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Retrograde-outflow percutaneous isolated hepatic perfusion using cisplatin: A pilot study on pharmacokinetics and feasibility

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Abstract

Objectives

This study aimed to evaluate the feasibility and underlying pharmacokinetics of the retrograde-outflow technique for percutaneous isolated hepatic perfusion (PIHP).

Methods

Retrograde-outflow PIHP was performed in 12 male pigs (weight, 37–44 kg) by redirecting hepatic outflow through the portal vein. Blood with cisplatin (2.5 mg/kg) in an extracorporeal circuit was circulated through the liver under isolation using rotary pumps with balloon catheters. Hepatic angiographic examinations were conducted during perfusion, and histopathological examinations of the organs were conducted after perfusion. The maximum platinum concentration (C max), area under the concentration-time curve (AUC), and chronologic laboratory data were measured.

Results

Retrograde-outflow isolated hepatic angiography confirmed that contrast media flowed into the portal veins in all 12 pigs. The hepatic veins and inferior vena cava were not opacified. Hepatic C max (86.3 mg/l) was 39-fold greater than systemic C max (2.2 mg/l), and hepatic AUC (1330.8 min · mg/l) was 30-fold greater than systemic AUC (44.6 min · mg/l). Histopathological examinations revealed no ischaemic changes or other abnormalities in the liver, duodenum, small intestine, or colon. Within 1 week of the procedure, chronologic laboratory data (n = 3) normalized or returned to pre-therapy levels.

Conclusions

The retrograde-outflow technique appears to enable safe and feasible PIHP therapy.

Key Points

• The portal vein acted as an outflow tract under retrograde-outflow PIHP.

• Plasma hepatic-to-systemic exposure ratio was 39.2 for the maximum platinum concentration.

• Plasma hepatic-to-systemic exposure ratio was 29.8 for the AUC.

• The retrograde-outflow technique appears to enable safe and feasible PIHP.

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References

  1. Yoon SS, Tanabe KK (1999) Surgical treatment and other regional treatments for colorectal cancer liver metastases. Oncologist 4:197–208

    CAS  PubMed  Google Scholar 

  2. Kemeny N, Fata F (2001) Hepatic-arterial chemotherapy. Lancet Oncol 2:418–428

    Article  CAS  PubMed  Google Scholar 

  3. Nouso K, Miyahara K, Uchida D et al (2013) Effect of hepatic arterial infusion chemotherapy of 5-fluorouracil and cisplatin for advanced hepatocellular carcinoma in the Nationwide Survey of Primary Liver Cancer in Japan. Br J Cancer 109:1904–1907

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Tsai WL, Lai KH, Liang HL et al (2014) Hepatic Arterial Infusion Chemotherapy for Patients with Huge Unresectable Hepatocellular Carcinoma. Plos One. doi:10.1371/journal.pone.0092784

    Google Scholar 

  5. Yamada R, Sato M, Kawabata M, Nakatsuka H, Nakamura K, Takashima S (1983) Hepatic artery embolization in 120 patients with unresectable hepatoma. Radiology 148:397–401

    Article  CAS  PubMed  Google Scholar 

  6. Uchida H, Matsuo N, Sakaguchi H, Nagano N, Nishimine K, Ohishi H (1993) Segmental embolotherapy for hepatic cancer: keys to success. Cardiovasc Interv Radiol 16:67–71

    Article  CAS  Google Scholar 

  7. Ackerman BN (1972) Experimental studies on the circulatory dynamics of intrahepatic tumor blood supply. Cancer 29:435–439

    Article  CAS  PubMed  Google Scholar 

  8. Kan Z, Ivancev K, Lunderquist A et al (1993) In vivo microscopy of hepatic tumors in animal models: a dynamic investigation of blood supply to hepatic metastases. Radiology 187:621–626

    Article  CAS  PubMed  Google Scholar 

  9. Kan Z, Wallace S (1997) Transcatheter liver lobar ablation: an experimental trial in an animal model. Eur Radiol 7:1071–1075

    Article  CAS  PubMed  Google Scholar 

  10. Vahrmeijer AL, van Dierendonck JH, Keizer HJ et al (2000) Increased local cytostatic drug exposure by isolated hepatic perfusion: a phase I clinical and pharmacologic evaluation of treatment with high dose melphalan in patients with colorectal cancer confined to the liver. Br J Cancer 82:1539–1546

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Christoforidis D, Martinet O, Lejeune FJ, Mosimann F (2002) Isolated liver perfusion for non-resectable liver tumours: a review. Eur J Surg Oncol 28:875–890

    Article  CAS  PubMed  Google Scholar 

  12. Rothbarth J, Pijl ME, Vahrmeijer AL et al (2003) Isolated hepatic perfusion with high-dose melphalan for the treatment of colorectal metastasis confined to the liver. Br J Surg 90:1391–1397

    Article  CAS  PubMed  Google Scholar 

  13. Alexander HR Jr, Bartlett DL, Libutti SK et al (2009) Analysis of factors associated with outcome in patients undergoing isolated hepatic perfusion for unresectable liver metastases from colorectal cancer. Ann Surg Oncol 16:1852–1859

    Article  PubMed  Google Scholar 

  14. van Iersel LB, Gelderblom H, Vahrmeijer AL et al (2008) Isolated hepatic melphalan perfusion of colorectal liver metastases: outcome and prognostic factors in 154 patients. Ann Oncol 19:1127–1134

    Article  PubMed  Google Scholar 

  15. Zeh HJ III, Brown CK, Holtzman MP et al (2009) A phase I study of hyperthermic isolated hepatic perfusion with oxaliplatin in the treatment of unresectable liver metastases from colorectal cancer. Ann Surg Oncol 16:385–394

    Article  PubMed  Google Scholar 

  16. Savier E, Azoulay D, Huguet E, Lokiec F, Gil-Delgado M, Bismuth H (2003) Percutaneous isolated hepatic perfusion for chemotherapy: a phase 1 study. Arch Surg 138:325–332

    Article  PubMed  Google Scholar 

  17. Pingpank JF, Libutti SK, Chang R et al (2005) Phase I study of hepatic arterial melphalan infusion and hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies. J Clin Oncol 23:3465–3474

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Ravikumar TS, Pizzorno G, Bodden W et al (1994) Percutaneous hepatic vein isolation and high-dose hepatic arterial infusion chemotherapy for unresectable liver tumors. J Clin Oncol 12:2723–2736

    CAS  PubMed  Google Scholar 

  19. Rothbarth J, Tollenaar RA, Schellens JH et al (2004) Isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: recent trends and perspectives. Eur J Cancer 40:1812–1824

    Article  CAS  PubMed  Google Scholar 

  20. Murata S, Itai Y, Asato M et al (1995) Effect of temporary occlusion of hepatic vein on dual blood supply in the liver: evaluation with spiral CT. Radiology 197:351–356

    Article  CAS  PubMed  Google Scholar 

  21. Murata S, Itai Y, Satake M et al (1997) Changes in contrast enhancement of hepatocellular carcinoma and liver: effect of temporary occlusion of a hepatic vein evaluated with spiral CT. Radiology 202:715–720

    Article  CAS  PubMed  Google Scholar 

  22. van Ijken MG, de Bruijn EA, de Boeck G, ten Hagen TL, van der Sijp JR, Eggermont AM (1998) Isolated hypoxic hepatic perfusion with tumor necrosis factor-α, melphalan, and mitomycin C using balloon catheter techniques a pharmacokinetic study in pigs. Ann Surg 228:763–770

    Article  PubMed Central  PubMed  Google Scholar 

  23. Hafström LR, Holmberg SB, Naredi PL et al (1994) Isolated hyperthermic liver perfusion with chemotherapy for liver malignancy. Surg Oncol 3:103–108

    Article  PubMed  Google Scholar 

  24. Ortega-Deballon P, Facy O, Consolo D et al (2010) Hypoxic single-pass isolated hepatic perfusion of hypotonic cisplatin: Safety study in the pig. Ann Surg Oncol 17:898–906

    Article  PubMed  Google Scholar 

  25. Rothbarth J, Sparidans RW, Beijnen JH et al (2002) Reduced liver uptake of arterially infused melphalan during retrograde rat liver perfusion with unaffected liver tumour uptake. J Pharmacol Exp Ther 303:736–740

    Article  CAS  PubMed  Google Scholar 

  26. Murata S, Jeppsson B, Lunderquist A, Ivancev K (2014) Hemodynamics in rat liver tumor model during retrograde-outflow isolated hepatic perfusion with aspiration from the portal vein: angiography and in vivo microscopy. Acta Radiol 55:737–744

    Article  PubMed  Google Scholar 

  27. Marinelli A, van de Velde CJ, Kuppen PJ et al (1990) A comparative study of isolated liver perfusion versus hepatic artery infusion with mitomycin C in rats. Br J Cancer 62:891–896

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Marinelli A, van Dierendonck JH, van Brakel GM et al (1991) Increasing the effective concentration of melphalan in experimental rat liver tumours: comparison of isolated liver perfusion and hepatic artery infusion. Br J Cancer 64:1069–1075

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. van Etten B, Brunstein F, van Ijken MG et al (2004) Isolated hypoxic hepatic perfusion with orthograde or retrograde flow in patients with irresectable liver metastases using percutaneous balloon catheter techniques: a phase I and II study. Ann Surg Oncol 11:598–605

    Article  PubMed  Google Scholar 

  30. Kan Z, Ivanchev K, Lunderquist A (1994) Peribiliary plexa—important pathways for shunting of iodized oil and silicon rubber solution from the hepatic artery to the portal vein: an experimental study in rats. Invest Radiol 29:671–676

    Article  CAS  PubMed  Google Scholar 

  31. Pilati P, Mocellin S, Rossi CR et al (2004) True versus mild hyperthermia during isolated hepatic perfusion: effects on melphalan pharmacokinetics and liver function. World J Surg 28:775–781

    Article  PubMed  Google Scholar 

  32. Mocellin S, Pilati P, Da Pian P et al (2007) Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease. Ann Surg Oncol 14:802–809

    Article  PubMed  Google Scholar 

  33. van Iersel LB, Veriaan MR, Vahrmeijer AL et al (2007) Hepatic artery infusion of high-dose melphalan at reduced flow during isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: a clinical and pharmacologic evaluation. Eur J Surg Oncol 33:874–881

    Article  PubMed  Google Scholar 

  34. Beheshti MV, Denny DF Jr, Glickman MG et al (1992) Percutaneous isolated liver perfusion for treatment of hepatic malignancy: preliminary report. J Vasc Interv Radiol 3:453–458

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The scientific guarantor of this publication is Satoru Murata. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. This study has received funding by grants from the Third Term Comprehensive Control Research for Cancer, the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceuticals and Medical Devices Agency (PMDA) of the Ministry of Health, Labor and Welfare, and the Grant-in-Aid for Scientific Research (S and B) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. No complex statistical methods were necessary for this paper. Institutional Review Board approval was not required because this was an experimental animal study. Written informed consent was not required for this study because this was an experimental animal study. Approval from the institutional animal care committee was obtained. Some study subjects or cohorts have not been previously reported. Methodology: prospective, experimental, performed at one institution.

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Authors and Affiliations

  1. Department of Radiology/Center for Advanced Medical Technology, Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo, 113-8602, Japan

    Satoru Murata, Shiro Onozawa, Takahiko Mine, Tatsuo Ueda, Fumie Sugihara, Daisuke Yasui & Shin-ichiro Kumita

  2. Department of Diagnostic Radiology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha Kashiwa, Chiba, 277-8577, Japan

    Mitsuo Satake

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  1. Satoru Murata
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Correspondence to Satoru Murata.

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Murata, S., Onozawa, S., Mine, T. et al. Retrograde-outflow percutaneous isolated hepatic perfusion using cisplatin: A pilot study on pharmacokinetics and feasibility. Eur Radiol 25, 1631–1638 (2015). https://doi.org/10.1007/s00330-014-3558-2

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  • DOI: https://doi.org/10.1007/s00330-014-3558-2

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