Odd Helge GILJA1, 3, Spiros KOTOPOULIS1, 2, Georg DIMCEVSKI1, 3, Dag HOEM4, Bjørn Tore GIERTSEN5, Emmet MCCORMACK5, Michiel POSTEMA1, 2
1National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, 2Department of Physics and Technology, University of Bergen, 3Department of Clinical Medicine, University of Bergen, 4Department of Surgery, Haukeland University Hospital, 5Department of Clinical Sciences, University of Bergen
Pancreatic adenocarcinoma（PDAC）is a great challenge to treat due to aggressive biology, late diagnosis, encasement of large blood vessels and/or the presence of metastasis; hence surgery is rarely an option. Chemotherapy produces modest responses but is not curative in this setting, mainly because its use is severely hampered by toxic effects to vital organs. As a result, the survival is very low. The mortality of the inoperable patients is 50％within 3 months and 90％within 12 months. We aimed to develop an orthotopic PDAC mouse model and to test the concept of sonoporation and its safety. The aims of the Phase I study were to investigate the safety and the ability of inducing sonoporation in a clinical setting, using commercially available technology, to increase the patients’treatment cycles and to possibly increase the overall survival in patients with pancreatic adenocarcinoma. For the clinical study, 10 Patients were treated using a customized configuration of a commercial clinical ultrasound scanner（GE LOGIQ 9）over a time period of 31.5 min following standard chemotherapy treatment with gemcitabine. SonoVue was injected intravenously during the treatment with the aim of inducing sonoporation. To ensure microbubbles were present throughout the whole treatment, 0.5 ml of contrast agent followed by 5 ml saline were injected every 3.5 min, i.e., at T = 30.0，33.5，37.0，40.5，44.0，47.5，51.0，54.5，and 58.0min. A single vial（4.5 ml）was used throughout each treatment. Treatment was stopped at T=61.5 min. The total cumulated ultrasound treatment time was only 18.9 s. Gemcitabine was administered by intravenous infusion at a dose of 1000 mg/m2 over 30 min. We found in mice very good safety and reduced tumor growth in the sonoporation group. The 10 patients were able to undergo an increased number of treatment cycles; from an average of 8 cycles, to an average of 14 cycles when comparing to a historical control group of 80 patients. In the first two out of five patients treated（published data, ref below）, the maximum tumor diameter was temporally decreased to 80±5％and permanently to 70±5％of their original size, while the other patients showed reduced growth. Compared to historical data, there was increased survival with 60％of patients surviving 12 months. In conclusion, it is feasible to safely combine ultrasound, microbubbles, and chemotherapy both in an experimental and clinical setting to increase the number of treatment cycles. Our study also indicates increased survival in patients with inoperable, locally advanced pancreatic adenocarcinoma. 【References】 1.Postema M, Gilja OH. Ultrasound-directed drug delivery. Curr Pharm Biotechnol 2007;8（6）:355-361. 2.Kotopoulis S, Delalande A, Popa M, Mamaeva V, Dimcevski G, Gilja OH, Postema M, Gjertsen BT, McCormack E. Sonoporation-Enhanced Chemotherapy Significantly Reduces Primary Tumour Burden in an Orthotopic Pancreatic Cancer Xenograft. Mol Imaging Biol. 2013 Jul 23．［Epub ahead of print］PubMed PMID: 23877869. 3.Kotopoulis S, Dimcevski G, Gilja OH, Hoem D, Postema M. Treatment of human pancreatic cancer using combined ultrasound, microbubbles, and gemcitabine: A clinical case study. Med Phys. 2013 Jul;40（7）:072902. doi: 10.1118/1.4808149. PubMed PMID: 23822453. 4.Postema M, Gilja OH. Contrast-enhanced and targeted ultrasound. WJG 2011;7,17（1）:28-41.