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

INTRODUCTION: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSION: 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).

How to Implement Pressurized Intraperitoneal Aerosol Chemotherapy into a National Health System Scenario: A Single-Center Retrospective Analysis of Costs and Economic Sustainability at a High-Volume Italian Hospital.

PIPAC is a new surgical procedure and a viable treatment option for PSM patients, due to promising therapeutic outcomes, minimal invasiveness, limited surgical morbidity, and systemic toxicity side effects. However, its implementation throughout hospitals is hard to obtain due to its fragile economical sustainability. A retrospective health economic analysis was conducted in order to evaluate the cost of hospitalization for patients undergoing PIPAC treatment at Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, in Rome. The average cost of a PIPAC procedure was defined based on the cost of surgery (cost of surgical material, operating room, intraperitoneal chemotherapy), hospital stay, diagnostic examinations, and drugs used during the stay. A total of 493 PIPAC procedures were performed on 222 patients with peritoneal metastases or primary peritoneal cancer from 2017 to 2023. Since the mean remuneration for each PIPAC hospitalization is €5916 and the mean expenditure per hospitalization is €6538, this results in an operating profit per PIPAC hospitalization of -€622. The reimbursement of PIPAC treatment by the Italian National Health System currently only partially covers the hospital's costs. Development of specific codes and adequate reimbursement for PIPAC by recognizing this procedure as a proper treatment for peritoneal carcinomatosis is essential.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.

The Road to Technical Proficiency in Cytoreductive Surgery for Peritoneal Carcinomatosis: Risk-Adjusted Cumulative Summation Analysis.

Background: Cytoreductive surgery (CRS) is a technically demanding procedure, and there is considerable debate about its safe application. This study investigated the learning curve for CRS and the clinical outcomes of consecutive patients treated by a single surgeon at a single institution. Methods: We collected 251 consecutive patients who underwent CRS for peritoneal metastases by a single surgeon at Fondazione Policlinico Universitario A. Gemelli IRCCS, between January 2016 and December 2020. The learning curve was estimated using the cumulative summation analysis (CUSUM) for operative time (OT). Risk-adjusted CUSUM (RA-CUSUM) charts were developed using a composite variable (surgical failure), defined as the occurrence of at least one of the following events: major postoperative complications (Clavien-Dindo grade ≥3), blood loss ≥500 mL, incomplete cytoreduction. Three learning phases were thus derived from the RA-CUSUM analysis, and were compared in terms of perioperative outcomes. Results: CUSUM-OT showed that the operation time improved significantly after the 161th case. RA-CUSUM analysis allowed to break the CRS learning curve into three different phases: phase 1, "the learning phase" (cases 1-99), phase 2 "the experienced phase" (cases 100-188), and phase 3, "the mastership phase" (cases 189-251). The rate of major postoperative complications decreased significantly over the three phases (p = 0.019). Operative time decreased significantly as well (p = 0.031) and was significantly shorter in phase 3 with respect to the other two phases (phase 3 vs phase 2: 420 min vs 500 min, p = 0.017; phase 3 vs phase 1: 420 min vs 503 min, p = 0.021). Blood loss consistently decreased throughout the three phases (p = 0.001). The rate of incomplete cytoreduction was significantly lower in phase 3 than in phase 2 (4.8% vs 14.6%, p = 0.043). Conclusion: The CRS failure rate stabilized after the first 99 cases, and the complete surgical proficiency was achieved after 189 cases. A standardised and mentored learning model is a safer strategy to shorten the learning process, to reduce morbidity and mortality, to improve oncologic outcomes.

Feasibility and safety of PIPAC combined with additional surgical procedures: PLUS study.

BACKGROUND: PIPAC (Pressurized IntraPeritoneal Aerosol Chemotherapy) is a minimally invasive approach relying on physical principles for improving intraperitoneal drug delivery, including optimizing the homogeneity of drug distribution through an aerosol. Feasibility and safety of the new approach are now consolidated and data on its effectiveness are continuously increasing. Although any surgical procedure associated with PIPAC had always been discouraged due to the high risk of complications, surgical practice is constantly changing: with growing expertise, more and more surgical teams associate PIPAC with surgery. METHODS: PLUS study is part of the retrospective international cohort studies including 10 centers around the world (India, Italy, France, Germany, Belgium, Russia, Saudi Arabia, Switzerland) and 96 cases of combined approaches evaluated through a propensity score analysis. RESULTS: the procedures most frequently associated with PIPAC were not only adhesiolysis, omentectomy, adnexectomy, umbilical/inguinal hernia repairs, but also more demanding procedures such as intestinal resections, gastrectomy, splenectomy, bowel repair/stoma creation. Although the evidence is currently limited, PLUS study demonstrated that PIPAC associated with additional surgical procedures is linked to an increase of surgical time (p < 0.001), length of stay (p < 0.001) and medical complication rate (p < 0.001); the most frequently reported medical complications were mild or moderate in severity, such as abdominal pain, nausea, ileus and hyperthermia. No difference in terms of surgical complications was registered; neither reoperation or postoperative deaths were reported. CONCLUSIONS: these results suggest that PIPAC can be safely combined in expert centers with additional surgeries. Widespread change of practice should be discouraged before the results of ongoing prospective studies are available.

The prognostic value of skeletal muscle index on clinical and survival outcomes after cytoreduction and HIPEC for peritoneal metastases from colorectal cancer: A systematic review and meta-analysis.

BACKGROUND: Cytoreductive surgery (CRS) and hypertermic intraperitoneal chemotherapy (HIPEC) represent the most effective strategy to manage peritoneal metastases (PM). This systematic review and meta-analysis aimed to assess the impact of body composition on clinical outcomes in patients with PM. METHODS: A systematic literature search was performed using Medline, Web of Science and EMBASE databases from inception to the 20st August 2020. Data were independently extracted by 3 authors. Newcastle-Ottawa Scale was used to assess quality and risk of bias of studies. Pooled analyses were performed using Mantel-Haenszel method to estimate overall effect size with mean differences or odd ratios (ORs) and 95% confidence interval (CI). The primary outcome was postoperative complication (POC) rate, while secondary outcomes were severe POC and postoperative mortality. RESULTS: A total of 4 studies were included in the systematic review and meta-analysis, including 582 patients. A significant association between low skeletal muscle mass and POC was found (OR 1.45, 95% CI 1.04 to 2.03; p = 0.03), while no differences were found in terms operative time, estimated blood loss, length of hospital stay, and postoperative mortality (p > 0.05). CONCLUSIONS: Low skeletal muscle mass at diagnosis is a valid prognostic factor for POC development in colorectal and PM patients undergoing CRS. Prospective and larger studies are needed to better investigate the role of CT scan derived body composition and to understand how to implement this tool in clinical practice.

Systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC): A case report of a multimodal treatment for peritoneal metastases of pancreatic origin.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) with peritoneal metastases (PM) has a dismal prognosis and palliative systemic chemotherapy, which represents the standard treatment option, has significant pharmacokinetics limitations and low efficacy. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new method of drug delivery that is expected to maximize exposure of peritoneal nodules to antiblastic agents. A combination of systemic chemotherapy and PIPAC may be valuable. PRESENTATION OF CASE: A 55 years old male affected by PDAC with synchronous PM underwent a multimodal treatment comprising systemic chemotherapy and PIPAC without any procedural-related adverse events. Tumor genomic profiling evaluation from peritoneal biopsies addressed further tailored systemic chemotherapy. DISCUSSION: The presented case illustrates the possibility of adding PIPAC to systemic chemotherapy with a fair tolerance profile and good quality of life while allowing monitoring of therapy-response and tailoring of the antiblastic treatment.