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!