Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model

Cancers

Alexander Tolios¹  Karolin Thiel²  Nick Seyfried²  Ingmar Königsrainer²  Alfred Königsrainer²  Markus Quante²  Markus W. Löffler²  Can Yurttas²  Stefan Beckert²  Tarkan Jäger³  Matthias Schwab⁴  Markus Burkard⁵  Sascha Venturelli⁵  Hans-Georg Rammensee⁶  Joseph Kauer⁶  Benedikt Oswald⁶  Franziska Herster⁶ 

[1] Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria;Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany;Department of Surgery, Paracelsus Medical University, Müllner Hauptstraße 48, 5020 Salzburg, Austria;German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, 72076 Tübingen, Germany;Institute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstr. 30, 70599 Stuttgart, Germany;Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany;

关键词: PRODIGE 7 trial;    peritoneal metastasis;    peritoneal carcinomatosis;    colorectal cancer;    micrometastasis model;   

DOI  :  10.3390/cancers14051158

来源: DOAJ

【 摘 要 】

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) was considered a promising treatment for patients with peritoneal metastasis from colorectal cancer. However, the recently published randomized controlled PRODIGE 7 trial failed to demonstrate survival benefits through the addition of short-term oxaliplatin-based HIPEC. Constituting a complex multifactorial treatment, we investigated HIPEC in a preclinical model concerning the elimination of minimal tumor residues, thereby aiming to better understand the size of effects and respective clinical trial results. Patient samples of peritoneal perfusates obtained during HIPEC treatments and oxaliplatin-containing solutions at clinically relevant dosages, conforming with established HIPEC protocols, were assessed regarding their ability to eliminate modelled ~100 µm thickness cancer cell layers. Impedance-based real-time cell analysis and classical end-point assays were used. Flow cytometry was employed to determine the effect of different HIPEC drug solvents on tumor cell properties. Effectiveness of peritoneal perfusate patient samples and defined oxaliplatin-containing solutions proved limited but reproducible. HIPEC simulations for 30 min reduced the normalized cell index below 50% with peritoneal perfusates from merely 3 out of 9 patients within 72 h, indicating full-thickness cytotoxic effects. Instead, prolonging HIPEC to 1 h enhanced these effects and comprised 7 patients’ samples, while continuous drug exposure invariably resulted in complete cell death. Further, frequently used drug diluents caused approximately 25% cell size reduction within 30 min. Prolonging oxaliplatin exposure improved effectiveness of HIPEC to eliminate micrometastases in our preclinical model. Accordingly, insufficient penetration depth, short exposure time, and the physicochemical impact of drug solvents may constitute critical factors.

【 授权许可】

Unknown