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In Reply:

Memorial Sloan-Kettering Cancer Center, New York, NY

We appreciate the interest Dr Fiorentini et al showed in our paper. Their suggestion is that we use irinotecan instead of floxuridine (FUDR) via hepatic arterial infusion (HAI) pump to treat patients after liver resection.^1,2 They reason that if thymydylate synthetase (TS) levels in liver metastases are high, FUDR may not be the appropriate drug. However, we have demonstrated in previous work that in patients being treated with FUDR, the levels of TS did not affect survival.³ This may be because with regional therapy, high levels of the drug can be administered, and this may overcome the negative effect seen in patients with high TS levels when systemic fluorouracil (FU) is used.

Fiorentini et al give rational pharmacologic reasons to use HAI irinotecan therapy. In their phase II study, there was a 30% (four of 12 patients)⁴ response rate in patients with HAI irinotecan, while in a phase II study at Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY) using HAI FUDR and dexamethasone (Dex) plus systemic irinotecan, the response rate even in previously treated patients was 74% (28 of 38 patients).⁵ In addition, there is no information that irinotecan is extracted by the liver. In fact, the maximum tolerated dose (MTD) when administered via HAI is similar to the MTD when given intravenously.⁶

The objective in our adjuvant study after liver resection using HAI FUDR and Dex with systemic irinotecan was to have better control of the extrahepatic disease. As mentioned by Fiorentini et al, we felt that extrahepatic control with systemic FU was not enough because lung metastases express higher levels of TS.⁷ As far as local control, we felt that studies at MSKCC showed good local control with no recurrence in the liver in 70% of patients receiving HAI FUDR plus Dex plus systemic FU/leucovorin versus 40% receiving systemic therapy alone.² Perhaps systemic irinotecan could improve local control.

Author's Disclosures of Potential Conflicts of Interest

The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Honoraria: Nancy E. Kemeny, Codman, Sanofi, Pfizer. Research Funding: Nancy E. Kemeny, Codman, Sanofi, Pfizer. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.

REFERENCES

1. Kemeny N, Jarnagin W, Gonen M, et al: Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer. J Clin Oncol 21:3303-3309, 2003[Abstract/Free Full Text]

2. Kemeny N, Huang Y, Cohen AM, et al: Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341:2039-2048, 1999[Abstract/Free Full Text]

3. Gonen M, Hummer A, Zervoudakis A, et al: Thymidylate synthase expression in hepatic tumors is a predictor of survival and progression in patients with resectable metastatic colorectal cancer. J Clin Oncol 21:406-412, 2003[Abstract/Free Full Text]

4. Fiorentini G, Ricci Lucci S, Giovanis P, et al: Irinotecan hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: Results of a phase I clinical study. Tumori 87:388-390, 2001[Medline]

5. Kemeny N, Gonen M, Sullivan D, et al: Phase I study of hepatic arterial infusion of floxuridine and dexamethasone with systemic irinotecan for unresectable hepatic metastases from colorectal cancer. J Clin Oncol 19:2687-2695, 2001[Abstract/Free Full Text]

6. van Riel JM, Van Groeningen CJ, Kedde MA, et al: Continuous administration of irinotecan by hepatic arterial infusion: A phase I and pharmacokinetic study. Clin Cancer Res 8:405-412, 2002[Abstract/Free Full Text]

7. Gorlick R, Metzger R, Danenberg KD, et al: Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma. J Clin Oncol 16:1465-1469, 1998[Abstract/Free Full Text]

Related Correspondence

• Is There a New Drug Beyond Floxuridine for Intra-Arterial Hepatic Chemotherapy in Liver Metastases From Colorectal Cancer?
  G. Fiorentini, S. Rossi, P. Bernardeschi, M. Cantore, and S. Guadagni
  JCO 2005 23: 2105 [Full Text]

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