Testing for dihydropyrimidine dehydrogenase deficiency in New Zealand to improve the safe use of 5-fluorouracil and capecitabine in cancer patients
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Intravenous 5-fluorouracil (5-FU) and oral capecitabine (which forms 5-FU) are commonly used in New Zealand to treat a range of solid tumour types, particularly gastrointestinal and breast cancers. Routine use of these agents carries a risk of treatment-limiting toxicities, including diarrhoea, mucositis, myelosuppression, Hand-Foot syndrome and sometimes cardiotoxicity. Overall, severe (Common Terminology Criteria for Adverse Events grade 3 or greater) toxicities are observed in up to one third of individuals and are fatal for approximately 1% of patients.[[1–4]]
5-FU is extensively (>80%) eliminated from the body by the enzyme dihydropyrimidine dehydrogenase (DPD), and decreased activity of this enzyme can result in severe to life-threatening toxicity. Inherited differences in DPD activity are well characterised as a cause of hereditary thymine-uracilemia.[[5]] This autosomal codominant inherited disorder is rare, with around 0.2% of people having complete deficiency (homozygotes) and about 3% of people of European ancestry have a partial deficiency (heterozygotes). These individuals are typically asymptomatic until challenged with 5-FU or capecitabine.
DPYD genotyping
It is well established that loss of function (LoF) polymorphisms in the DPYD gene that encodes the DPD enzyme have high sensitivity for prediction of risk of 5-FU/capecitabine-induced severe to life-threatening toxicity.[[3,6–14]] These LoF variants (Table 1) have high specificity (~80–100%) for prediction of severe toxicity risk. However, due to scarcity of these variants (~3% of a population), variant testing has poor sensitivity (<25%) for severe toxicity. This poor sensitivity may be due to either the presence of other rare (private) mutations in DPYD or low expression of the enzyme due to epigenetic mechanisms. This low sensitivity has led to some reluctance from clinicians to incorporate routine pre-screening of patients prior to use of 5-FU/capecitabine-containing regimens.
Evidence based DPYD genotype-based dosage adjustment guidelines have been extensively disseminated within the pharmacogenomics community (Table 1).[[15–17]]
Table 1: The key loss of function DPYD gene variants that should be assessed in patients prior to treatment. View Table 1.
Severe toxicity due to this enzyme deficiency often occurs in the first cycle of treatment. It is now clear from large prospective clinical trials that pre-screening patients for these DPYD[[LoF]] variants, combined with recommended dose adjustments prior to first dose, improves the therapeutic index of 5-FU/capecitabine.[[3]] Indeed that multicentre study of 1,103 evaluable patients found that genotype-guided dosing (compared to an historical cohort) decreased the relative risk (RR) of severe fluoropyrimidine-related toxicity. Patients who were DPYD*13 carriers and given a 50% dose decrease experienced no toxicity compared with RR of 4.30 (95% CI 2.10–8.80) in the historical cohort. In DPYD*2A carriers who received 50% dose decrease, there was significant decrease in RR from 2.87 (2.14–3.86) to 1.31 (0.63–2.73). Of note, the genotype-guided dose decrease was increased at subsequent cycles in 13% of the DPYD variant carriers, and this was not tolerated in most of these individuals. Other studies have also demonstrated that DPYD*2A carriers given a 50% dose reduction had a significant decrease in grade ≥3 toxicity from 73% (95% CI 58% to 85%) in historical controls to 28% (10% to 53%).[[19]] Similar decreases in toxicity risk in DPYD*2A carriers from 77% to 18% following genotype-guided dose adjustment have also been reported.[[20]]
Importantly genotype-guided dose adjustment produces similar plasma concentrations of 5-FU as observed in wildtype individuals receiving a standard dosage.[[3,19]] Therefore, genotype-guided dosage adjustment is not expected to alter clinical effectiveness. This has been formally tested in one study,[[20]] which found similar median overall and progression-free survival between genotype-guided dosing in DPYD*2A carriers and wild-type (matched pairs). There was no difference in hazard ratio (HR) for overall survival (HR 0.82, 95%CI 0.47–1.43; p=0.47) or progression free-survival (HR 0.83, 95%CI 0.47-1.5, p=0.83), confirming that genotype-guided dosing is unlikely to alter clinical effectiveness.
Cost effectiveness
The cost effectiveness of DPYD genotyping to prevent severe 5-FU/capecitabine toxicity is also well established.[[10]] A recent study (n=571, Italian patients) showed that the cost of management of the adverse effects of 5-FU/capecitabine is substantially higher in patients positive for any of the four DPYD[[LoF]] variant alleles compared with those wildtype for these variants (€3,712 vs €1,010).[[21]] Moreover, these DPYD[[LoF]] patients also had worse survival, and this results in decreased quality-adjusted life years (QALY) (3.62±0.70 years vs 4.18±0.61 years). Substantial evidence has also reported that a genotype-guided dosage approach is cost effective because it decreases the costs of prolonged hospitalisation of toxicity cases. Pre-screening patients (n=2,038) for a single DPYD variant (*2A), followed by 50% dose reduction for carriers of this variant, decreased treatment costs from €2,817 to €2,772.[[19]] A similar pre-emptive genotype-guided dose reduction study in 2,617 Canadian patients also indicated that this approach is suitable, based on the assumption that DPYD*2A carriers have an average hospitalisation of 15 days.[[22]] Of note, we recently reported in a smaller study that the median length of stay for New Zealand patients with severe 5-FU/capecitabine induced toxicity was seven days (range 2–17 days).[[23]] Finally, a prospective study that included all four DPYD[[LoF]] variants in the genetic screen prior to dosage adjustment demonstrated a net healthcare cost-saving of €51, confirming previous simulation studies of cost–benefit for prevention of a single adverse event (neutropenia).[[24,25]]
Phenotyping for dihydropyrimidine dehydrogenase enzyme deficiency
Although DPYD[[LoF]] genotyping clearly is of considerable value, the poor sensitivity of this test means that the risk of severe 5-FU/capecitabine toxicity in most patients is still poorly predicted.[[26]] Screening for enzyme activity has been proposed as an additional method of detecting at-risk individuals. Phenotypic assays have been developed to assess the degradation rate of 5-FU in leucocytes, plasma uracil concentrations, or challenge dosing with uracil or thymine.[[23,27–29]] A prospective study of a thymine challenge dose for detecting patients at risk of severe toxicity is currently underway across New Zealand (ACTRN12617001109392). Preliminary data suggest that this approach may be more sensitive than endogenous uracil levels.[[27]] However, there is currently a lack of prospective validation confirming that dose adjustments based upon endogenous uracil levels lead to a decreased incidence of severe toxicity and maintain effectiveness, although a study to investigate this has started (NCT04194957).
Pharmacokinetically guided dose‐individualisation
Data from thirteen clinical studies have shown that therapeutic drug monitoring (TDM) of infusional 5-FU improves both safety and clinical effectiveness (reviewed in Beumer et al[[30]]). The International Association of Therapeutic Drug Monitoring and Clinical Toxicology recommend that the therapeutic exposure range for a 46 h infusion schedule of 5-FU is an area under the curve (AUC) between 20–30 mg.h/L.[[30]] This approach has highlighted that, although approximately 20% of patients have elevated AUC (indicative of DPD enzyme deficiency), many patients receiving standard dosages do not achieve target AUC and may be underdosed.[[31,32]] One concern with the TDM-based approach is that patients are initially exposed to a full dose (prior to dosage adjustment), and because severe fluoropyrimidine‐related toxicity will occur rapidly in DPD‐deficient patients, pharmacokinetically guided dose‐individualisation cannot prevent this risk. Notably, TDM of the 5-FU concentrations achieved after oral capecitabine dosing has not been established. Moreover, the precision of pharmacokinetically guided dosage adjustment for capecitabine may be limited by the available tablet sizes (150 mg and 500 mg).[[33]] Both the European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA) recommend TDM for infusional 5-FU.
Renal impairment
Whilst inherited variation can account for some of the variability in plasma concentrations of 5-FU and risk of excessive toxicity other factors, such as co-medications (eg, sorivudine) and renal impairment, also play a role. Although urinary excretion is a minor pathway for 5-FU elimination, a number of studies have reported a significant association between creatinine clearance and 5-FU related toxicity.[[23,34–37]] Following dosing with either infusional 5-FU or oral capecitabine, the incidence of severe to life-threatening toxicity is higher in patients with moderate renal impairment (30–50 mL/min creatinine clearance) than patients with normal function (>80 mL/min).[[35]] The mechanism by which renal impairment increases risk of toxicity is unclear since this does not substantially impact the pharmacokinetics of capecitabine and its metabolites, including 5-FU.[[38]] The relationship between poor renal function and infusional 5-FU pharmacokinetics is not well studied, but there is little effect on 5-FU plasma AUC.[[39]] For patients with moderate renal impairment (30–50 mL/min), capecitabine dosage adjustment is recommended, and it is contraindicated in patients with poor renal function (<30 mL/min).[[35,40]] In contrast, no dosage adjustments are recommended in patients with moderate renal impairment treated with infusional 5-FU, even though they have the same increased risk of toxicity as those treated with capecitabine.
Other risk factors
Older age, female sex and worse performance status have been reported as possible risk factors. To some extent, age and performance status may be covariates of low renal function. Importantly, males have 26% higher total body clearance of 5-FU.[[41]] This could explain the significantly higher AUC observed in females compared to males and hence the increased risk of supratherapeutic concentrations following standard dosages.[[41]]
Regulatory agency and oncology society recommendations
Despite the ~25% sensitivity of DPYD testing for prediction of which patients are at risk of severe toxicity (due in part to other risk factors or rare DPYD variants), pre-screening patients prior to fluoropyrimidine treatment for four DPYD[[LoF]] variants (*2A, *13, *9B and HapB3) has recently been recommended by the EMA.[[42]] The UK MHRA have followed the same recommendations.[[43]] The UK Chemotherapy Board have also published guidelines on their website.[[44]] French, German and Belgian jurisdictions have provided consensus documents regarding testing,[[45–47]] and the province of Quebec in Canada has implemented this practice.[[22]] Most recently, the American Society of Clinical Oncologists has provided information regarding targeted DPYD testing.[[48]] Although the Cancer Institute of New South Wales eviQ resource[[49]] provides information about testing for DPYD, this test is not reimbursed in Australia.
In addition, the EMA recommend endogenous plasma uracil testing prior to initiating a 5-FU-containing treatment regimen.[[42]] In the Netherlands, when it is not possible to undertake genotyping, DPD enzyme activity testing in leucocytes has been adopted into clinical practice.[[17]]
Of note, uridine triacetate has FDA approval for treatment of unintentional overdose of 5-FU/capecitabine. But this antidote must be administered within 96 h of overdose, and the effectiveness in patients with early onset severe-adverse reactions is less clear.[[50]]
New Zealand perspective
As part of the ongoing clinical trial (ACTRN12617001109392), genotyping for the four key DPYD[[LoF]] variants is currently being undertaken in New Zealand by an accredited facility (Grafton Clinical Genomics). The laboratory-based costs for this genotyping are relatively low and the turnaround time within the Auckland region for a clinical test is expected to be short (<1–2 days). In addition, a validated liquid chromatography tandem mass spectrometry (LCMS/MS)-based assay, which can be used to measure both plasma 5-FU levels for pharmacokinetically guided dose adjustment, as well endogenous uracil levels, is currently available at Canterbury Health Laboratories, Christchurch, New Zealand.[[51]]
To date, most of the studies regarding DPYD[[LoF]] have focused on populations of primarily European ancestry. The minor allele frequencies of these alleles are much lower in individuals of East Asian ancestry compared with Europeans (Table 1), and a different prevalence of these genetic risk factors has also been reported for people of South Asian ancestry.[[52]] An additional LoF variant that associates with toxicity has been identified in people of African ancestry.[[53]] However, the prevalence of novel LoF variants in people of Māori or Pacific Island ancestry, and possible associations with toxicity risk, are not known.
The antidote (uridine triacetate) is a high-cost medicine and is not registered in New Zealand.
Summary
In New Zealand, there is currently no regulatory obligation to screen for dihydropyrimidine dehydrogenase deficiency prior to treatment with 5-FU or capecitabine. However, there is now substantial evidence that targeted genotyping for DPYD[[LoF]] variants (*2A, *13, *9B and HapB3) followed by dose adjustment is a cost-effective way to decrease severe toxicity whilst maintaining clinical effectiveness. We suggest that it is now an appropriate time for New Zealand oncologists to advocate for routine access to DPYD genotyping within their district health boards. Furthermore, for patients receiving continuous infusional 5-FU, access to TDM should also become part of routine clinical practice. We also highlight that moderate renal function appears to be an under-appreciated non-genetic risk factor. Finally, although some overseas jurisdictions have recommended using endogenous uracil levels for phenotyping for DPD deficiency, the prospective validation of this is currently lacking. Determination of whether prospective phenotyping with a challenge dose of thymine is an improvement on genotyping alone will be reported following the conclusion of our current clinical trial (ACTRN12617001109392).
Summary
Abstract
Aim
Dihydropyrimidine dehydrogenase deficiency is a rare inherited disorder. Approximately 3% of people of European ancestry are likely to have a partial deficiency in this enzyme. These individuals are typically asymptomatic until exposed to 5-fluorouracil (5-FU) or capecitabine (which forms 5-FU) for treatment of gastrointestinal or breast cancer. These individuals are then at considerably increased risk of severe to life-threatening adverse events. There are four well established risk variants within the DPYD gene that encodes dihydropyrimidine dehydrogenase. Although consensus guidelines for genotype-guided dosing of 5-FU and capecitabine have existed for a number of years, the implementation of this type of personalised medicine has not been widely adopted. This viewpoint covers the current state of knowledge about both genotype and phenotype testing, as well as the reported cost-savings and clinical effectiveness of pre-screening patients followed by dose-adjustment. Recent recommendations by agencies and professional societies, both in Europe and the USA, highlight the need for New Zealand oncologists to begin an informed discussion about whether it is now an appropriate time to advocate for routine access to testing for this enzyme deficiency in New Zealand cancer patients.
Method
Results
Conclusion
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
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Testing for dihydropyrimidine dehydrogenase deficiency in New Zealand to improve the safe use of 5-fluorouracil and capecitabine in cancer patients
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Intravenous 5-fluorouracil (5-FU) and oral capecitabine (which forms 5-FU) are commonly used in New Zealand to treat a range of solid tumour types, particularly gastrointestinal and breast cancers. Routine use of these agents carries a risk of treatment-limiting toxicities, including diarrhoea, mucositis, myelosuppression, Hand-Foot syndrome and sometimes cardiotoxicity. Overall, severe (Common Terminology Criteria for Adverse Events grade 3 or greater) toxicities are observed in up to one third of individuals and are fatal for approximately 1% of patients.[[1–4]]
5-FU is extensively (>80%) eliminated from the body by the enzyme dihydropyrimidine dehydrogenase (DPD), and decreased activity of this enzyme can result in severe to life-threatening toxicity. Inherited differences in DPD activity are well characterised as a cause of hereditary thymine-uracilemia.[[5]] This autosomal codominant inherited disorder is rare, with around 0.2% of people having complete deficiency (homozygotes) and about 3% of people of European ancestry have a partial deficiency (heterozygotes). These individuals are typically asymptomatic until challenged with 5-FU or capecitabine.
DPYD genotyping
It is well established that loss of function (LoF) polymorphisms in the DPYD gene that encodes the DPD enzyme have high sensitivity for prediction of risk of 5-FU/capecitabine-induced severe to life-threatening toxicity.[[3,6–14]] These LoF variants (Table 1) have high specificity (~80–100%) for prediction of severe toxicity risk. However, due to scarcity of these variants (~3% of a population), variant testing has poor sensitivity (<25%) for severe toxicity. This poor sensitivity may be due to either the presence of other rare (private) mutations in DPYD or low expression of the enzyme due to epigenetic mechanisms. This low sensitivity has led to some reluctance from clinicians to incorporate routine pre-screening of patients prior to use of 5-FU/capecitabine-containing regimens.
Evidence based DPYD genotype-based dosage adjustment guidelines have been extensively disseminated within the pharmacogenomics community (Table 1).[[15–17]]
Table 1: The key loss of function DPYD gene variants that should be assessed in patients prior to treatment. View Table 1.
Severe toxicity due to this enzyme deficiency often occurs in the first cycle of treatment. It is now clear from large prospective clinical trials that pre-screening patients for these DPYD[[LoF]] variants, combined with recommended dose adjustments prior to first dose, improves the therapeutic index of 5-FU/capecitabine.[[3]] Indeed that multicentre study of 1,103 evaluable patients found that genotype-guided dosing (compared to an historical cohort) decreased the relative risk (RR) of severe fluoropyrimidine-related toxicity. Patients who were DPYD*13 carriers and given a 50% dose decrease experienced no toxicity compared with RR of 4.30 (95% CI 2.10–8.80) in the historical cohort. In DPYD*2A carriers who received 50% dose decrease, there was significant decrease in RR from 2.87 (2.14–3.86) to 1.31 (0.63–2.73). Of note, the genotype-guided dose decrease was increased at subsequent cycles in 13% of the DPYD variant carriers, and this was not tolerated in most of these individuals. Other studies have also demonstrated that DPYD*2A carriers given a 50% dose reduction had a significant decrease in grade ≥3 toxicity from 73% (95% CI 58% to 85%) in historical controls to 28% (10% to 53%).[[19]] Similar decreases in toxicity risk in DPYD*2A carriers from 77% to 18% following genotype-guided dose adjustment have also been reported.[[20]]
Importantly genotype-guided dose adjustment produces similar plasma concentrations of 5-FU as observed in wildtype individuals receiving a standard dosage.[[3,19]] Therefore, genotype-guided dosage adjustment is not expected to alter clinical effectiveness. This has been formally tested in one study,[[20]] which found similar median overall and progression-free survival between genotype-guided dosing in DPYD*2A carriers and wild-type (matched pairs). There was no difference in hazard ratio (HR) for overall survival (HR 0.82, 95%CI 0.47–1.43; p=0.47) or progression free-survival (HR 0.83, 95%CI 0.47-1.5, p=0.83), confirming that genotype-guided dosing is unlikely to alter clinical effectiveness.
Cost effectiveness
The cost effectiveness of DPYD genotyping to prevent severe 5-FU/capecitabine toxicity is also well established.[[10]] A recent study (n=571, Italian patients) showed that the cost of management of the adverse effects of 5-FU/capecitabine is substantially higher in patients positive for any of the four DPYD[[LoF]] variant alleles compared with those wildtype for these variants (€3,712 vs €1,010).[[21]] Moreover, these DPYD[[LoF]] patients also had worse survival, and this results in decreased quality-adjusted life years (QALY) (3.62±0.70 years vs 4.18±0.61 years). Substantial evidence has also reported that a genotype-guided dosage approach is cost effective because it decreases the costs of prolonged hospitalisation of toxicity cases. Pre-screening patients (n=2,038) for a single DPYD variant (*2A), followed by 50% dose reduction for carriers of this variant, decreased treatment costs from €2,817 to €2,772.[[19]] A similar pre-emptive genotype-guided dose reduction study in 2,617 Canadian patients also indicated that this approach is suitable, based on the assumption that DPYD*2A carriers have an average hospitalisation of 15 days.[[22]] Of note, we recently reported in a smaller study that the median length of stay for New Zealand patients with severe 5-FU/capecitabine induced toxicity was seven days (range 2–17 days).[[23]] Finally, a prospective study that included all four DPYD[[LoF]] variants in the genetic screen prior to dosage adjustment demonstrated a net healthcare cost-saving of €51, confirming previous simulation studies of cost–benefit for prevention of a single adverse event (neutropenia).[[24,25]]
Phenotyping for dihydropyrimidine dehydrogenase enzyme deficiency
Although DPYD[[LoF]] genotyping clearly is of considerable value, the poor sensitivity of this test means that the risk of severe 5-FU/capecitabine toxicity in most patients is still poorly predicted.[[26]] Screening for enzyme activity has been proposed as an additional method of detecting at-risk individuals. Phenotypic assays have been developed to assess the degradation rate of 5-FU in leucocytes, plasma uracil concentrations, or challenge dosing with uracil or thymine.[[23,27–29]] A prospective study of a thymine challenge dose for detecting patients at risk of severe toxicity is currently underway across New Zealand (ACTRN12617001109392). Preliminary data suggest that this approach may be more sensitive than endogenous uracil levels.[[27]] However, there is currently a lack of prospective validation confirming that dose adjustments based upon endogenous uracil levels lead to a decreased incidence of severe toxicity and maintain effectiveness, although a study to investigate this has started (NCT04194957).
Pharmacokinetically guided dose‐individualisation
Data from thirteen clinical studies have shown that therapeutic drug monitoring (TDM) of infusional 5-FU improves both safety and clinical effectiveness (reviewed in Beumer et al[[30]]). The International Association of Therapeutic Drug Monitoring and Clinical Toxicology recommend that the therapeutic exposure range for a 46 h infusion schedule of 5-FU is an area under the curve (AUC) between 20–30 mg.h/L.[[30]] This approach has highlighted that, although approximately 20% of patients have elevated AUC (indicative of DPD enzyme deficiency), many patients receiving standard dosages do not achieve target AUC and may be underdosed.[[31,32]] One concern with the TDM-based approach is that patients are initially exposed to a full dose (prior to dosage adjustment), and because severe fluoropyrimidine‐related toxicity will occur rapidly in DPD‐deficient patients, pharmacokinetically guided dose‐individualisation cannot prevent this risk. Notably, TDM of the 5-FU concentrations achieved after oral capecitabine dosing has not been established. Moreover, the precision of pharmacokinetically guided dosage adjustment for capecitabine may be limited by the available tablet sizes (150 mg and 500 mg).[[33]] Both the European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA) recommend TDM for infusional 5-FU.
Renal impairment
Whilst inherited variation can account for some of the variability in plasma concentrations of 5-FU and risk of excessive toxicity other factors, such as co-medications (eg, sorivudine) and renal impairment, also play a role. Although urinary excretion is a minor pathway for 5-FU elimination, a number of studies have reported a significant association between creatinine clearance and 5-FU related toxicity.[[23,34–37]] Following dosing with either infusional 5-FU or oral capecitabine, the incidence of severe to life-threatening toxicity is higher in patients with moderate renal impairment (30–50 mL/min creatinine clearance) than patients with normal function (>80 mL/min).[[35]] The mechanism by which renal impairment increases risk of toxicity is unclear since this does not substantially impact the pharmacokinetics of capecitabine and its metabolites, including 5-FU.[[38]] The relationship between poor renal function and infusional 5-FU pharmacokinetics is not well studied, but there is little effect on 5-FU plasma AUC.[[39]] For patients with moderate renal impairment (30–50 mL/min), capecitabine dosage adjustment is recommended, and it is contraindicated in patients with poor renal function (<30 mL/min).[[35,40]] In contrast, no dosage adjustments are recommended in patients with moderate renal impairment treated with infusional 5-FU, even though they have the same increased risk of toxicity as those treated with capecitabine.
Other risk factors
Older age, female sex and worse performance status have been reported as possible risk factors. To some extent, age and performance status may be covariates of low renal function. Importantly, males have 26% higher total body clearance of 5-FU.[[41]] This could explain the significantly higher AUC observed in females compared to males and hence the increased risk of supratherapeutic concentrations following standard dosages.[[41]]
Regulatory agency and oncology society recommendations
Despite the ~25% sensitivity of DPYD testing for prediction of which patients are at risk of severe toxicity (due in part to other risk factors or rare DPYD variants), pre-screening patients prior to fluoropyrimidine treatment for four DPYD[[LoF]] variants (*2A, *13, *9B and HapB3) has recently been recommended by the EMA.[[42]] The UK MHRA have followed the same recommendations.[[43]] The UK Chemotherapy Board have also published guidelines on their website.[[44]] French, German and Belgian jurisdictions have provided consensus documents regarding testing,[[45–47]] and the province of Quebec in Canada has implemented this practice.[[22]] Most recently, the American Society of Clinical Oncologists has provided information regarding targeted DPYD testing.[[48]] Although the Cancer Institute of New South Wales eviQ resource[[49]] provides information about testing for DPYD, this test is not reimbursed in Australia.
In addition, the EMA recommend endogenous plasma uracil testing prior to initiating a 5-FU-containing treatment regimen.[[42]] In the Netherlands, when it is not possible to undertake genotyping, DPD enzyme activity testing in leucocytes has been adopted into clinical practice.[[17]]
Of note, uridine triacetate has FDA approval for treatment of unintentional overdose of 5-FU/capecitabine. But this antidote must be administered within 96 h of overdose, and the effectiveness in patients with early onset severe-adverse reactions is less clear.[[50]]
New Zealand perspective
As part of the ongoing clinical trial (ACTRN12617001109392), genotyping for the four key DPYD[[LoF]] variants is currently being undertaken in New Zealand by an accredited facility (Grafton Clinical Genomics). The laboratory-based costs for this genotyping are relatively low and the turnaround time within the Auckland region for a clinical test is expected to be short (<1–2 days). In addition, a validated liquid chromatography tandem mass spectrometry (LCMS/MS)-based assay, which can be used to measure both plasma 5-FU levels for pharmacokinetically guided dose adjustment, as well endogenous uracil levels, is currently available at Canterbury Health Laboratories, Christchurch, New Zealand.[[51]]
To date, most of the studies regarding DPYD[[LoF]] have focused on populations of primarily European ancestry. The minor allele frequencies of these alleles are much lower in individuals of East Asian ancestry compared with Europeans (Table 1), and a different prevalence of these genetic risk factors has also been reported for people of South Asian ancestry.[[52]] An additional LoF variant that associates with toxicity has been identified in people of African ancestry.[[53]] However, the prevalence of novel LoF variants in people of Māori or Pacific Island ancestry, and possible associations with toxicity risk, are not known.
The antidote (uridine triacetate) is a high-cost medicine and is not registered in New Zealand.
Summary
In New Zealand, there is currently no regulatory obligation to screen for dihydropyrimidine dehydrogenase deficiency prior to treatment with 5-FU or capecitabine. However, there is now substantial evidence that targeted genotyping for DPYD[[LoF]] variants (*2A, *13, *9B and HapB3) followed by dose adjustment is a cost-effective way to decrease severe toxicity whilst maintaining clinical effectiveness. We suggest that it is now an appropriate time for New Zealand oncologists to advocate for routine access to DPYD genotyping within their district health boards. Furthermore, for patients receiving continuous infusional 5-FU, access to TDM should also become part of routine clinical practice. We also highlight that moderate renal function appears to be an under-appreciated non-genetic risk factor. Finally, although some overseas jurisdictions have recommended using endogenous uracil levels for phenotyping for DPD deficiency, the prospective validation of this is currently lacking. Determination of whether prospective phenotyping with a challenge dose of thymine is an improvement on genotyping alone will be reported following the conclusion of our current clinical trial (ACTRN12617001109392).
Summary
Abstract
Aim
Dihydropyrimidine dehydrogenase deficiency is a rare inherited disorder. Approximately 3% of people of European ancestry are likely to have a partial deficiency in this enzyme. These individuals are typically asymptomatic until exposed to 5-fluorouracil (5-FU) or capecitabine (which forms 5-FU) for treatment of gastrointestinal or breast cancer. These individuals are then at considerably increased risk of severe to life-threatening adverse events. There are four well established risk variants within the DPYD gene that encodes dihydropyrimidine dehydrogenase. Although consensus guidelines for genotype-guided dosing of 5-FU and capecitabine have existed for a number of years, the implementation of this type of personalised medicine has not been widely adopted. This viewpoint covers the current state of knowledge about both genotype and phenotype testing, as well as the reported cost-savings and clinical effectiveness of pre-screening patients followed by dose-adjustment. Recent recommendations by agencies and professional societies, both in Europe and the USA, highlight the need for New Zealand oncologists to begin an informed discussion about whether it is now an appropriate time to advocate for routine access to testing for this enzyme deficiency in New Zealand cancer patients.
Method
Results
Conclusion
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
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Testing for dihydropyrimidine dehydrogenase deficiency in New Zealand to improve the safe use of 5-fluorouracil and capecitabine in cancer patients
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Intravenous 5-fluorouracil (5-FU) and oral capecitabine (which forms 5-FU) are commonly used in New Zealand to treat a range of solid tumour types, particularly gastrointestinal and breast cancers. Routine use of these agents carries a risk of treatment-limiting toxicities, including diarrhoea, mucositis, myelosuppression, Hand-Foot syndrome and sometimes cardiotoxicity. Overall, severe (Common Terminology Criteria for Adverse Events grade 3 or greater) toxicities are observed in up to one third of individuals and are fatal for approximately 1% of patients.[[1–4]]
5-FU is extensively (>80%) eliminated from the body by the enzyme dihydropyrimidine dehydrogenase (DPD), and decreased activity of this enzyme can result in severe to life-threatening toxicity. Inherited differences in DPD activity are well characterised as a cause of hereditary thymine-uracilemia.[[5]] This autosomal codominant inherited disorder is rare, with around 0.2% of people having complete deficiency (homozygotes) and about 3% of people of European ancestry have a partial deficiency (heterozygotes). These individuals are typically asymptomatic until challenged with 5-FU or capecitabine.
DPYD genotyping
It is well established that loss of function (LoF) polymorphisms in the DPYD gene that encodes the DPD enzyme have high sensitivity for prediction of risk of 5-FU/capecitabine-induced severe to life-threatening toxicity.[[3,6–14]] These LoF variants (Table 1) have high specificity (~80–100%) for prediction of severe toxicity risk. However, due to scarcity of these variants (~3% of a population), variant testing has poor sensitivity (<25%) for severe toxicity. This poor sensitivity may be due to either the presence of other rare (private) mutations in DPYD or low expression of the enzyme due to epigenetic mechanisms. This low sensitivity has led to some reluctance from clinicians to incorporate routine pre-screening of patients prior to use of 5-FU/capecitabine-containing regimens.
Evidence based DPYD genotype-based dosage adjustment guidelines have been extensively disseminated within the pharmacogenomics community (Table 1).[[15–17]]
Table 1: The key loss of function DPYD gene variants that should be assessed in patients prior to treatment. View Table 1.
Severe toxicity due to this enzyme deficiency often occurs in the first cycle of treatment. It is now clear from large prospective clinical trials that pre-screening patients for these DPYD[[LoF]] variants, combined with recommended dose adjustments prior to first dose, improves the therapeutic index of 5-FU/capecitabine.[[3]] Indeed that multicentre study of 1,103 evaluable patients found that genotype-guided dosing (compared to an historical cohort) decreased the relative risk (RR) of severe fluoropyrimidine-related toxicity. Patients who were DPYD*13 carriers and given a 50% dose decrease experienced no toxicity compared with RR of 4.30 (95% CI 2.10–8.80) in the historical cohort. In DPYD*2A carriers who received 50% dose decrease, there was significant decrease in RR from 2.87 (2.14–3.86) to 1.31 (0.63–2.73). Of note, the genotype-guided dose decrease was increased at subsequent cycles in 13% of the DPYD variant carriers, and this was not tolerated in most of these individuals. Other studies have also demonstrated that DPYD*2A carriers given a 50% dose reduction had a significant decrease in grade ≥3 toxicity from 73% (95% CI 58% to 85%) in historical controls to 28% (10% to 53%).[[19]] Similar decreases in toxicity risk in DPYD*2A carriers from 77% to 18% following genotype-guided dose adjustment have also been reported.[[20]]
Importantly genotype-guided dose adjustment produces similar plasma concentrations of 5-FU as observed in wildtype individuals receiving a standard dosage.[[3,19]] Therefore, genotype-guided dosage adjustment is not expected to alter clinical effectiveness. This has been formally tested in one study,[[20]] which found similar median overall and progression-free survival between genotype-guided dosing in DPYD*2A carriers and wild-type (matched pairs). There was no difference in hazard ratio (HR) for overall survival (HR 0.82, 95%CI 0.47–1.43; p=0.47) or progression free-survival (HR 0.83, 95%CI 0.47-1.5, p=0.83), confirming that genotype-guided dosing is unlikely to alter clinical effectiveness.
Cost effectiveness
The cost effectiveness of DPYD genotyping to prevent severe 5-FU/capecitabine toxicity is also well established.[[10]] A recent study (n=571, Italian patients) showed that the cost of management of the adverse effects of 5-FU/capecitabine is substantially higher in patients positive for any of the four DPYD[[LoF]] variant alleles compared with those wildtype for these variants (€3,712 vs €1,010).[[21]] Moreover, these DPYD[[LoF]] patients also had worse survival, and this results in decreased quality-adjusted life years (QALY) (3.62±0.70 years vs 4.18±0.61 years). Substantial evidence has also reported that a genotype-guided dosage approach is cost effective because it decreases the costs of prolonged hospitalisation of toxicity cases. Pre-screening patients (n=2,038) for a single DPYD variant (*2A), followed by 50% dose reduction for carriers of this variant, decreased treatment costs from €2,817 to €2,772.[[19]] A similar pre-emptive genotype-guided dose reduction study in 2,617 Canadian patients also indicated that this approach is suitable, based on the assumption that DPYD*2A carriers have an average hospitalisation of 15 days.[[22]] Of note, we recently reported in a smaller study that the median length of stay for New Zealand patients with severe 5-FU/capecitabine induced toxicity was seven days (range 2–17 days).[[23]] Finally, a prospective study that included all four DPYD[[LoF]] variants in the genetic screen prior to dosage adjustment demonstrated a net healthcare cost-saving of €51, confirming previous simulation studies of cost–benefit for prevention of a single adverse event (neutropenia).[[24,25]]
Phenotyping for dihydropyrimidine dehydrogenase enzyme deficiency
Although DPYD[[LoF]] genotyping clearly is of considerable value, the poor sensitivity of this test means that the risk of severe 5-FU/capecitabine toxicity in most patients is still poorly predicted.[[26]] Screening for enzyme activity has been proposed as an additional method of detecting at-risk individuals. Phenotypic assays have been developed to assess the degradation rate of 5-FU in leucocytes, plasma uracil concentrations, or challenge dosing with uracil or thymine.[[23,27–29]] A prospective study of a thymine challenge dose for detecting patients at risk of severe toxicity is currently underway across New Zealand (ACTRN12617001109392). Preliminary data suggest that this approach may be more sensitive than endogenous uracil levels.[[27]] However, there is currently a lack of prospective validation confirming that dose adjustments based upon endogenous uracil levels lead to a decreased incidence of severe toxicity and maintain effectiveness, although a study to investigate this has started (NCT04194957).
Pharmacokinetically guided dose‐individualisation
Data from thirteen clinical studies have shown that therapeutic drug monitoring (TDM) of infusional 5-FU improves both safety and clinical effectiveness (reviewed in Beumer et al[[30]]). The International Association of Therapeutic Drug Monitoring and Clinical Toxicology recommend that the therapeutic exposure range for a 46 h infusion schedule of 5-FU is an area under the curve (AUC) between 20–30 mg.h/L.[[30]] This approach has highlighted that, although approximately 20% of patients have elevated AUC (indicative of DPD enzyme deficiency), many patients receiving standard dosages do not achieve target AUC and may be underdosed.[[31,32]] One concern with the TDM-based approach is that patients are initially exposed to a full dose (prior to dosage adjustment), and because severe fluoropyrimidine‐related toxicity will occur rapidly in DPD‐deficient patients, pharmacokinetically guided dose‐individualisation cannot prevent this risk. Notably, TDM of the 5-FU concentrations achieved after oral capecitabine dosing has not been established. Moreover, the precision of pharmacokinetically guided dosage adjustment for capecitabine may be limited by the available tablet sizes (150 mg and 500 mg).[[33]] Both the European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA) recommend TDM for infusional 5-FU.
Renal impairment
Whilst inherited variation can account for some of the variability in plasma concentrations of 5-FU and risk of excessive toxicity other factors, such as co-medications (eg, sorivudine) and renal impairment, also play a role. Although urinary excretion is a minor pathway for 5-FU elimination, a number of studies have reported a significant association between creatinine clearance and 5-FU related toxicity.[[23,34–37]] Following dosing with either infusional 5-FU or oral capecitabine, the incidence of severe to life-threatening toxicity is higher in patients with moderate renal impairment (30–50 mL/min creatinine clearance) than patients with normal function (>80 mL/min).[[35]] The mechanism by which renal impairment increases risk of toxicity is unclear since this does not substantially impact the pharmacokinetics of capecitabine and its metabolites, including 5-FU.[[38]] The relationship between poor renal function and infusional 5-FU pharmacokinetics is not well studied, but there is little effect on 5-FU plasma AUC.[[39]] For patients with moderate renal impairment (30–50 mL/min), capecitabine dosage adjustment is recommended, and it is contraindicated in patients with poor renal function (<30 mL/min).[[35,40]] In contrast, no dosage adjustments are recommended in patients with moderate renal impairment treated with infusional 5-FU, even though they have the same increased risk of toxicity as those treated with capecitabine.
Other risk factors
Older age, female sex and worse performance status have been reported as possible risk factors. To some extent, age and performance status may be covariates of low renal function. Importantly, males have 26% higher total body clearance of 5-FU.[[41]] This could explain the significantly higher AUC observed in females compared to males and hence the increased risk of supratherapeutic concentrations following standard dosages.[[41]]
Regulatory agency and oncology society recommendations
Despite the ~25% sensitivity of DPYD testing for prediction of which patients are at risk of severe toxicity (due in part to other risk factors or rare DPYD variants), pre-screening patients prior to fluoropyrimidine treatment for four DPYD[[LoF]] variants (*2A, *13, *9B and HapB3) has recently been recommended by the EMA.[[42]] The UK MHRA have followed the same recommendations.[[43]] The UK Chemotherapy Board have also published guidelines on their website.[[44]] French, German and Belgian jurisdictions have provided consensus documents regarding testing,[[45–47]] and the province of Quebec in Canada has implemented this practice.[[22]] Most recently, the American Society of Clinical Oncologists has provided information regarding targeted DPYD testing.[[48]] Although the Cancer Institute of New South Wales eviQ resource[[49]] provides information about testing for DPYD, this test is not reimbursed in Australia.
In addition, the EMA recommend endogenous plasma uracil testing prior to initiating a 5-FU-containing treatment regimen.[[42]] In the Netherlands, when it is not possible to undertake genotyping, DPD enzyme activity testing in leucocytes has been adopted into clinical practice.[[17]]
Of note, uridine triacetate has FDA approval for treatment of unintentional overdose of 5-FU/capecitabine. But this antidote must be administered within 96 h of overdose, and the effectiveness in patients with early onset severe-adverse reactions is less clear.[[50]]
New Zealand perspective
As part of the ongoing clinical trial (ACTRN12617001109392), genotyping for the four key DPYD[[LoF]] variants is currently being undertaken in New Zealand by an accredited facility (Grafton Clinical Genomics). The laboratory-based costs for this genotyping are relatively low and the turnaround time within the Auckland region for a clinical test is expected to be short (<1–2 days). In addition, a validated liquid chromatography tandem mass spectrometry (LCMS/MS)-based assay, which can be used to measure both plasma 5-FU levels for pharmacokinetically guided dose adjustment, as well endogenous uracil levels, is currently available at Canterbury Health Laboratories, Christchurch, New Zealand.[[51]]
To date, most of the studies regarding DPYD[[LoF]] have focused on populations of primarily European ancestry. The minor allele frequencies of these alleles are much lower in individuals of East Asian ancestry compared with Europeans (Table 1), and a different prevalence of these genetic risk factors has also been reported for people of South Asian ancestry.[[52]] An additional LoF variant that associates with toxicity has been identified in people of African ancestry.[[53]] However, the prevalence of novel LoF variants in people of Māori or Pacific Island ancestry, and possible associations with toxicity risk, are not known.
The antidote (uridine triacetate) is a high-cost medicine and is not registered in New Zealand.
Summary
In New Zealand, there is currently no regulatory obligation to screen for dihydropyrimidine dehydrogenase deficiency prior to treatment with 5-FU or capecitabine. However, there is now substantial evidence that targeted genotyping for DPYD[[LoF]] variants (*2A, *13, *9B and HapB3) followed by dose adjustment is a cost-effective way to decrease severe toxicity whilst maintaining clinical effectiveness. We suggest that it is now an appropriate time for New Zealand oncologists to advocate for routine access to DPYD genotyping within their district health boards. Furthermore, for patients receiving continuous infusional 5-FU, access to TDM should also become part of routine clinical practice. We also highlight that moderate renal function appears to be an under-appreciated non-genetic risk factor. Finally, although some overseas jurisdictions have recommended using endogenous uracil levels for phenotyping for DPD deficiency, the prospective validation of this is currently lacking. Determination of whether prospective phenotyping with a challenge dose of thymine is an improvement on genotyping alone will be reported following the conclusion of our current clinical trial (ACTRN12617001109392).
Summary
Abstract
Aim
Dihydropyrimidine dehydrogenase deficiency is a rare inherited disorder. Approximately 3% of people of European ancestry are likely to have a partial deficiency in this enzyme. These individuals are typically asymptomatic until exposed to 5-fluorouracil (5-FU) or capecitabine (which forms 5-FU) for treatment of gastrointestinal or breast cancer. These individuals are then at considerably increased risk of severe to life-threatening adverse events. There are four well established risk variants within the DPYD gene that encodes dihydropyrimidine dehydrogenase. Although consensus guidelines for genotype-guided dosing of 5-FU and capecitabine have existed for a number of years, the implementation of this type of personalised medicine has not been widely adopted. This viewpoint covers the current state of knowledge about both genotype and phenotype testing, as well as the reported cost-savings and clinical effectiveness of pre-screening patients followed by dose-adjustment. Recent recommendations by agencies and professional societies, both in Europe and the USA, highlight the need for New Zealand oncologists to begin an informed discussion about whether it is now an appropriate time to advocate for routine access to testing for this enzyme deficiency in New Zealand cancer patients.
Method
Results
Conclusion
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
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Testing for dihydropyrimidine dehydrogenase deficiency in New Zealand to improve the safe use of 5-fluorouracil and capecitabine in cancer patients
Intravenous 5-fluorouracil (5-FU) and oral capecitabine (which forms 5-FU) are commonly used in New Zealand to treat a range of solid tumour types, particularly gastrointestinal and breast cancers. Routine use of these agents carries a risk of treatment-limiting toxicities, including diarrhoea, mucositis, myelosuppression, Hand-Foot syndrome and sometimes cardiotoxicity.
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