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

SIMPLE SUMMARY: Absence of survival benefits when adding hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin to cytoreductive surgery in peritoneal metastasis from colorectal cancer has recently been shown in the randomized controlled PRODIGE 7 trial. We therefore aimed to investigate...

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Autores principales: Seyfried, Nick, Yurttas, Can, Burkard, Markus, Oswald, Benedikt, Tolios, Alexander, Herster, Franziska, Kauer, Joseph, Jäger, Tarkan, Königsrainer, Ingmar, Thiel, Karolin, Quante, Markus, Rammensee, Hans-Georg, Venturelli, Sascha, Schwab, Matthias, Königsrainer, Alfred, Beckert, Stefan, Löffler, Markus W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909393/
https://www.ncbi.nlm.nih.gov/pubmed/35267468
http://dx.doi.org/10.3390/cancers14051158
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author Seyfried, Nick
Yurttas, Can
Burkard, Markus
Oswald, Benedikt
Tolios, Alexander
Herster, Franziska
Kauer, Joseph
Jäger, Tarkan
Königsrainer, Ingmar
Thiel, Karolin
Quante, Markus
Rammensee, Hans-Georg
Venturelli, Sascha
Schwab, Matthias
Königsrainer, Alfred
Beckert, Stefan
Löffler, Markus W.
author_facet Seyfried, Nick
Yurttas, Can
Burkard, Markus
Oswald, Benedikt
Tolios, Alexander
Herster, Franziska
Kauer, Joseph
Jäger, Tarkan
Königsrainer, Ingmar
Thiel, Karolin
Quante, Markus
Rammensee, Hans-Georg
Venturelli, Sascha
Schwab, Matthias
Königsrainer, Alfred
Beckert, Stefan
Löffler, Markus W.
author_sort Seyfried, Nick
collection PubMed
description SIMPLE SUMMARY: Absence of survival benefits when adding hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin to cytoreductive surgery in peritoneal metastasis from colorectal cancer has recently been shown in the randomized controlled PRODIGE 7 trial. We therefore aimed to investigate the effects of this treatment modality in a preclinical micrometastasis model. Cancer cells were incubated with either patient samples obtained during HIPEC procedures or with defined oxaliplatin-containing solutions prepared according to clinically established HIPEC protocols. Our results demonstrate a limited effectiveness of short-term HIPEC in simulations with oxaliplatin to eliminate micrometastases, although we used platinum-sensitive cell lines for our model. Since these results are in line with findings from current research, our studies might offer further convincing evidence and potential explanations for HIPEC futility observed in clinical application. ABSTRACT: 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.
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spelling pubmed-89093932022-03-11 Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model Seyfried, Nick Yurttas, Can Burkard, Markus Oswald, Benedikt Tolios, Alexander Herster, Franziska Kauer, Joseph Jäger, Tarkan Königsrainer, Ingmar Thiel, Karolin Quante, Markus Rammensee, Hans-Georg Venturelli, Sascha Schwab, Matthias Königsrainer, Alfred Beckert, Stefan Löffler, Markus W. Cancers (Basel) Article SIMPLE SUMMARY: Absence of survival benefits when adding hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin to cytoreductive surgery in peritoneal metastasis from colorectal cancer has recently been shown in the randomized controlled PRODIGE 7 trial. We therefore aimed to investigate the effects of this treatment modality in a preclinical micrometastasis model. Cancer cells were incubated with either patient samples obtained during HIPEC procedures or with defined oxaliplatin-containing solutions prepared according to clinically established HIPEC protocols. Our results demonstrate a limited effectiveness of short-term HIPEC in simulations with oxaliplatin to eliminate micrometastases, although we used platinum-sensitive cell lines for our model. Since these results are in line with findings from current research, our studies might offer further convincing evidence and potential explanations for HIPEC futility observed in clinical application. ABSTRACT: 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. MDPI 2022-02-24 /pmc/articles/PMC8909393/ /pubmed/35267468 http://dx.doi.org/10.3390/cancers14051158 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Seyfried, Nick
Yurttas, Can
Burkard, Markus
Oswald, Benedikt
Tolios, Alexander
Herster, Franziska
Kauer, Joseph
Jäger, Tarkan
Königsrainer, Ingmar
Thiel, Karolin
Quante, Markus
Rammensee, Hans-Georg
Venturelli, Sascha
Schwab, Matthias
Königsrainer, Alfred
Beckert, Stefan
Löffler, Markus W.
Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model
title Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model
title_full Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model
title_fullStr Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model
title_full_unstemmed Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model
title_short Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model
title_sort prolonged exposure to oxaliplatin during hipec improves effectiveness in a preclinical micrometastasis model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909393/
https://www.ncbi.nlm.nih.gov/pubmed/35267468
http://dx.doi.org/10.3390/cancers14051158
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