| Coverage Policy Manual | |
| Policy #: | 2010006 |
| Category: | Laboratory |
| Initiated: | October 2009 |
| Last Review: | April 2024 |
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| Genetic Test: Laboratory and Genetic Testing for Use of 5-Fluorouracil in Patients with Cancer | |
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| Description: |
5-FU 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 interpatient variability in systemic drug exposure, as measured by plasma concentration or, more accurately, by AUC techniques. AUC is a measure of 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 also 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.
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.
Myriad Genetics has developed a PCR test, TheraGuide®, to assess certain mutations in DPYD and TYMS. The Myriad Genetics website estimates that “up to 25% of individuals have variations in the DPYD and/or TYMS genes that are associated with an increased risk of toxicity to 5-FU.”6 ARUP Laboratories also offers DPYD and TYMS mutation testing (ARUP, 2015).
Regulatory Status
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 was offered by Saladax Biomedical as a laboratory-developed test, but has has been discontinued. 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 (f-FU toxicity and chemotherapeutic resonse, 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.
Coding
There is no specific CPT coding for the My5-FU test. According to the company, the following code is used:
84999: Unlisted chemistry procedure.
Effective for 2011, there is a specific HCPCS “S” code for the My5-FU test –
S3722 – Dose optimization by area-under-the-curve (AUC) analysis for infusional 5-fluorouracil (5-FU)
The TheraGuide testing might be reported with the following codes:
CPT code 81400 which includes the following test –
DPYD (dihydropyrimidine dehydrogenase) (eg, 5-fluorouracil/5-FU and capecitabine drug metabolism),
IVS14+1G>A variant
And CPT code 81401 which includes the following test:
TYMS (thymidylate synthetase) (eg, 5-fluorouracil/5-FU drug metabolism), tandem repeat variant
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Policy/ Coverage: |
Effective March 2015
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of 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 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For members with contracts without primary coverage criteria, the use of 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Testing for genetic variations in dipyrimidine dehydrogenase (DPYD) or thymidylate synthase (TYMS) to guide 5-FU dosing and/or treatment choice in patients with cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. For members with contracts without primary coverage criteria, the use of TheraGuide® testing for genetic variations in dipyrimidine dehydrogenase (DPYD) or thymidylate synthase (TYMS) to guide 5-FU dosing and/or treatment choice in patients with cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective January 2013 to February 2015
Genetic testing for DYPD and/or TYMS functional variants for predicting toxicity to 5-Fluorouracil (5-FU)/Capecitabine-based chemotherapy does not meet ABCBS Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without Primary Coverage Criteria, genetic testing for DYPD and/or TYMS functional variants for predicting toxicity to 5-fluorouracil (5-FU)/capecitabine-based chemotherapy is considered investigational. Investigational services are exclusions in the member benefit certificate of coverage.
Effective prior to January 2013
Genetic testing with the TheraGuide 5-FUtm test for predicting toxicity to 5-Fluorouracil (5-FU)/Capecitabine-based chemotherapy does not meet ABCBS Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without Primary Coverage Criteria, genetic testing for predicting toxicity to 5-fluorouracil (5-FU)/capecitabine-based chemotherapy with the TheraGuide 5-FUtm test is considered investigational. Investigational services are exclusions in the member benefit certificate of coverage.
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| Rationale: |
5-Fluorouracil and Clinical Use
5-Fluorouracil (5-FU) is a pyrimidine analog, antineoplastic antimetabolite; 5-FU has been used for many years to treat solid tumors, eg, colorectal adenocarcinoma. The U.S. Food and Drug Administration (FDA)-approved indication of 5-FU is for “palliative management of carcinoma of the colon, rectum, breast, stomach, and pancreas” (TEVAParenteral Medicines, Inc., 2012)
Colon Cancer
Potentiated by leucovorin (LV), 5-FU is the basis for several standard treatment regimens currently recommended by the National Comprehensive Cancer Network (NCCN) for the treatment of colorectal cancer (CRC) (NCCN Colon Cancer, 2015; NCCN Rectal Cancer, 2015) For stage II CRC, NCCN recommends adjuvant therapy primarily for disease with high-risk features, individualized for each patient; for stage III disease, oxaliplatin in combination with 5-FU/LV is the preferred standard of care. Based on results from the 2009 European Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial (Andre, 2009), in which the addition of oxaliplatin to a regimen of LV and infusional 5-FU every 2 weeks (ie, a FOLFOX [leucovorin calcium, fluorouracil, oxaliplatin] regimen) significantly increased disease-free (DFS) and overall survival (OS), the FOLFOX regimen is recommended for patients with stage III CRC. A FOLFOX regimen also improves progression-free survival (PFS) in patients with advanced (ie, metastatic) CRC who are able to tolerate intensive versus single-agent 5-FU therapy, (de Gramont, 2000; Giacchetti, 2000) and FOLFOX may be considered for patients with high-risk stage II disease. Other 5-FU-based combination chemotherapy regimens are options in advanced disease. In patients with advanced or metastatic colon cancer, bolus 5-FU regimens seem to be more toxic than infusional regimens and are considered inappropriate when coadministered with either irinotecan (a topoisomerase inhibitor) or oxaliplatin (NCCN Colon Cancer, 2015; NCCN Rectal Cancer, 2015).
Head and Neck Cancers
5-FU has for many years been a component, with cisplatin, of induction therapy for squamous cell carcinoma of the head and neck in patients with advanced locoregional disease, yielding high rates of overall and complete clinical response. The addition of docetaxel was shown to improve survival, and this 3-drug combination is now considered the standard of care for induction chemotherapy (NCCN Head and Neck Cancer, 2014; Posner, 2008). Typical 5-FU administration is by continuous infusion (Beneton, 2007). 5-FU also is a component of several combination chemotherapy regimens used for primary systemic therapy in conjunction with radiotherapy, and of 2 combination regimens for recurrent, unresectable, or metastatic disease (NCCN Head and Neck Cancer, 2014).
Measuring Exposure to 5-Fluorouracil
Patient exposure to 5-FU is most accurately described by estimating the area under the curve (AUC), 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)‒inactivating genetic variants that can greatly reduce or abolish 5-FU catabolism. As a result, both inter- and intrapatient variability in 5-FU plasma concentration during the course of administration is high.
As noted, determination of 5-FU AUC requires complex technology and expertise that may not be readily available in a clinical laboratory setting. In the United States, Saladax Biomedical offers a commercial immunoassay, My5-FU™, that quantifies plasma 5-FU concentration from a blood sample drawn during continuous infusion at steady state (18-44 hours after the start of infusion) and provides a dose adjustment algorithm to maintain plasma 5-FU AUC between 20 to 30 mg/h/L during the next cycle (Saladax Biomedical, inc,, 2015). The dosing algorithm is based on that developed by Kaldate et al (2012) using OnDose® (now called My5-FU™) in patients with CRC treated with FOLFOX.17 Technical specifications for OnDose® can still be found on the Myriad Genetics website, which describes the test as a “competitive, homogeneous, 2-reagent nanoparticle agglutination immunoassay” (OnDose, 2010). Although a search of large clinical laboratories did not find tests for 5-FU AUC listed, it is possible that other clinical laboratories measure 5-FU levels by methods other than the specific method used by Saladax Biomedical.
Modifying 5-Fluorouracil Exposure to Improve Outcomes
A 2009 TEC Special Report reviewed the evidence for 5-FU AUC measurement to help modify subsequent 5-FU treatment doses to improve response and reduce toxicity (BCBSA TEC, 2009). Early evidence from small, cohort studies showed that in general, the incidence of grade 3 to 4 toxicity (mainly neutropenia, diarrhea, mucositis, hand-foot syndrome) increased with higher systemic exposure to 5-FU. This association has been extensively studied in head and neck cancer and in CRC. In addition, most studies reported statistically significant positive associations between 5-FU exposure and tumor response.
Based on these early results, various strategies have been tried to reduce variability in 5-FU pharmacokinetics, improve treatment efficacy, and decrease toxicity. In particular, individual pharmacokinetic dose adaptation can be accomplished by monitoring plasma 5-FU area under the curve AUC) at steady state during each treatment cycle and adjusting administered 5-FU dose for the next treatment cycle to achieve a target AUC value established as maximally efficacious and minimally toxic. The hypothesis is that individual 5-FU dose modulation to a target AUC value that is just below the threshold for severe toxicity could minimize toxicity while improving response.
The results of single-arm trials of AUC-targeted 5-FU dose adjustment in advanced CRC patients suggested consistently improved tumor response (Gamelin, 1998; Boisdron-Celle, 2002; Ychou, 2003). Similar, although less compelling results were seen in single-arm trials of AUC targeted 5-FU dosing in head and neck cancer (Milano, 1994; Santini, 1989). The best contemporary evidence in support of AUC-targeted dosing consists of 2 randomized controlled trials (RCTs), one enrolling patients with CRC and the other patients with head and neck cancer. No trials of any design were identified for 5-FU dose adjustment in other malignancies.
Gamelin et al (1998) (Gamelin, 1998) developed a chart for weekly dose adjustment based on the results of an earlier, similar single-arm study (Gamelin, 1996) in which dose was increased by prespecified increments and intervals up to a maximum dose or the first signs of toxicity. In an RCT enrolling patients with metastatic CRC, Gamelin et al (2008)26 reported significantly improved tumor response (33.6% vs 18.3%, respectively; p<0.001) and a trend toward improved survival (40.5% vs 29.6%, respectively; p=0.08) in the experimental arm using AUC-targeted dosing (by high-performance liquid chromatography) for single-agent 5-FU. However, the authors 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%-7%) (Andre, 2009; de Gramont, 2000). In the latter 2 trials, delivery over a longer time period for both 5-FU (22 hours vs 8 hours) and LV (2 hours vs bolus), which is characteristic of currently recommended 5-FU treatment regimens, likely minimized toxicity. The administration schedule used in the Gamelin et al (2008) (Gamelin, 2008) trial is “rarely used in current practice in most countries” as described in an accompanying editorial by Walko and McLeod (Walko, 2008) and is absent from current guidelines.1 Additional optimization studies would be needed to apply 5-FU exposure monitoring and AUC-targeted dose adjustment to a more standard single-agent 5-FU treatment regimen, with validation in a comparative trial versus a fixed-dose regimen.
In 2012, the same group conducted a retrospective analysis to compare their dose adjustment protocol in a FOLFOX regimen for patients with CRC (n=118) with patients treated with FOLFOX administered in standard fashion according to body surface area. (n=39) (Capitain, 2012).In the dose-adjusted group, the therapeutic dose at 3 months was 110% of the theoretic dose. Grade 3/4 toxicity was 1.7% for diarrhea, 0.8% for mucositis, 18% for neutropenia, and 12% for thrombocytopenia; corresponding numbers were 12%, 15%, 25% and 10%, respectively, in the standard group. At 3 and 6 months, objective response in the dose-adjusted group was 70% and 56%, respectively; at 3 months, objective response in the standard group was 46%. Median OS and median PFS were 28 and 16 months, respectively, in the dose-adjusted group, and 22 and 10 months, respectively, in the standard group. As the authors note, this proof of principle study needs confirmation in a randomized trial.
Fety et al (1998), in an RCT in patients with locally advanced head and neck cancer, used a different method of dose adjustment and reported overall 5-FU exposures in head and neck cancer patients that were significantly reduced in the dose-adjustment arm compared with the fixed-dose arm (Fety, 1998). This resulted in reduced toxicity but no improvement in clinical response. The dose adjustment method in this trial may have been too complex, because the 12 patients with protocol violations in this treatment arm (of 61 enrolled) all were related to 5-FU dose adjustment miscalculations. Because patients with protocol violations were removed from analysis, results did not reflect “real-world” results of the dose adjustment method. In addition, the induction therapy regimen used 2 drugs, not the current standard of 3 and, therefore, generalizability of results to current clinical practice is limited.
Test Performance
My5-FU™
Analytic Validity
Analytic validity is the technical performance (ie, reproducibility) of a test.
In 2014, Freeman et al published a diagnostic assessment report for the National Institute of Health and Care Excellence (NICE) on the My5-FU™ assay for guiding dose adjustment in patients receiving 5-FU chemotherapy by continuous infusion (Freeman, 2014). Evidence for analytic validity included validation data provided by the manufacturer, which were judged to have a high risk of bias. Overall, correlation between My5-FU™ and reference standards tests (high-pressure liquid chromatography or liquid chromatography–mass spectrometry) was considered good. It was unclear whether observed variability between My5-FU™ and reference standard tests is clinically significant.
Beumer et al (2009) compared OnDose® (now called My5-FU™) assay results with liquid chromatography-tandem mass spectrometry results; the slope of the correlation was 1.04 (ideal=1.00) and the r value was 0.99 (ideal=1.00) (Beumer, 2009).
Büchel et al (2013) compared My5-FU™ assay performance on the Roche Cobas® Integra 800 analyzer with liquid chromatography-tandem mass spectrometry and 3 other analyzers (Olympus AU400®, Roche Cobas® c6000, Thermo Fisher CDx90®) (Buchel, 2013). Serum samples were collected from 32 patients with gastrointestinal cancers who were receiving 5-FU infusion therapy at a single center in Switzerland. My5-FU™ was validated for linearity (ie, correlated linearly within <10% of true 5-FU concentrations from 100 mg/mL-1750 mg/mL), precision, accuracy, recovery, sample carryover, and dilution integrity. Of several plasma compounds tested for potential interference, only lipids were found to exceed manufacturer’s specification. This was attributed to a freezing effect, and the authors recommended storage of plasma samples at 39°F (4°C) until analysis, or frozen for longer periods. In comparison with other tests, My5-FU™ had a 7% proportional (ie, dose-dependent) bias toward higher values compared with chromatography-spectrometry, and a 1.6% or less proportional bias toward higher values compared with the other 3 analyzers.
Clinical Validity
Clinical validity is a test’s association with outcomes.
Kline et al (2013) assessed OnDose® (now called My5-FU™) in a retrospective study of patients with stage II/III (n=35) or stage IV or recurrent (n=49) CRC who received 5-FU regimens at a single center in the United States (Kline, 2014). Patients who required radiotherapy were excluded. Thirty-eight patients chose pharmacokinetic monitoring with OnDose®, and 46 patients were dosed by body surface area (BSA). Median PFS did not differ by dosing strategy in stage IV or recurrent patients (14 months with AUC monitoring vs 10 months BSA dosing; log-rank test, p=0.16), but did differ in stage II/III patients (p=0.04). Thirty-seven percent of stage IV or recurrent patients in both dosing strategy groups experienced grade 3 toxicity. Among stage II/III patients, 32% of AUC-monitored patients and 69% of BSA-dosed patients experienced grade 3 toxicity (Fisher exact test, p=0.04). Onset of adverse events also was delayed in the AUC-monitored group (6 or 7 months vs 2 months in the BSA-dose group; log-rank test, p=0.01).
OnDose® (now called My5-FU™) was clinically validated for patients with CRC in an observational analysis reported as a commentary by Saam et al (2011) (Saam, 2011). Sequential patients (n=357) were treated with constant infusion 5-FU using current adjuvant or metastatic treatment protocols with or without bevacizumab. Samples were drawn at least 2 hours after the start of and before the end of each infusion and sent to Myriad Genetics Laboratories for analysis. Sixty-two patients (17%) were studied longitudinally across 4 sequential sample submissions (ie, four 5-FU treatment infusions), of which 5% were within the target AUC after the first infusion. By the fourth infusion, this number rose to 37% and outliers were reduced. The use of bevacizumab did not affect results. No information on response or toxicity was reported.
Clinical Utility
Clinical utility is a test’s impact on patient outcomes.
No prospective trials comparing outcomes with AUC-adjusted 5-FU dosing with standard BSA-based dosing were identified.
TheraGuide®
A 2009 TEC Assessment reviewed the evidence for pharmacogenetic testing to predict 5-FU toxicity (BCBSA, 2010). DPYD and TYMS mutation testing did not meet TEC criteria. The author noted that the tests had “poor ability to identify patients likely to experience severe 5-FU 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 mutations in DPD or TS genes” (BCBSA TEC, 2010).
Analytic Validity
The Myriad Genetics website reports technical specifications for TheraGuide® (Myriad Poro, 2009). DPYD and TYMS mutation testing both are polymerase chain reaction (PCR) tests. The entire coding sequence of DPYD, comprising 23 coding exons and 690 introns, is analyzed. TYMS is analyzed for the number of base pair tandem repeats in the 5’ untranslated region. Analytic specificity and sensitivity were assessed in 60 samples from unselected individuals. No false positives or false negatives were reported. The estimated incidence of errors that may be due to specimen handling, amplification reactions, or analysis is less than 1%. Testing results are reported as high, moderate, or low risk or “genetic variant of uncertain significance.”
Specific recommendations for treatment selection and/or 5-FU dose modification or discontinuation based on genetic testing results are not provided. Some authors have developed dosing paradigms based on DPYD results, (Caudle, 2013; Keiser, 2008), but these have not been prospectively correlated with outcomes such as reduced toxicity.
ARUP Laboratories uses PCR to assess 5 mutations in DPYD (the 3 identified mutations in TheraGuide® plus c. 85T>C and c.-1590T>C) and 2 mutations in TYMS (5’ promoter-enhancer region and 3’ untranslated region.5 Results are reported as positive (mutation detected) or negative (no mutation detected). On its website, ARUP Laboratories reports analytical sensitivity and specificity of 99%; clinical sensitivity and specificity are unknown. The website also notes, “Only targeted mutations in the DPYD and TYMS genes will be detected by this panel. Diagnostic errors can occur due to rare sequence variations [not detected by the test]…Genotyping does not replace the need for therapeutic drug monitoring or clinical observation” (ARUP, 2015).
Clinical Validity: Toxicity
Schwab et al (2008) enrolled 683 patients who were receiving 5-FU for colon or other gastrointestinal cancers, cancers of unknown primary, or breast cancer in a genotype study (Schwab, 2008). Seven different 5-FU regimens (monotherapy or in combination with folate or levamisole [not FDA-approved]) administered by bolus or by infusion were included. Patients were genotyped for the DPYD splice site mutation DPYD*2A (IVS14+1G>A), which leads to a nonfunctional enzyme, and for TYMS tandem repeats. Sensitivity, specificity, and positive and negative predictive value for overall toxicity, diarrhea, mucositis, and leukopenia were calculated. Although heterozygosity for DPYD*2A had 99% specificity for serious toxicity, sensitivity ranged from 6% to 13%. Tandem repeats in TYMS were neither sensitive nor specific indicators of serious toxicity. Clinical factors also were examined for association with toxicity. Overall and in the group of 13 patients who were heterozygous for DPYD*2A, women were more likely than men to develop severe toxicity (overall odds ratio, 1.9; 95% confidence interval, 1.26 to 2.87; p=0.002), most commonly mucositis. Bolus administration of 5-FU was a significant, independent predictor of severe toxicity overall. In an accompanying editorial, Ezzedin and Diasio (2008) observed that “genetic tests proposed for the prediction of patients at risk of developing toxicity to FU remain underdeveloped, with a high percentage of false-negative predictions because of the absence of a comprehensive molecular approach that could account for all elements associated with FU toxicity (genetic, epigenetic, and nongenetic), including impairment of cell signaling pathways and/or DNA damage response, which may significantly influence the cellular response to FU” (Ezzeldin, 2008). The editorialists also commented that “the recent use of multiple treatment modalities in cancer patients has further complicated the development of a straightforward predictive test” (Ezzeldin, 2008).
Similar associations between 5-FU toxicity and polymorphisms in DPYD and TYMS have been confirmed in subsequent meta-analyses, (Li, 2014; Rosmarin, 2014) and other studies,(Froehlich, 2015; Sun, 2014) including 2 studies of homogenous patient groups enrolled in RCTs (Rosmarin, 2014; Lee, 2014) Cancer types and specific mutations studied varied across these reports.
In 2013, Loganayagam et al reported similar results from a study of 430 patients treated with 5-FU-based (43%) or capecitabine-based chemotherapy (57%) for colorectal or other gastrointestinal cancers or cancers of unknown primary (Loganayagam, 2013). Sensitivity and specificity of the 3 identified DPYD mutations of the TheraGuide® test (c.1905+1 G>A, c.2846A>T, and c.1679T>G) for grade 3/4 diarrhea, mucositis, or neutropenia were 1% to 3% and 100%, respectively. Positive and negative predictive values were greater than 99% and 76% to 77%, respectively.
A 2011 review of DPYD mutations associated with 5-FU toxicity noted a lack of consistent correspondence between deleterious variants and DPYD activity across studies (Amstutz, 2011). The authors attributed this to variation in allele frequencies across geographic populations studied, nonstandard toxicity assessments, and differences in 5-FU chemotherapy regimens.
Clinical Validity: Survival
A 2013 meta-analysis from China included 11 studies that assessed TYMS mutations (5’ tandem repeats and a single nucleotide substitution [G>C] within triplet repeats) and survival outcomes (Wang, 2013). Patients had gastric or CRC and received 5-FU with or without leucovorin with or without levamisole. Three studies (total N=311) were eligible for pooled analysis of OS. Statistical heterogeneity was not assessed. Patients who were homozygous for triplet repeats (3R/3R) had improved OS compared with patients who were homozygous for doublet repeats (2R/2R) or compound heterozygous (2R/3R), contrary to expectation.
Clinical Utility
In a multi-center phase 2 study, Goff et al (2014) prospectively genotyped 42 adults with gastric or gastroesophageal junction cancer for TSER tandem repeats (Goff, 2014). Twenty-five patients who had TSER 2R/2R or 2R/3R genotypes received modified FOLFOX-6 (5-FU intravenous push and intravenous infusion with oxaliplatin and leucovorin every 2 weeks) until unacceptable toxicity or disease progression (median, 5.5 cycles); patients homozygous for triplet repeats (3R/3R) were excluded. Overall response rate in 23 evaluable patients was 39% (9 partial responses and no complete responses), which was worse than a 43% historical overall response rate in unselected patients. Overall response rate in 6 patients homozygous for doublet repeats (2R/2R) was 83% (5 partial responses and no complete responses). Median OS and PFS in the entire cohort (secondary outcomes, 11.3 and 6.2 months, respectively) also were similar to those reported in unselected populations. The study was stopped early before meeting target enrollment (minimum 75 patients) due to insufficient funding.
Magnani et al (2013) reported a study of 180 cancer patients receiving fluoropyrimidines (5-FU or capecitabine) who underwent DPYD analysis for the 1905+1 G>A mutation by high-pressure liquid chromatography (Magnani, 2013). Four patients were heterozygous carriers. Of these, 3 patients received 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 mutations found in mismatch repair genes.
No prospective trials comparing outcomes with or without pretreatment DPYD and/or TYMS testing were identified.
Ongoing and Unpublished Clinical Trials
Three clinical studies of AUC-guided dosing of 5-FU were identified at ClinicalTrials.gov:
Three studies of DPYD and/or TYMS testing before use of fluoropyrimidines were identified:
Summary of Evidence
Prior evidence supports the wide variability of 5-fluorouracil (5-FU) plasma levels when patients are placed on a fixed-dose regimen; high exposure is associated with toxicity, but higher exposure up to the limits of toxicity is also associated with better tumor response to treatment. Area under the curve (AUC) laboratory testing methods to better measure 5-FU exposure during treatment of cancer and validated algorithms to modify subsequent dosing may improve response and reduce toxicity. However, currently available evidence is limited and insufficient to draw conclusions about the impact of 5-FU exposure measurement and AUC-targeted dose adjustment on outcomes of patients administered contemporary chemotherapy regimens for colorectal or head and neck cancer. Given the lack of relevant studies, a similar conclusion is reached for use of 5-FU in other cancers.
Impaired function of enzymes in 5-FU metabolic pathways may contribute to toxicity and/or reduced efficacy. However, current evidence for pretreatment testing for genetic mutations in dihydropyrimidine dehydrogenase (DPYD) and/or thymidylate synthase (TYMS) comprises associational studies only. Impacts on treatment selection and 5-FU dosing have not been demonstrated. Evidence for improved outcomes in patients eligible for 5-FU chemotherapy is lacking.
Practice Guidelines and Position Statements
National Comprehensive Cancer Network Guidelines
Although current National Comprehensive Cancer Network guidelines acknowledge that the “selection, dosing, and administration of anticancer agents and the management of associated toxicities are complex,” they do not recommend AUC-guided 5-FU dosing or genetic testing for DPYD and/or TYMS mutations in patients with colon (NCCN Colon Cancer, 2015), rectal (NCCN Rectal Cancer, 2015), breast,(NCCN, Breast Cancer, 2015) gastric (NCCN Gastric Cancer, 2015), pancreatic cancer (NCCN Pancreatic Cancer, 2015), or head and neck cancers (NCCN Head and Neck Cancer, 2015).
Clinical Pharmacogenetics Implementation Consortium
The Clinical Pharmacogenetics Implementation Consortium (CPIC) was formed in 2009 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, CPIC published an evidence-based guideline for DPYD genotype and fluoropyrimidine dosing (Caudle, 2013). The guideline does not address the issue of testing.
National Institute for Health and Care Excellence
In 2014, NICE published evidence-based diagnostics guidance on the My5-FU assay for guiding 5-FU chemotherapy dose adjustment (NICE, 2014). The guidance states, “The My5-FU assay is only recommended for use in research for guiding dose adjustment in people having fluorouracil chemotherapy by continuous infusion. The My5-FU assay shows promise and the development of robust evidence is recommended to demonstrate its utility in clinical practice.”
2016 Update
A literature search conducted through February 2016 did not reveal any new randomized controlled trials or any new information that would prompt a change in the coverage intent. Two publications identified are summarized below.
In 2016, Yang et al published a meta-analysis of data from the 2 RCTs described above (ie, Gamelin et al and Fety et al), as well as from 3 observational studies (Yang, 2016). In a pooled analysis, the overall response rate was significantly higher with pharmacokinetic AUC monitored 5-FU therapy than with standard body surface area (BSA)‒based monitoring (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.41 to 2.95). In terms of toxicity, incidence of diarrhea (3 studies), neutropenia (3 studies) and hand-foot syndrome (2 studies) did not differ significantly between the pharmacokinetic and BSA monitoring strategies. The rate of mucositis was significantly lower in the BSA monitored group (3 studies; OR=0.16; 95% CI, 0.04 to 0.63). Most data were from observational studies, which are subject to selection and observational biases.
One prospective trial compared outcomes with pretreatment DPYD*2A testing with historical controls. This study, published in 2016 by Deenen et al, included cancer patients intending to undergo treatment with fluoropyrimidine-based therapy (5-FU or capecitabine) (Deenen, 2016). Genotyping for DPYD*2A was performed prior to 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 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 (28%; 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-FU-based therapy than with capecitabine-based therapy. Limitations of the study include that patients were not randomized to a management strategy and that historical, rather than concurrent, controls were used.
2017 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
2018 Update
A literature search was conducted through November 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
TESTING FOR DPYD OR TYMS VARIANTS AFFECTING 5-FU DOSE ADJUSTMENT
Toxicity
Vásquez et al prospectively evaluated 197 patients who were treated with 5-FU between 2013 and 2015 (Vasquez, 2017). All patients were given the European Organization for Research and Treatment of Cancer quality of life assessment; there was a significant link between low European Organization for Research and Treatment of Cancer scores and the patient’s risk of developing severe toxicity. However, no significant association between variants in methylenetetrahydrofolate reductase (MTHFR) or TYMS tandem repeats and severe toxicity could be identified.
Nahid et al prospectively evaluated 161 patients with CRC who were treated with 5-FU based chemotherapy (Nahid, 2017). Of these patients, clinical follow-up was available for 139 patients. Within this population, DPYD*2A was significantly associated with grade 3 or 4 toxicity (p=0.023). The MTHFR C677T variant was associated with increased efficacy of treatment (p=0.006). The authors recommended confirmation of these findings in a larger population.
Efficacy
Smyth et al published a randomized phase 3 trial of 456 patients treated for gastroesophageal cancer either with surgery alone or with surgery augmented with 5-FU chemotherapy (Smyth, 2017). Of these patients, genetic tests were performed for 289 patients. The primary outcome was any association between 10 germline variants, including tandem repeats in the TYMS gene, and response rates, survival, or toxicity. Of the genes evaluated, none showed a variant significantly associated with chemotherapy-related toxicity. Of patients who received chemotherapy, there was a significant association between the TYMS 2R/2R genotype and longer survival: for these patients, median OS was not reached during the study, while patients with TYMS 2R/3R or 3R/3R genotypes, respectively, had a median OS of 1.44 or 1.60 years (p=0.005). Trialists noted that patients with TYMS 2R/2R genotype seemed to benefit from the chemotherapy treatment, with a significant interaction between treatment arm and genotype (p=0.029). No relationship between genotype and chemotherapy toxicity was noted. The trial was limited by the lack of tissue samples for all patients.
PRACTICE GUIDELINES AND POSITION STATEMENTS
Clinical Pharmacogenetics Implementation Consortium
A 2017 update to the CPIC guidelines was published by Amstutz et al (CPIC, 2018). As in 2013, the primary focus of the guidelines was on the DPYD genotype and implications for dosing of fluoropyrimidine. In the 2017 update, CPIC 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 CPIC listed the c.190511G>A, c.1679T>G, c.2846A>T, and c.1129-5923C>G variants, as affecting 5-FU toxicity. 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-FU-based treatments, or exclude them, depending on the patient’s level of DPYD activity. 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.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Practice Guidelines and Position Statements
Clinical Pharmacogenetics Implementation Consortium
The CPIC (2009) 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. The CPIC (2013) published evidence-based guidelines for DPYD genotype and fluoropyrimidine dosing (Caudle, 2013). The guidelines did not address testing.
An update to the CPIC guidelines was published by Amstutz et al (Amstutz, 2018). As in 2013, the primary focus of the guidelines was on the DPYD genotype and implications for dosing of fluoropyrimidine. In the update, the CPIC 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 CPIC listed the c.190511G>A, c.1679T>G, c.2846A>T, and c.1129-5923C>G variants, as affecting 5-FU toxicity. 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-FU-based treatments, or exclude them, depending on the patient’s level of DPYD activity. 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
National Institute for Health and Care Excellence
The National Institute of Health and Care Excellence published evidence-based diagnostics guidance on the 5-FU assay for 5-FU chemotherapy dose adjustment (Nice, 2014). The guidance stated: “The My5-FU assay is only recommended for use in research for guiding dose adjustment in people having fluorouracil chemotherapy by continuous infusion. The My5-FU assay shows promise and the development of robust evidence is recommended to demonstrate its utility in clinical practice.”
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2019, the International Association of Therapeutic Drug Monitoring and Clinical Toxicology published recommendations for therapeutic drug monitoring of 5-Fluorouracil therapy (Beumer, 2019). The work was supported in part by grants from the National Cancer Institute National Institutes of Health. Several authors reported relationships with Saladax, the manufacturer of the My5-fluorouracil test. 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.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Deng et al conducted an RCT in patients with advanced colorectal cancer who were treated with 5-fluorouracil (FOLFOX or FOLFIRI) (Deng, 2020). 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 body surface area 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 partial response or stable disease.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. "My 5-fluorouracil™" removed from policy statement because this test is no longer commercially available in the U.S. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
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 (Longley, 2003).
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-fluorouracilchemotherapy regimen and patient population (Patel, 2014). 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.
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 (Wilhelm, 2016).
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The impact of DPYD variant testing was evaluated and preemptive fluoropyrimidine (5-fluorouracil or capecitabine)dose reductions on the rate of toxicity in patients with gastrointestinal cancers in the United Kingdom (Lau, 2023). 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), 33patients (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).
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Amstutz U, Froehlich TK, Largiader CR.(2011) Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. Pharmacogenomics 2011; 12(9):1321-36. Amstutz U, Henricks LM, Offer SM, et al.(2018) Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. 2017 update. Clin Pharmacol Ther. Feb 2018;103(2):210-216. PMID 29152729 Andre T, Boni C, Navarro M et al.(2009) Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009; 27(19):3109-16. Anthem Blue Cross [website]. Genotype Testing for Genetic Polymorphisms to Determine Drug-Metabolizer Status. GENEOoo10. Updated February 26,2009. Available at: http://www.anthem.com/ca/medicalpolicies/policies/ mpyw_a050309.htm. Accessed May 3,2009. ARUP Laboratories.(2014) 5-Fluorouracil (5-FU) Toxicity and Chemotherapeutic Response, 7 Mutations. Available online at: http://ltd.aruplab.com/Tests/Pub/2007228. Last accessed February, 2014. Beneton M, Chapet S, Blasco H et al.(2007) Relationship between 5-fluorouracil exposure and outcome in patients receiving continuous venous infusion with or without concomitant radiotherapy. Br J Clin Pharmacol 2007; 64(5):613-21. Beumer JH, Boisdron-Celle M, Clarke W et al.(2009) Multicenter evaluation of a novel nanoparticle immunoassay for 5-fluorouracil on the Olympus AU400 analyzer. Therap Drug Monit 2009; 31(6):688-94. Beumer JH, Chu E, Allegra C, et al.(2019) Therapeutic Drug Monitoring in Oncology: International Association of Therapeutic Drug Monitoring and Clinical Toxicology Recommendations for 5-Fluorouracil Therapy. Clin. Pharmacol. Ther. 2019 Mar;105(3). PMID 29923599 Blue Cross and Blue Shield Association Technology Evaluation Center (TEC).(2009) TEC Special Report: Laboratory Testing to Allow Area Under the Curve (AUC) –Targeted 5-Fluorouracil Dosing for Patients Administered Chemotherapy for Cancer. TEC Assessments 2009; Volume 24, Tab 10. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC).(2010) Pharmacogenetic Testing to Predict Serious Toxicity From 5-Fluorouracil (5-FU) for Patients Administered 5-FUBased Chemotherapy for Cancer. TEC Assessments 2010; volume 24, tab 13. Blue Cross Blue Shield (BC/BS) Association [website]. Special Report Pharmacogenomics of Cancer-Gandidate Genes. November 2007 Available at: http://www.bcbs.com/blueresources/teclvols/22/22_05.pdf. Accessed May 3, 2009 Boige V, Vincent M, Alexandre P, et al.(2016) DPYD genotyping to predict adverse events following treatment with flourouracil-based adjuvant chemotherapy in patients with stage III colon cancer: a secondary analysis of the PETACC-8 Randomized Clinical Trial. JAMA Oncol. Jan 21 2016. PMID 26794347 Boisdron-Celle M, Craipeau C, Brienza S et al.(2002) Influence of oxaliplatin on 5-fluorouracil plasma clearance and clinical consequences. Cancer Chemother Pharmacol 2002; 49(3):235-43. Buchel B, Sistonen J, Joerger M et al.(2013) Comparative evaluation of the My5-FU immunoassay and LCMS/MS in monitoring the 5-fluorouracil plasma levels in cancer patients. Clin Chem Lab Med 2013; 51(8):1681-8. Capitain O, Asevoaia A, Boisdron-Celle M et al.(2012) Individual fluorouracil dose adjustment in FOLFOX based on pharmacokinetic follow-up compared with conventional body-area-surface dosing: a phase II, proof-of-concept study. Clin Colorectal Cancer 2012; 11(4):263-7. Capltaln O, Boisdron-Celle M, Poirier AL, at al.(2008) The Influence of fluorouracil outcome parameters on tolerance and efficacy In patients with advanced colorectal cancer Phannacogenomlcs J. 2008;8(4):256-267 Caudle KE, Thorn CF, Klein TE et al.(2013) Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Therap 2013; 94(6):640-5. Centers for Disease Control and Prevention (CDC) [website]. Evaluation of Genetic Testing. ACCE: A CDC Sponsored Project Carried Out by the Foundation of Blood Research. Updated December 11, 2007. Available at: http://www.cdc.govlgenomlcs/gtesting/ACCE.htm. Accessed May 1, 2009. Centers for Medicare & Medicaid Services (CMS) [website]. Medicare Coverage Database [search: 5-fluorouraci~. 2009 Available at: http://www.cms.hhs.gov/mcd/search.asp. Accessed May 1, 2009 ClinicalTrials.gov [website]. Association of Dihydropyrimidine Dehydrogenase (DPYD) Variants With Toxicity Related to Capecitabine. NCT00478686. Updated February 19, 2009b. Available at: http://clinicaltria/s.gov/ct2/show/ NCT00478686. Accessed May 3,2009 Coalition of State Genetics Coordinators (CSGC) [website]. State Genetics websites. 2007. Available at: http:// www.stategeneticscoordinators.orglstatesites/statesites.htm. Accessed May 1, 2009 Computer Retrieval of Information on Scientific Projects (CRISP) [website]. Current and Historical Awards (19722009) Query Fonn. 2009. Available at: http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. Accessed May 3, 2009. Cremolini CC, Del Re MM, Antoniotti CC, et al.(2018) DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer. Oncotarget, 2018 Mar 1;9(8). PMID 29487697. de Gramont A, Figer A, Seymour M et al.(2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18(16):2938-47. Deenen MJ, Meulendijks D, Cats A, et al.(2016) Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis. J Clin Oncol. Jan 20 2016;34(3):227-234. PMID 26573078 Deng R, Shi L, Zhu W, et al.(2020) Pharmacokinetics-based Dose Management of 5-Fluorouracil Clinical Research in Advanced Colorectal Cancer Treatment. Mini Rev Med Chem. 2020; 20(2): 161-167. PMID 31660826 Evaluation of Genomic Applications in Practice and Prevention (EGAPP) [website). About EGAPP. 2008 Available at: http://www.egappreviews.org/about.htm. Accessed May 1,2009 Ezzeldin HH, Diasio RB.(2008) Predicting Fluorouracil Toxicity: Can We Finally Do It? J Clin Oncol 2008; 26(13):2080-82. Fety R, Rolland F, Barberi-Heyob M et al.(1998) Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicentric randomized trial in patients with locally advanced head and neck carcinomas. Clin Cancer Res 1998; 4(9):2039-45. Food and Drug Administration (FDA) [website). Center for Devices and Radiological Health (CDRH). ClIA -Clinical Laboratory Improvement Amendments. Updated November 18, 2005. Available at: http://www.fda.gov/cdrhlclia. Accessed May 1, 2009 Freeman K, Connock M, Cummins E, et al.(2015) Fluorouracil plasma monitoring: systematic review and economic evaluation of the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion. Health Technol Assess. Nov 2015;19(91):1-322. PMID 26542268 Freeman K, Saunders MP, Uthman OA, et al.(2016) Is monitoring of plasma 5-fluorouracil levels in metastatic / advanced colorectal cancer clinically effective? A systematic review. BMC Cancer. Jul 25 2016;16:523. PMID 27456697 Gamelin E, Boisdron-Celle M, Delva R et al.(1998) Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients. J Clin Oncol 1998; 16(4):1470-8. Gamelin E, Delva R, Jacob J et al.(2008) Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol 2008; 26(13):2099-105. Gamelin E, Delva R, Jacob J et al.(2008) Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol 2008; 26(13):2099-105. Gamelin EC, Danquechin-Dorval EM, Dumesnil YF et al.(1996) Relationship between 5-fluorouracil (5-FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5-FU. Cancer 1996; 77(3):441-51. Giacchetti S, Perpoint B, Zidani R et al.(2000) Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000; 18(1):136-47. Goekkurt E, Hoehn S, Wolschke C, et al.(2006) PolymorphIsms of glutathione S*transferases (GST) and thymldylate synthase (TS)-novel predictors for response and survival In gastric cancer patients. Br J Cancer. 2006;94(2):281-286 Goff LW, Thakkar N, Du L, et al.(2014) Thymidylate synthase genotype-directed chemotherapy for patients with gastric and gastroesophageal junction cancers. PLoS One. 2014; 9(9): e107424. PMID 25232828 Grem JL.(2002) 5-Fluorouracil and its biomodulation in the management of colorectal cancer. Saltz LB, ed. Colorectal Cancer: Multimodality Management. Totowa, NJ: Humana Press; 2002. Gudgeon JM, McClain MR, Palomaki GE, Williams MS.(2007) Rapid ACCE: experience with a rapid and structured approach for evaluating gene-based testing. Genet Med. 2007;9(7):473-478 Henricks LL, Lunenburg CC, de Man FF, et al.(2018) DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol., 2018 Oct 24;19(11). PMID 30348537. Henricks LL, van Merendonk LL, Meulendijks DD, et al.(2018) Effectiveness and safety of reduced-dose fluoropyrimidine therapy in patients carrying the DPYD*2A variant: A matched pair analysis. Int. J. Cancer, 2018 Nov 30;144(9). PMID 30485432. Kaldate RR, Haregewoin A, Grier CE et al.(2012) Modeling the 5-fluorouracil area under the curve versus dose relationship to develop a pharmacokinetic dosing algorithm for colorectal cancer patients receiving FOLFOX6. Oncologist 2012; 17(3):296-302. Kawakami K, Salonga 0, Park JM, et al.(2001) Different lengths of a polymorphic repeat sequence In the thymldylate synthase gene affect translational efficiency but not Its gene expression. Clin Cancer Res. 2001 ;7(12):4096-4101 Keiser WL.(2008) The role of pharmacogenetics in the management of flourouracil-based toxicity. Commun Oncol 2008;5(suppl 12):1–8. Available online at: http://www.oncologypractice.com/co/journal/abstracts/0510s1201.html. Last accessed February, 2014. Kline CL, Schiccitano A, Zhu J et al.(2013) Personalized Dosing via Pharmacokinetic Monitoring of 5- Fluorouracil Might Reduce Toxicity in Early- or Late-Stage Colorectal Cancer Patients Treated With Infusional 5-Fluorouracil-Based Chemotherapy Regimens. Clin Colorectal Cancer 2013 Nov 20. [Epub ahead of print]. Konings IR, Sleijfer S, Mathijssen RH et al(2011) tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study. Cancer Chemother Pharmacol 2011; 67(5):1055-62. Largillier R, Etienne~Grimaldi MC, Formento JL, at al.(2006) Pharmacogenetics of capecitabine in advanced breast cancer patients Clin Cancer Res. 2006;12(18):5496-5502 Loganayagam A, Arenas Hernandez M, Corrigan A et al.(2013) Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer 2013; 108(12):2505-15. Longley DB, Harkin DP, Johnston PG.(2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. May 2003; 3(5): 330-8. PMID 12724731 Maekawa K, Saeki M, Saito Y, et al.(2007) Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences. J Hum Genet. 2007;52(10):804-819 Magnani E, Farnetti E, Nicoli D et al.(2013) Fluoropyrimidine toxicity in patients with dihydropyrimidine dehydrogenase splice site variant: the need for further revision of dose and schedule. Intern Emerg Med 2013; 8(5):417-23. Marcuello E, Altes A, del Rio E, et al.(2004) Single nucleotide polymorphism in the 5' tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients Int J Cancer. 2004;112(5):733-737 Mattison LK, Foune J, Desmond RA, et al.(2006) Increased prevalence of dihydropyrimjdine dehydrogenase deficiency in African-Americans compared with Caucasians Clin Cancer Res. 2006;12(18):5491-5495 Milano G, Etienne MC, Renee N et al.(1994) Relationship between fluorouracil systemic exposure and tumor response and patient survival. J Clin Oncol 1994; 12(6):1291-5. Myriad Genetic Laboratories Inc. [website]. CLiA Certification. 200gb. Available at http://www.myriadtests.com/docl Myriad_CLlA_Certification.pdf. Accessed May 1, 2009 Myriad Genetic Laboratories Inc. [website]. TheraGujde-5-FUlM Technical Specifications Updated January 8, 2009. Available at: http://www.myriadtests.com/provider/doclTheraGuide-5-FU-Tehcnical-Specifications.pdf. Accessed May 1,2009 Myriad Pro™.(2009) TheraGuide® 5-FU Technical Specifications, February 2009. Available online at: https://www.myriadpro.com/additional-products/chemotoxicity/managing-chemotoxicity/. Lastaccessed February, 2014. Myriad Pro™.(2014) TheraGuide® 5-FU FAQs. Available online at: https://www.myriadpro.com/additionalproducts/chemotoxicity/theraguide-5-fu-faqs/. Last accessed February, 2014. Nahid NA, Apu MNH, Islam MR, et al.(2018) DPYD*2A and MTHFR C677T predict toxicity and efficacy, respectively, in patients on chemotherapy with 5-fluorouracil for colorectal cancer. Cancer Chemother Pharmacol. Jan 2018;81(1):119-129. PMID 29134491 National Comprehensive Cancer Network (NCCN).(2010) Clinical Practice Guidelines in Oncology: Colon Cancer, V.2.2011; and Head and Neck Cancers, V.2.2010. Available at: http://www.nccn.org/index.asp. Accessed January, 2011. National Comprehensive Cancer Network (NCCN).(2013) Clinical Practice Guidelines in Oncology: Gastric Cancer, version 2.2013. Available online at: http://www.nccn.org/index.asp. Last accessed February, 2014. National Comprehensive Cancer Network (NCCN).(2013) Clinical Practice Guidelines in Oncology: Head and Neck Cancer, version 2.2013. Available online at: http://www.nccn.org/index.asp. Last accessed February, 2014. National Comprehensive Cancer Network (NCCN).(2014) Clinical Practice Guidelines in Oncology: Breast Cancer, version 1.2014 (discussion update in progress). Available online at: http://www.nccn.org/index.asp. Last accessed February, 2014. National Comprehensive Cancer Network (NCCN).(2014) Clinical Practice Guidelines in Oncology: Pancreatic Cancer, version 1.2014 (discussion update in progress). Available online at: http://www.nccn.org/index.asp. Last accessed February, 2014. National Comprehensive Cancer Network (NCCN).(2014) Clinical Practice Guidelines in Oncology: Rectal Cancer, version 3.2014. Available online at: http://www.nccn.org/index.asp. Last accessed February, 2014. National Institute for Health and Care Excellence (NICE).(2014) Fluorouracil chemotherapy: The My5-FU assay for guiding dose adjustment [DG16]. https://www.nice.org.uk/guidance/dg16. Accessed January 31, 2023. National Newborn Screening and Genetics Resource Center (NNSGRC) [website). National Newbom Screening Status Report. Updated April 15, 2009. Available at: http://genes-r-us.uthscsa.edu/nbsdisorders.pdf. Accessed May 1, 2009 OnDose® Technical Specifications, Myriad Genetic Laboratories, Inc. June 2010. http://www.myriad.com/lib/technical-specifications/OnDose%20Tech%20Specs_6_10.pdf Patel JN, O'Neil BH, Deal AM, et al.(2014) A community-based multicenter trial of pharmacokinetically guided 5-fluorouracil dosing for personalized colorectal cancer therapy. Oncologist. Sep 2014; 19(9): 959-65. PMID 25117066 Posner M, Vermorken JB.(2008) Induction therapy in the modern era of combined-modality therapy for locally advanced head and neck cancer. Semin Oncol 2008; 35(3):221-8. PRNewswire.(2013) Saladax Biomedical Laboratories to Offer the Full Portfolio of MyCare™ Therapeutic Dose Management Assays in the United States. February 11, 2013. Available online at: http://www.prnewswire.com/news-releases/saladax-biomedical-laboratories-to-offer-the-fullportfolio-of-mycare-therapeutic-dose-management-assays-in-the-united-states-190681031.html. Last accessed February, 2014. Rosmarin D, Palles C, Church D, et al.(2014) Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol. Apr 01 2014; 32(10): 1031-9. PMID 24590654 Saam J, Critchfield GC, Hamilton SA et al.(2011) Body surface area-based dosing of 5-fluoruracil results in extensive interindividual variability in 5-fluorouracil exposure in colorectal cancer patients on FOLFOX regimens. Clin Colorectal Cancer 2011; 10(3):203-6. Saladax Biomedical, Inc.(2014) MyPatient MyDecision My5-FU™ Brochure. Available online at: http://www.mycaretests.com/hcp-resources/mycare-tests-menu/my5-fu/brochure/. Last accessed February, 2014. Salamone SJ, Beumer JH, Egorin MJ et al.(2008) A multi-center evaluation of a rapid immunoassay to quantitate 5-fluorouracil (5-FU) in plasma. HOPA/ISOPP 2008 Conference June 2008. Salgado J, Zabafegui N, Gil C, at al.(2007) Polymorphisms in the thymidylate synthase and dihydropyrimidine dehydrogenase genes predict response and toxicity to capecitabine-raltitrexed in colorectal cancer. Oncol Rep. 2007; 17(2):325-328 Santini J, Milano G, Thyss A et al.(1989) 5-FU therapeutic monitoring with dose adjustment leads to an improved therapeutic index in head and neck cancer. Br J Cancer 1989; 59(2):287-90. Schwab M, Zanger UM, Marx C et al.(2008) Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-Related Severe Toxicity: A Prospective Clinical Trial by the German 5-FU Toxicity Study Group. J Clin Oncol 2008; 26(13):2131-38. Seck K, Riemer S, Kates R, et al.(2005) Analysis of the DPYD gene implicated in 5•f!uorouracil catabolism in a cohort of Caucasian individuals. Clin Cancer Res. 2005;11(16}:5886-5892 Showalter SL, Showalter TN, Witkiewicz A, et al.(2008) Evaluating the drug-target relationship between thymidylate synthase expression and tumor response to 5-fluorouracil. Is it time to move forward? Cancer Bioi Ther. 2008;7(7}:986-994 Smyth E, Zhang S, Cunningham D, et al.(2017) Pharmacogenetic analysis of the UK MRC (Medical Research Council) MAGIC Trial: association of polymorphisms with toxicity and survival in patients treated with perioperative epirubicin, cisplatin, and 5-fluorouracil (ECF) chemotherapy. Clin Cancer Res. Dec 15 2017;23(24):7543-7549. PMID 28972045 Stoehlmacher J, Park OJ, at al.(2004) A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5FU/oxaliplatin combination chemotherapy in refractory coloractal cancer. Br J Cancer. 2004;91(2):344-354 Techology Evaluation Center(2010) Laboratory Testing to Allow Area Under the Curve (AUC) –Targeted 5-Fluorouracil Dosing for Patients Administered Chemotherapy for Cancer. June 2010; vol 24, no. 19. Teva Parenteral Medicines, Inc.(2012) Adrucil® (fluorouracil) injection prescribing information, August 2012. Available online at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e0794add-67a7-4308-93e9-f889472716cc. Last accessed February, 2014. Ulrich CM, Bigler J, Bostick R, et al.(2002) Thymidylate synthase promoter polymorphism, interaction with folate intake, and risk of colorectal adenomas. Cancer Res. 2002;62(12):3361-3364 Ulrich CM, Bigler J, Vellcer CM, et al.(2000) Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism In the thymldylate synthase gene. Cancer Epidemlol Biomarkers Prev.2000;9(12):1381-1385 Van Kullenburg AB, Melnsma R, Zoetekouw L, Van Gannlp AH.(2002) High prevalence of the IVS14 + 1G>A mutation In the dlhydropyrimldlne dehydrogenase gene of patients with severe 5•fluorouracll-assoclated toxIcity Pharmacogenetics. 2002; 12(7):555-558 Vázquez C, Orlova M, Angriman F, et al.(2017) Prediction of severe toxicity in adult patients under treatment with 5- fluorouracil: a prospective cohort study. Anticancer Drugs. Oct 2017;28(9):1039-1046. PMID 28723867 Walko CM, McLeod HL.(2008) Will we ever be ready for blood level-guided therapy? J Clin Oncol 2008; 26(13):2078-9. Wang YC, Xue HP, Wang ZH et al. Wang YC, Xue HP, Wang ZH et al.(2013) An integrated analysis of the association between Ts gene polymorphisms and clinical outcome in gastric and colorectal cancer patients treated with 5-Fu-based regimens. Mol Biol Rep 2013; 40(7):4637-44. Wei X, Mcleod HL. McMurrough J. et al.(1996) Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J Clin Invest. 1996;98(3):610-615 Wilhelm M, Mueller L, Miller MC, et al.(2016) Prospective, Multicenter Study of 5-Fluorouracil Therapeutic Drug Monitoring in Metastatic Colorectal Cancer Treated in Routine Clinical Practice. Clin Colorectal Cancer. Dec 2016; 15(4): 381-388. PMID 27256667 Yang R, Zhang Y, Zhou H, et al.(2016) Individual 5-Fluorouracil Dose Adjustment via Pharmacokinetic Monitoring Versus Conventional Body-Area-Surface Method: A Meta-Analysis. Ther Drug Monit. Feb 2016;38(1):79-86. PMID 26309030 Ychou M, Duffour J, Kramar A et al.(2003) Individual 5-FU dose adaptation in metastatic colorectal cancer: results of a phase II study using a bimonthly pharmacokinetically intensified LV5FU2 regimen. Cancer Chemother Pharmacol 2003; 52(4):282-90. |
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