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Published in: Annals of Surgical Oncology 5/2008

Open Access 01-05-2008 | Hepatic and Pancreatic Tumors

Isolated Hypoxic Hepatic Perfusion with Retrograde Outflow in Patients with Irresectable Liver Metastases; A New Simplified Technique in Isolated Hepatic Perfusion

Authors: Cornelis Verhoef, MD, Johannes H. W. de Wilt, MD, PhD, Flavia Brunstein, MD, PhD, Andreas W. K. S. Marinelli, MD, PhD, Boudewijn van Etten, MD, PhD, Maarten Vermaas, MD, Gunther Guetens, PhD, Gert de Boeck, PhD, Ernst A. de Bruijn, PhD, Alexander M. M. Eggermont, MD, PhD

Published in: Annals of Surgical Oncology | Issue 5/2008

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Abstract

Background

Isolated hepatic perfusion with high-dose chemotherapy is a treatment option for patients with irresectable metastases confined to the liver. Prolonged local control and impact on survival have been claimed. Major drawbacks are magnitude and costs of the procedure. We developed an isolated hypoxic hepatic perfusion (IHHP) with retrograde outflow without the need for a heart-lung machine.

Patients and Methods

Twenty-four consecutive patients with irresectable metastases of various origins were treated. IHHP inflow was via the hepatic artery, outflow via the portal vein with occlusion of the retrohepatic caval vein. Radiolabeled albumine was used for leakage monitoring. Melphalan was used at 1–2 mg/kg. A 25-minute perfusion period was followed by a complete washout. Local and systemic melphalan concentrations were determined.

Results

Compared with oxygenated classical IHP, the IHPP procedure reduced operation time from >8 h to 4 hours, blood loss from >4000 to 900 cc and saved material and personnel costs. Leakage was 0% with negligible systemic toxicity and 0% perioperative mortality. Tumor response: complete response (CR) in 4%, partial response (PR) in 58%, and stable disease (SD) in 13%. Median time to progression was 9 months (2–24 months); pharmacokinetics demonstrated intrahepatic melphalan concentrations more than 9 fold higher than postperfusion systemic concentrations.

Conclusions

IHPP is a relatively simple procedure with reduced costs, reduced blood loss, no mortality, limited toxicity, and response rates comparable to classic IHP. The median duration of 9 months of tumor control should be improved. Hereto, vasoactive drugs, will be explored in further studies.
Literature
1.
go back to reference Sasson AR, Sigurdson ER. Surgical treatment of liver metastases. Semin Oncol J 2002; 29:107–18CrossRef Sasson AR, Sigurdson ER. Surgical treatment of liver metastases. Semin Oncol J 2002; 29:107–18CrossRef
2.
go back to reference Malafosse R, Penna C, Sa CA, et al. Surgical management of hepatic metastases from colorectal malignancies. Ann Oncol 2001; 12:887–94PubMedCrossRef Malafosse R, Penna C, Sa CA, et al. Surgical management of hepatic metastases from colorectal malignancies. Ann Oncol 2001; 12:887–94PubMedCrossRef
3.
go back to reference Wagner JS, Adson MA, Van Heerden JA, et al. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984; 199:502–8PubMedCrossRef Wagner JS, Adson MA, Van Heerden JA, et al. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann Surg 1984; 199:502–8PubMedCrossRef
4.
go back to reference Verhoef C, de Wilt JHW, Verheul HMW. Angiogenesis inhibitors: perspectives in medical, surgical and radiation oncology. Curr Pharm Des 2006; 12:2623–30PubMedCrossRef Verhoef C, de Wilt JHW, Verheul HMW. Angiogenesis inhibitors: perspectives in medical, surgical and radiation oncology. Curr Pharm Des 2006; 12:2623–30PubMedCrossRef
5.
go back to reference Salmon JS, Lockhart AC, Berlin J. Anti-angiogenic treatment of gastrointestinal malignancies. Cancer Invest 2005; 23:712–26PubMedCrossRef Salmon JS, Lockhart AC, Berlin J. Anti-angiogenic treatment of gastrointestinal malignancies. Cancer Invest 2005; 23:712–26PubMedCrossRef
6.
7.
go back to reference Daly JM, Kemeny N, Sigurdson E, et al. Regional infusion for colorectal hepatic metastases. A randomized trial comparing the hepatic artery with the portal vein. Arch Surg 1987; 122:1273–7PubMed Daly JM, Kemeny N, Sigurdson E, et al. Regional infusion for colorectal hepatic metastases. A randomized trial comparing the hepatic artery with the portal vein. Arch Surg 1987; 122:1273–7PubMed
9.
go back to reference Sterchi JM. Hepatic artery infusion for metastatic neoplastic disease. Surg Gynaecol Obstet 1985; 160:477–89 Sterchi JM. Hepatic artery infusion for metastatic neoplastic disease. Surg Gynaecol Obstet 1985; 160:477–89
10.
go back to reference Alexander HRJ, Bartlett DL, Libutti SK. Current status of isolated hepatic perfusion with or without tumor necrosis factor for the treatment of unresectable cancers confined to liver. Oncologist 2000; 5:416–24PubMedCrossRef Alexander HRJ, Bartlett DL, Libutti SK. Current status of isolated hepatic perfusion with or without tumor necrosis factor for the treatment of unresectable cancers confined to liver. Oncologist 2000; 5:416–24PubMedCrossRef
11.
go back to reference Bartlett DL, Libutti SK, Figg WD, et al. Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer. Surgery 2001; 129:176–87PubMedCrossRef Bartlett DL, Libutti SK, Figg WD, et al. Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer. Surgery 2001; 129:176–87PubMedCrossRef
12.
go back to reference Marinelli A, de Brauw LM, Beerman H, et al. Isolated liver perfusion with mitomycin C in the treatment of colorectal cancer metastases confined to the liver. Jpn J Clin Oncol 1996; 26:341–50PubMed Marinelli A, de Brauw LM, Beerman H, et al. Isolated liver perfusion with mitomycin C in the treatment of colorectal cancer metastases confined to the liver. Jpn J Clin Oncol 1996; 26:341–50PubMed
13.
go back to reference Vahrmeijer AL, van Dierendonck JH, Keizer HJ, et al. 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 2000; 82:1539–46PubMedCrossRef Vahrmeijer AL, van Dierendonck JH, Keizer HJ, et al. 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 2000; 82:1539–46PubMedCrossRef
14.
go back to reference de Vries MR, Borel Rinkes IH, van der Velde CJ, et al. Isolated hepatic perfusion with tumor necrosis factor alpha and melphalan: experimental studies in pigs and phase I data from humans. Recent Results Cancer Res 1998; 147:107–19PubMed de Vries MR, Borel Rinkes IH, van der Velde CJ, et al. Isolated hepatic perfusion with tumor necrosis factor alpha and melphalan: experimental studies in pigs and phase I data from humans. Recent Results Cancer Res 1998; 147:107–19PubMed
15.
go back to reference Rothbarth J, Pijl ME, Vahrmeijer AL, et al. Isolated hepatic perfusion with high-dose melphalan for the treatment of colorectal metastasis confined to the liver. Br J Surg 2003; 90:1391–7PubMedCrossRef Rothbarth J, Pijl ME, Vahrmeijer AL, et al. Isolated hepatic perfusion with high-dose melphalan for the treatment of colorectal metastasis confined to the liver. Br J Surg 2003; 90:1391–7PubMedCrossRef
16.
go back to reference Alexander HR Jr, Libutti SK, Pingpank JF, et al. Isolated hepatic perfusion for the treatment of patients with colorectal cancer liver metastases after irinotecan-based therapy. Ann Surg Oncol 2005; 12:138–44PubMedCrossRef Alexander HR Jr, Libutti SK, Pingpank JF, et al. Isolated hepatic perfusion for the treatment of patients with colorectal cancer liver metastases after irinotecan-based therapy. Ann Surg Oncol 2005; 12:138–44PubMedCrossRef
17.
go back to reference van Etten B, Brunstein F, van IJken MG, et al. 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 2004; 11:598–605PubMedCrossRef van Etten B, Brunstein F, van IJken MG, et al. 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 2004; 11:598–605PubMedCrossRef
18.
go back to reference van IJken MG, de Bruijn EA, de Boeck G, et al. Isolated hypoxic hepatic perfusion with tumor necrosis factor-alpha, melphalan, and mitomycin C using balloon catheter techniques: a pharmacokinetic study in pigs. Ann Surg 1998; 228:763–70PubMedCrossRef van IJken MG, de Bruijn EA, de Boeck G, et al. Isolated hypoxic hepatic perfusion with tumor necrosis factor-alpha, melphalan, and mitomycin C using balloon catheter techniques: a pharmacokinetic study in pigs. Ann Surg 1998; 228:763–70PubMedCrossRef
19.
go back to reference WHO Handbook for Reporting Results of Cancer Treatment. 600 Geneva, World Health Organization. 1979 WHO Handbook for Reporting Results of Cancer Treatment. 600 Geneva, World Health Organization. 1979
20.
go back to reference Tjaden UR, de Bruijn EA. Chromatographic analysis of anticancer drugs. J Chromatogr 1990; 531:235–94PubMedCrossRef Tjaden UR, de Bruijn EA. Chromatographic analysis of anticancer drugs. J Chromatogr 1990; 531:235–94PubMedCrossRef
21.
go back to reference Rothbarth J, Woutersen RA, Sparidans RW, et al. Melphalan antitumor efficacy and hepatotoxicity: the effect of variable infusion duration in the hepatic artery. J Pharmacol Exp Ther 2003; 305:1098–103PubMedCrossRef Rothbarth J, Woutersen RA, Sparidans RW, et al. Melphalan antitumor efficacy and hepatotoxicity: the effect of variable infusion duration in the hepatic artery. J Pharmacol Exp Ther 2003; 305:1098–103PubMedCrossRef
22.
go back to reference Teicher BA, Lazo JS, Sartorelli AC. Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells. Cancer Res 1981; 41:73–81PubMed Teicher BA, Lazo JS, Sartorelli AC. Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells. Cancer Res 1981; 41:73–81PubMed
23.
go back to reference Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 1989; 49:6449–65PubMed Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 1989; 49:6449–65PubMed
24.
go back to reference Rothbarth J, Tollenaar RA, Schellens JH, et al. Isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: recent trends and perspectives. Eur J Cancer 2004; 40:1812–24PubMedCrossRef Rothbarth J, Tollenaar RA, Schellens JH, et al. Isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: recent trends and perspectives. Eur J Cancer 2004; 40:1812–24PubMedCrossRef
25.
go back to reference Rothbarth J, Sparidans RW, Beijnen JH, et al. Reduced liver uptake of arterially infused melphalan during retrograde rat liver perfusion with unaffected liver tumor uptake. J Pharmacol Exp Ther 2002; 303:736–40PubMedCrossRef Rothbarth J, Sparidans RW, Beijnen JH, et al. Reduced liver uptake of arterially infused melphalan during retrograde rat liver perfusion with unaffected liver tumor uptake. J Pharmacol Exp Ther 2002; 303:736–40PubMedCrossRef
26.
go back to reference Grover A, Alexander HR Jr. The past decade of experience with isolated hepatic perfusion. Oncologist 2004; 9:653–64PubMedCrossRef Grover A, Alexander HR Jr. The past decade of experience with isolated hepatic perfusion. Oncologist 2004; 9:653–64PubMedCrossRef
27.
go back to reference de Wilt JH, van Etten B, Verhoef C, et al. Isolated hepatic perfusion: experimental evidence and clinical utility. Surg Clin North Am 2004; 84:627–41PubMedCrossRef de Wilt JH, van Etten B, Verhoef C, et al. Isolated hepatic perfusion: experimental evidence and clinical utility. Surg Clin North Am 2004; 84:627–41PubMedCrossRef
28.
go back to reference Brunstein F, Eggermont AMM, aan de Wiel-Ambagtsheer G, et al. Synergistic antitumor effects of histamine plus melphalan in isolated hepatic perfusion for liver metastases. Ann Surg Oncol 2007; 14:795–801PubMedCrossRef Brunstein F, Eggermont AMM, aan de Wiel-Ambagtsheer G, et al. Synergistic antitumor effects of histamine plus melphalan in isolated hepatic perfusion for liver metastases. Ann Surg Oncol 2007; 14:795–801PubMedCrossRef
29.
go back to reference Hoving S, Brunstein F, aan de Wiel-Ambagtsheer G, et al. Synergistic antitumor response of interleukin 2 with melphalan in isolated limb perfusion in soft tissue sarcoma-bearing rats. Cancer Res 2005; 65:4300–8PubMedCrossRef Hoving S, Brunstein F, aan de Wiel-Ambagtsheer G, et al. Synergistic antitumor response of interleukin 2 with melphalan in isolated limb perfusion in soft tissue sarcoma-bearing rats. Cancer Res 2005; 65:4300–8PubMedCrossRef
30.
31.
go back to reference Seregard S, Kock E. Prognostic indicators following enucleation for posterior uveal melanoma. A multivariate analysis of long-term survival with minimized loss to follow-up. Acta Ophthalmol Scand 1995; 73:340–4PubMedCrossRef Seregard S, Kock E. Prognostic indicators following enucleation for posterior uveal melanoma. A multivariate analysis of long-term survival with minimized loss to follow-up. Acta Ophthalmol Scand 1995; 73:340–4PubMedCrossRef
32.
go back to reference Gragoudas ES, Egan KM, Seddon JM, et al. Survival of patients with metastases from uveal melanoma. Ophthalmology 1991; 98:383–9; discussion 390 Gragoudas ES, Egan KM, Seddon JM, et al. Survival of patients with metastases from uveal melanoma. Ophthalmology 1991; 98:383–9; discussion 390
33.
go back to reference Kath R, Hayungs J, Bornfeld N, et al. Prognosis and treatment of disseminated uveal melanoma. Cancer 1993; 72:2219–23PubMedCrossRef Kath R, Hayungs J, Bornfeld N, et al. Prognosis and treatment of disseminated uveal melanoma. Cancer 1993; 72:2219–23PubMedCrossRef
34.
go back to reference Albert DM, Niffenegger AS, Willson JK. Treatment of metastatic uveal melanoma: review and recommendations. Surv Ophthalmol 1992:429–38PubMedCrossRef Albert DM, Niffenegger AS, Willson JK. Treatment of metastatic uveal melanoma: review and recommendations. Surv Ophthalmol 1992:429–38PubMedCrossRef
35.
go back to reference Noter SL, Rothbarth J, Pijl ME, et al. Isolated hepatic perfusion with high-dose melphalan for the treatment of uveal melanoma metastases confined to the liver. Melanoma Res 2004; 14:67–72PubMedCrossRef Noter SL, Rothbarth J, Pijl ME, et al. Isolated hepatic perfusion with high-dose melphalan for the treatment of uveal melanoma metastases confined to the liver. Melanoma Res 2004; 14:67–72PubMedCrossRef
36.
go back to reference Feldman ED, Pingpank JF, Alexander HR Jr. Regional treatment options for patients with ocular melanoma metastatic to the liver. Ann Surg Oncol 2004; 11:290–7PubMedCrossRef Feldman ED, Pingpank JF, Alexander HR Jr. Regional treatment options for patients with ocular melanoma metastatic to the liver. Ann Surg Oncol 2004; 11:290–7PubMedCrossRef
37.
go back to reference Alexander HR Jr, Libutti SK, Pingpank JF, et al. Hyperthermic isolated hepatic perfusion using melphalan for patients with ocular melanoma metastatic to liver. Clin Cancer Res 2003; 9:6343–9PubMed Alexander HR Jr, Libutti SK, Pingpank JF, et al. Hyperthermic isolated hepatic perfusion using melphalan for patients with ocular melanoma metastatic to liver. Clin Cancer Res 2003; 9:6343–9PubMed
Metadata
Title
Isolated Hypoxic Hepatic Perfusion with Retrograde Outflow in Patients with Irresectable Liver Metastases; A New Simplified Technique in Isolated Hepatic Perfusion
Authors
Cornelis Verhoef, MD
Johannes H. W. de Wilt, MD, PhD
Flavia Brunstein, MD, PhD
Andreas W. K. S. Marinelli, MD, PhD
Boudewijn van Etten, MD, PhD
Maarten Vermaas, MD
Gunther Guetens, PhD
Gert de Boeck, PhD
Ernst A. de Bruijn, PhD
Alexander M. M. Eggermont, MD, PhD
Publication date
01-05-2008
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 5/2008
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-007-9714-z

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