{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:51:39Z","timestamp":1787507499354,"version":"build-2736575974"},"reference-count":52,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Peritoneal metastases (PM) represent a common and challenging manifestation of several gastrointestinal and gynecologic malignancies. Bidirectional treatment\u2014combining Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with systemic chemotherapy\u2014has emerged as a strategy to enhance locoregional control while maintaining systemic coverage. Objective: This systematic review aimed to analyze the study design, characteristics, and timing of the treatments administered\u2014including the type of systemic chemotherapy, intraperitoneal agents used in PIPAC, and interval between administrations\u2014as well as the clinical outcomes, safety profile, and overall methodological quality of the available literature on bidirectional treatment for peritoneal metastases. Methods: A systematic literature search was conducted across the PubMed, Embase, and Cochrane Library databases up to April 2025. Studies were included if they reported clinical outcomes of patients undergoing bidirectional treatment. Data extraction focused on survival, response assessment (PRGS, PCI), adverse events, systemic and intraperitoneal regimens, treatment interval, and study methodology. Results: A total of 22 studies involving 1015 patients (742 treated with bidirectional therapy) were included. Median overall survival ranged from 2.8 to 19.6 months, with the most favorable outcomes observed in gastric and colorectal cancer cohorts. PRGS improvement after multiple PIPAC cycles was reported in &gt;80% of evaluable cases. High-grade adverse events (CTCAE \u2265 3) occurred in up to 17% of patients in most studies, with only one study reporting treatment-related mortality. However, methodological quality was generally moderate, with considerable heterogeneity in treatment protocols, response criteria, systemic regimens, and toxicity attribution. Conclusions: Bidirectional therapy with PIPAC and systemic chemotherapy appears to be a feasible and potentially effective strategy for selected patients with peritoneal metastases. Despite encouraging outcomes, definitive conclusions are limited by the retrospective nature and heterogeneity of available studies. Prospective standardized trials are needed to confirm efficacy, clarify patient selection, and optimize treatment protocols.<\/jats:p>","DOI":"10.3390\/cancers17152580","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T07:45:11Z","timestamp":1754466311000},"page":"2580","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Advances in Bidirectional Therapy for Peritoneal Metastases: A Systematic Review of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Combined with Systemic Chemotherapy"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7676-9658","authenticated-orcid":false,"given":"Manuela","family":"Robella","sequence":"first","affiliation":[{"name":"Unit of Surgical Oncology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9300-6059","authenticated-orcid":false,"given":"Marco","family":"Vitturini","sequence":"additional","affiliation":[{"name":"Centre for Biostatistics, Epidemiology and Public Health, Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3981-1145","authenticated-orcid":false,"given":"Andrea","family":"Di Giorgio","sequence":"additional","affiliation":[{"name":"Surgical Unit of Peritoneum and Retroperitoneum Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Aulicino","sequence":"additional","affiliation":[{"name":"General Surgery Department, Universita\u2019 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4521-8279","authenticated-orcid":false,"given":"Martin","family":"Hubner","sequence":"additional","affiliation":[{"name":"Department of Visceral Surgery, Lausanne University Hospital, University of Lausanne, 1005 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6994-8375","authenticated-orcid":false,"given":"Emanuele","family":"Koumantakis","sequence":"additional","affiliation":[{"name":"Centre for Biostatistics, Epidemiology and Public Health, Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felice","family":"Borghi","sequence":"additional","affiliation":[{"name":"Unit of Surgical Oncology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8309-079X","authenticated-orcid":false,"given":"Paolo","family":"Catania","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armando","family":"Cinquegrana","sequence":"additional","affiliation":[{"name":"Unit of Surgical Oncology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5835-5638","authenticated-orcid":false,"given":"Paola","family":"Berchialla","sequence":"additional","affiliation":[{"name":"Centre for Biostatistics, Epidemiology and Public Health, Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/S1470-2045(20)30599-4","article-title":"Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): A multicentre, randomised, open-label, phase 3 trial","volume":"22","author":"Elias","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rijken, A., Lurvink, R.J., Luyer, M.D.P., Nieuwenhuijzen, G.A.P., van Erning, F.N., van Sandick, J.W., and de Hingh, I.H.J.T. 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