Our objective is to help you choose the most effective chemotherapy drug for your patient, increase efficacy of the chemotherapeutic agent, and to reduce the toxicity and adverse side effects that the patient may experience during chemotherapy.
Why the DPD Enzyme Assay?
The DPD enzyme assay is performed to select those patients that are more likely to experience severe toxicity to the commonly prescribed chemotherapy drug 5-Fluorouracil caused by a deficiency in the DPD enzyme.
Fortunately, for each individual that is scheduled to receive a 5-FU based drug (ie Adrucil, Efudex, Fluoroplex, Xeloda, and Carac), a DPD enzyme assay can be performed to determine if the individual has normal or deficient DPD activity. If the patient is found to have deficient activity, then he/she could be at risk of severe toxicity when exposed to 5-FU, often with the very first dose. Patients with decreased or completely deficient DPD enzyme activity could be spared unnecessary toxic side effects as their dose can be decreased or an alternative treatment option can be considered.
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU, and there is ample evidence that a deficiency of DPD is associated with severe toxicity. Patients with complete or even a partial DPD enzyme deficiency have a reduced capacity to degrade 5-FU and are at risk of developing severe unanticipated 5-FU toxicity . In fact, it has been reported that approximately 40-50% of patients with grade 3-4 toxicity to 5-FU display decreased DPD enzyme activity [2, 3].
Adapted from Schwab et al. 5
In the US alone, 275,000 patients receive 5-FU based drugs each year.
According to the NIH, more than 1,300 patients die annually due to severe 5-FU toxicity.
Tsalic et al reported that 13% of patients treated with the Mayo Clinic Regimen (5FU with leucovorin) required hospitalization for 5-FU related toxicity (neutropenic fever, grade 3-4 mucositis, grade 3-4 diarrhea) with 2% of the patients suffering treatment related deaths.
In this same study, most of the episodes of severe toxicity (56%) and the toxic deaths (4 of the 5) were observed after the very first cycle of 5-FU .
In a more recent study, Schwab et al examined 683 patients receiving 5-FU and reported that 16.1% of the patients experienced grade 3-4 toxicity after 5-FU treatment .
Thus, the incidence of severe 5-FU toxicity is very common, and determining the patient’s risk for toxicity with the DPD enzyme assay prior to administration of the drug could decrease the number and severity of life-threatening side effects.
Why Order the DPD Enzyme Assay As Opposed to Genetic Screening of the DPYD Gene:
Both the DPD enzyme assay and genetic screening of the DPYD gene are performed for the same purpose: predicting severe 5-FU toxicity, yet the DPD enzyme assay is a more complete test and offers a method to predict cases of decreased DPD activity and 5-FU toxicity in more patients compared to the genetic screening tests.
Most laboratories that offer the genetic screening tests to predict toxicity to 5-Fluorouracil only test for the presence of a single mutation in the DPYD gene (IVS14+1 G>A, commonly referred to as DPYD *2A).
1.The DPYD *2A mutation has been reported to completely abolish DPD enzyme activity and lead to severe 5-FU toxicity . However, several studies demonstrate that screening for this mutation alone is not sufficient to predict 5-FU toxicity as only 24-28% of those patients that have grade 3-4 toxicity are heterozygous or homozygous for this mutation [7, 8].
2. To date, over 40 different mutations and polymorphisms have been identified in DPYD gene. The DPYD *2A mutation has proven to be the most common one among patients with severe toxicity, but at least 15 different mutations have been detected in patients with decreased DPD enzyme activity and severe 5-FU toxicity. [1, 9]. Thus, just screening for the presence of the DPYD *2A mutation is not sufficient, as multiple other mutations have also been reported and demonstrated to be associated with grade 3-4 5-FU toxicity.
Because the DPD enzyme assay measures the actual DPD enzyme activity, we get a quantitative measure of how the enzyme metabolizes 5-FU rather than simply inferring DPD activity and possible toxicity from only the presence of a single DPYD mutation. The measurement of DPD enzyme activity also allows for the identification of not only individuals with completely deficient activity, but also those patients with simply decreased DPD activity, who could potentially still tolerate 5-FU without severe side effects if administered a decreased dose.
Limitations: DPD is only one of several enzymes involved in the metabolism of 5-FU, so it is possible that an alteration in the activity of one of the other enzymes involved in the metabolic pathway could lead to 5-FU toxicity. However, DPD deficiency is the most commonly reported known cause of 5-FU toxicity.
Cost of Assay:
$ 400.00 to isolate the peripheral blood mononuclear cells from the blood specimen and perform the DPD enzyme assay. DPD enzyme assay results will be returned to the requesting physician within approximately 3 business days.
Health Insurance Reimbursement (for Alabama residents)
For Alabama residents with insurance coverage by Blue Cross Blue Shield of Alabama, ITT Labs is currently petitioning Blue Cross Blue Shield of Alabama to cover the DPD enzyme assay, and we will update the website as soon as we have more information regarding insurance reimbursement for the DPD enzyme deficiency test.
1.van Kuilenburg A. Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer 2004;40(7):939-950
2. Johnson MR and Diasio RB Importance of dihydropyrimidine dehydrogenase (DPD) deficiency in patients exhibiting toxicity following treatment with 5-fluorouracil. Adv Enzyme Regul, 41: 151-157, 2001.
3. van Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, Van Lenthe H, et al. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res 2000;6:4705-4712.
4. Tsalic M, Bar-Sela G, Beny A, Visel B, Haim, N. Severe toxicity related to 5-fluorouracil/leucovorin combination (The Mayo Clinic Regimen). Am J Clin Oncol 2003;26(1):103-106.
5. Schwab M, Zanger U, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M, German 5-FU Toxicity Study Group. Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 2008;26(13):2131-2138.
6. Johnson MR, Hageboutros A, Wang K, High L, Smith J, Diasio RB. Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. Clin Cancer Res 1999;5:2006-2011
7. van Kuilenburg A, Meinsma R, Zoetekouw L, van Gennip A. High prevalence of the IVS14 +1G>A mutation in the dihydropyrimidine dehydrogenase gene of patients with severe 5-fluorouracil-associated toxicity. Pharmacogenetics 2002;12(7):555-8.
8. Raida M, Schwabe W, Hausler P, van Kuilenburg AB, van Gennip AH, Behnke D, Hoffken K. Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5’-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)- related toxicity compared with controls. Clin Cancer Res 2001;7(9):2832-2839.
9. Morel A, Boisdron-Celle M, Fey L, Lainé-Cessac P, Gamelin E. Identification of a novel mutation in the dihydropyrimidine dehydrogenase gene in a patient with a lethal outcome following 5-fluorouracil administration and the determination of its frequency in a population of 500 patients with colorectal carcinoma. Clin Biochem 2007;40(1-2):11-17.