Phase I trial of low-dose, prolonged continuous infusion fluorouracil plus interferon-alfa: evidence for enhanced fluorouracil toxicity without pharmacokinetic perturbation

Joseph A. Sparano, Scott Wadler, Robert B. Diasio, Ruiwen Zhang, Zhihang Lu, Edward L. Schwartz, Avi Israel Einzig, Peter H. Wiernik

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Abstract

Purpose: To determine the maximum-tolerable dose (MTD) of fluorouracil (5-FU) administered as a low-dose, prolonged continuous intravenous infusion (PCI) plus interferon-alfa (IFN-α) that would permit treatment for at least 28 consecutive days, and to determine the effect of IFN-α on 5-FU pharmacokinetics. Patients and Methods: Twenty-six assessable patients with advanced cancer received low-dose PCI 5-FU (150, 200, 250, and 300 mg/m2/d) plus IFN-α, 5 × 106 IU/m2 administered subcutaneously (SC) at hour 48 of the 5-FU infusion, then thrice weekly thereafter in cohorts of at least three patients. Treatment continued until treatment-limiting toxicity (TLT) developed, such as mucositis, diarrhea, or fatigue. Escalation to the next 5-FU dose level occurred if none of three or zero to two of six patients developed TLT before day 28. Quantitation of plasma 5-FU concentration by high-performance liquid chromatography was performed in 15 patients. Data were standardized using the Cosinor method and compared before and after IFN-α administration using the paired t test. Results: The mean number of days of continuous 5-FU therapy for patients receiving 150, 200, 250, and 300 mg/m2/d of 5-FU plus IFN alfa-2a (IFN-α2a) was 75, 54, 37, and 22 days, respectively. The MTD of PCI 5-FU by our criteria that could be combined with IFN-α was 250 mg/m2/d. Comparison of the standardized pharmacokinetic data showed no significant effect of IFN-α on plasma 5-FU concentration, and no alteration of the normal circadian variation in plasma 5-FU concentration that was evident before IFN-α administration. Objective response occurred in patients with adenocarcinoma of the pancreas (n = 3), kidney (n = 2), and lung (n = 1). Conclusion: IFN-α substantially enhanced the gastrointestinal toxicity of low-dose PCI 5-FU without affecting 5-FU pharmacokinetics, contrary to previous reports using alternative 5-FU schedules in which IFN-α-related enhancement of 5-FU toxicity was attributable to reduced 5-FU clearance. Our findings suggest that under certain conditions, mechanisms other than altered 5-FU pharmacokinetics may be responsible for the ability of IFN-α to enhance the toxic effects of 5-FU.

Original languageEnglish (US)
Pages (from-to)1609-1617
Number of pages9
JournalJournal of Clinical Oncology
Volume11
Issue number8
StatePublished - 1993

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Interferon-alpha
Fluorouracil
Pharmacokinetics
Intravenous Infusions
Therapeutics
Mucositis
Poisons

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I trial of low-dose, prolonged continuous infusion fluorouracil plus interferon-alfa : evidence for enhanced fluorouracil toxicity without pharmacokinetic perturbation. / Sparano, Joseph A.; Wadler, Scott; Diasio, Robert B.; Zhang, Ruiwen; Lu, Zhihang; Schwartz, Edward L.; Einzig, Avi Israel; Wiernik, Peter H.

In: Journal of Clinical Oncology, Vol. 11, No. 8, 1993, p. 1609-1617.

Research output: Contribution to journalArticle

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title = "Phase I trial of low-dose, prolonged continuous infusion fluorouracil plus interferon-alfa: evidence for enhanced fluorouracil toxicity without pharmacokinetic perturbation",
abstract = "Purpose: To determine the maximum-tolerable dose (MTD) of fluorouracil (5-FU) administered as a low-dose, prolonged continuous intravenous infusion (PCI) plus interferon-alfa (IFN-α) that would permit treatment for at least 28 consecutive days, and to determine the effect of IFN-α on 5-FU pharmacokinetics. Patients and Methods: Twenty-six assessable patients with advanced cancer received low-dose PCI 5-FU (150, 200, 250, and 300 mg/m2/d) plus IFN-α, 5 × 106 IU/m2 administered subcutaneously (SC) at hour 48 of the 5-FU infusion, then thrice weekly thereafter in cohorts of at least three patients. Treatment continued until treatment-limiting toxicity (TLT) developed, such as mucositis, diarrhea, or fatigue. Escalation to the next 5-FU dose level occurred if none of three or zero to two of six patients developed TLT before day 28. Quantitation of plasma 5-FU concentration by high-performance liquid chromatography was performed in 15 patients. Data were standardized using the Cosinor method and compared before and after IFN-α administration using the paired t test. Results: The mean number of days of continuous 5-FU therapy for patients receiving 150, 200, 250, and 300 mg/m2/d of 5-FU plus IFN alfa-2a (IFN-α2a) was 75, 54, 37, and 22 days, respectively. The MTD of PCI 5-FU by our criteria that could be combined with IFN-α was 250 mg/m2/d. Comparison of the standardized pharmacokinetic data showed no significant effect of IFN-α on plasma 5-FU concentration, and no alteration of the normal circadian variation in plasma 5-FU concentration that was evident before IFN-α administration. Objective response occurred in patients with adenocarcinoma of the pancreas (n = 3), kidney (n = 2), and lung (n = 1). Conclusion: IFN-α substantially enhanced the gastrointestinal toxicity of low-dose PCI 5-FU without affecting 5-FU pharmacokinetics, contrary to previous reports using alternative 5-FU schedules in which IFN-α-related enhancement of 5-FU toxicity was attributable to reduced 5-FU clearance. Our findings suggest that under certain conditions, mechanisms other than altered 5-FU pharmacokinetics may be responsible for the ability of IFN-α to enhance the toxic effects of 5-FU.",
author = "Sparano, {Joseph A.} and Scott Wadler and Diasio, {Robert B.} and Ruiwen Zhang and Zhihang Lu and Schwartz, {Edward L.} and Einzig, {Avi Israel} and Wiernik, {Peter H.}",
year = "1993",
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T1 - Phase I trial of low-dose, prolonged continuous infusion fluorouracil plus interferon-alfa

T2 - evidence for enhanced fluorouracil toxicity without pharmacokinetic perturbation

AU - Sparano, Joseph A.

AU - Wadler, Scott

AU - Diasio, Robert B.

AU - Zhang, Ruiwen

AU - Lu, Zhihang

AU - Schwartz, Edward L.

AU - Einzig, Avi Israel

AU - Wiernik, Peter H.

PY - 1993

Y1 - 1993

N2 - Purpose: To determine the maximum-tolerable dose (MTD) of fluorouracil (5-FU) administered as a low-dose, prolonged continuous intravenous infusion (PCI) plus interferon-alfa (IFN-α) that would permit treatment for at least 28 consecutive days, and to determine the effect of IFN-α on 5-FU pharmacokinetics. Patients and Methods: Twenty-six assessable patients with advanced cancer received low-dose PCI 5-FU (150, 200, 250, and 300 mg/m2/d) plus IFN-α, 5 × 106 IU/m2 administered subcutaneously (SC) at hour 48 of the 5-FU infusion, then thrice weekly thereafter in cohorts of at least three patients. Treatment continued until treatment-limiting toxicity (TLT) developed, such as mucositis, diarrhea, or fatigue. Escalation to the next 5-FU dose level occurred if none of three or zero to two of six patients developed TLT before day 28. Quantitation of plasma 5-FU concentration by high-performance liquid chromatography was performed in 15 patients. Data were standardized using the Cosinor method and compared before and after IFN-α administration using the paired t test. Results: The mean number of days of continuous 5-FU therapy for patients receiving 150, 200, 250, and 300 mg/m2/d of 5-FU plus IFN alfa-2a (IFN-α2a) was 75, 54, 37, and 22 days, respectively. The MTD of PCI 5-FU by our criteria that could be combined with IFN-α was 250 mg/m2/d. Comparison of the standardized pharmacokinetic data showed no significant effect of IFN-α on plasma 5-FU concentration, and no alteration of the normal circadian variation in plasma 5-FU concentration that was evident before IFN-α administration. Objective response occurred in patients with adenocarcinoma of the pancreas (n = 3), kidney (n = 2), and lung (n = 1). Conclusion: IFN-α substantially enhanced the gastrointestinal toxicity of low-dose PCI 5-FU without affecting 5-FU pharmacokinetics, contrary to previous reports using alternative 5-FU schedules in which IFN-α-related enhancement of 5-FU toxicity was attributable to reduced 5-FU clearance. Our findings suggest that under certain conditions, mechanisms other than altered 5-FU pharmacokinetics may be responsible for the ability of IFN-α to enhance the toxic effects of 5-FU.

AB - Purpose: To determine the maximum-tolerable dose (MTD) of fluorouracil (5-FU) administered as a low-dose, prolonged continuous intravenous infusion (PCI) plus interferon-alfa (IFN-α) that would permit treatment for at least 28 consecutive days, and to determine the effect of IFN-α on 5-FU pharmacokinetics. Patients and Methods: Twenty-six assessable patients with advanced cancer received low-dose PCI 5-FU (150, 200, 250, and 300 mg/m2/d) plus IFN-α, 5 × 106 IU/m2 administered subcutaneously (SC) at hour 48 of the 5-FU infusion, then thrice weekly thereafter in cohorts of at least three patients. Treatment continued until treatment-limiting toxicity (TLT) developed, such as mucositis, diarrhea, or fatigue. Escalation to the next 5-FU dose level occurred if none of three or zero to two of six patients developed TLT before day 28. Quantitation of plasma 5-FU concentration by high-performance liquid chromatography was performed in 15 patients. Data were standardized using the Cosinor method and compared before and after IFN-α administration using the paired t test. Results: The mean number of days of continuous 5-FU therapy for patients receiving 150, 200, 250, and 300 mg/m2/d of 5-FU plus IFN alfa-2a (IFN-α2a) was 75, 54, 37, and 22 days, respectively. The MTD of PCI 5-FU by our criteria that could be combined with IFN-α was 250 mg/m2/d. Comparison of the standardized pharmacokinetic data showed no significant effect of IFN-α on plasma 5-FU concentration, and no alteration of the normal circadian variation in plasma 5-FU concentration that was evident before IFN-α administration. Objective response occurred in patients with adenocarcinoma of the pancreas (n = 3), kidney (n = 2), and lung (n = 1). Conclusion: IFN-α substantially enhanced the gastrointestinal toxicity of low-dose PCI 5-FU without affecting 5-FU pharmacokinetics, contrary to previous reports using alternative 5-FU schedules in which IFN-α-related enhancement of 5-FU toxicity was attributable to reduced 5-FU clearance. Our findings suggest that under certain conditions, mechanisms other than altered 5-FU pharmacokinetics may be responsible for the ability of IFN-α to enhance the toxic effects of 5-FU.

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