Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.
This policy was created with a search of the MEDLINE database through February 2013. The following is a summary of the key literature to date.
5-Fluorouracil and Clinical Use
5-Fluorouracil (5-FU) is a pyrimidine analog that is an antineoplastic antimetabolite; 5-FU has been useful for many years in the treatment of solid tumors, including colorectal adenocarcinoma. Potentiated by leucovorin (LV), 5-FU is the basis for several standard treatment regimens currently recommended by the National Comprehensive Cancer Network (NCCN) in the treatment of colorectal cancer. (1) While it is recommended that adjuvant therapy for stage II colorectal cancer be limited primarily to disease with high-risk features and individualized for each patient, oxaliplatin in combination with 5-FU/LV is the preferred standard of care for treating patients with stage III disease. (1) Based on the results of the European “Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer” (MOSAIC) trial, (2) in which the addition of oxaliplatin to a regimen of LV and infusional 5-FU every 2 weeks (i.e., a FOLFOX [leucovorin calcium fluorouracil, oxaliplatin] regimen) significantly increased disease-free and overall survival, the FOLFOX regimen is recommended for patients with stage III colorectal cancer. (1) A FOLFOX regimen also improves progression-free survival (PFS) in patients with advanced (i.e., metastatic) colorectal cancer who are able to tolerate intensive versus single-agent 5-FU therapy. (3, 4) Other 5-FU-based combination chemotherapy regimens are also options in advanced disease. (1) FOLFOX may also be considered for individual patients with high-risk stage II disease. In terms of administration, infusional 5-FU regimens are considered less toxic than bolus regimens and are inappropriate when administered with either irinotecan or oxaliplatin. (1)
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. (1, 5) Typical 5-FU administration is also by continuous infusion. (6) 5-FU is also a component of several combination chemotherapy regimens that can be considered for primary systemic therapy administered in conjunction with radiotherapy and of 2 combination regimens recommended for recurrent, unresectable, or metastatic disease. (1)
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). Approximately 85% or more of administered 5-FU is inactivated and eliminated via the catabolic pathway; the remainder is metabolized via the anabolic pathway. Catabolism of 5-FU is controlled by the activity of dihydropyrimidine dehydrogenase (DPD). Because DPD is a saturable enzyme, the pharmacokinetics of 5-FU are strongly influenced by the dose and schedule of administration. (7) For example, 5-FU clearance is faster with continuous infusion compared to bolus administration, resulting in very different systemic exposure to 5-FU during the course of therapy.
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, impaired liver function, and the presence of inherited DPD-inactivating genetic variants that can greatly reduce or abolish 5-FU catabolism. As a result, both inter- and intra-patient 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 U.S., Myriad Genetics offers a commercial service called OnDose™ that quantitates plasma 5-FU concentration from a blood sample drawn during continuous infusion at steady state, calculates AUC by multiplying 5-FU concentration by the infusion duration, and compares the results to a target AUC range established for colorectal cancer patients. According to information from Myriad’s website, “OnDose test results are used to help optimize an individualized dose for the next cycle of 5-FU chemotherapy.” Myriad technical specifications for the 5-FU immunoassay describe the method and a summary of analytic validity data (replication, linearity, reportable range, interference, cross-reactivity, recovery, detection limit, stability, and comparison of methods), comparable to data summaries included in U.S. Food and Drug Administration [FDA]-cleared diagnostic test kits. Review of the data indicates thorough technical validation and reasonable assay performance. (8) The OnDose™ test result itself does not include a dose adjustment algorithm, but the references for published algorithms are provided. Although searches of large clinical laboratories did not find tests for 5-FU AUC on their listings, it is possible that other clinical laboratories measure 5-FU levels by methods other than the specific method used by Myriad Genetics.
Modifying 5-Fluorouracil Exposure to Improve Outcomes
Evidence supporting the use of 5-FU AUC measurement to help modify subsequent 5-FU treatment doses in order to improve response and reduce toxicity has been summarized and evaluated in a Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Special Report. (9) Early evidence from small, cohort studies showed that 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. This association has been studied extensively in head and neck cancer and in colorectal cancer. In addition, a majority of 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 the 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 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 colorectal cancer patients suggested consistency of improved tumor response. (10-12) Similar, although less compelling results were seen in single-arm trials of AUC targeted 5-FU dosing in head and neck cancer. (13, 14) The best contemporary evidence in support of AUC targeted dosing consists of 2 randomized, controlled trials (RCTs), one enrolling patients with colorectal cancer 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. (10) developed a chart for weekly dose adjustment based on the results of an earlier, similar single-arm study (15) 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 colorectal cancer, Gamelin et al. (16) reported significantly improved tumor response (33.6% versus 18.3%, respectively; p=0.0004) and a trend toward improved survival (40.5% versus 29.6%, respectively; p=0.08) in the experimental arm using AUC-targeted dosing. 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%).(2, 3) In the latter 2 trials, delivery over a longer time period for both 5-FU (22 hours vs. 8 hours) and leucovorin (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. (16) trial is “rarely used in current practice in most countries” as described in an accompanying editorial by Walko and McLeod (17) and is absent from current guidelines. (1) Additional optimization studies would be needed in order 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.
The same group more recently conducted a retrospective analysis of their dose adjustment protocol used in a FOLFOX regimen administered to patients with colorectal cancer (n=118) and compared to patients treated with FOLFOX administered in standard fashion according to body surface area.(n=39). (18) 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 thrombopenia; corresponding numbers were 12%, 15%, 25% and 10%, respectively, in the standard group. In the dose-adjusted group, the objective response rate was 70% at 3 months and 56% at 6 months; the corresponding result at 3 months for the standard group was 46%. Median overall survival and median progression-free survival in the dose-adjusted arm were 28 and 16 months, respectively; corresponding numbers for the standard group were 22 and 10 months. As the authors note, this proof of principle study needs confirmation in a randomized trial.
Fety et al., 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 to the fixed-dose arm. (19) This resulted in reduced toxicity but no improvement in clinical response. The dose adjustment method in this trial may have been too complex, as the 12 protocol violations in this treatment arm (of 61 enrolled) were all related to 5-FU dose adjustment miscalculations. Because patients with protocol violations were removed from analysis, results did not reflect the “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, these results are also limited in generalizability to current clinical practice.
None of these studies used the OnDose™ test. For technical validation, OnDose was directly compared to liquid chromatography-tandem mass spectrometry (20); the slope of the correlation was 1.03 (ideal: 1.00) and the r-value was 0.99 (ideal: 1.00). This test is clinically validated only for patients with colorectal cancer to determine 5-FU exposure and subsequent dose modification. Myriad Genetics cites Gamelin et al. (16) for clinical validation of AUC-targeted 5-FU dose adjustment and for information on how to modify the dose once 5-FU exposure has been determined. Gamelin et al. used high-performance liquid chromatography, similar to liquid chromatography-tandem mass spectrometry, to measure AUC. Thus, OnDose clinical validation is indirect; the only published clinical study using OnDose was reported in a commentary by Saam et al. describing the results of an observational analysis of sequential patients treated with constant infusion 5-FU using current adjuvant or metastatic treatment protocols with or without bevacizumab. (21) 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 were studied longitudinally across 4 sequential sample submissions (i.e., four 5-FU treatment infusions), of which only about 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.
Given the limitations of the existing evidence, the evidence is 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.
One clinical trial was started that was intended to directly compare OnDose-guided 5-FU dosing compared to standard dosing; the status of a non-U.S. trial is unknown; no other clinical trials have been found.
- NCT01468623 received November 2011, sponsored by Myriad Genetic Laboratories; the purpose of the study was to compare OnDose®-guided 5-FU dosing versus standard body surface area (BSA)-based dosing in patients with metastatic colorectal cancer treated with mFOLFOX6, with or without bevacizumab, to determine if the use of OnDose® achieves an improvement in the Overall Response Rate (ORR) relative to BSA dosing response. The study was terminated due to slow enrollment.
- NCT00943137 (Singapore) will determine the proportion of Asian patients achieving a target area under the curve using a pharmacokinetically guided 5-fluorouracil dose; the trial will also determine the safety and tolerability of dose adjusted 5-FU (verified 9-2009; updated information not available). Per the online ClinicalTrials.gov database, the recruitment status of this trial has not been verified in 2 years. There are no related publications by the principal investigator.
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 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, but currently available evidence is insufficient to support such testing. Because the impact of this testing on net health outcome is not known, this is considered experimental, investigational and unproven.
Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN) Guidelines
NCCN guidelines for colon cancer (version 3.2013) make no mention of the use of area under the curve-guided 5-FU dosing.
Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.