should dpd deficiency be searched before starting 5fu?€¦ · dpd phenotype endogene activity...
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Should DPD Deficiency be Searched
Before Starting 5FU?
Dr Julien TAIEB- HEGP
Paris
France
Disclosures
• Honoraria for Speaker, Consulting or Advisory Role:
Roche Genentech, Lilly, Servier, Sanofi, Celgene, AMGEN, SIRTEX, MerckSerono, Pierre Fabre and MSD
• Travel, Accommodations, Expenses:
Merck Serono, Celgene, Roche Genentech, Servier, Lilly.
2
XVIth century
Paracelse (1493-1541)
Everything is poison
And
Nothing is poison
The dosage makes the poison!
5FU a 60 year-old story
► Fluoropyrimidines (5FU, capecitabine)
low cost
Largely prescribed in adult solid tumors (GI, breast, Head and neck)
► Fluoropyrimidines are estimated to be responsible of:
- 0,1 to 1% toxic deaths
- 5% major toxicities (grade 4, hospitalization…)
- 15 to 30% 3-4 severe toxicities (hematological and GI)
(MAGIC JCO 1998; Grem et al. Invest New Drug 2000; Tsalic et al. Am J Clin Oncol 2003)
► Antidote (Uridine triacétate, Vistonuridine®) 50 000 € (low availability)
Fluoropyrimidines
5-FU metabolism
Inactive metabolites
► In France with an estimated : ~ 80 000-100 000 pts /year treated with5FU
Patients receiving a systemic CT Fluoropyrimidines estimate
(Sources INCa 2012) (FUSAFE)
- 65 000 GI cancers 83%
- 56 000 breast cancer 50%
- 13 000 head and neck 66%
► 500 deaths/ year
► 5000 major toxicities/ year
► can DPD deficiency testing help to avoid that?
5FU a toxic drug
► Frequency
Partial deficiency : 3 to 8%
Complete deficiency : 0.01 to 0.5 %
► Impact on toxicities
• Early toxicities : first 2 cycles generally
• Responsible for 20 to 60% of fluoropyrimidines related severe toxicities
• Complete deficiency may lead to patients’ death due to multi-organ failure
DPD deficiency
DPD deficiency: a 30 year-old story
DPD deficiency: Editorials since 25 years
DPD deficiency assessment was done…in some centers (30%)
DPD phenotype
Endogene activity
Uracile (U) Dihydro Uracile (UH2)DPD
Ratio UH2/ U allows to assess DPD activityUracilemia
Pre-analytic issues:• 1h30 room temperature• 4h if at 4°C• centrifugation• Immediatly Frozen• Generally in the morning
Sensitivity: 82%
Specificity: 80%
COST= 40 Euros
DPD genotype
Sensitivity: 25%
Specificity: 95%
• 4 variants of interest in caucasians (not for asians or africans):
Allelic frequency heterozygous homozygous score
DPYD*2A 0.5% Activity 50% 0% 0
DPYD*13 0.1% Activity 25% 0
C.2846 A>T 0.6% Activity 75% 0.5
Hap B3 2% Activity 65% 50% 0.5
• Score:• 0 : No 5FU• 0.5: 25% dose• 1: 50% dose• 1.5: 75% dose
COST= 110,7 Euros
Issues:• Only caucasians• Informed consent• Poor sensitivity
December 2018 (updated in April 2019):
Screening for dihydropyrimidine dehydrogenase deficiency to decrease the risk of severe toxicities related to fluoropyrimidines(5-fluorouracil or capecitabine)
Based on uracile plasma concentrations
Expression and interpretation of the results:
- uracilemia ≥ 150 ng/ml suggests complete DPD deficiency
- uracilemia ≥ 16 ng/ml and < 150 ng/ml suggests partial DPD deficiency
In case of DPD complete deficiency : Raltitrexed, Trifluridine tipiracile?
Guidelines and recommendations
• In our lab:
2017 : 780/yr
2018 : 3200/yr
2019 : 500/month!
• DPD deficiency has to be assessed by phenotype and reimbursed
• In France pharmacists are not allowed anymore to deliver 5FU or capecitabine without checking DPD
• Future ESMO recommandations?
Guidelines and recommandations
• Fluoropyrimidine are used since 60 years & DPD deficiency identified
as a risk factor since 30 years
• 5FU and capecitabine are responsible for hundreds of toxic deaths and
thousands of severe toxicities in Europe every year
• Testing DPD may avoid at least 30% of these unfavourable outcomes
Conclusions
• Should DPD Deficiency be Searched Before Starting 5FU?
• How?
• For who?
• If complete deficiency?
Conclusions
• YES !
• At least phenotype with uracilemia <16- 16 to 150 or > 150 ng/ml
• All patients before 5FU of capecitabine treatment
• No possible 5FU/capecitabine• Think trifluridine tipiracile and raltitrexed
Thanks to
Pr Olivier Bouché (Reims)
and to
Pr Marie Anne Loriot (Paris)
for their help and their slides!
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