Preliminary observations indicate variable patterns of plasma 5-fluorouracil (5-FU) levels during dose optimization of infusional 5-FU in colorectal cancer patients

Christina Leah Kline, Hassan S. Sheikh, Angelique Scicchitano, Rebecca Gingrich, Cheryl Beachler, Niklas K. Finnberg, Jiangang (Jason) Liao, Jeffrey Sivik, Wafik S. El-Deiry

Research output: Contribution to journalArticle

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Abstract

Efforts to improve efficacy and minimize toxicity have led to pharmacokinetic monitoring of plasma 5-fluorouracil (5-FU) levels in colorectal cancer patients undergoing chemotherapy. We observed variation in basal 5-FU levels in 21 patients and significant variation during subsequent dose optimization. Tumor KRAS , BRAF mutations and TS mRNA levels were determined. Regimens included FOLFOX6+Avastin (n = 8), FOLFOX6 (n = 11), FOLFIRI (n = 1) and FOLFOX4 (n = 1). Mutations identified in tumors included G12V KRAS (n = 2), G12A KRAS (n = 1), and V600E BRAF (n = 3). Six-of-11 patients with normalized tumor TS mRNA levels < 4.0 had a 5-FU AU C of 20 mg.h/L or greater, and 80% of patients (four of five) with TS levels > 4.0 had a plasma 5-FU AU C of less than or equal to 20 mg.h/L. Approximately 2/3 of patients achieved therapeutic 5-FU AU C levels with 0-2 dose adjustments while a sub-group of ∼1/3 of patients slowly achieved therapeutic levels (> 3-4 dose increases leading to supra-therapeutic 5-FU and subsequent reductions to lesser than original doses). Liver metastases and tumor TS levels did not fully account for variable 5-FU AU C optimization patterns. The 5-FU level during continuous infusion was half-therapeutic in one patient who received FOLFOX4. The observed heterogeneous patterns at baseline and during dose optimization of 5-FU levels suggest variations in 5-FU metabolism among treated patients. Physiological and/or genetic differences underlying heterogeneity in 5-FU levels during dose optimization require further study of patient demographics, single nucleotide polymorphisms in Dihydropyrimidine Dehydrogenase (DPD ), TS, or other genes that impact 5-FU metabolism and gene expression changes in liver after 5-FU therapy.

Original languageEnglish (US)
Pages (from-to)557-568
Number of pages12
JournalCancer Biology and Therapy
Volume12
Issue number7
DOIs
StatePublished - Oct 1 2011

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Fluorouracil
Colorectal Neoplasms
Neoplasms
Dihydrouracil Dehydrogenase (NADP)
Therapeutics
Messenger RNA
Mutation
Liver
Single Nucleotide Polymorphism
Pharmacokinetics
Demography
Neoplasm Metastasis
Gene Expression
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Kline, Christina Leah ; Sheikh, Hassan S. ; Scicchitano, Angelique ; Gingrich, Rebecca ; Beachler, Cheryl ; Finnberg, Niklas K. ; Liao, Jiangang (Jason) ; Sivik, Jeffrey ; El-Deiry, Wafik S. / Preliminary observations indicate variable patterns of plasma 5-fluorouracil (5-FU) levels during dose optimization of infusional 5-FU in colorectal cancer patients. In: Cancer Biology and Therapy. 2011 ; Vol. 12, No. 7. pp. 557-568.
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abstract = "Efforts to improve efficacy and minimize toxicity have led to pharmacokinetic monitoring of plasma 5-fluorouracil (5-FU) levels in colorectal cancer patients undergoing chemotherapy. We observed variation in basal 5-FU levels in 21 patients and significant variation during subsequent dose optimization. Tumor KRAS , BRAF mutations and TS mRNA levels were determined. Regimens included FOLFOX6+Avastin (n = 8), FOLFOX6 (n = 11), FOLFIRI (n = 1) and FOLFOX4 (n = 1). Mutations identified in tumors included G12V KRAS (n = 2), G12A KRAS (n = 1), and V600E BRAF (n = 3). Six-of-11 patients with normalized tumor TS mRNA levels < 4.0 had a 5-FU AU C of 20 mg.h/L or greater, and 80{\%} of patients (four of five) with TS levels > 4.0 had a plasma 5-FU AU C of less than or equal to 20 mg.h/L. Approximately 2/3 of patients achieved therapeutic 5-FU AU C levels with 0-2 dose adjustments while a sub-group of ∼1/3 of patients slowly achieved therapeutic levels (> 3-4 dose increases leading to supra-therapeutic 5-FU and subsequent reductions to lesser than original doses). Liver metastases and tumor TS levels did not fully account for variable 5-FU AU C optimization patterns. The 5-FU level during continuous infusion was half-therapeutic in one patient who received FOLFOX4. The observed heterogeneous patterns at baseline and during dose optimization of 5-FU levels suggest variations in 5-FU metabolism among treated patients. Physiological and/or genetic differences underlying heterogeneity in 5-FU levels during dose optimization require further study of patient demographics, single nucleotide polymorphisms in Dihydropyrimidine Dehydrogenase (DPD ), TS, or other genes that impact 5-FU metabolism and gene expression changes in liver after 5-FU therapy.",
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Preliminary observations indicate variable patterns of plasma 5-fluorouracil (5-FU) levels during dose optimization of infusional 5-FU in colorectal cancer patients. / Kline, Christina Leah; Sheikh, Hassan S.; Scicchitano, Angelique; Gingrich, Rebecca; Beachler, Cheryl; Finnberg, Niklas K.; Liao, Jiangang (Jason); Sivik, Jeffrey; El-Deiry, Wafik S.

In: Cancer Biology and Therapy, Vol. 12, No. 7, 01.10.2011, p. 557-568.

Research output: Contribution to journalArticle

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AU - Kline, Christina Leah

AU - Sheikh, Hassan S.

AU - Scicchitano, Angelique

AU - Gingrich, Rebecca

AU - Beachler, Cheryl

AU - Finnberg, Niklas K.

AU - Liao, Jiangang (Jason)

AU - Sivik, Jeffrey

AU - El-Deiry, Wafik S.

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N2 - Efforts to improve efficacy and minimize toxicity have led to pharmacokinetic monitoring of plasma 5-fluorouracil (5-FU) levels in colorectal cancer patients undergoing chemotherapy. We observed variation in basal 5-FU levels in 21 patients and significant variation during subsequent dose optimization. Tumor KRAS , BRAF mutations and TS mRNA levels were determined. Regimens included FOLFOX6+Avastin (n = 8), FOLFOX6 (n = 11), FOLFIRI (n = 1) and FOLFOX4 (n = 1). Mutations identified in tumors included G12V KRAS (n = 2), G12A KRAS (n = 1), and V600E BRAF (n = 3). Six-of-11 patients with normalized tumor TS mRNA levels < 4.0 had a 5-FU AU C of 20 mg.h/L or greater, and 80% of patients (four of five) with TS levels > 4.0 had a plasma 5-FU AU C of less than or equal to 20 mg.h/L. Approximately 2/3 of patients achieved therapeutic 5-FU AU C levels with 0-2 dose adjustments while a sub-group of ∼1/3 of patients slowly achieved therapeutic levels (> 3-4 dose increases leading to supra-therapeutic 5-FU and subsequent reductions to lesser than original doses). Liver metastases and tumor TS levels did not fully account for variable 5-FU AU C optimization patterns. The 5-FU level during continuous infusion was half-therapeutic in one patient who received FOLFOX4. The observed heterogeneous patterns at baseline and during dose optimization of 5-FU levels suggest variations in 5-FU metabolism among treated patients. Physiological and/or genetic differences underlying heterogeneity in 5-FU levels during dose optimization require further study of patient demographics, single nucleotide polymorphisms in Dihydropyrimidine Dehydrogenase (DPD ), TS, or other genes that impact 5-FU metabolism and gene expression changes in liver after 5-FU therapy.

AB - Efforts to improve efficacy and minimize toxicity have led to pharmacokinetic monitoring of plasma 5-fluorouracil (5-FU) levels in colorectal cancer patients undergoing chemotherapy. We observed variation in basal 5-FU levels in 21 patients and significant variation during subsequent dose optimization. Tumor KRAS , BRAF mutations and TS mRNA levels were determined. Regimens included FOLFOX6+Avastin (n = 8), FOLFOX6 (n = 11), FOLFIRI (n = 1) and FOLFOX4 (n = 1). Mutations identified in tumors included G12V KRAS (n = 2), G12A KRAS (n = 1), and V600E BRAF (n = 3). Six-of-11 patients with normalized tumor TS mRNA levels < 4.0 had a 5-FU AU C of 20 mg.h/L or greater, and 80% of patients (four of five) with TS levels > 4.0 had a plasma 5-FU AU C of less than or equal to 20 mg.h/L. Approximately 2/3 of patients achieved therapeutic 5-FU AU C levels with 0-2 dose adjustments while a sub-group of ∼1/3 of patients slowly achieved therapeutic levels (> 3-4 dose increases leading to supra-therapeutic 5-FU and subsequent reductions to lesser than original doses). Liver metastases and tumor TS levels did not fully account for variable 5-FU AU C optimization patterns. The 5-FU level during continuous infusion was half-therapeutic in one patient who received FOLFOX4. The observed heterogeneous patterns at baseline and during dose optimization of 5-FU levels suggest variations in 5-FU metabolism among treated patients. Physiological and/or genetic differences underlying heterogeneity in 5-FU levels during dose optimization require further study of patient demographics, single nucleotide polymorphisms in Dihydropyrimidine Dehydrogenase (DPD ), TS, or other genes that impact 5-FU metabolism and gene expression changes in liver after 5-FU therapy.

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