Medical Policy: 02.04.71
Original Effective Date: April 2018
Reviewed: April 2021
Revised: April 2021
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
DPD stands for dihydropyrimidine dehydrogenase. It is an enzyme made by the liver that helps our body break down thymine and uracil. DPD deficiency happens when we have low or no levels of the DPD enzyme. It is very rare to have no DPD (a complete DPD deficiency) but it is slightly more common to have low or very low levels (a partial deficiency). The Dihydropyrimidine dehydrogenase (DPYD) gene helps to control the production of DPD in our bodies. There are a number of changes (mutations) in the DPYD gene that can cause DPD deficiency. The enzyme has the ability to break down fluoropyrimidines. Fluoropyrimidines include 5-fluorouracil (5-FU, Adrucil®) and capecitabine (Xeloda®). Treatment is mostly administered by body size and in the best of cases after a few basic biological examinations such as a hemogram and renal status, without taking into consideration any individual particularities, whether genetic or epigenetic. Among potential toxicity risk factors one can find individual metabolic differences linked to genetic modifications of metabolism enzymes as well as differences in the chemical receptors and transporters.
Fluoropyrimidines (5-Fluorouracil (5-FU) and its derivative capecitabine) are widely used antineoplastic chemotherapy drugs. 5-FU has been used for many years to treat solid tumors. Although the benefits of 5-fluoroucil-based therapy is prolonging survival, major side effects are seen in many individuals receiving the drugs. In general, the incidence of grade 3 or 4 toxicity (mainly neutropenia, diarrhea, mucositis, and hand-foot syndrome) increases with higher systemic exposure to 5-FU. Several studies have reported statistically significant positive associations between 5-FU exposure and tumor response. In current practice, however, 5-FU dose is reduced when symptoms of severe toxicity appear but is seldom increased to promote efficacy. Lab algorithm tests and genetic tests have garnered recent interest in optimizing dosage.
So far, research has shown that people with DPD deficiency usually develop severe side effects after the first few doses of fluorouracil or capecitabine. To avoid the risk of severe and potentially fatal reactions, the manufactures of both 5-FU and the oral fluoropyrimidine recommend that the drugs are contraindicated in patients with known DPD deficiency.
Variability in systemic exposure to 5-fluorouracil (5-FU) is thought to directly impact 5-FU tolerability and efficacy. The standard approach is dosing according to body surface area. Two alternative approaches have been proposed for modifying use of 5-FU: (1) dosing based on determined area under the curve serum concentration target and (2) genetic testing for variants affecting 5-FU metabolism. For genetic testing, currently available polymerase chain reaction tests assess specific variants in genes encoding dihydropyrimidine reductase (DPYD) and thymidylate synthase (TYMS) in the catabolic and anabolic pathways of 5-FU metabolism there are several testing options for DPYD genotype, although, at present most test only for the DPYD 2A variant. Approximately 10% of individuals receiving fluoropyrimidines have severe side effects from fluorouracil and capecitabine. But not everyone has a DPD deficiency. The testing to determine the likelihood of intolerance is unreliable at this time. Additional studies are needed before the use of DPD deficiency as a predictive molecular marker for fluoropyrimidines toxicity can be recommended as a standard of care.
Patient exposure to 5-FU is most accurately described by estimating the AUC (area under the curve), the total drug exposure over a defined period of time. 5-FU exposure is influenced by method of administration, circadian variation, liver function, and the presence of inherited dihydropyrimidine reductase (DPYD). Catabolism of 5-FU is controlled by the activity of DPYD. Because DPYD is a saturable enzyme, the pharmacokinetics of 5-FU are strongly influenced by the dose and schedule of administration.
Uracil breath test (UraBT) consists of measuring CO2 in exhaled breath after ingestion of 2-13C-uracil to evaluate pyrimidine (and 5FU) catabolism. Breath tests are still at very early stages of development.
Based on known 5-FU pharmacology, it is possible to determine a sampling scheme for area under the curve (AUC) determination and to optimize an AUC target and dose-adjustment algorithm for a particular 5-FU chemotherapy regimen and patient population. For each AUC value or range, the algorithm defines the dose adjustment during the next chemotherapy cycle most likely to achieve the target AUC without overshooting and causing severe toxicity.
Dihydropyrimidine dehydrogenase (DPD) enzyme – encoded by DPYD gene. This enzyme catabolizes >80% of 5-FU into an inactive form that is eliminated in the urine (rate limiting enzyme). Reduced DPD activity can lead to the accumulation of active 5-FU metabolite, increasing the risk for 5-FU toxicity.
Thymidylate synthase (TYMS) enzyme – encoded by TYMS gene, this is the primary target for 5-FU. The remaining 5-FU drug is metabolized by different enzymes into an active form that inhibits the synthesis of DNA and RNA by competitive inhibition of TYMS or by direct incorporation of cytotoxic metabolites into nucleic acids. TYMS gene variants result in reduced expression of TYMS and may be associated with higher clinical responsiveness to 5-FU therapy and increased risk of toxicity.
Lack of detection of the targeted DPYD and TYMS variants does not rule out risk for 5-FU toxicity or predict degree of responsiveness to 5-FU.
In 2015, Freeman et al published a health technology assessment (HTA) on the My5-FU assay to guide dose adjustment in patients receiving 5-FU chemotherapy by continuous infusion. The report was conducted on behalf of the National Institute of Health and Care Excellence (NICE). The assessment included a review of studies on the accuracy of the My5-FU assay compared with a reference standard test, high-performance liquid chromatography (HPLC) or liquid chromatography–mass spectrometry (LC-MS). Three studies were included, as well as information provided by the manufacturer. Risk of bias was difficult to assess due to incomplete reporting. In particular, it was unclear whether there was complete reporting of failed samples or outliers, which could result in overly optimistic estimates of accuracy.
No RCTs or nonrandomized comparative studies were identified comparing health outcomes in cancer patients who did and did not have 5-FU dose adjustment using the My5-FU assay and who were treated with chemotherapy regimens used in current clinical practice. A systematic review of the available literature found a significantly higher response rate with BSA-based monitoring and no significant difference in toxicity.
Universal pretreatment DPYD genotyping remains controversial, however, and the NCCN Panel does not support it at this time. Although current National Comprehensive Cancer Network (NCCN) guidelines acknowledge that the “selection, dosing, and administration of anticancer agents and the management of associated toxicities are complex,” NCCN does not recommend use of area under the curve guidance for 5-fluorouracil (5-FU) dosing or genetic testing for DPYD and/or TYMS variants in patients with colon, rectal, breast, gastric, pancreatic cancer, or head and neck cancers.
The IATDMCT released guidelines on the dosing of 5-FU. With regards to assessing systemic
exposure to 5-FU, the IATDMCT noted that area-under-curve (AUC) was the “accepted and clinically relevant” metric. They also noted that a relationship existed between 5-FU AUC and clinical activity (as well as toxicity. They go on to state, “It should be noted that statistically significant correlations between 5- FU exposure and toxicity have been observed across several disease types (squamous cell carcinoma of the head and neck (SCCHYN), nasopharyngeal cancer, and CRC), disease settings (metastatic, locally advanced), and dosing types (bolus, infusion).”
Concerning the use of the uracil breath test, the IATDMCT states, “The uracil breath test does not help in determining the correct does and is not recommended for clinical use” (2019).
Currently, U.S. Food and Drug Administration (FDA)-approved tests for 5-FU AUC measurement and for DPYD/TYMS mutation testing are unavailable. My5-FU™ is offered by Saladax Biomedical as a laboratory-developed test; other clinical laboratories may offer in-house assays to measure 5-FU AUC. Similarly, TheraGuide® was offered by Myriad Genetics as a laboratory-developed test but has been discontinued. Other laboratories may offer in-house assays for DPYD and TYMS mutation testing, and ARUP Laboratories offers a test that is equivalent to TheraGuide (5-FU toxicity and chemotherapeutic response, 7 mutations test). Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratories offering such tests as a clinical service must meet general regulatory standards of the Clinical Laboratory Improvement Act (CLIA) and must be licensed by CLIA for high-complexity testing. Both Saladax Biomedical and Myriad Genetics are CLIA-licensed laboratories.
For more information regarding personalized testing for pharmacotherapy please see policy 02.04.64.
My5-FU™ testing or other assays (e.g. DPD 5-FU GenotypeR (Quest Diagnostics)) for determining 5-fluorouracil area under the curve in order to adjust 5-fluorouracil (5-FU) dose is considered investigational.
Testing for genetic variants in Dihydropyrimidine dehydrogenase (DPYD) or thymidylate synthase (TYMS) genes to guide 5-FU dosing and/or treatment choice is considered investigational.
Uracil breath tests (UraBT) to aid in managing dose adjustment in individuals undergoing 5-fluorouracil chemotherapy is considered investigational.
No RCTs or nonrandomized comparative studies were identified comparing health outcomes in cancer patients who did and did not have 5-FU dose adjustment using the My area under the curve assays and who were treated with chemotherapy regimens used in current clinical practice. The genetic testing to predict drug metabolism have not been proven to change health outcomes at this time. The poor predictive value of genetic testing for DPYD/TYMS remains a barrier to recommendation for testing.
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