Phase I Trial of Hepatic Artery Infusion of 5-Iodo-2″-deoxyuridine and 5-Fluorouracil in Patients with Advanced Hepatic Malignancy

Biochemically Based Combination Chemotherapy

Scot C. Remick, Al B Benson III, James L. Weese, James K.V. Willson, Guillermo Ramirez, George W. Wirtanen, Dona B. Alberti, Lavonne M. Nieting, Kendra D. Tutsch, Paul H. Fischer, Donald L. Trump

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Abstract

Eighteen patients with hepatic metastases primarily from colorectal carcinoma were treated on a phase I protocol employing hepatic artery infusion (HAI) of 5-fluorouracil (FUra) and 5-iodo-2'-deoxyuridine (IdUrd) via an implantable infusion pump. Patients received a 14-day continuous HAI of 300 mg/day FUra. During days 8–14 of therapy, patients received IdUrd as a separate 3-h HAI daily × 7. Treatment cycles were repeated every 28 days. IdUrd was escalated from 0.1 to 2.86 mg/kg/day × 7. Myelosuppression and stomatitis were mild and not dose limiting. Hepatotoxicity was dose limiting and similar to that reported for 5-fluoro-2″-deoxyuridine alone administered as a 14-day infusion every month. One patient developed a clinical picture consistent with sclerosing cholangitis and another had biopsy-proven cholestasis and triaditis. Catheter complications occurred in 7 of 18 patients. Plasma concentrations of FUra during the 7-day continuous HAI of FUra alone were consistently either undetectable or very low (≤0.1 μm). At level 3 (1.0 mg/kg/day IdUrd) and beyond, measurable plasma concentrations of FUra, iodouracil, and IdUrd were found at the end of the daily 3-h infusion of IdUrd. The maximum tolerated dose of IdUrd as administered in this trial is 2.2 mg/kg/day × 7 and the recommended starting dose for further clinical investigation is 1.7 mg/kg/day × 7.

Original languageEnglish (US)
Pages (from-to)6437-6442
Number of pages6
JournalCancer Research
Volume49
Issue number22
StatePublished - Nov 15 1989

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Idoxuridine
Deoxyuridine
Hepatic Artery
Combination Drug Therapy
Fluorouracil
Liver
Neoplasms
Implantable Infusion Pumps
Sclerosing Cholangitis
Stomatitis
Maximum Tolerated Dose
Cholestasis
Colorectal Neoplasms
Catheters
Neoplasm Metastasis
Biopsy
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Remick, Scot C. ; Benson III, Al B ; Weese, James L. ; Willson, James K.V. ; Ramirez, Guillermo ; Wirtanen, George W. ; Alberti, Dona B. ; Nieting, Lavonne M. ; Tutsch, Kendra D. ; Fischer, Paul H. ; Trump, Donald L. / Phase I Trial of Hepatic Artery Infusion of 5-Iodo-2″-deoxyuridine and 5-Fluorouracil in Patients with Advanced Hepatic Malignancy : Biochemically Based Combination Chemotherapy. In: Cancer Research. 1989 ; Vol. 49, No. 22. pp. 6437-6442.
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title = "Phase I Trial of Hepatic Artery Infusion of 5-Iodo-2″-deoxyuridine and 5-Fluorouracil in Patients with Advanced Hepatic Malignancy: Biochemically Based Combination Chemotherapy",
abstract = "Eighteen patients with hepatic metastases primarily from colorectal carcinoma were treated on a phase I protocol employing hepatic artery infusion (HAI) of 5-fluorouracil (FUra) and 5-iodo-2'-deoxyuridine (IdUrd) via an implantable infusion pump. Patients received a 14-day continuous HAI of 300 mg/day FUra. During days 8–14 of therapy, patients received IdUrd as a separate 3-h HAI daily × 7. Treatment cycles were repeated every 28 days. IdUrd was escalated from 0.1 to 2.86 mg/kg/day × 7. Myelosuppression and stomatitis were mild and not dose limiting. Hepatotoxicity was dose limiting and similar to that reported for 5-fluoro-2″-deoxyuridine alone administered as a 14-day infusion every month. One patient developed a clinical picture consistent with sclerosing cholangitis and another had biopsy-proven cholestasis and triaditis. Catheter complications occurred in 7 of 18 patients. Plasma concentrations of FUra during the 7-day continuous HAI of FUra alone were consistently either undetectable or very low (≤0.1 μm). At level 3 (1.0 mg/kg/day IdUrd) and beyond, measurable plasma concentrations of FUra, iodouracil, and IdUrd were found at the end of the daily 3-h infusion of IdUrd. The maximum tolerated dose of IdUrd as administered in this trial is 2.2 mg/kg/day × 7 and the recommended starting dose for further clinical investigation is 1.7 mg/kg/day × 7.",
author = "Remick, {Scot C.} and {Benson III}, {Al B} and Weese, {James L.} and Willson, {James K.V.} and Guillermo Ramirez and Wirtanen, {George W.} and Alberti, {Dona B.} and Nieting, {Lavonne M.} and Tutsch, {Kendra D.} and Fischer, {Paul H.} and Trump, {Donald L.}",
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Remick, SC, Benson III, AB, Weese, JL, Willson, JKV, Ramirez, G, Wirtanen, GW, Alberti, DB, Nieting, LM, Tutsch, KD, Fischer, PH & Trump, DL 1989, 'Phase I Trial of Hepatic Artery Infusion of 5-Iodo-2″-deoxyuridine and 5-Fluorouracil in Patients with Advanced Hepatic Malignancy: Biochemically Based Combination Chemotherapy', Cancer Research, vol. 49, no. 22, pp. 6437-6442.

Phase I Trial of Hepatic Artery Infusion of 5-Iodo-2″-deoxyuridine and 5-Fluorouracil in Patients with Advanced Hepatic Malignancy : Biochemically Based Combination Chemotherapy. / Remick, Scot C.; Benson III, Al B; Weese, James L.; Willson, James K.V.; Ramirez, Guillermo; Wirtanen, George W.; Alberti, Dona B.; Nieting, Lavonne M.; Tutsch, Kendra D.; Fischer, Paul H.; Trump, Donald L.

In: Cancer Research, Vol. 49, No. 22, 15.11.1989, p. 6437-6442.

Research output: Contribution to journalArticle

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T1 - Phase I Trial of Hepatic Artery Infusion of 5-Iodo-2″-deoxyuridine and 5-Fluorouracil in Patients with Advanced Hepatic Malignancy

T2 - Biochemically Based Combination Chemotherapy

AU - Remick, Scot C.

AU - Benson III, Al B

AU - Weese, James L.

AU - Willson, James K.V.

AU - Ramirez, Guillermo

AU - Wirtanen, George W.

AU - Alberti, Dona B.

AU - Nieting, Lavonne M.

AU - Tutsch, Kendra D.

AU - Fischer, Paul H.

AU - Trump, Donald L.

PY - 1989/11/15

Y1 - 1989/11/15

N2 - Eighteen patients with hepatic metastases primarily from colorectal carcinoma were treated on a phase I protocol employing hepatic artery infusion (HAI) of 5-fluorouracil (FUra) and 5-iodo-2'-deoxyuridine (IdUrd) via an implantable infusion pump. Patients received a 14-day continuous HAI of 300 mg/day FUra. During days 8–14 of therapy, patients received IdUrd as a separate 3-h HAI daily × 7. Treatment cycles were repeated every 28 days. IdUrd was escalated from 0.1 to 2.86 mg/kg/day × 7. Myelosuppression and stomatitis were mild and not dose limiting. Hepatotoxicity was dose limiting and similar to that reported for 5-fluoro-2″-deoxyuridine alone administered as a 14-day infusion every month. One patient developed a clinical picture consistent with sclerosing cholangitis and another had biopsy-proven cholestasis and triaditis. Catheter complications occurred in 7 of 18 patients. Plasma concentrations of FUra during the 7-day continuous HAI of FUra alone were consistently either undetectable or very low (≤0.1 μm). At level 3 (1.0 mg/kg/day IdUrd) and beyond, measurable plasma concentrations of FUra, iodouracil, and IdUrd were found at the end of the daily 3-h infusion of IdUrd. The maximum tolerated dose of IdUrd as administered in this trial is 2.2 mg/kg/day × 7 and the recommended starting dose for further clinical investigation is 1.7 mg/kg/day × 7.

AB - Eighteen patients with hepatic metastases primarily from colorectal carcinoma were treated on a phase I protocol employing hepatic artery infusion (HAI) of 5-fluorouracil (FUra) and 5-iodo-2'-deoxyuridine (IdUrd) via an implantable infusion pump. Patients received a 14-day continuous HAI of 300 mg/day FUra. During days 8–14 of therapy, patients received IdUrd as a separate 3-h HAI daily × 7. Treatment cycles were repeated every 28 days. IdUrd was escalated from 0.1 to 2.86 mg/kg/day × 7. Myelosuppression and stomatitis were mild and not dose limiting. Hepatotoxicity was dose limiting and similar to that reported for 5-fluoro-2″-deoxyuridine alone administered as a 14-day infusion every month. One patient developed a clinical picture consistent with sclerosing cholangitis and another had biopsy-proven cholestasis and triaditis. Catheter complications occurred in 7 of 18 patients. Plasma concentrations of FUra during the 7-day continuous HAI of FUra alone were consistently either undetectable or very low (≤0.1 μm). At level 3 (1.0 mg/kg/day IdUrd) and beyond, measurable plasma concentrations of FUra, iodouracil, and IdUrd were found at the end of the daily 3-h infusion of IdUrd. The maximum tolerated dose of IdUrd as administered in this trial is 2.2 mg/kg/day × 7 and the recommended starting dose for further clinical investigation is 1.7 mg/kg/day × 7.

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