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Subject:  Dihydropyrimidine Dehydrogenase (DPD) Deficiency Puts Patients at Grave Risk When Treated with Fluoropyrimidines

Background:

• Fluoropyrimidine drugs (e.g. fluorouracil, oral capecitabine (Xeloda), referred to 5-FU hereafter) are used in the chemotherapy treatment of patients with gastro-intestinal (colon, rectal, anal), head/neck, and breast cancers, plus other malignancies.
• 5-FU relies solely on the DPD enzyme to metabolize the drug to keep it from damaging healthy cells: this is a single point of failure. Medical journals have acknowledged this risk for over nearly 30-years ^1,2.
• DPD deficiency is clearly called out as a contraindication on the Xeloda (capecitabine) label.
• The warnings section of the FDA insert label for 5-FU states:

Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and

neurotoxicity) associated with 5-fluorouracil has been attributed to deficiency of

dihydropyrimidine dehydrogenase activity. A few patients have been rechallenged with 5-

fluorouracil and despite 5-fluorouracil dose lowering, toxicity recurred and

progressed with worse morbidity. Absence of this catabolic enzyme appears to

result in prolonged clearance of 5-fluorouracil.

Facts:

• Medical journals have documented the incidence of severe toxicity (grade 3 or 4) to be greater than a rare occurrence.  An estimated 500-1000 US patients die annually due to 5-FU toxicity²; between 10-40% of the patients suffer severe toxic reactions. Depending on the regimen, 5-FU causes death in  0.5% up to 3% of treated patients. ^3-7
• Though the DPD deficiency is a known risk, pre-screening is not a requirement or encouraged:
• • Patient advocacy groups, e.g. the American Cancer Society, advise patients to avoid treatment with 5-FU if they have been told they suffer from DPD deficiency -- however, one typically does not know they have the deficiency unless tested.
  • Pre-screening is not required by regulatory agencies, the National Comprehensive Cancer Network’s (NCCN’s) medical guidelines, or by health insurers.

• DPD deficiency:
• • Is known as a genetic condition.  Tests are available to detect the most commonly found gene pattern that causes the deficiency but not every genetic combination has been identified to date.  Because of this, there is no consensus among the medical profession on how to test for this deficiency.
  • Epigenetics such as transcription factors could play an additional role in DPD deficency ⁴, ⁸
  • Factors other than genetics (e.g. drug to drug interactions and circadian variations), however, also contribute to deficient levels of the DPD enzyme that put 5-FU patients at risk. 4,8 
    

• Blue Cross Blue Shield reported in 2010 that 30% of patients treated with 5-FU suffer severe toxicity. The same report concluded that genetic testing offered poor predictive value for 5-FU toxicity or dose reduction. 7
• Studies in France, Holland, Italy have shown that the use of “functional”, not genetic, pre-screening tests which determine enzyme levels of patients drastically reduce toxicities and fatalities. ^8,9,10,11,12
• The cost to perform the functional test (dihydrouracil/uracil ratio assessment from a patient’s plasma) is estimated to cost less than $80/patient¹⁰ -- unfortunately this test is not widely available in the USA at this time.  A pharmaco-economic study presented at the American Society of Clinical Onlcology  meeting in 2009 showed how the cost of a patient’s stay in the hospital while recovering from a toxic reaction is considerably greater than this functional test ¹³ .
• Journal articles since 2010 increasingly suggest the benefit of starting treatment at reduced dosage levels that are then adjusted based on a patient’s ability to metabolize 5-FU.⁴ 
• The Colon Cancer Alliance encourages patients to discuss with their doctor the use of a My 5-FU test to monitor the drug's impact after the start of chemotherapy (see Hope.)

Citations:

¹  Zhu, A X., et al, Dihydropyrimidine Dehydrogenase and Thymidylate Synthase Polymorphisms and Their Association with 5-Fluorouracil/Leucovorin Chemotherapy in Colorectal Cancer, Clinical ColorectalVol 3, No. 4 (2004), 225:235.

² Tuchman M, et al. Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity.  N Engl J Med. 1985 Jul 25;313(4):245-9.

³ Caudle, K Eet al, Clinical Phamacogenetics Implementation Consortium Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoroupyrimidine Dosing, Clinical Phamacogenetics Implementation Consortium, posted online Oct 2013.

⁴ Ciccolini, J, et al, Routine Dihydropyrimidine Dehydrogenase Testing for Anticipating 5-Fluorouracil Related Severe Toxicities: Hype or Hope?, Clinical Colorectal Cancer, Vol 9, No. 4 (2010), 224:228.

⁵Saif, W M, Pharmacokinetically Guided Dose Adjustment of 5-Fluorouracil: A Rational Approach to Improving Therapeutic Outcomes, Journal National Cancer Institute, (2009);101: 1543-1552. 

⁶ Tsalic M, et al.  Severe toxicity related to the 5-fluorouracil/leucovorin combination (the Mayo Clinic regimen): a prospective study in colorectal cancer patients. Am J Clin Oncol. 2003 Feb;26(1):103-6.

⁷ Piper, M., et al, Pharmacogenetic Testing to Predict Serious Toxicity From 5-Fluorouracil (5-FU) for Patients Administered 5-FU Based Chemotherapy for Cancer, Technology Evaluation Center (Blue Cross Blue Shield), Assessment Program (2010) Vol 24, No. 13.

⁸ Mercier C, et al. Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy. Clin Colorectal Cancer. 2006 Nov;6(4):288-96.

⁹ Gamelin, E, et al, Individual Fluorouracil Dose Adjustment Based on Pharmacokinetic Follow-up Compared With Conventional Dosage: Results of a Multi-Center Randomized Trial of Patients With Metastatic Colorectal Cancer, Journal of Clinical Oncology, Vol 26, No. 13 (2008), 2099:2105.

¹⁰  Ciccolini J, et al.  A rapid and inexpensive method for anticipating severe toxicity to fluorouracil and fluorouracil-based chemotherapy.  Ther Drug Monit. 2006 Oct;28(5):678-85.

¹¹   Woloch, C, et al, Population Pharmacokinetic Analysis of 5-FU and 5-FDHU in Colorectal Cancer Patients: Search for Biomarkers Associated with Gastro-Intestinal Toxicity, Current Topics in Medicinal Chemistry, (2012), Vol 12, No. 15, 1713:1719.

¹² Yang CG, et al.  DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity.  Cancer Chemother Pharmacol. 2011 Jan;67(1):49-56.

¹³ Mercier, C. Et al. Pharmacoeconomic Study In Head And Neck Cancer Patients: Impact Of Prospective Dpd Deficiency Screening With 5-Fluorouracil (5-Fu) Dose Tailoring On Toxicities-Related Costs.  ASCO annual meeting proceedings, June 2008, Orlando, USA. Abstract in J Clin Oncol No. 21S (June  Supplement), 2009.