Cancers 2023, 15, 1067. https://doi.org/10.3390/cancers15041067 www.mdpi.com/journal/cancers Article Metronomic Chemotherapy Based on Topotecan or Topotecan and Cyclophosphamide Combination (CyTo) in Advanced, Pretreated Ovarian Cancer Piotr J. Wysocki 1,2, *, Mateusz Łobacz 1 , Paweł Potocki 1,2 , Łukasz Kwinta 1,2 , Anna Michałowska-Kaczmarczyk 1,2 , Agnieszka Słowik 1 , Kamil Konopka 1,2 and Anna Buda-Nowak 1 1 Department of Oncology, Jagiellonian University—Medical College Hospital, 31-501 Cracow, Poland 2 Department of Oncology, Jagiellonian University—Medical College, 31-008 Cracow, Poland * Correspondence: piotr.wysocki@uj.edu.pl Simple Summary: In this retrospective analysis of 72 advanced ovarian cancer patients, we have evaluated the safety and activity of orally-administered metronomic chemotherapy (MC) based on single agent topotecan or a combination of topotecan and cyclophosphamide (CyTo regimen). In this difficult population, metronomic chemotherapy demonstrated a clinically meaningful activity and good safety profile. The MC provided a clinical benefit in the majority of treated patients, with fewer than 15% not benefitting from this treatment (biochemical or radiographic progression). The median PFS in the whole population was 3.65 months, but the median PFS in patients with a bio- chemical response to MC (18.2% of patients) reached 10.7 months. The study also showed that over- weight or obese patients had significantly better outcomes on MC than patients with BMI <25 kg/m 2 . This analysis established the CyTo regimen as the preferred MC to be evaluated in a phase II clinical trial currently under construction. Abstract: Patients with advanced ovarian cancer (OC) have a detrimental prognosis. The options for systemic treatment of advanced OC in later lines of treatment are limited by the availability of active therapies and their applicability to often fragile, exhausted patients with poor performance status. Metronomic chemotherapy (MC) is a concept of a continuous administration of cytotoxic drugs, which is characterized by multidirectional activity (anti-proliferative, anti-angiogenic, and anti-immunosuppressive) and low toxicity. We have performed a retrospective analysis of consec- utive, advanced, chemo-refractory OC patients treated with MC based on single-agent topotecan (1 mg p.o. q2d) or on a topotecan (1 mg q2d) and cyclophosphamide (50 mg p.o. qd) combination (CyTo). Metronomic chemotherapy demonstrated promising activity, with 72% and 86% of patients achieving biochemical or objective disease control and 18% and 27% of patients achieving a bio- chemical or objective response, respectively. The median PFS in the whole population was 3.65 months, but the median PFS in patients with a biochemical response to MC (18.2% of patients) reached 10.7 months. The study also suggested that overweight or obese patients had significantly better outcomes on MC than patients with BMI <25 kg/m 2 . This article is the first report in the liter- ature on metronomic chemotherapy based on a topotecan + cyclophosphamide combination (CyTo). The CyTo regimen demonstrated safety, clinical activity, and potential broad clinical applicability in advanced OC patients and will be evaluated in a forthcoming clinical trial. Keywords: ovarian cancer; metronomic chemotherapy; salvage treatment; topotecan; topotecan + cyclophosphamide; BMI Citation: Wysocki, P.J.; Łobacz, M.; Potocki, P.; Kwinta, Ł.; Michałowska- Kaczmarczyk, A.; Słowik, A.; Konopka, K.; Buda-Nowak, A. Metronomic Chemotherapy Based on Topotecan or Topotecan and Cyclophosphamide Combination (CyTo) in Advanced, Pretreated Ovarian Cancer. Cancers 2023, 15, 1067. https://doi.org/10.3390/cancers 15041067 Academic Editor: Simon Langdon Received: 29 December 2022 Revised: 5 February 2023 Accepted: 6 February 2023 Published: 7 February 2023 Copyright: © 2023 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https://cre- ativecommons.org/licenses/by/4.0/).