Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: Experience of 4-years

Muhammad Wasif Saif, Kostas Syrigos, Ranee Mehra, Lori K. Mattison, Robert B Diasio

Research output: Contribution to journalArticle

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Abstract

Objectives: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. Methodology: Twenty-three patients were tested for DPD deficiency after excessive toxicities from 5-FU and/or capecitabine. DPD activity was evaluated by Peripheral Blood Mononuclear Cell (PBMC) radioassay, genotyping of DPYD gene by Denaturing High Performance Liquid Chromatography (DHPLC), or 2-13C uracil breath test (UraBT). Results: Of 23 patients with excessive toxicities from 5-FU and/or capecitabine, 7 (30%) were DPD deficient with a median age of 66 years, M:F ratio = 1.3:1 and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). DPD activity ranged from 0.064 - 0.18nmol/min/mg. Three patients were treated with bolus 5-FU/LV, two with capecitabine, and two with high dose bolus 5-FU with 2′, 3′, 5′-tri-O-acetyluridine. Toxicities included mucositis (71%), diarrhea (43%), skin rash (43%), memory loss/altered mental status (43%), cytopenias (43%), nausea (29%), hypotension (14%), respiratory distress (14%) and acute renal failure (14%) Re-challenge with capecitabine in one patient after the Mayo regimen caused grade 3 hand-foot syndrome. Genotypic analysis of the DPYD gene in one patient with severe leucopenia demonstrated a heterozygous mutation (IVS14+1 G>A, DPYD). The UraBT in two patients revealed 1 to be DPD-deficient (DOB50 of 112.8; PDR of 49.4%) and borderline normal values (DOB50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths among DPD-deficient patients (28%). Conclusions: DPD deficiency was observed in several ethnicities. Akin to 5-FU, capecitabine can also lead to severe toxicities in DPD-deficient patients. Screening patients for DPD deficiency prior to administration of 5-FU or capecitabine using UraBT could potentially lower risk of toxicity. Future studies should validate this technique.

Original languageEnglish (US)
Pages (from-to)832-839
Number of pages8
JournalPakistan Journal of Medical Sciences
Volume23
Issue number6
StatePublished - Oct 2007

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Dihydropyrimidine Dehydrogenase Deficiency
Fluorouracil
Neoplasms
Breath Tests
Uracil
Hand-Foot Syndrome
Mucositis
Memory Disorders
Leukopenia
Exanthema
Acute Kidney Injury
African Americans
Hypotension
Nausea
Genes
Capecitabine
Diarrhea

Keywords

  • 5-Fluorouracil
  • Capecitabine
  • DPD
  • DPYD gene
  • Fluoropyrimidines
  • HFS
  • Mucositis
  • Neutropenia
  • Uridine

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies : Experience of 4-years. / Saif, Muhammad Wasif; Syrigos, Kostas; Mehra, Ranee; Mattison, Lori K.; Diasio, Robert B.

In: Pakistan Journal of Medical Sciences, Vol. 23, No. 6, 10.2007, p. 832-839.

Research output: Contribution to journalArticle

Saif, Muhammad Wasif ; Syrigos, Kostas ; Mehra, Ranee ; Mattison, Lori K. ; Diasio, Robert B. / Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies : Experience of 4-years. In: Pakistan Journal of Medical Sciences. 2007 ; Vol. 23, No. 6. pp. 832-839.
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title = "Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: Experience of 4-years",
abstract = "Objectives: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. Methodology: Twenty-three patients were tested for DPD deficiency after excessive toxicities from 5-FU and/or capecitabine. DPD activity was evaluated by Peripheral Blood Mononuclear Cell (PBMC) radioassay, genotyping of DPYD gene by Denaturing High Performance Liquid Chromatography (DHPLC), or 2-13C uracil breath test (UraBT). Results: Of 23 patients with excessive toxicities from 5-FU and/or capecitabine, 7 (30{\%}) were DPD deficient with a median age of 66 years, M:F ratio = 1.3:1 and ethnicities included Caucasian (71{\%}), African-American (14{\%}) and South-Asian (14{\%}). DPD activity ranged from 0.064 - 0.18nmol/min/mg. Three patients were treated with bolus 5-FU/LV, two with capecitabine, and two with high dose bolus 5-FU with 2′, 3′, 5′-tri-O-acetyluridine. Toxicities included mucositis (71{\%}), diarrhea (43{\%}), skin rash (43{\%}), memory loss/altered mental status (43{\%}), cytopenias (43{\%}), nausea (29{\%}), hypotension (14{\%}), respiratory distress (14{\%}) and acute renal failure (14{\%}) Re-challenge with capecitabine in one patient after the Mayo regimen caused grade 3 hand-foot syndrome. Genotypic analysis of the DPYD gene in one patient with severe leucopenia demonstrated a heterozygous mutation (IVS14+1 G>A, DPYD). The UraBT in two patients revealed 1 to be DPD-deficient (DOB50 of 112.8; PDR of 49.4{\%}) and borderline normal values (DOB50 of 130.9; PDR of 52.5{\%}) in a second patient. There were 2 toxicity-related deaths among DPD-deficient patients (28{\%}). Conclusions: DPD deficiency was observed in several ethnicities. Akin to 5-FU, capecitabine can also lead to severe toxicities in DPD-deficient patients. Screening patients for DPD deficiency prior to administration of 5-FU or capecitabine using UraBT could potentially lower risk of toxicity. Future studies should validate this technique.",
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T1 - Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies

T2 - Experience of 4-years

AU - Saif, Muhammad Wasif

AU - Syrigos, Kostas

AU - Mehra, Ranee

AU - Mattison, Lori K.

AU - Diasio, Robert B

PY - 2007/10

Y1 - 2007/10

N2 - Objectives: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. Methodology: Twenty-three patients were tested for DPD deficiency after excessive toxicities from 5-FU and/or capecitabine. DPD activity was evaluated by Peripheral Blood Mononuclear Cell (PBMC) radioassay, genotyping of DPYD gene by Denaturing High Performance Liquid Chromatography (DHPLC), or 2-13C uracil breath test (UraBT). Results: Of 23 patients with excessive toxicities from 5-FU and/or capecitabine, 7 (30%) were DPD deficient with a median age of 66 years, M:F ratio = 1.3:1 and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). DPD activity ranged from 0.064 - 0.18nmol/min/mg. Three patients were treated with bolus 5-FU/LV, two with capecitabine, and two with high dose bolus 5-FU with 2′, 3′, 5′-tri-O-acetyluridine. Toxicities included mucositis (71%), diarrhea (43%), skin rash (43%), memory loss/altered mental status (43%), cytopenias (43%), nausea (29%), hypotension (14%), respiratory distress (14%) and acute renal failure (14%) Re-challenge with capecitabine in one patient after the Mayo regimen caused grade 3 hand-foot syndrome. Genotypic analysis of the DPYD gene in one patient with severe leucopenia demonstrated a heterozygous mutation (IVS14+1 G>A, DPYD). The UraBT in two patients revealed 1 to be DPD-deficient (DOB50 of 112.8; PDR of 49.4%) and borderline normal values (DOB50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths among DPD-deficient patients (28%). Conclusions: DPD deficiency was observed in several ethnicities. Akin to 5-FU, capecitabine can also lead to severe toxicities in DPD-deficient patients. Screening patients for DPD deficiency prior to administration of 5-FU or capecitabine using UraBT could potentially lower risk of toxicity. Future studies should validate this technique.

AB - Objectives: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. Methodology: Twenty-three patients were tested for DPD deficiency after excessive toxicities from 5-FU and/or capecitabine. DPD activity was evaluated by Peripheral Blood Mononuclear Cell (PBMC) radioassay, genotyping of DPYD gene by Denaturing High Performance Liquid Chromatography (DHPLC), or 2-13C uracil breath test (UraBT). Results: Of 23 patients with excessive toxicities from 5-FU and/or capecitabine, 7 (30%) were DPD deficient with a median age of 66 years, M:F ratio = 1.3:1 and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). DPD activity ranged from 0.064 - 0.18nmol/min/mg. Three patients were treated with bolus 5-FU/LV, two with capecitabine, and two with high dose bolus 5-FU with 2′, 3′, 5′-tri-O-acetyluridine. Toxicities included mucositis (71%), diarrhea (43%), skin rash (43%), memory loss/altered mental status (43%), cytopenias (43%), nausea (29%), hypotension (14%), respiratory distress (14%) and acute renal failure (14%) Re-challenge with capecitabine in one patient after the Mayo regimen caused grade 3 hand-foot syndrome. Genotypic analysis of the DPYD gene in one patient with severe leucopenia demonstrated a heterozygous mutation (IVS14+1 G>A, DPYD). The UraBT in two patients revealed 1 to be DPD-deficient (DOB50 of 112.8; PDR of 49.4%) and borderline normal values (DOB50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths among DPD-deficient patients (28%). Conclusions: DPD deficiency was observed in several ethnicities. Akin to 5-FU, capecitabine can also lead to severe toxicities in DPD-deficient patients. Screening patients for DPD deficiency prior to administration of 5-FU or capecitabine using UraBT could potentially lower risk of toxicity. Future studies should validate this technique.

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KW - Capecitabine

KW - DPD

KW - DPYD gene

KW - Fluoropyrimidines

KW - HFS

KW - Mucositis

KW - Neutropenia

KW - Uridine

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