Laboratory and Genetic Testing for Use of 5-Fluorouracil in Patients With Cancer

POLICY NUMBER

A.2.04.68

DESCRIPTION

Variability in systemic exposure to 5-fluorouracil chemotherapy is thought to directly impact 5-fluorouracil tolerability and efficacy. The standard approach is dosing according to body surface area. Two alternative approaches have been proposed for modifying use of 5-fluorouracil:

1. Dosing based on the determined area under the curve serum concentration target, and

2. Genetic testing for variants affecting 5-fluorouracil 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-fluorouracil metabolism, respectively.

5-fluorouracil

The agent 5-fluorouracil is a widely used antineoplastic chemotherapy drug that targets the thymidylate synthase (TYMS) enzyme, which is involved in DNA production. 5-fluorouracil has been used for many years to treat solid tumors (eg, colon and rectal cancer, head and neck cancer). In general, the incidence of grade 3 or 4 toxicity (ie, mainly neutropenia, diarrhea, mucositis, and hand-foot syndrome) increases with higher systemic exposure to 5-fluorouracil. Several studies have also reported statistically significant positive associations between 5-fluorouracil exposure and tumor response. In current practice, however, 5-fluorouracil dose is reduced when symptoms of severe toxicity appear, but is seldom increased to promote efficacy.

Based on known 5-fluorouracil pharmacology, it is possible to determine a sampling scheme for the area under the curve determination and to optimize an area under the curve target and dose-adjustment algorithm for a particular 5-fluorouracil chemotherapy regimen and patient population. For each area under the curve value or range, the algorithm defines the dose adjustment during the next chemotherapy cycle most likely to achieve the target area under the curve without overshooting and causing severe toxicity.

In clinical research studies, 5-fluorouracil 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.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Assay testing for 5-fluorouracil blood plasma concentrations and genetic testing for variants in DPYD and TYMS for predicting the risk of 5-fluorouracil toxicity and chemotherapeutic response (ARUP Laboratories) are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test. The My5-FU assay is no longer marketed by Saladax Biomedical or Myriad Genetics in the United States. It is possible that therapeutic drug monitoring for 5-FU is available at a given institution as an in-house assay.

POLICY

Assay testing for determining 5-fluorouracil area under the curve in order to adjust 5-fluorouracil dose for individuals with cancer is considered investigational.

Testing for genetic variants in dipyrimidine dehydrogenase (DPYD) or thymidylate synthase (TYMS) genes to guide 5-fluorouracil dosing and/or treatment choice in individuals with cancer is considered investigational.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

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 HISTORY

07/21/2011: 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.

03/27/2017: Policy description updated regarding laboratory testing to measure exposure to 5-FU. Policy statement updated to change "mutations" to "variants." Policy guidelines updated regarding standard terminology for variant classification; added genetic counseling information.

12/21/2017: Code Reference section updated to add new 2018 CPT codes 81232 and 81346.

04/04/2018: Policy description updated. Policy statements unchanged. Policy Guidelines updated regarding genetic counseling.

04/04/2019: Policy reviewed; no changes.

08/13/2019: Policy reviewed; no changes.

04/15/2020: Policy description updated to remove sections regarding measuring exposure to 5-fluorouracil and genetic testing. Second investigational statement updated to add "genes."

05/26/2021: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to remove genetics nomenclature and genetic counseling information.

05/12/2022: Policy reviewed; no changes.

04/14/2023: Policy updated to remove "My 5-fluorouracil™" as this test is no longer commercially available in the U.S. Policy statement revised to state that assay testing for determining 5-fluorouracil area under the curve in order to adjust 5-fluorouracil dose for individuals with cancer is considered investigational. It previously stated: My 5-fluorouracil™ assay testing or other types of assays for determining 5-fluorouracil area under the curve in order to adjust 5-fluorouracil dose for colorectal cancer patients or other cancer patients is considered investigational.

04/18/2024: Policy reviewed; no changes.

04/17/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.68

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.