivariate analysis identified prognostic factors for OS and PFS. From 2015-2020, 234 consecutive patients were studied, from which 192 patients were included and stratified by platinum sensitivity for analysis. Patients with early recurrence, within one postoperative month, were excluded. Baseline characteristics were similar between the groups regarding platinum sensitivity (platinum sensitive (PS) and resistant (PR)), but chemotherapy frequency differed, as did PCI before PIPAC. Median PCI decreased in both groups after three cycles of PIPAC (PS 16 vs. 12, p < 0.001; PR 24 vs. 20, p = 0.009). Overall morbidity was 22%, with few severe complications (4-8%) or mortality (0-3%). Higher pathological response and longer OS (22 vs. 11m, p = 0.012) and PFS (12 vs. 7m, p = 0.033) were observed in the PS group. Multivariate analysis (OS/PFS) identified ascites (HR 4.02, p < 0.001/5.22, p < 0.001), positive cytology at first PIPAC (HR 3.91, p = 0.002/1.96, p = 0.035), and ≥ 3 PIPACs (HR 0.30, p = 0.002/0.48, p = 0.017) as independent prognostic factors of overall survival/progression-free survival. With low morbidity and mortality rates, PIPAC is a safe option for palliative treatment of advanced ovarian cancer. Promising results were observed after 3 PIPAC, which did improve the peritoneal burden. However, further research is needed to evaluate the potential role of PIPAC as an independent prognostic factor.

The effect of electrostatic high pressure nebulization on the stability, activity and ex vivo distribution of ionic self-assembled nanomedicines

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is applied to treat unresectable peritoneal metastasis (PM), an advanced, end-stage disease with a poor prognosis. Electrostatic precipitation of the aerosol (ePIPAC) is aimed at improving the intraperitoneal (IP) drug distribution and tumor penetration. Also, the combination of nanoparticles (NPs) as drug delivery vehicles and IP aerosolization as administration method has been proposed as a promising tool to treat PM. There is currently limited knowledge on how electrostatic precipitation (ePIPAC) and high pressure nebulization (PIPAC) affects the performance of electrostatically formed complexes. Therefore, the stability, in vitro activity and ex vivo distribution and tissue penetration of negatively charged cisPt-pArg-HA NPs and positively charged siRNA-RNAiMAX NPs was evaluated following PIPAC and ePIPAC. Additionally, a multidirectional Medspray® nozzle was developed and compared with the currently used Capnopen® nozzle. For both NP types, PIPAC and ePIPAC did not negatively influence the in vitro activity, although limited aggregation of siRNA-RNAiMAX NPs was observed following nebulization with the Capnopen®. Importantly, ePIPAC was linked to a more uniform distribution and higher tissue penetration of the NPs aerosolized by both nozzles, independent on the NPs charge. Finally, compared to the Capnopen®, an increased NP deposition was observed at the top of the ex vivo model following aerosolization with the Medspray® nozzle, which indicates that this device possesses great potential for IP drug delivery purposes. Statement of SignificanceAerosolized drug delivery in the peritoneal cavity holds great promise to treat peritoneal cancer. In addition, electrostatic precipitation of the aerosol to the peritoneal tissue is aimed at improving the drug distribution and tumor penetration. The combination of nanoparticles (NPs), which are nano-sized drug delivery vehicles, and aerosolization has been proposed as a promising tool to treat peritoneal cancer. However, there is currently limited knowledge on how electrostatic precipitation and aerosolization affect the performance of electrostatically formed NPs. Therefore, the stability, activity, distribution and penetration of negatively and positively charged NPs was evaluated after aerosolization and electrostatic precipitation. Additionally, to further optimize the local drug distribution, a multidirectional spray nozzle was developed and compared with the currently used nozzle.

Oxaliplatin-induced peripheral neurotoxicity in colorectal cancer patients: mechanisms, pharmacokinetics and strategies.

Oxaliplatin-based chemotherapy is a standard treatment approach for colorectal cancer (CRC). However, oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe dose-limiting clinical problem that might lead to treatment interruption. This neuropathy may be reversible after treatment discontinuation. Its complicated mechanisms are related to DNA damage, dysfunction of voltage-gated ion channels, neuroinflammation, transporters, oxidative stress, and mitochondrial dysfunction, etc. Several strategies have been proposed to diminish OIPN without compromising the efficacy of adjuvant therapy, namely, combination with chemoprotectants (such as glutathione, Ca/Mg, ibudilast, duloxetine, etc.), chronomodulated infusion, dose reduction, reintroduction of oxaliplatin and topical administration [hepatic arterial infusion chemotherapy (HAIC), pressurized intraperitoneal aerosol chemotherapy (PIPAC), and hyperthermic intraperitoneal chemotherapy (HIPEC)]. This article provides recent updates related to the potential mechanisms, therapeutic strategies in treatment of OIPN, and pharmacokinetics of several methods of oxaliplatin administration in clinical trials.

Impact of Body Mass Index on Postoperative Pain and Opioid Administration After Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new surgical technique, developed for the treatment of peritoneal carcinomatosis (PC). In this retrospective observational study we assessed the impact of body mass index (BMI) on postoperative pain and opioid consumption. We analyzed pain scores after 100 PIPAC procedures using either oxaliplatin or doxorubicin-cisplatin performed in 49 patients with PC between July 2016 and September 2020. The patients were divided into 3 groups (BMI <18.5, 18.5 ≥ BMI < 25, BMI≥25). Pain was self-rated on a visual analogue scale (VAS) from 0 to 10. Univariate logistic regression analysis identified oxaliplatin and PCI score to be associated with moderate to severe pain (VAS 4-10 at 8 am D1) after adjustment on BMI (OR [95% CI]; 3.26[1.00 - 10.65] p=0.050) and (OR [95% CI]; 1.09[1.01 - 1.17] p=0.019). The level of pain appeared significantly different between the treatment groups (median 2.5[0; 5] vs 0[0; 2.5] p=0.0017) irrespective of BMI (p =0.705 and p=0.118). Multivariate logistic regression analysis identified moderate to severe pain and synchronous PC to be associated with greater use of opioids (OR [95% CI]: 3.91 [1.24 - 12.32]) and (OR [95% CI]: 5.16 [1.71 - 15.58]; respectively. Opioids were administered after 45 procedures (45%) and was comparable between the treatment groups. Opioid administration and length-of-stay were similar among BMI bands. BMI is not related to postoperative pain or opioid use, howevermoderate to severe pain and synchronous PC are factors associated with requiring opioids.

Should we exclude patients with peritoneal carcinosis of colorectal origin and high PCI from CRS + HIPEC?

International guidelines exclude from surgery patients with peritoneal carcinosis of colorectal origin and a peritoneal cancer index (PCI) ≥ 16. This study aims to analyze the outcomes of patients with colorectal peritoneal carcinosis and PCI greater or equal to 16 treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) (CRS + HIPEC). We retrospectively performed a multicenter observational study involving three Italian institutions, namely the IRCCS Policlinico San Matteo in Pavia, the M. Bufalini Hospital in Cesena, and theASST Papa Giovanni XXIII Hospital in Bergamo. The study included all patients undergoing CRS + HIPEC for peritoneal carcinosisfrom colorectal origin from November 2011 to June 2022. The study included 71 patients: 56 with PCI < 16 and 15 with PCI ≥ 16. Patients with higher PCI had longer operative times and a statistically significant higher rate of not complete cytoreduction, with a Completeness of Cytoreduction score (CC) 1 (microscopical disease) of 30.8% (p = 0.004). The 2-year OS was 81% for PCI < 16 and 37% for PCI ≥ 16 (p < 0.001). The 2-years DFS was 29% for PCI < 16 and 0% for PCI ≥ 16 (p < 0.001). The 2-year peritoneal DFS for patients with PCI < 16 was 48%, and for patients with PCI ≥ 16 was 57% (p = 0.783). CRS and HIPEC provide reasonable local disease control for patients with carcinosis of colorectal origin and PCI ≥ 16. Such results form the basis for new studies to reassess the exclusion of these patients, as set out in the current guidelines, from CRS and HIPEC. This therapy, combined with new therapeutical strategies, i.e., pressurized intraperitoneal aerosol chemotherapy (PIPAC), could offer reasonable local control of the disease, preventing local complications. As a result, it increases the patient's chances of receiving chemotherapy to improve the systemic control of the disease.