Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-6bf8c574d5-nvqbz Total loading time: 0 Render date: 2025-03-09T14:48:57.178Z Has data issue: false hasContentIssue false

4 - Pharmacologic Principles of Regional Therapy in the Treatment of Liver Metastases or Primary Liver Tumors

from PART I - PRINCIPLES OF ONCOLOGY

Published online by Cambridge University Press:  18 May 2010

By
Fidel David Huitzil Melendez  and
Nancy Kemeny
Edited by
Jean-François H. Geschwind  and
Michael C. Soulen
Fidel David Huitzil Melendez
Affiliation:
Gastrointestinal Oncology Fellow, Memorial Sloan-Kettering Cancer Center New York, NY
Nancy Kemeny
Affiliation:
Professor of Medicine, Weill Medical College of Cornell University New York, NY
Jean-François H. Geschwind
Affiliation:
The Johns Hopkins University School of Medicine
Michael C. Soulen
Affiliation:
University of Pennsylvania School of Medicine
Get access

Summary

The rationale for regional chemotherapy is to maximize drug concentrations and tumor drug uptake in the target organ and minimize systemic toxicity (1). For regional drug delivery to successfully impact relevant outcomes, several important principles regarding tumor biology, drug pharmacology and delivery systems must be fulfilled (2). The model of liver metastasis from colorectal cancer complies with these principles, as colorectal cancer has a regional pattern of dissemination, with the liver being the only site of metastatic disease for long periods in some cases (3). Other salient features include the selective supply of blood to liver metastases by the hepatic artery (4) and availability of active drugs with suitable pharmacokinetic properties (5).

In this chapter, pharmacological concepts of regional therapy will be reviewed. Desirable pharmacokinetic and pharmacodynamic characteristics of drugs considered for evaluation in the hepatic arterial infusion (HAI) model of regional drug delivery will be discussed, using floxuridine (FUDR) as a model, in the context of patients with colorectal liver-only metastases (CRLM). Also, an evaluation of the pharmacology of currently approved agents for the treatment of metastatic colon cancer and their hypothetical value for regional drug delivery will be preformed. Results of Phase I and Phase II trials of HAI with these drugs, if available, will be explained in terms of the previously established pharmacologic rationale. Finally, for active drugs not already tested, a critical analysis will be done of the available pharmacokinetics data to determine the likelihood of successful incorporation of these drugs to HAI-based therapeutics.

Type
Chapter
Information
Interventional Oncology
Principles and Practice
 , pp. 38 - 52
Publisher: Cambridge University Press
Print publication year: 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Collins, J M. Pharmacologic rationale for regional drug delivery. J Clin Oncol 1984; 2: 498–504.CrossRefGoogle ScholarPubMed
Kemeny NE, D'Angelica M, and Saldinger PF. Intra-arterial chemotherapy for liver tumors. In: Blumgart, LH. (ed.), Surgery of the Liver, Biliary Tract and Pancreas, pp. 1321–1337. Elsevier Mosby: Philadelphia 2007.Google Scholar
Weiss, L. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol 1986; 150(3): 195–203.CrossRefGoogle Scholar
Sigurdson, E R. Tumor and liver drug uptake following hepatic artery and portal vein infusion. J Clin Oncol 1987; 5(11): 1836–1840.CrossRefGoogle ScholarPubMed
Ensminger, W D. A clinical-pharmacological evaluation of hepatic arterial infusions of 5-fluoro-2′-deoxyuridine and 5-fluorouracil. Cancer Res 1978; 38(11 Pt 1): 3784–3792.Google ScholarPubMed
Arteaga, C L and Baselga, J. Clinical trial design and end points for epidermal growth factor receptor-targeted therapies: Implications for drug development and practice. Clin Cancer Res 2003; 9(5): 1579–1589.Google ScholarPubMed
Ensminger, W D. Intrahepatic arterial infusion of chemotherapy: pharmacologic principles. Semin Oncol 2002; 29(2): 119–15.CrossRefGoogle ScholarPubMed
Laar, J A. Comparison of 5-fluoro-2′-deoxyuridine with 5-fluorouracil and their role in the treatment of colorectal cancer. Eur J Cancer 1998; 34(3): 296–306.CrossRefGoogle ScholarPubMed
Park, J G. Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human colorectal carcinoma cell lines. J Natl Cancer Inst 1988; 80(19): 1560–1564.CrossRefGoogle ScholarPubMed
Wagner, J G. Steady-state nonlinear pharmacokinetics of 5-fluorouracil during hepatic arterial and intravenous infusions in cancer patients. Cancer Res 1986; 46(3): 1499–1506.Google ScholarPubMed
Ragnhammar, P. A systematic overview of chemotherapy effects in colorectal cancer. Acta Oncol 2001; 40(2–3): 282–308.CrossRefGoogle ScholarPubMed
Boublil, J L. Continuous 5-day regional chemotherapy by 5-fluorouracil in colon carcinoma: Pharmacokinetic evaluation. Br J Cancer 1985; 52(1): 15–20.CrossRefGoogle ScholarPubMed
Goldberg, J A. Pharmacokinetics and pharmacodynamics of locoregional 5 fluorouracil (5FU) in advanced colorectal liver metastases. Br J Cancer 1988; 57(2): 186–189.CrossRefGoogle Scholar
Grage, T, et al. Results of a prospective randomized study of hepatic artery infusion with 5-fluorourcail vs intravenous 5-fluorouracil in patients with hepatic metastases from colorectal cancer: A Central Oncology Group study. Surgery 1979; 86: 550–555.Google Scholar
Iyer, L and Ratain, M J. Clinical pharmacology of camptothecins. Cancer Chemother Pharmacol 1998; 42(Suppl): S31–S43.CrossRefGoogle ScholarPubMed
Abigerges, D. Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 1995; 13(1): 210–221.CrossRefGoogle ScholarPubMed
Herben, V M. Phase I and pharmacokinetic study of irinotecan administered as a low-dose, continuous intravenous infusion over 14 days in patients with malignant solid tumors. J Clin Oncol 1999; 17(6): 1897–1905.CrossRefGoogle ScholarPubMed
Ohe, Y. Phase I study and pharmacokinetics of CPT-11 with 5-day continuous infusion. J Natl Cancer Inst 1992; 84(12): 972–974.CrossRefGoogle ScholarPubMed
Riel, J M. Continuous administration of irinotecan by hepatic arterial infusion: a phase I and pharmacokinetic study. Clin Cancer Res 2002; 8: 408–412.Google ScholarPubMed
Riel, J M. Continuous infusion of hepatic arterial irinotecan in pretreated patients with colorectal cancer metastatic to the liver. Ann Oncol 2004; 15(1): 59–63.CrossRefGoogle ScholarPubMed
Desoize, B and Madoulet, C. Particular aspects of platinum compounds used at present in cancer treatment. Crit Rev Oncol Hematol 2002; 42(3): 317–325.CrossRefGoogle ScholarPubMed
Kweekel, D M, Gelderblom, H, and Guchelaar, H J. Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy. Cancer Treatment Reviews 2005; 31(2): 90–105.CrossRefGoogle ScholarPubMed
Kornmann, M. Oxaliplatin exerts potent in vitro cytotoxicity in colorectal and pancreatic cancer cell lines and liver metastases. Anticancer Res 2000; 20(5A): 3259–3264.Google ScholarPubMed
Raymond, E. Oxaliplatin: A review of preclinical and clinical studies. Ann Oncol 1998; 9(10): 1053–1071.CrossRefGoogle ScholarPubMed
Rothenberg, M I. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol 2003; 21: 2059–2069.CrossRefGoogle ScholarPubMed
Tournigand, C. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 2004; 22(2): 229–237.CrossRefGoogle ScholarPubMed
Graham, M A. Clinical pharmacokinetics of oxaliplatin: A critical review. Clin Cancer Res 2000; 6(4): 1205–1218.Google ScholarPubMed
Kern, W. Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin in combination with folinic acid and 5-fluorouracil in patients with hepatic metastases from colorectal cancer. Ann Oncol 2001; 12(5): 599–603.CrossRefGoogle Scholar
Guthoff, I. Hepatic artery infusion using oxaliplatin in combination with 5-fluorouracil, folinic acid and mitomycin C: Oxaliplatin pharmacokinetics and feasibility. Anticancer Res 2003; 23(6D): 5203–5208.Google ScholarPubMed
Mancuso, A. Hepatic arterial continuous infusion (HACI) of oxaliplatin in patients with unresectable liver metastases from colorectal cancer. Anticancer Res 2003; 23(2C): 1917–1922.Google ScholarPubMed
Fiorentini, G. Oxaliplatin hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: A phase I–II clinical study. Anticancer Res 2004; 24(3b): 2093–2096.Google ScholarPubMed
Ducreux, M. Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: A trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol 2005; 23(22): 4881–4887.CrossRefGoogle ScholarPubMed
Kim, K J. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362(6423): 841–844.CrossRefGoogle ScholarPubMed
Jain, R K. Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med 2001; 7(9): 987–989.CrossRefGoogle ScholarPubMed
Kabbinavar, F. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21(1): 60–65.CrossRefGoogle ScholarPubMed
Hurwitz, H. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350(23): 2335–2342.CrossRefGoogle ScholarPubMed
Hsei VC, et al. Population pharmacokinetic (PK) analysis of bevacizumab (BV) in cancer subjects. In ASCO Annual Meeting 2001.
Herbst, R S. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol 2005; 23(11): 2544–2555.CrossRefGoogle ScholarPubMed
Chung, K Y. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005; 23(9): 1803–1810.CrossRefGoogle Scholar
Scaltriti, M and Baselga, J. The epidermal growth factor receptor pathway: A model for targeted therapy. Clin Cancer Res 2006; 12(18): 5268–5272.CrossRefGoogle ScholarPubMed
Goldstein, N I. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995; 1(11): 1311–1318.Google Scholar
Baselga, J. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 2000; 18(4): 904–914.CrossRefGoogle ScholarPubMed
Saltz, L B. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004; 22(7): 1201–1208.CrossRefGoogle ScholarPubMed
Cunningham, D. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351(4): 337–345.CrossRefGoogle ScholarPubMed
Cohenuram, M and Saif, M W. Panitumumab, the first fully human monoclonal antibody: From the bench to the clinic. Anticancer Drugs 2007; 18(1): 7–15.CrossRefGoogle ScholarPubMed
Rowinsky, E K. Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer. J Clin Oncol 2004; 22(15): 3003–3015.CrossRefGoogle ScholarPubMed
Hecht, J P. ABX-EGF monotherapy in patients (pts) with metastatic colorectal cancer (mCRC): An updated analysis. In ASCO Annual Meeting 2004.Google Scholar
Hecht, J P. Panitumumab in combination with 5-fluorouracil, leucovorin, and irinotecan (IFL) or FOLFIRI for first-line treatment of metastatic colorectal cancer (mCRC). In Gastrointestinal Cancers Symposium. 2006. San Francisco.Google Scholar
Peeters M, et al. A Phase 3, multicenter, randomized controlled trial of panitumumab plus best supportive care (BSC) vs. BSC alone in patients with metastatic colorectal cancer. In American Association for Cancer Research Annual Meeting 2006.
Lobo, E D, Hansen, R J, and Balthasar, J P. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 2004; 93(11): 2645–2668.CrossRefGoogle ScholarPubMed
Brody T. Introductions and definitions. In: Minneman, K (ed.), Brody's Human Pharmacology, pp. 3–8. Philadelphia: Elsevier-Mosby, 2005.Google Scholar
Somogyi A. Clinical pharmacokinetics and issues in therapeutics. In: Minneman, K (ed.), Brody's Human Pharmacology, pp. 41–56. Philadelphia: Elsevier-Mosby, 2005.Google Scholar
Hollenberg P. Absorption, distribution, metabolism, and elimination. In: Minneman, K (ed.), Brody's Human Pharmacology, pp. 27–39. Philadelphia: Elsevier-Mosby, 2005.Google Scholar
Minneman K P. Receptors and concentration-response relationships. In: Minneman, K (ed.), Brody's Human Pharmacology, pp. 9–25. Philadelphia: Elsevier-Mosby, 2005.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×