title: Drug delivery systems for ovarian cancer treatment: a systematic review and meta-analysis of animal studies.
abstract: Current ovarian cancer treatment involves chemotherapy that has serious limitations, such as rapid clearance, unfavorable biodistribution and severe side effects. To overcome these limitations, drug delivery systems (DDS) have been developed to encapsulate chemotherapeutics for delivery to tumor cells. However, no systematic assessment of the efficacy of chemotherapy by DDS compared to free chemotherapy (not in a DDS) has been performed for animal studies. Here, we assess the efficacy of chemotherapy in DDS on survival and tumor growth inhibition in animal studies. We searched PubMed and EMBASE (via OvidSP) to systematically identify studies evaluating chemotherapeutics encapsulated in DDS for ovarian cancer treatment in animal studies. Studies were assessed for quality and risk of bias. Study characteristics were collected and outcome data (survival/hazard ratio or tumor growth inhibition) were extracted and used for meta-analyses. Meta-analysis was performed to identify and explore which characteristics of DDS influenced treatment efficacy. A total of 44 studies were included after thorough literature screening (2,735 studies found after initial search). The risk of bias was difficult to assess, mainly because of incomplete reporting. A total of 17 studies (377 animals) and 16 studies (259 animals) could be included in the meta-analysis for survival and tumor growth inhibition, respectively. In the majority of the included studies chemotherapeutics entrapped in a DDS significantly improved efficacy over free chemotherapeutics regarding both survival and tumor growth inhibition. Subgroup analyses, however, revealed that cisplatin entrapped in a DDS did not result in additional tumor growth inhibition compared to free cisplatin, although it did result in improved survival. Micelles did not show a significant tumor growth inhibition compared to free chemotherapeutics, which indicates that micelles may not be a suitable DDS for ovarian cancer treatment. Other subgroup analyses, such as targeted versus non-targeted DDS or IV versus IP administration route, did not identify specific characteristics of DDS that affected treatment efficacy. This systematic review shows the potential, but also the limitations of chemotherapy by drug delivery systems for ovarian cancer treatment. For future animal research, we emphasize that data need to be reported with ample attention to detailed reporting.
authors.affiliation: Department of Biochemistry, Radboud university medical center , Nijmegen , The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Raavé
authors.affiliation: Systematic Review Centre for Laboratory Animal Experimentation, Central Animal Facility, Radboud university medical center , Nijmegen , The Netherlands.
authors.forename: Rob B M
authors.initials: RB
authors.lastname: de Vries
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud university medical center , Nijmegen , The Netherlands.
authors.forename: Leon F
authors.initials: LF
authors.lastname: Massuger
authors.affiliation: Department of Biochemistry, Radboud university medical center , Nijmegen , The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: Department of Biochemistry, Radboud university medical center , Nijmegen , The Netherlands.
authors.forename: Willeke F
authors.initials: WF
authors.lastname: Daamen
keywords: Animal studies; Drug delivery systems; Meta-analysis; Ovarian cancer; Systematic review