Photochemical Internalization of Gemcitabine Is Safe and Effective in Locally Advanced Inoperable Cholangiocarcinoma

Trojan, Joerg; Hoffmeister, Albrecht; Neu, Bruno; Kasper, Stefan; Dechene, Alexander; Juergensen, Christian; Schirra, Joerg; Jakobs, Ralf; Palmer, Dan; Selbo, Pal; Olivecrona, Hans; Finnesand, Lena; Hogset, Anders; Walday, Per und Sturgess, Richard (2022): Photochemical Internalization of Gemcitabine Is Safe and Effective in Locally Advanced Inoperable Cholangiocarcinoma. In: Oncologist, Bd. 27, Nr. 6: S. 430-433

Abstract

Background Photochemical internalization (PCI) is a novel technology for light-induced enhancement of the local therapeutic effect of cancer drugs, utilizing a specially designed photosensitizing molecule (fimaporfin). The photosensitizing molecules are trapped in endosomes along with macromolecules or drugs. Photoactivation of fimaporfin disrupts the endosomal membranes so that drug molecules are released from endosomes inside cells and can reach their therapeutic target in the cell cytosol or nucleus. Compared with photodynamic therapy, the main cytotoxic effect with PCI is disruption of the endosomal membrane resulting in delivery of chemotherapy drug, and not to the photochemical reactions per se. In this study we investigated the effect of PCI with gemcitabine in patients with inoperable perihilar cholangiocarcinoma (CCA). Methods The in vitro cytotoxic effect of PCI with gemcitabine was studied on two CCA-derived cell lines. In a fimaporfin dose-escalation phase I clinical study, we administered PCI with gemcitabine in patients with perihilar CCA (n = 16) to establish a safe and tolerable fimaporfin dose and to get early signals of efficacy. The patients enrolled in the study had tumors in which the whole length of the tumor could be illuminated from the inside of the bile duct, using an optical fiber inserted via an endoscope (). Fimaporfin was administered intravenously at day 0;gemcitabine (i.v.) and intraluminal biliary endoscopic laser light application on day 4;followed by standard gemcitabine/cisplatin chemotherapy. Results Preclinical experiments showed that PCI enhanced the effect of gemcitabine. In patients with CCA, PCI with gemcitabine was well tolerated with no dose-limiting toxicities, and no unexpected safety signals. Disease control was achieved in 10 of 11 evaluable patients, with a clearly superior effect in the two highest dose groups. The objective response rate (ORR) was 42%, including two complete responses, while ORR at the highest dose was 60%. Progression-free survival at 6 months was 75%, and median overall survival (mOS) was 15.4 months, with 22.8 months at the highest fimaporfin dose. Conclusion Photochemical internalization with gemcitabine was found to be safe and resulted in encouraging response and survival rates in patients with unresectable perihilar CCA.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1083-7159
• Sprache: Englisch