Medical Policy

Policy Num:     11.003.073
Policy Name:    Laboratory and Genetic Testing for Use of 5-Fluorouracil in Patients with Cancer
Policy ID:          [11.003.073]  [Ac / B / M- / P-]  [2.04.68]

Last Review:      April 15, 2024
Next Review:      April 20, 2025
 

Related Policies: None

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

Summary

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.

Summary of Evidence

For individuals who have cancer for whom treatment with 5-fluorouracil is indicated who receive laboratory assays to determine 5-fluorouracil area under the curve, the evidence includes randomized controlled trials (RCTs), observational studies, and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and treatment-related morbidity. Several analyses of patients with colorectal cancer have evaluated clinical validity. Two studies found that the rate of severe toxicity was significantly lower in patients with metastatic colorectal cancer who received dosing using pharmacokinetic monitoring versus body surface area (BSA); however, progression-free survival was not significantly different between groups. Most RCTs and nonrandomized studies comparing health outcomes were either single-center or did not use 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. Most observational data were derived from studies conducted in the 1980s when different chemotherapy protocols were used. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have cancer for whom treatment with 5-fluorouracil is indicated who receive genetic testing for variants (eg, in DPYD and TYMS) affecting 5-fluorouracil metabolism, the evidence includes observational studies, and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and treatment-related morbidity. A TEC Assessment (2010) concluded that DPYD and TYMS variant testing had poor prognostic capacity to identify patients likely to experience severe 5-fluorouracil toxicity. Since the publication of that assessment, no prospective trials comparing the efficacy and toxicity outcomes in patients who did and did not undergo pretreatment DPYD and/or TYMS testing have been published. Three prospective observational studies used a historical control group and 1 also used a matched-pairs analysis to compare outcomes in patients who received genotype-based dosing to those who received standard dosing. No differences in overall survival, progression-free survival, or tumor progression were observed. Risk of serious toxicity was higher in DPYD allele carriers who received genotype-based dosing compared to wild-type patients but lower when compared to historical controls who were carriers but received standard dosing. The evidence is limited by retrospective data collection, use of historical control groups, small sample sizes, and missing data. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to determine whether the use of laboratory or genetic testing improves the net health outcome by guiding 5-fluorouracil dosing and/or treatment in individuals with cancer.

POLICY statement

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 GUIDELINES

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

Some plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

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.^1, 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 also have 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.^2,3, 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.

Regulatory Status

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-fluorouracil is available at a given institution as an in-house assay.

RATIONALE

This evidence review was created in February 2011 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through January 12, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of the condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

The primary goal of therapeutic drug monitoring, pharmacogenomics testing, and personalized medicine is to achieve better clinical outcomes compared with the standard of care. Drug response varies greatly between individuals, and genetic factors are known to play a role. However, in most cases, the genetic variation only explains a modest portion of the variance in the individual response because clinical outcomes are also affected by a wide variety of factors including alternate pathways of metabolism and patient- and disease- related factors that may affect absorption, distribution, and elimination of the drug. Therefore, an assessment of clinical utility cannot be made by a chain of evidence from clinical validity data alone. In such cases, evidence evaluation requires studies that directly demonstrate that the therapeutic drug monitoring strategy or pharmacogenomic test alters clinical outcomes; it is not sufficient to demonstrate that the test predicts a disorder or a phenotype.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Laboratory Testing to Determine 5-fluorouracil Area Under the Curve for Dose Adjustment

Clinical Context and Test Purpose

The purpose of laboratory testing in individuals with cancer for whom 5-fluorouracil is indicated is to use test results to guide 5-fluorouracil dosing so that the therapeutic impact is maximized and the toxicity is decreased.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with cancer who have an indication for 5-fluorouracil treatment.

Interventions

The test being considered is laboratory assays to determine 5-fluorouracil area under the curve.

individuals exposure to 5-fluorouracil is most accurately described by estimating the area under the curve, the total drug exposure over a defined period of time. 5-fluorouracil exposure is influenced by the method of administration, circadian variation, liver function, and the presence of inherited dihydropyrimidine reductase (DPYD)-inactivating genetic variants that can greatly reduce or abolish 5-fluorouracil metabolism. As a result, both inter- and intra-individual variability in 5-fluorouracil plasma concentration during administration is high.

Determination of 5-fluorouracil area under the curve requires complex technology and expertise that may not be readily available in a clinical laboratory setting.

The association between area under the curve-monitored versus body surface area (BSA) dosing strategies has been examined in colorectal cancer patients who received 5-fluorouracil regimens.^4,5,

Comparators

The following practice is currently being used to make decisions about dosing of 5-fluorouracil: standard BSA-based dosing.

Body surface area-based dosing is associated with wide variability in pharmacokinetic parameters leading to significant differences in individual exposure. Nevertheless, BSA-based dosing is the standard for most chemotherapeutic agents.

Outcomes

There is a relatively narrow therapeutic window for 5-fluorouracil and levels of exposure leading to toxicity and efficacy overlap. Therefore, both safety and efficacy outcomes are of interest in evaluating evidence.

The general outcomes of interest related to 5-fluorouracil toxicity are types of severe toxicity such as cardiotoxicity, neutropenia, diarrhea, mucositis, and hand-foot syndrome.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer-term outcomes and adverse effects, single-arm studies were sought that capture longer periods of follow-up and/or larger populations.

• Duplicative or studies with overlapping populations were excluded.

Review of Evidence

Meta-Analysis

Yang et al (2016) published a meta-analysis of data from the 2 RCTs described below (Gamelin et al [2008]^6, and Fety et al [1998]^7,), as well as from 3 observational studies.^8, In a pooled analysis, the overall response rate was significantly higher with pharmacokinetic area under the curve-monitored 5-fluorouracil therapy than with standard BSA-based monitoring (odds ratio, 2.04; 95% confidence interval [CI], 1.41 to 2.95). In terms of toxicity, the incidence of diarrhea (3 studies), neutropenia (3 studies), and hand-foot syndrome (2 studies) did not differ significantly between the pharmacokinetic- and BSA-based monitoring strategies. The rate of mucositis was significantly lower in the BSA-monitored group (3 studies; odds ratio, 0.16; 95% CI, 0.04 to 0.63). Most data were from observational studies, which are subject to selection and observational biases.

Randomized Controlled Trials

The best contemporary evidence supporting area under the curve-targeted dosing consists of 3 RCTs, 2 enrolling patients with colorectal cancer and the other enrolling patients with head and neck cancer. No trials of any design were identified for 5-fluorouracil dose adjustment in other malignancies. The characteristics and key results of the RCTs are summarized in Tables 1 and 2.

Deng et al (2020) conducted an RCT in patients with advanced colorectal cancer who were treated with 5-fluorouracil (FOLFOX or FOLFIRI).^9, 5-fluorouracil was dosed using BSA for all patients in the first period, then patients were randomized to receive area under the curve-guided dosing (adjusted via an algorithm) or BSA-guided dosing for subsequent periods. The percentage of patients in the therapeutic window (area under the curve between 20 to 30 mg/h/L) was 24.52% with BSA-dosing. With the area under the curve dosing, the percentage of patients in the therapeutic range was 18.42% in the first period which increased to 89.71% in the sixth (and final) period. In the area under the curve-guided dosing, grade 3 toxicities were reduced and more patients experienced a clinical benefit, defined as a partial response or stable disease.

In an RCT enrolling patients with metastatic colorectal cancer, Gamelin et al (2008) reported significantly improved tumor response (33.6% vs. 18.3%, respectively; p<.001) and a trend toward improved survival (40.5% vs. 29.6%, respectively; p=.08) in the experimental arm using area under the curve-targeted dosing (by high-performance liquid chromatography) for single-agent 5-fluorouracil compared with fixed dosing.^6, However, trialists also reported 18% grade 3 to 4 diarrhea in the fixed-dose control arm, higher than reported in comparable arms of 2 other large chemotherapy trials (5% to 7%).^10,11, In the latter 2 trials, the delivery over a longer time period for both 5-fluorouracil (22 hours vs. 8 hours) and leucovorin (2 hours vs. bolus), which is characteristic of currently recommended 5-fluorouracil treatment regimens, likely minimized toxicity. The administration schedule used in the Gamelin et al (2008) trial^6, is rarely used in clinical practice and is absent from available guidelines.^5, Additional optimization studies would be needed to apply 5-fluorouracil exposure monitoring and area under the curve-targeted dose adjustment to a more standard single-agent 5-fluorouracil treatment regimen, with validation in a comparative trial versus a fixed-dose regimen.

Fety et al (1998) in an RCT of patients with locally advanced head and neck cancer, used a different method of dose adjustment and reported overall 5-fluorouracil exposures in head and neck cancer patients that were significantly reduced in the dose-adjustment arm compared with the fixed-dose arm.^7, This reduced toxicity but did not improve clinical response. The dose-adjustment method in this trial might have been too complex because the 12 patients with protocol violations in this treatment arm (of 61 enrolled) all were related to 5-fluorouracil dose adjustment miscalculations. Because patients with protocol violations were removed from the analysis, results did not reflect “real-world” results of the dose-adjustment method. Also, the induction therapy regimen used 2 drugs, not the current standard of 3; therefore, the generalizability of results to current clinical practice is limited.

Table 1. Summary of Key Randomized Trials Characteristics

5-FU: 5-fluorouracil; AUC: area under the curve; BSA: body surface area; CRC: colorectal cancer; FU: fluoropyrimidine; HPLC: high performance liquid chromatography; NR: not reported.

Table 2. Summary of Key Randomized Trials Results

AUC: area under the curve; BSA: body surface area; NR: not reported; PFS: progression free survival

Tables 3 and 4 display notable limitations identified in each study.

Table 3. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
^e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true positives, true negatives, false positives, false negatives cannot be determined).

Table 4. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).
^b Blinding key: 1. Not blinded to results of reference or other comparator tests.
^c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.
^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.
^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison to other tests not reported.

Single-Arm Studies

The results of single-arm trials of area under the curve-targeted 5-fluorouracil dose adjustment in advanced colorectal cancer patients have suggested consistently improved tumor response.^12,13,14, Similar, although less compelling, results were seen in single-arm trials of area under the curve-targeted 5-fluorouracil dosing in head and neck cancer.^15,16, Gamelin et al (1998) developed a chart for weekly dose adjustment based on the results of an earlier, similar single-arm study (1996)^17, in which the dose was increased by prespecified increments and intervals up to a maximum dose or the first signs of toxicity.

Section Summary: Laboratory Testing to Determine 5-fluorouracil Area Under the Curve for Dose Adjustment

Most RCTs and nonrandomized comparative studies comparing health outcomes were either single-center or did not use chemotherapy regimens used in current clinical practice. One recent RCT did find a clinical and safety benefit of use of area under the curve-targeted 5-fluorouracil dosing in patients with colorectal cancer. A systematic review of the available literature found a significantly higher response rate with BSA-based monitoring and no significant difference in toxicity. Most data were from observational studies, several of which were conducted in the 1980s when different chemotherapy protocols were used.

For individuals who have cancer for whom treatment with 5-fluorouracil is indicated who receive laboratory assays to determine 5-fluorouracil area under the curve, the evidence includes randomized controlled trials (RCTs), observational studies, and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and treatment-related morbidity. Several analyses of patients with colorectal cancer have evaluated clinical validity. Two studies found that the rate of severe toxicity was significantly lower in patients with metastatic colorectal cancer who received dosing using pharmacokinetic monitoring versus body surface area (BSA); however, progression-free survival was not significantly different between groups. Most RCTs and nonrandomized studies comparing health outcomes were either single-center or did not use 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. Most observational data were derived from studies conducted in the 1980s when different chemotherapy protocols were used. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Testing for DPYD or TYMS Variants Affecting 5-fluorouracil Dose Adjustment

Clinical Context and Test Purpose

The purpose of genetic testing in individuals with cancer for whom 5-fluorouracil is indicated is to use test results to guide 5-fluorouracil dosing so that the therapeutic impact is maximized and the toxicity is decreased.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with cancer who have an indication for 5-fluorouracil treatment.

Interventions

The test being considered is genetic testing for variants (eg, in DPYD and TYMS) affecting 5-fluorouracil metabolism.

5-fluorouracil 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-fluorouracil is inactivated and eliminated via the catabolic pathway; the remainder is metabolized via the anabolic pathway.

Catabolism of 5-fluorouracil is controlled by the activity of dihydropyrimidine reductase (DPYD). Because DPYD is a saturable enzyme, the pharmacokinetics of 5-fluorouracil are strongly influenced by the dose and schedule of administration.^18, For example, 5-fluorouracil clearance is faster with continuous infusion than with bolus administration, resulting in very different systemic exposure to 5-fluorouracil during the course of therapy. Genetic variants in DPYD, located on chromosome 1, can lead to reduced 5-fluorouracil catabolism and increased toxicity. Many variants have been identified (eg, IVS14+1G>A [also known as DPYD*2A], 2846A>T [D949V]). DPYD deficiency is an autosomal codominantly inherited trait.^19,

The anabolic pathway metabolizes 5-fluorouracil to an active form that inhibits DNA and RNA synthesis by competitive inhibition of thymidylate synthase (TYMS) or by incorporation of cytotoxic metabolites into nascent DNA.^20, Genetic variants in TYMS can cause tandem repeats in the TYMS enhancer region (TSER). One variant leads to 3 tandem repeats (TSER*3) and has been associated with 5-fluorouracil resistance due to increased tumor TYMS expression compared with the TSER*2 variant (2 tandem repeats) and wild-type forms.

A number of studies have evaluated the association between variants in the DPYD and/or TYMS genes and 5-fluorouracil toxicity. Cancer types and specific variants differed across these reports.^{21,22,23,24,25,26,}

Comparators

The following practice is currently being used to make decisions about dosing of 5-fluorouracil: standard BSA-based dosing.

Outcomes

There is a relatively narrow therapeutic window for 5-fluorouracil and levels of exposure leading to toxicity and efficacy overlap. The beneficial outcome of a true-positive (identifying a variant that would have caused severe toxicity) is prevention of toxicity. However, the harmful outcome of a false-positive is withholding or premature cessation of effective chemotherapy which may compromise chemotherapy effectiveness.

Therefore, both safety and efficacy outcomes are of interest in evaluating evidence. The outcomes of interest related to 5-fluorouracil toxicity are types of severe toxicity such as cardiotoxicity, neutropenia, diarrhea, mucositis, and hand-foot syndrome.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer-term outcomes and adverse effects, single-arm studies were sought that capture longer periods of follow-up and/or larger populations.

• Duplicative or studies with overlapping populations were excluded.

Review of Evidence

A TEC Assessment (2010) concluded that DPYD and TYMS variant testing did not meet TEC criteria.^27, The Assessment noted that the tests had “poor ability to identify patients likely to experience severe 5-fluorouracil toxicity. Although genotyping may identify a small fraction of patients for whom serious toxicity is a moderate to strong risk factor, most patients who develop serious toxicity do not have variants in DPD or TS genes.”^27,

Prospective Nonrandomized Studies

Several recent, prospective, observational studies have reported safety and effectiveness outcomes in patients who received genetic testing prior to receiving a 5-fluorouracil-based chemotherapy regimen. Characteristics and results of these studies are shown in Tables 5 and 6. Three of these, conducted by the same research group in the Netherlands, used historical controls,^28,29,30, and 1 also included a matched-pairs analysis using previously-collected data.^29, The others were single-arm, uncontrolled studies.^31,32,33, No prospective trials comparing efficacy and safety outcomes using concurrent control groups with or without pretreatment DPYD and/or TYMS testing were identified.

Henricks et al (2019) included 3 comparison groups in a prospective cohort study in which patients received genotyping prior to treatment as part of routine care.^29, Group 1 (n=40) were DPYD*2A carriers treated with an approximately 50% reduced fluoropyrimidine dose. Group 2 (n=1606) were wild-type patients who had been identified as part of an earlier study (Deenan et al [2016];^28, discussed below) and treated with a standard dose. Group 3 (n=86) were DPYD*2A carriers, identified from the literature, treated with a standard dose. Safety outcomes for the first 18 of the 40 patients in Group 1 were previously reported in Deenan et al (2016).^28, Patients in Group 1 were matched to those in Group 2 for the primary analysis for covariables known to influence treatment outcome. The primary effectiveness endpoint was overall survival. Secondary endpoints were progression-free survival and tumor response. Of the patients included in Groups 1 and 2, 96% of patients were White, 1% of patients were Southeast Asian, 1.3% of patients were African, and 1.7% of patients did not have their ethnicity or race described.

In matched-pair comparisons, Groups 1 and 2 did not differ on overall survival (hazard ratio, 0.82; 95% CI, 0.47 to 1.43; p=.47), progression-free survival (hazard ratio, 0.83; 95% CI, 0.47 to 1.50; p=.54), or tumor response (0% vs. 5% complete response; 20% vs. 34% partial response; p>.99), suggesting that the lower dose did not have a detrimental effect on treatment response in DPYD*2A carriers. The incidence of treatment-related toxicity, including overall toxicity, gastrointestinal toxicity, hematological toxicity, and hand-foot syndrome, was higher in the genotype-guided dosing group compared to wild-type patients, but differences were not statistically significant. Compared to the historical literature cohort who had received standard dosing, Group 1 patients had a lower risk of severe toxicity (77% vs. 18%; p<.001). There were no treatment-related deaths in the genotype-guided group, compared to 7 of 86 (8%) in the historical cohort. This study had several methodological limitations. Although patients were prospectively genotyped, data collection of outcomes was retrospective. A historical control group was used for the assessment of adverse events. There was a relatively large amount of missing data, a small sample size, and the study was underpowered. Because it was conducted at a single institution, its results may not be generalizable to other settings.

Deenan et al (2016) compared outcomes for pretreatment DPYD*2A testing with historical controls.^28, The study included cancer patients intending to undergo treatment with fluoropyrimidine-based therapy (5-fluorouracil or capecitabine).^28, Genotyping for DPYD*2A was performed before treatment, and dosing was adjusted based on the alleles identified. Patients with heterozygous variant alleles were treated with a reduced (ie, ≥50%) starting dose of fluoropyrimidine for 2 cycles, and the dosage was then individualized based on tolerability. No homozygous variant allele carriers were identified. Safety outcomes were compared with historical controls. Twenty-two (1.1%) of 2038 patients were heterozygous for DPYD*2A. Eighteen (82%) of these 22 patients were treated with reduced doses of capecitabine. Five (23%; 95% CI, 10% to 53%) patients experienced grade 3 or higher toxicity. In historical controls with DPYD*2A variant alleles, the rate of grade 3 or higher toxicity was 73% (95% CI, 58% to 85%). The historical controls were more likely to be treated with 5-fluorouracil-based therapy than with capecitabine-based therapy. Trial limitations included a lack of randomization to a management strategy and the use of historical, rather than concurrent, controls. Relevant diversity was also not well represented, as 96% of patients were White, 1% of patients were Asian, and 3% of patients did not have their ethnicity or race described.

Henricks et al (2018) conducted a prospective study of adult patients with cancer who were intended to start fluoropyrimidine-based therapy.^30, Patients were enrolled from 17 hospitals in the Netherlands. Dose reductions were based on genotyping: heterozygous DPYD variant allele carriers received an initial dose reduction of either 25% (for c.2846A>T and c.1236G>A) or 50% (for DPYD*2A and c.1679T>G). The researchers compared adverse events in the prospectively genotyped group who received genotype-based dosing, wild-type patients identified through prospective genotyping, and a historical control group of patients from a previously published meta-analysis who were DPYD variant carriers but did not receive genotype-guided dosing. The primary outcome was the frequency of severe treatment-related toxicity. Survival and response were not assessed. There was a higher incidence of grade 3 or higher toxicity in the genotype-dosing group compared to wild-type patients (39% vs. 23%; p=.0013). The relative risk for severe toxicity in DPYD*2A carriers who did not have genotype-guided dosing was 2.87 (95% CI, 2.14 to 3.86), compared to 1.31 (0.63 to 2.73) in the cohort that received genotype-based dosing. The main limitation of this study is its use of a historical control group, with no control for confounders in the analysis. Relevant diversity was also not well represented, as 95% of patients were White, 2% of patients were Asian, 2% of patients were Black, and 1% of patients did not have their ethnicity or race described.

Cremolini et al (2018) ^33, reported chemotherapy-related adverse events experienced by patients with metastatic colon cancer who were enrolled in the phase III RCT and treated with first-line FOLFOXIRI plus bevacizumab or FOLFIRI plus bevacizumab. Of 508 randomized patients, 443 (87%) were genotyped for DPYD and UGT1A1 variants. All patients received study treatments as planned doses; dosage was not adjusted based on genotyping. Overall 8 of 10 patients who were DPYD carriers experienced grade 3 or higher adverse events. An advantage of this study was that it used prospectively and systematically collected data on adverse events. It is limited by the lack of a comparison group and because genotype-based dosing was not used.

Goff et al (2014) prospectively genotyped 42 adults who had gastric or gastroesophageal junction cancer for TSER tandem repeats.^31, Of the 26 patients included initially in the study, 88% of patients were White, 8% were African American, and 4% did not have their race or ethnicity described. Twenty-five patients who had TSER 2R/2R or 2R/3R genotypes received a modified 5-fluorouracil chemotherapy regimen until unacceptable toxicity or disease progression (median, 5.5 cycles); patients homozygous for triplet repeats (3R/3R) were excluded. The overall response rate in 23 evaluable patients was 39% (9 partial responses, no complete responses), which was worse than a 43% historical overall response rate in unselected patients. The overall response rate in 6 patients homozygous for doublet repeats (2R/2R) was 83% (5 partial responses, no complete responses). Median overall survival and progression-free survival in the entire cohort (secondary outcomes) were 11.3 months and 6.2 months, respectively; these rates were similar to those reported in unselected populations. The study was stopped before meeting target enrollment (minimum of 75 patients) due to insufficient funding.

Magnani et al (2013) reported on 180 cancer patients receiving fluoropyrimidines (5-fluorouracil or capecitabine) who underwent DPYD analysis for the 1905+1 G>A variant by high-performance liquid chromatography.^32, Four patients were heterozygous carriers. Of these, 3 patients received a dose reduction of 50% to 60% but still experienced severe toxicities requiring hospitalization. One patient did not receive chemotherapy based on DPYD genotype and the presence of other variants found in mismatch repair genes.

Table 5. Summary of Key Nonrandomized Trials Characteristics

DPYD: dihydropyrimidine reductase; FU: fluoropyrimidine; RCT: randomized controlled trial; TSER: thymidylate synthase enhancer region.

Table 6. Summary of Key Nonrandomized Trials Results

CI: confidence interval; DPYD: dihydropyrimidine reductase; NA: not applicable; NR: not reported; RR: relative risk.

Tables 7 and 8 display notable limitations identified in each study.

Table 7. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity, and predictive values);
4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
^e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Table 8. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).
^b Blinding key: 1. Not blinded to results of reference or other comparator tests.
^c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.
^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.
^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.

Retrospective Studies

Lau et al. (2023) evaluated the impact of DPYD variant testing and preemptive fluoropyrimidine (5-fluorouracil or capecitabine) dose reductions on the rate of toxicity in patients with gastrointestinal cancers in the United Kingdom.^34, Patients with a DPYD heterozygous variant received a dose reduction of 25% to 50%. Among 370 fluoropyrimidine-naïve patients who underwent DPYD genotyping before receiving chemotherapy regimens containing capecitabine (n=236) or 5-fluorouracil (n=134), 33 patients (8.8%) were heterozygous DPYD variant carriers and 337 (91.2%) were wild type. The mean relative dose intensity for the first dose was 54.2% (range, 37.5% to 75%) for DPYD heterozygous carriers and 93.2% (range, 42.9% to 100%) for DPYD wild-type carriers. The rate of grade 3 or higher toxicity was similar amongst DPYD and wild-type variant carriers (25.7% [89/337] vs 12.1% [4/33], respectively; p=.0924).

Section Summary: Testing for DPYD or TYMS Variants Affecting 5-fluorouracil Dose Adjustment

A 2010 TEC Assessment concluded that DPYD and TYMS variant testing had a poor ability to identify patients likely to experience severe 5-fluorouracil toxicity. Since the publication of the TEC Assessment, no prospective trials comparing the efficacy and toxicity outcomes in patients who did and did not undergo pretreatment DPYD and/or TYMS testing have been published. Three prospective observational studies used a historical control group and 1 also used a matched-pairs analysis to compare outcomes in patients who received genotype-based dosing to those who received standard dosing. No differences in overall survival, progression-free survival or tumor progression were observed. Risk of serious toxicity was higher in DPYD allele carriers who received genotype-based dosing compared to wild-type patients but lower when compared to historical controls who were carriers but received standard dosing. The evidence is limited by retrospective data collection, use of historical control groups, small sample sizes, and missing data.

For individuals who have cancer for whom treatment with 5-fluorouracil is indicated who receive genetic testing for variants (eg, in DPYD and TYMS) affecting 5-fluorouracil metabolism, the evidence includes observational studies, and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and treatment-related morbidity. A TEC Assessment (2010) concluded that DPYD and TYMS variant testing had poor prognostic capacity to identify patients likely to experience severe 5-fluorouracil toxicity. Since the publication of that assessment, no prospective trials comparing the efficacy and toxicity outcomes in patients who did and did not undergo pretreatment DPYD and/or TYMS testing have been published. Three prospective observational studies used a historical control group and 1 also used a matched-pairs analysis to compare outcomes in patients who received genotype-based dosing to those who received standard dosing. No differences in overall survival, progression-free survival, or tumor progression were observed. Risk of serious toxicity was higher in DPYD allele carriers who received genotype-based dosing compared to wild-type patients but lower when compared to historical controls who were carriers but received standard dosing. The evidence is limited by retrospective data collection, use of historical control groups, small sample sizes, and missing data. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Clinical Pharmacogenetics Implementation Consortium

In 2009, the Clinical Pharmacogenetics Implementation Consortium (CPIC) was formed as a shared project between PharmGKB, an internet research tool developed by Stanford University, and the Pharmacogenomics Research Network of the National Institutes of Health. In 2013, the Clinical Pharmacogenetics Implementation Consortium published evidence-based guidelines for DPYD genotype and fluoropyrimidine dosing.^19, The guidelines did not address testing.

An update to the Clinical Pharmacogenetics Implementation Consortium (2017) guidelines was published by Amstutz et al (2018).^35, As in 2013, the primary focus of the guidelines was on the DPYD genotype and implications for dosing of fluoropyrimidine. In the 2017 update, the Clinical Pharmacogenetics Implementation Consortium noted that genetic testing for DPYD may include “resequencing of the complete coding regions” or may be confined to analysis of particular risk variants, among which Clinical Pharmacogenetics Implementation Consortium listed the c.1905+1G>A , c.1679T>G, c.2846A>T, and c.1129-5923C>G variants, as affecting 5-fluorouracil toxicity. Additional alleles potentially associated with 5-fluorouracil toxicity were added in online updates to the guideline's tables in 2020.^36, The guideline further noted that, while other genes (TYMS, MTHFR) may be tested for variants, the clinical utility of such tests is yet unproven. In patients who have undergone genetic testing and who are known carriers of a DPYD risk variant, the guidelines recommended that caregivers strongly reduce the dosage of 5-fluorouracil-based treatments, or exclude them, depending on the patient’s level of DPYD activity. The CPIC advised follow-up therapeutic drug monitoring to guard against underdosing and cautioned that genetic tests could be limited to known risk variants and, therefore, not identify other DPYD variants.

International Association of Therapeutic Drug Monitoring and Clinical Toxicology

In 2019, the International Association of Therapeutic Drug Monitoring and Clinical Toxicology published recommendations for therapeutic drug monitoring of 5-fluorouracil therapy.^37, The work was supported in part by grants from the National Institutes of Health National Cancer Institute. Several authors reported relationships with Saladax, the manufacturer of the My5-FU assay available in Europe. The committee concluded that there was sufficient evidence to strongly recommend therapeutic drug monitoring for the management of 5-fluorouracil therapy in patients with early or advanced colorectal cancer and patients with squamous cell carcinoma of head-and-neck cancer receiving common 5-fluorouracil dosing regimens.

National Comprehensive Cancer Network Guidelines

National Comprehensive Cancer Network (NCCN) guidelines do not recommend use of area under the curve guidance for 5-fluorouracil dosing or genetic testing for DPYD and/or TYMS variants in patients with colon,^38, rectal,^39, breast,^40, gastric,^41, pancreatic,^42, or head and neck cancers.^43,

The colon cancer guideline discusses the use of genetic testing for DPYD and the risk of severe toxicity after a standard dose of a fluoropyrimidine. Although the guideline discusses evidence for genetic testing for DPYD, it states: "Because fluoropyrimidines are a pillar of therapy in colorectal cancer (CRC) and it is not known with certainty that given DPYD variants are associated with this risk and/or that dose adjustments do not impact efficacy, the NCCN Panel does not recommend universal pretreatment DPYD genotyping at this time."

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

There are currently no relevant ongoing trials. Some unpublished trials that might influence this review are listed in Table 9.

Table 9. Summary of Key Trials

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

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Deny: Investigational.

Economic Impact

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