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Implantable Pump For Long-Term Chemotherapy Administration Via the Hepatic Artery: Has It Fulfilled Its Promise?

University of Medicine and Dentistry of New Jersey; Robert Wood Johnson Medical School; The Cancer Institute of New Jersey, Brunswick, NJ

The 1983 editorial was written to highlight an article from Weiss et al¹ utilizing an implantable pump, a technical advance that allowed long-term, relatively safe, hepatic artery infusions (HAI) of chemotherapy for patients with primary or metastatic lesions in the liver.^2,3 Metastatic spread to the liver occurs in 50% to 60% of patients with colorectal cancer, and eventually leads to death in those individuals not cured by surgery, because of tumor size, involvement of both lobes, or insufficient liver reserve. Long-term intra-arterial chemotherapy has the potential to deliver higher doses of drug to the tumors compared with systemic treatment and with less systemic toxicity. The ideal drug in this regard is florodeoxyuridine (FUDR), as it is metabolized rapidly by the liver (first pass); thus, only small amounts escape into the circulation.

What has happened during the past 25 years? As predicted in the editorial, the implantable pump has allowed "the exploration of other drugs and dosage schedules, as well as innovative techniques to deliver drugs at the tumor site."¹ Various drugs have been delivered via HAI to treat colorectal cancer; however, no single agent has been proven to be better than FUDR. The addition of LV has increased the response rate, and dexamethasone (Dex) has decreased the incidence of biliary toxicity, the major toxicity of HAI.⁴ Drawbacks to the use of implanted pumps for HAI have been the cost, and the need for an experienced team of surgeons and medical oncologists.⁵ The effort required and the lack of clear benefit,⁶ together with advances in the systemic treatment of liver metastases from colorectal cancer have relegated this approach to a few centers with expertise and with innovative ideas that attempt to utilize HAI to deliver novel therapies, such as replicating viruses to the tumor,^7,8 or to use intra-arterial FUDR in combination with systemic therapy to deal with systemic spread of tumor despite control of liver metastases.

Two recent studies deserve mention. The first is a Cancer and Leukemia Group B study⁹ that illustrates the difficulty of doing a randomized trial of HAI versus systemic drug delivery. In this multi-institutional 24-month trial that took 4 years to accumulate 135 patients, the overall survival was significantly longer for patients receiving FUDR/LV/Dex via HAI (24 months) as compared with patients treated with systemic fluorouracil/LV using the 5-day schedule (20 months). Previous studies demonstrated a doubling of the response rate with HAI, but not an increase in survival.⁶ The second recent study of note added either systemic oxaliplatin plus irinotecan to intra-arterial FUDR/Dex or systemic oxaliplatin, FU/LV to intra-arterial FUDR. Although a small study, the responses of patients were 90% for the first regimen and 87% for the second regimen. Remarkably, seven of 18 patients treated with the oxalopitecan plus irinotecan plus FUDR/Dex regimen became operable and had residual tumor resected.¹⁰

Where do we go from here? Clearly, as systemic therapy of colorectal cancer improves, we may eventually forgo the use of HAI and the need for the implantable pump. However, given that the best way to deliver a fluoropyrimidine to patients with hepatic metastases from colorectal cancer is via HAI, the combination of systemic chemotherapy and intra-arterial chemotherapy with FUDR, in patients with isolated liver metastases that are not candidates for resection makes sense. This option seems also to more effective in patients with liver metastases in first relapse after initial therapy as compared with systemic therapy.¹¹ The implantable pump has fulfilled its promise, and we look forward to additional innovative use of this method to deliver antitumor agents to the liver to improve the outcome of patients with liver metastases from colorectal cancer.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Weiss GR, Garnick MB, Osteen RT, et al: Long term hepatic arterial infusion of 5-fluorodeoxuridine for liver metastasis using an implantable infusion pump. J Clin Oncol 1:337-334, 1983[Abstract]

2. Ensminger N, Niederhuber J, Dakhil S, et al: Totally implanted drug delivery system for hepatic arterial chemotherapy. Cancer Treat Rep 65:393-400, 1981[Medline]

3. Barone RM, Byfield JE, Goldfarb PB, et al: Intra-arterial chemotherapy using an implantable infusion pump and liver irradiation for the treatment of hepatic metastasis. Cancer 50:850-862, 1982[Medline]

4. Kemeny N, Conti JA, Cohen A, et al: Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma. J Clin Oncol 12:2288-2295, 1994[Abstract/Free Full Text]

5. Allen PJ, Nissan A, Picon AI, et al: Technical complications and durability of hepatic artery infusion pumps for unresectable colorectal liver metastases: An institutional experience of 544 consecutive cases. J Am Coll Surg 201:57-65, 2005[CrossRef][Medline]

6. Mocellin S, Pilati P, Lise M, et al: Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: The end of an era? J Clin Oncol 25:5649-5654, 2007[Abstract/Free Full Text]

7. Kemeny N, Brown K, Covey A, et al: Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver. Hum Gene Ther 17:1214-1224, 2006[CrossRef][Medline]

8. Reid T, Galanis E, Abbruzzese J, et al: Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: A phase I trial. Gene Ther 8:1618-1626, 2001[CrossRef][Medline]

9. Kemeny N, Niedzwiecki D, Hollis D, et al: Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: A randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol 24:1395-1403, 2006[Abstract/Free Full Text]

10. Kemeny N, Jarnagin W, Paty P, et al: Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. J Clin Oncol 23:4888-4896, 2005[Abstract/Free Full Text]

11. Gallagher DJ, Capanu M, Raggio G, et al: Hepatic arterial infusion plus systemic irinotecan in patients with unresectable hepatic metastases from colorectal cancer previously treated with systemic oxaliplatin: A retrospective analysis. Ann Oncol 18:1995-1999, 2007[Abstract/Free Full Text]

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This Article Full Text (PDF) From JCO 1983 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Google Scholar Articles by Bertino, J. R. PubMed PubMed Citation Articles by Bertino, J. R. Related Articles Related Article