Annals of Surgical Oncology

, Volume 1, Issue 5, pp 389–399 | Cite as

Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: A phase I study

  • Steven A. Curley
  • Robert A. Newman
  • Thomas B. Dougherty
  • George M. Fuhrman
  • Diana L. Stone
  • Jeffrey A. Mikolajek
  • Sal Guercio
  • Ann Guercio
  • C. Humberto Carrasco
  • M. Tien Kuo
  • David C. Hohn


Background: We performed a phase I study of a novel system of complete hepatic venous isolation and extracorporeal chemofiltration in patients with unresectable hepatocellular carcinoma (HCC) to determine (a) whether systemic exposure to doxorubicin could be limited after high-dose hepatic arterial infusion (HAI), and (b) the hepatic maximum tolerated dose (MTD) of doxorubicin.

Methods: Ten patients with biopsy-proven HCC were treated with 20-min HAI of doxorubicin (17 total treatments). Two patients were treated with doxorubicin 60 mg/m2, three patients were treated at 90 mg/m2, and five patients received 120 mg/m2. A newly developed dual-balloon vena cava catheter was advanced from the femoral vein, and the balloons were inflated to isolate and capture total hepatic venous outflow. The hepatic venous blood was pumped through extracorporeal carbon chemofilters before return of the blood to the systemic circulation.

Results: Peak systemic doxorubicin levels were an average 85.6% lower than were peak prefilter levels (p<0.01). Because all catheters were placed percutaneously and because the chemofiltration markedly limited systemic chemotherapy exposure, patients were discharged 1 day after 16 of the 17 treatments. The hepatic and systemic MTD of doxorubicin in this treatment protocol was 120 mg/m2.

Conclusions: This novel system of complete hepatic venous isolation and chemofiltration limits systemic chemotherapy toxicity and will allow use of higher doses of chemotherapeutic agents to treat HCC.

Key Words

Hepatocellular cancer Venous isolation Hemofiltration Doxorubicin 


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  1. 1.
    Linsell A. Primary liver cancer: epidemiology and etiology. In: Wanebo JH, ed.Hepatic and biliary cancer. New York: Marcel Dekker, 1987:3–15.Google Scholar
  2. 2.
    Rustgi V. Epidemiology of hepatocellular cancer.Ann Intern Med 1988;108:390–401.PubMedGoogle Scholar
  3. 3.
    Olweny CLM, Toya T, Katongole-Mbidde E, Mugerwa J, Kyalwazi SK, Cohen H. Treatment of hepatocellular carcinoma with adriamycin.Cancer 1975;36:1250–7.PubMedGoogle Scholar
  4. 4.
    Bern MM, McDermott W, Cady B, Oberfield RA, Trey C, Clouse E, et al. Intra-arterial hepatic infusion and intravenous adriamycin for treatment of hepatocellular carcinoma.Cancer 1978;42:399–405.PubMedGoogle Scholar
  5. 5.
    Garnick MB, Ensminger WD, Israel M. A clinical-pharmacologic evaluation of hepatic arterial infusion of adriamycin.Cancer Res 1979;39:4105–10.PubMedGoogle Scholar
  6. 6.
    Chen HSG, Gross JF. Intra-arterial infusion of anticancer drugs: theoretic aspects of drug delivery and review of responses.Cancer Treatment Rep 1980;64:31–40.Google Scholar
  7. 7.
    Harris PA, Gross JF. Preliminary pharmacokinetic model for adriamycin (NSC-123127).Cancer Chemother Rep 1975;59:819–25.PubMedGoogle Scholar
  8. 8.
    Ballet F, Vrignaud P, Robert J, Rey C, Poupon R. Hepatic extraction, metabolism, and biliary excretion of doxorubicin in the isolated perfused rat liver.Cancer Chemother Pharmacol 1987;19:240–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Frei E, Canellos GP. Dose: a critical factor in cancer chemotherapy.Am J Med 1980;69:585–94.CrossRefPubMedGoogle Scholar
  10. 10.
    Robert J. Extraction of anthracyclines from biologic fluids for HPLC evaluation.J Liquid Chromatogr 1980;3:1561–72.Google Scholar
  11. 11.
    O'Connell MJ, Hahn RG, Rubin J, Moertel CG. Chemotherapy of malignant hepatomas with sequential intra-arterial doxorubicin and systemic 5-fluorouracil and semustine.Cancer 1988;62:1041–3.PubMedGoogle Scholar
  12. 12.
    Kemeny N, Daly J, Reichman B, Geller N, Botet J, Oderman P. Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma.Ann Intern Med 1987;107:459–65.PubMedGoogle Scholar
  13. 13.
    Hohn DC, Stagg RJ, Friedman MA, Hannigan JF, Rayner A, Ignoffo RJ, Chase J, et al. A randomized trial of continuous intravenous versus hepatic intra-arterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group trial.J Clin Oncol 1989;7:1646–54.PubMedGoogle Scholar
  14. 14.
    Legha SS, Benjamin RS, MacKay B, Ewer M, Wallace S, Valdivieso M, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion.Ann Intern Med 1982;96:133–9.PubMedGoogle Scholar
  15. 15.
    Dedrick RL. Arterial drug infusion: pharmacokinetic problems and pitfalls.J Natl Cancer Inst 1988;80:84–9.PubMedGoogle Scholar
  16. 16.
    Collins JM. Pharmacologic rationale for regional drug delivery.J Clin Oncol 1984;2:498–504.PubMedGoogle Scholar
  17. 17.
    Sasaki Y, Imaoka S, Hasegawa Y, Nakahanos, Ishikawa O, Ohigashi O, et al. Changes in distribution of hepatic blood flow induced by intra-arterial infusion of angiotensin II in human hepatic cancer.Cancer 1985;55:311–6.PubMedGoogle Scholar
  18. 18.
    Wright KC, Wallace S, Benjamin RS, Dodd GD. Experimental comparison between hepatic artery infusion and occlusion-infusion of adriamycin.Cancer Drug Delivery 1987;4:33–41.PubMedGoogle Scholar
  19. 19.
    Stagg RJ, Venook AP, Chase JL, Lewis BJ, Warren RS, Roh M, Mulvihill SJ, et al. Alternating hepatic intra-arterial floxuridine and fluorouracil: a less toxic regimen of liver metastases from colorectal cancer.J Natl Cancer Inst 1991;83:423–8.PubMedGoogle Scholar
  20. 20.
    Winchester JF, Rahman A, Tilstone WJ, Kessler A, Mortensen L. Sorbent removal of adriamycinin vitro andin vivo.Cancer Treatment Rep 1979;63:1787–93.Google Scholar
  21. 21.
    Kihara T, Nakazawa H, Agishi T, Honda H, Ota K. Superiority of selective bolus infusion and simultaneous rapid removal of anticancer agents by charcoal hemoperfusion in cancer treatment.Trans Am Soc Artificial Intern Organs 1988;34:581–4.Google Scholar
  22. 22.
    Aigner KR, Muller H, Walther H. Drug filtration in high-dose regional chemotherapy. In: Aigner KR, Patt YZ, Link KH, Kreidler J, eds.Contributions to oncology. Basel, Switzerland: Karger, 1988:261–73.Google Scholar
  23. 23.
    Oldfield EH, Dedrick RL, Yeager RL, Clark WC, DeVroom HD, Chatterji DC. Reduced systemic drug exposure by combining intra-arterial chemotherapy with hemoperfusion of regional venous drainage.J Neurosurg 1985;63:726–32.PubMedGoogle Scholar
  24. 24.
    Teates CD. Radiologic techniques in the diagnosis and treatment of liver tumors. In: Wanebo HJ, ed.Hepatic and biliary cancer. New York: Marcel Dekker, 1987:57–95.Google Scholar
  25. 25.
    Beasley RP, Linn CC, Hwang LY. Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22,707 men in Taiwan.Lancet 1981;2:1129–32.PubMedGoogle Scholar
  26. 26.
    Nakanuma J, Ohta G. Morphology of cirrhosis and occurrence of hepatocellular carcinoma in alcoholics with and without HBsAg and in nonalcoholic HBsAg positive patients: a comparative study.Liver 1983;3:231–7.PubMedGoogle Scholar
  27. 27.
    Curley SA, Byrd DR, Newman RA, Ellis HJ, Chase J, Carrasco CH, Cleary K, et al. Reduction of systemic drug exposure following hepatic arterial infusion of doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration.Surgery 1993;114:579–85.PubMedGoogle Scholar
  28. 28.
    Curley SA, Stone DL, Fuhrman GM, Hohn DC, Siddik ZH, Newman RA. Increased doxorubicin levels in hepatic tumors with reduced systemic drug exposure achieved with complete hepatic venous isolation and extracorporeal chemofiltration.Cancer Chemother Pharmacol 1993;33:251–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Curley SA, Byrd DR, Newman RA, Carrasco CH, Cromeens D, Ellis HJ, Chase J, et al. Hepatic arterial infusion chemotherapy with complete hepatic venous isolation and extracorporeal chemofiltration: a feasibility study of a novel system.Anticancer Drugs 1991;2:175–83.PubMedGoogle Scholar
  30. 30.
    Moscow JA, Cowan KH. Multidrug resistance. In: Pinedo HM, Longo DL, Chabner BA, eds.Cancer chemotherapy and biologic response modifiers annual 12. New York: Elsevier Science, 1991:91–109.Google Scholar
  31. 31.
    Moscow JA, Fairchild CR, Madden MJ, Ransom DT, Wieand HS, O'Brien EE. Expression of anionic glutathione-S-transferase and P-glycoprotein in human tissues and tumors.Cancer Res 1989;49:1422–8.PubMedGoogle Scholar
  32. 32.
    Ford JM, Hait WN. Pharmacology of drugs that alter multidrug resistance in cancer.Pharmacol Rev 1990;42:155–99.PubMedGoogle Scholar
  33. 33.
    Sridhar R, Dwivedi C, Anderson J, Baker PB, Desai P, Engineer FN. Effects of verapamil on the acute toxicity of doxorubicinin vivo.J Natl Cancer Inst 1992;84:1653–60.PubMedGoogle Scholar

Copyright information

© The Society of Surgical Oncology, Inc. 1994

Authors and Affiliations

  • Steven A. Curley
    • 6
  • Robert A. Newman
    • 2
  • Thomas B. Dougherty
    • 1
  • George M. Fuhrman
    • 6
  • Diana L. Stone
    • 2
  • Jeffrey A. Mikolajek
    • 1
  • Sal Guercio
    • 5
  • Ann Guercio
    • 5
  • C. Humberto Carrasco
    • 3
  • M. Tien Kuo
    • 4
  • David C. Hohn
    • 6
  1. 1.Department of AnesthesiologyUniversity of Texas M. D. Anderson Cancer CenterUSA
  2. 2.Department of Clinical InvestigationsUniversity of Texas M. D. Anderson Cancer CenterUSA
  3. 3.Department of Diagnostic RadiologyUniversity of Texas M. D. Anderson Cancer CenterUSA
  4. 4.Department of Molecular PathologyUniversity of Texas M. D. Anderson Cancer CenterUSA
  5. 5.Department of Cardiac PerfusionTexas Heart InstituteHoustonUSA
  6. 6.Department of Surgical OncologyThe University of Texas M. D. Anderson Cancer CenterHoustonUSA

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