www.know_the_risk_of_5fu_chemotherapy.com
This is a starter, not an exhaustive, list of medical journal articles that will prepare you and your doctor to discuss how you should start your personalized treatment plan.
Risk Awareness
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Zhu, Andrew X., et al, Dihydropyrimidine Dehydrogenase
and Thymidylate Synthase Polymorphisms and Their Association with 5-Fluorouracil/Leucovorin Chemotherapy in Colorectal Cancer,
Clinical Colorectal Vol 3, No. 4 (2004),
225:235.
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"It is likely that at least 500-1000 patients will die from 5-FU toxicity each year, and these deaths are potentially preventable
if patients at risk for severe toxicity could be identified prior to therapy." pg 225
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Weekly administration of 5-FU at a dose of 500 mg/m2 given by bolus500mg/m2 intravenous (I.V.) injection together with high-dose
LV (500 mg/m2) is a widely used schedule and the subject of the studies described in this paper. This regimen is well tolerated by the majority of patients; however, a significant number of patients (10%-15%) encounter
severe or life-threatening side effects." (emphasis added). Pg 225-226
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…"5-FU toxicity is not a rare condition; 3%-10% of patients experience grade 4 toxicity and 15%-20% of patients experience grade 3
toxicity." pg 233
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Caudle, K E, Diasio, R B, et al, Clinical
Phamacogenetics Implementation Consortium Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoroupyrimidine Dosing, Clinical Phamacogenetics Implementation Consortium, posted online
Oct 2013.
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"Approximately 10-40% of 5-fluorouracil patients develop severe, and sometimes life-threatening, toxicity (neutropenia, nausea,
vomiting, severe diarrhea, stomatitis, mucositis, hand-foot syndrome, and neuropathy)." pg 3
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Ciccolini, Joseph, et al, Routine Dihyrdopyrimidine
Dehydrogenase Testing for Anticipating 5-Fluorouracil Related Severe Toxicities: Hype or Hope?, Clinical Colorectal Cancer, Vol 9, No. 4 (2010),
224:228.
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…'drug to drug interactions and circadian variations are non-genetic causes regularly evoked to explain the large interpatient
variability observed in DPD's activity. Consequently, the number of deficient patients who are at risk for developing
severe/lethal toxicities upon being administered standard 5-FU or oral 5-FU is probably markedly higher than the mere frequency of the genetic mutations identified so far."
pg 224 (empahasis added)
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Gamelin, Erick, 5-Fluorouracil Dose Management in
Special Cases: Dihydropyrimidine Dehydrogenase Deficiency and Dose Management, Highlights from 5-Fluorouracil Drug Management
Pharmacokinetics and Pharmacogenomics Workshop in January 2007, Clinical Colorectal Cancer
(Mar 2007)
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Studies have indicated that major or complete DPD deficiency is not a rare and isolated occurrence and is manifested in 5%-8% of
patients.43,44 It provokes early and very severe multivisceral toxicity that can be life threatening in instances of severe deficiency, with an estimated 0.8% mortality rate, as reported in
various clinical trials in the adjuvant and metastatic settings.45-47"
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"Several techniques have been reported to identify patients with DPD deficiency. Genotyping can be a method of choice because of
its high specificity; however, genotyping alone cannot identify all patients who have a low clearance rate of 5-FU
(emphasis added). Studies have shown that this test is 40%-50% sensitive in identifying patients at risk of high grades of
toxicity.47-55
Risk Management Practices
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Caudle, K E, Diasio, R B, et al, Clinical
Phamacogenetics Implementation Consortium Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoroupyrimidine Dosing, Clinical Phamacogenetics Implementation Consortium, posted online
Oct 2013.
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"Studies using dose reduction of 5-fluorouracil in patients with DPD deficiency, as evidenced by the use of one of these
functional tests, have shown a reduction in drug-related toxicities while maintaining efficacy in these patients." pg 3
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Dosing for patients with variants of the gene affecting the ability to produce the DPD enzyme should be reduced to prevent
severe/fatal toxicities. "...our recommendation is to start with at least a 50% reduction of the starting dose; followed by an increase in dose in patients experiencing no or clinically
tolerable toxicity to maintain efficacy; and a decrease in dose in patients who do not tolerate the starting dose, to minimize toxicities." pg 3
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Pre-Screening, Dosage Monitoring
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Traore, Sory; Boisdron-Celle, Michele, et al, DPD
Deficiency: Medicoeconomic Evaluation of Pre-Treatment Screening of 5-FU Toxicity, Abstract #410, Journal of Clinical Oncology, 30, 2012.
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"Pre-treatment screening test combining genetic and phenotype
reduced the incidence of toxicities associated with 5-FU, it avoided deaths due to 5-FU and its additional cost was less than the cost of care of toxicity that it
avoided.”
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Ciccolini, Joseph, et al, Routine Dihyrdopyrimidine
Dehydrogenase Testing for Anticipating 5-Fluorouracil Related Severe Toxicities: Hype or Hope?, Clinical Colorectal Cancer, Vol 9, No. 4 (2010),
224:228.
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Overall, the amount of clinical evidence warranting preliminary screening for variations in 5-FU dispositions as a way to
ensure better safety in handling 5-FU is increasing, regardless of the methodology used eventually. When performed,
DPD-based dose tailoring has systematically led to improved clinical outcome in 5-FU treated patients." (emphasis
added)
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In addition to screening for DPD deficiency, authors also offer that "the issue of DPD status determination could be adequately and exhaustively addressed using phenotype-based methods (e.g., with surrogate tests
or with pharamacokinetically guided dose adjustment strategies), in addition to specific genotype screening."
(emphasis added) pg 227
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C. Mercier, et al, Pharmacoeconomic study in head
and neck cancer patients: Impact of prospective DPD deficiency screening with 5-fluorouracil (5-FU) dose tailoring on toxicities-related costs, from the 2009 American Society of Clinical Oncologists (ASCO) Annual Mtg, Abstract # 6515, Citation: Journal of Clinical Oncology 27: 15s, 2009
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"Developing an adaptative dosing strategy based upon DPD status evaluation led to a dramatic reduction of the incidence of
5-FU-related severe toxicities, while maintaining optimal efficacy. Subsequently, extra-cost (medication + hospitalization costs) required to manage the toxicities fell down from $6,279 to
$294/patient. Overall, this study advocates that systematic screening for DPD deficiency could be cost-efficient in the setting of 5-FU-based chemotherapies, with a reduction of 95% of the
extra-costs.”
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Gamelin, Erick, 5-Fluorouracil Dose Management in
Special Cases: Dihydropyrimidine Dehydrogenase Deficiency and Dose Management, Highlights from 5-Fluorouracil Drug Management
Pharmacokinetics and Pharmacogenomics Workshop in January 2007, Clinical Colorectal Cancer
(Mar 2007)
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"A complementary approach based upon phenotype has been developed, which measures the dihydrouracil/uracil ratio." pg
412
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"Used in combination, the genotypic and phenotypic approaches optimally identify patients at risk for toxicity because of DPD
deficiency. Used along with pharmacokinetically-guided dose management, a greater number of at-risk patients can benefit from treatment with the same level of safety and efficacy as
non–DPD-deficient patients." Pg 412-3