Safety of Endoscopic-Ultrasound-Guided Portal Injection Chemotherapy using Drug-Eluting Microbeads in a Porcine Model
Keywords:Chemotherapy, doxorubicin, endoscopic ultrasound, irinotecan, safety.
Background and Aims: Patients with diffuse liver metastases have systemic chemotherapy as their only treatment option. We developed Endoscopic Ultrasound (EUS)-guided portal injection chemotherapy (EPIC) to increase drug levels in hepatic tissue as a novel new liver directed therapy.
Methods: Sixteen anesthetized pigs were treated with 50 mg of irinotecan (n=8) or doxorubicin (n=8). Half (n=4) of the animals in each drug group were treated with EPIC-injected microbeads or EUS-guided chemotherapy without beads into the inferior vena cava (control). Animals were observed twice daily for 7 days for signs of clinical toxicities. Tissue samples were harvested for histology and drug levels. Blood counts and chemistries were determined pre-treatment and at 7 days.
Results: No toxicities as evidenced by abnormal animal behavior were observed. No significant changes occurred in blood chemistry or blood counts in the irinotecan groups. For doxorubicin, systemic injection significantly decreased albumin, hemoglobin, and white blood cell count (P<.05), with no changes after EPIC. Hepatic histology showed mild foreign body reactions around the beads. No significant histologic changes were seen in other tissue sites. Neither irinotecan nor SN-38 was detectable at 7 days. For doxorubicin, no drug was detected in the plasma or bone marrow. The mean (SD) doxorubicin hepatic levels were non-significantly increased with EPIC vs control (181  vs 151  ng/g). Cardiac doxorubicin levels were significantly lower with EPIC (15  vs 138  ng/g; P=.02).
Conclusions: EPIC using drug-eluting microbeads was safe in this animal model. For doxorubicin, EPIC may be safer than systemic injection.
Faigel DO, Lake DF, Landreth TL, Kelman CC, Marler RJ. EUS-guided portal injection chemotherapy for treatment of hepatic metastases: feasibility in the acute porcine model. Gastrointest Endosc 2016; 83(2): 444-6. https://doi.org/10.1016/j.gie.2015.08.064 DOI: https://doi.org/10.1016/j.gie.2015.08.064
Martin RC, Robbins K, Tomalty D, et al. Transarterial chemoembolisation (TACE) using irinotecan-loaded beads for the treatment of unresectable metastases to the liver in patients with colorectal cancer: an interim report. World J Surg Oncol 2009; 7: 80. https://doi.org/10.1186/1477-7819-7-80 DOI: https://doi.org/10.1186/1477-7819-7-80
Martin R, Geller D, Espat J, et al. Safety and efficacy of trans arterial chemoembolization with drug-eluting beads in hepatocellular cancer: a systematic review. Hepatogastroenterology 2012; 59(113): 255-60.
Martin RC, Joshi J, Robbins K, et al. Hepatic intra-arterial injection of drug-eluting bead, irinotecan (DEBIRI) in unresectable colorectal liver metastases refractory to systemic chemotherapy: results of multi-institutional study. Ann Surg Oncol 2011; 18(1): 192-8. https://doi.org/10.1245/s10434-010-1288-5 DOI: https://doi.org/10.1245/s10434-010-1288-5
Viudez A, Ramirez N, Hernandez-Garcia I, Carvalho FL, Vera R, Hidalgo M. Nab-paclitaxel: a flattering facelift. Crit Rev Oncol Hematol 2014; 92(3): 166-80. https://doi.org/10.1016/j.critrevonc.2014.06.001 DOI: https://doi.org/10.1016/j.critrevonc.2014.06.001
Clark ME, Smith RR. Liver-directed therapies in metastatic colorectal cancer. J Gastrointest Oncol 2014; 5(5): 374-87.
Xing M, Kooby DA, El-Rayes BF, Kokabi N, Camacho JC, Kim HS. Locoregional therapies for metastatic colorectal carcinoma to the liver: an evidence-based review. J Surg Oncol 2014; 110(2): 182-96. https://doi.org/10.1002/jso.23619 DOI: https://doi.org/10.1002/jso.23619
Nguyen KT, Gamblin TC, Geller DA. World review of laparoscopic liver resection: 2,804 patients. Ann Surg 2009; 250(5): 831-41. https://doi.org/10.1097/SLA.0b013e3181b0c4df DOI: https://doi.org/10.1097/SLA.0b013e3181b0c4df
Strickler JH, Hurwitz HI. Palliative treatment of metastatic colorectal cancer: what is the optimal approach? Curr Oncol Rep 2014; 16(1): 363. https://doi.org/10.1007/s11912-013-0363-z DOI: https://doi.org/10.1007/s11912-013-0363-z
Michl P, Gress TM. Current concepts and novel targets in advanced pancreatic cancer. Gut 2013; 62(2): 317-26. https://doi.org/10.1136/gutjnl-2012-303588 DOI: https://doi.org/10.1136/gutjnl-2012-303588
Thota R, Pauff JM, Berlin JD. Treatment of metastatic pancreatic adenocarcinoma: a review. Oncology (Williston Park) 2014; 28(1): 70-4.
Taylor RR, Tang Y, Gonzalez MV, Stratford PW, Lewis AL. Irinotecan drug eluting beads for use in chemoembolization: in vitro and in vivo evaluation of drug release properties. Eur J Pharm Sci 2007; 30(1): 7-14. https://doi.org/10.1016/j.ejps.2006.09.002 DOI: https://doi.org/10.1016/j.ejps.2006.09.002
Namur J, Wassef M, Millot JM, Lewis AL, Manfait M, Laurent A. Drug-eluting beads for liver embolization: concentration of doxorubicin in tissue and in beads in a pig model. J Vasc Interv Radiol 2010; 21(2): 259-67. Erratum in: J Vasc Interv Radiol 2010; 21(4): 596. https://doi.org/10.1016/j.jvir.2009.10.026 DOI: https://doi.org/10.1016/j.jvir.2009.10.026
Lotrionte M, Biondi-Zoccai G, Abbate A, et al. Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am J Cardiol 2013; 112(12): 1980-4. https://doi.org/10.1016/j.amjcard.2013.08.026 DOI: https://doi.org/10.1016/j.amjcard.2013.08.026
Paschos KA, Majeed AW, Bird NC. Natural history of hepatic metastases from colorectal cancer – pathobiological pathways with clinical significance. World J Gastroenterol 2014; 20(14): 3719-3737. https://doi.org/10.3748/wjg.v20.i14.3719 DOI: https://doi.org/10.3748/wjg.v20.i14.3719
Fukuda R, Kelly B, Semenza GL. Vascular Endothelial Growth Factor Gene Expression in Colon Cancer Cells Exposed to Prostaglandin E2 Is Mediated by Hypoxia-inducible Factor 1. Cancer Research 2003; 63: 2330-2334.
Ben-Shabat I, Hansson C, Sternby Eilard M, et al. Isolated hepatic perfusion as a treatment for liver metastases of uveal melanoma. J Vis Exp 2015; 95: e53490. https://doi.org/10.3791/52490 DOI: https://doi.org/10.3791/52490
Sperling J, Ziemann C, Gittler A, Benz-Weiser A, Menger MD, Kollmar O. Tumour growth of rat liver metastases is inhibited by hepatic arterial infusion of the mTOR-inhibitor temsirolimus after portal branch ligation. Clin Exp Metastasis 2015; 32(4): 313-21. https://doi.org/10.1007/s10585-015-9707-4 DOI: https://doi.org/10.1007/s10585-015-9707-4
Xu Y, Li Jing, Wang X, et al. Detection of circulating tumor cells using negative enrichment immunofluorescence an in situ hybridization system in pancreatic cancer. Int J Mol Sci 2017; 18(4): 622. https://doi.org/10.3390/ijms18040622 DOI: https://doi.org/10.3390/ijms18040622