Marcelo Simonsen ^1,2* Rossana Veronica Mendoza Lopez ³ Simone Maistro ³ Lucas Takeshi Ikeoka ⁴ Glaucia Fernanda de Lima Pereira ³ Ademar Benevolo Lugao ⁵ José Carlos Sadalla ⁶ Maria Lúcia Hirata Katayama ^3* Maria Aparecida Azevedo Koike Folgueira ³

• ¹ Gynecologic department, Hospital do Servidor Público Estadual, São Paulo, São Paulo, Brazil
• ² Radiology and oncology, ICESP (Instituto do Câncer do Estado de São Paulo), hospital das Clínicas Faculdade de Medicina - USP, São Paulo, Brazil
• ³ Radiology and oncology - comprehensive center for precision oncology and translational investigation oncologic center, ICESP (Instituto do Câncer do Estado de São Paulo), hospital das Clínicas Faculdade de Medicina - USP, São Paulo, Brazil
• ⁴ undergraduate program, University of São Paulo, São Paulo, Rio Grande do Sul, Brazil
• ⁵ Nuclear and Energy Research Institute, Instituto de Pesquisas Energéticas e Nucleares (IPEN), São Paulo, São Paulo, Brazil
• ⁶ Gynecology and obstetrics department, ICESP (Instituto do Câncer do Estado de São Paulo), hospital das Clínicas Faculdade de Medicina - USP, São Paulo, Brazil

Introduction: Intraperitoneal chemotherapy for ovarian cancer treatment has controversial benefits as most methodologies are associated with significant morbidity. We carried out a systematic review to compare tumor response between intraperitoneal chemotherapy delivered via drug delivery systems (DDSs) and free intraperitoneal chemotherapy in animal models of ovarian cancer. Methods: Based on PRISMA and SYRCLE guidelines, we identified 38 studies for review, of which 20, were used in the meta-analysis. We evaluated outcome, through tumor volume and tumor weight and, toxicity, through animal weight. Analysis was based on drugs employed and treatment duration. Results: Most studies were performed on mice. Ovarian cancer cell lines most commonly used to induce xenografts were SKOV3 (19 studies) and A2780 (6 studies). Intraperitoneal device, also known as drug delivery systems (DDS), consisted in nanoparticles, hydrogels, lipid polymer and others. The most commonly used drugs were paclitaxel and cisplatin. Most studies used as the control treatment the same chemotherapy applied free intraperitoneally and tumor response/ animal weight were evaluated weakly. There was a small benefit in overall tumor reduction in animals treated with intraperitoneal chemotherapy applied through the slow release device compared with animals treated with intraperitoneal free chemotherapy, as evaluated through tumor weight (SMD: -1.06; 95% CI: -1.34, -0.78) and tumor volume (SMD: -3.72; 95% CI: -4.47, -2.97), a benefit that was seen in most weekly evaluations and for most chemotherapy drugs, such as carboplatin (tumor weight SMD: -5.60 (95% CI: -7.83, -3.37), paclitaxel (tumor weight: -1.18; 95% CI: -1.52—0.83), and cisplatin (tumor volume SMD: -2.85; 95% CI: -3.66, -2.04) carboplatin (tumor volume: SMD: -12.71 (95% CI: -17.35, -8.07) ; cisplatin (tumor volume: SMD: -7.76 (95% CI: -9.88, -5.65); paclitaxel (tumor volume: SMD: -2.85; 95% CI: -3.66, -2.04).Regarding animal weight, there was no weight reduction in animals treated with intraperitoneal chemotherapy applied through the slow-release device compared with animals treated with intraperitoneal free chemotherapy. Conclusion: slow-release devices are overall safe and effective in animal models of ovarian cancer. It was not possible to evaluate which one is the most promising device to treat ovarian cancer, because many different types were used to apply chemotherapy intraperitoneally.