Pakistan Journal of Medical Sciences

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Volume 23

October - December 2007 (Part-II)

Number  6


 

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

M. Wasif Saif1, Kostas Syrigos2, Ranee Mehra3, Lori K. Mattison4, Robert B Diasio5

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.

KEY WORDS: 5-Fluorouracil, Fluoropyrimidines, Capecitabine, Uridine, DPD, DPYD gene, Neutropenia, HFS, Mucositis.

Source of Funding: This work was supported in part by NIH grant CA 62164

Pak J Med Sci    October - December 2007 (Part-II)    Vol. 23 No. 6    832-839


1. Muhammad Wasif Saif,
2. Kostas Syrigos,
3. Ranee Mehra,
1-3: Yale University School of Medicine, New Haven, CT
Athens Medical School, Sotiria General Hospital,
Athens, Greece
4. Lori K. Mattison,
5. Robert B. Diasio,
4,5: Mayo Clinic, Rochester, MN.

Correspondence

M.Wasif Saif, MD; MBBS,
Associate Professor,
Yale University School of Medicine
Section of Medical Oncology,
333 Cedar Street; FMP 116,
New Haven, CT 06520, USA
Email: wasif.saif@yale.edu

* Received for Publication: September 4, 2007
* Accepted: September 28, 2007



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