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Dosing of 5-fluorouracil (5-FU) in cancer patients to a predetermined area under the curve (AUC) target has been proposed as a method to reduce variability in systemic exposure to 5-FU, reduce toxicity, and improve tumor response. Accurate AUC determination relies on sampling at a pharmacokinetically appropriate time, as well as on an accurate method of 5-FU laboratory measurement. Available measurement methods are complex and require the expertise to develop an in-house assay, making them less amenable to routine clinical laboratory settings. One commercially available alternative is Myriad Genetics’ OnDose™, a diagnostic test that is designed to measure colorectal cancer patients’ exposure to 5-FU, to help oncologists adjust and optimize 5-FU dosing and improve patient outcomes.
5-Fluorouracil is a widely used antineoplastic chemotherapy drug with a narrow therapeutic index; doses recommended for effectiveness are often limited by hematologic and gastrointestinal toxicity. Moreover, patients administered the same fixed dose, continuous infusion regimen of 5-FU have wide intra- and inter-patient variability in systemic drug exposure as measured by plasma concentration or, more accurately, by area under the curve techniques (AUC). AUC is a measure of the systemic drug exposure in an individual over a defined period of time.
In general, the incidence of grade 3 to 4 toxicity (mainly neutropenia, diarrhea, mucositis, and hand-foot syndrome) increases with higher systemic exposure to 5-FU. Several studies have also 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 seldom increased to promote efficacy.
Based on known 5-FU pharmacology, it is possible to determine a sampling scheme for 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.
In clinical research studies, 5-FU blood plasma levels most recently have been determined by high-performance liquid chromatography or liquid chromatography coupled with tandem mass spectrometry. Both methods require expertise to develop an in-house assay and may be less amenable to routine clinical laboratory settings. One commercially available alternative is Saladax Biomedical’s My5-FU™, an immunoassay designed to measure patients' exposure to 5-FU to help oncologists adjust and optimize 5-FU dosing. My5-FU™ was originally marketed in the U.S. by Myriad Genetics as OnDose® under patents licensed from Saladax Biomedical (Bethlehem, PA). In June 2013, rights to the assay reverted to Saladax Biomedical.
Metabolism of 5-Fluorouracil
5-FU is a pyrimidine antagonist, similar in structure to the normal pyrimidine building blocks of RNA (uracil) and DNA (thymine). More than 80% of administered 5-FU is inactivated and eliminated via the catabolic pathway; the remainder is metabolized via the anabolic pathway.
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® is offered by Myriad Genetics as a laboratory-developed test; other laboratories may offer in-house assays for DPYD and TYMS mutation testing (eg, ARUP Laboratories). 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.
My5-FU™ testing or other types of assays for determining 5-fluorouracil area under the curve in order to adjust 5-FU dose for colorectal cancer patients or other cancer patients is considered investigational.
TheraGuide® testing for genetic mutations in dipyrimidine dehydrogenase (DPYD) or thymidylate synthase (TYMS) to guide 5-FU dosing and/or treatment choice in patients with cancer is considered investigational.
POLICY GUIDELINESInvestigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY07/21/2011: Approved by Medical Policy Advisory Committee.
04/26/2012: Policy reviewed; no changes.
07/19/2013: Policy reviewed; no changes to policy statement. Added HCPCS code S3722 to the Code Reference section.
07/11/2014: Policy description updated regarding metabolism of 5-Fluorouracil and tests. Policy title changed from "Laboratory Testing to Allow Area Under the Curve (AUC) Targeted 5-Fluorouracil (5-FU) Dosing for Patients Administered 5-FU for Cancer" to "Laboratory and Genetic Testing for Use of 5-Fluorouracil in Patients With Cancer" to reflect the expanded scope of the policy. Policy statement revised to add the following: 1) My5-FU™ testing or other types of assays for determining 5-fluorouracil area under the curve in order to adjust 5-FU dose for colorectal cancer patients or other cancer patients is considered investigational. 2) TheraGuide® testing for genetic mutations in dipyrimidine dehydrogenase (DPYD) or thymidylate synthase (TYMS) to guide 5-FU dosing and/or treatment choice in patients with cancer is considered investigational. It previously stated that OnDose™ testing or other types of assays for determining 5-fluorouracil area under the curve in order to adjust 5-FU dose for colorectal cancer patients or other cancer patients is considered investigational.
08/18/2015: Code Reference section updated for ICD-10.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.68
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.