Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model
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 thr...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-02-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/5/1158 |
| _version_ | 1797475570626330624 |
|---|---|
| author | Nick Seyfried Can Yurttas Markus Burkard Benedikt Oswald Alexander Tolios Franziska Herster Joseph Kauer Tarkan Jäger Ingmar Königsrainer Karolin Thiel Markus Quante Hans-Georg Rammensee Sascha Venturelli Matthias Schwab Alfred Königsrainer Stefan Beckert Markus W. Löffler |
| author_facet | Nick Seyfried Can Yurttas Markus Burkard Benedikt Oswald Alexander Tolios Franziska Herster Joseph Kauer Tarkan Jäger Ingmar Königsrainer Karolin Thiel Markus Quante Hans-Georg Rammensee Sascha Venturelli Matthias Schwab Alfred Königsrainer Stefan Beckert Markus W. Löffler |
| author_sort | Nick Seyfried |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T20:46:00Z |
| format | Article |
| id | doaj.art-c0a5c79fb11c489f8ce9e7ded36a0d17 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T20:46:00Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-c0a5c79fb11c489f8ce9e7ded36a0d172023-11-23T22:46:46ZengMDPI AGCancers2072-66942022-02-01145115810.3390/cancers14051158Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis ModelNick Seyfried0Can Yurttas1Markus Burkard2Benedikt Oswald3Alexander Tolios4Franziska Herster5Joseph Kauer6Tarkan Jäger7Ingmar Königsrainer8Karolin Thiel9Markus Quante10Hans-Georg Rammensee11Sascha Venturelli12Matthias Schwab13Alfred Königsrainer14Stefan Beckert15Markus W. Löffler16Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, GermanyDepartment of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, GermanyInstitute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstr. 30, 70599 Stuttgart, GermanyInterfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, GermanyDepartment of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, AustriaInterfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, GermanyInterfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, GermanyDepartment of Surgery, Paracelsus Medical University, Müllner Hauptstraße 48, 5020 Salzburg, AustriaDepartment of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, GermanyDepartment of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, GermanyDepartment of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, GermanyInterfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, GermanyInstitute of Nutritional Sciences, Department of Nutritional Biochemistry, University of Hohenheim, Garbenstr. 30, 70599 Stuttgart, GermanyGerman Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, 72076 Tübingen, GermanyDepartment of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, GermanyDepartment of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, GermanyDepartment of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, GermanyCytoreductive 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.https://www.mdpi.com/2072-6694/14/5/1158PRODIGE 7 trialperitoneal metastasisperitoneal carcinomatosiscolorectal cancermicrometastasis model |
| spellingShingle | Nick Seyfried Can Yurttas Markus Burkard Benedikt Oswald Alexander Tolios Franziska Herster Joseph Kauer Tarkan Jäger Ingmar Königsrainer Karolin Thiel Markus Quante Hans-Georg Rammensee Sascha Venturelli Matthias Schwab Alfred Königsrainer Stefan Beckert Markus W. Löffler Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model Cancers PRODIGE 7 trial peritoneal metastasis peritoneal carcinomatosis colorectal cancer 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 | PRODIGE 7 trial peritoneal metastasis peritoneal carcinomatosis colorectal cancer micrometastasis model |
| url | https://www.mdpi.com/2072-6694/14/5/1158 |
| work_keys_str_mv | AT nickseyfried prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT canyurttas prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT markusburkard prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT benediktoswald prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT alexandertolios prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT franziskaherster prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT josephkauer prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT tarkanjager prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT ingmarkonigsrainer prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT karolinthiel prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT markusquante prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT hansgeorgrammensee prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT saschaventurelli prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT matthiasschwab prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT alfredkonigsrainer prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT stefanbeckert prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel AT markuswloffler prolongedexposuretooxaliplatinduringhipecimproveseffectivenessinapreclinicalmicrometastasismodel |