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Variability in systemic exposure to 5-fluorouracil (5-FU) is thought to directly impact 5-FU tolerability and efficacy. Two approaches have been proposed for modifying use of 5-FU:
5-Fluorouracil is a widely used antineoplastic chemotherapy drug that targets TYMS, an enzyme involved in DNA production. 5-FU has 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 3/4 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 is 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.
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.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. Both Saladax Biomedical and Myriad Genetics are CLIA-licensed laboratories. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test. My5-FU™ (Saladax Biomedical) is available under the auspices of CLIA. Other clinical laboratories may offer in-house assays to measure 5-fluorouracil (5-FU) area under the curve. Similarly, TheraGuide® (Myriad Genetics) was 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).
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.
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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Investigative 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.
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.
03/01/2016: Policy description updated regarding approaches for modifying use of 5-FU. Policy statements unchanged.
06/09/2016: Policy number A.2.04.68 added. Policy description updated regarding laboratory-developed tests. Second investigational policy statement updated to remove "TheraGuide®" from the statement because this test is no longer commercially available. Policy statements otherwise unchanged.
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.
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