Safety of topical 5-FU cream in patients carrying a clinically relevant DPYD variant

Actinic keratosis (AK) is the most frequent premalignant skin lesion in
patients with a Caucasian ethnicity. In a Dutch population-based study with
2063 participants, almost 38% had one or more AK. This UV-induced lesion can
eventually transform into squamous cell carcinoma (SCC). The most effective
treatment of actinic keratosis is topical 5% fluorouracil cream (Efudix; 5-FU
cream). 5-FU cream is also registered for treatment of Morbus Bowen and
superficial basal-cell carcinoma.
5-fluorouracil (5-FU) is an antineoplastic agent belonging to the
fluoropyrimidines. Fluoropyrimidines can be administered as an intravenous
solution (5-FU), as an oral prodrug (Capecitabine), or as a cream (Efudix). The
intravenous and oral form are frequently used in the treatment of multiple
cancers e.g. colorectal, gastric and breast cancer. Deficiency of
dihydropyrimidine dehydrogenase (DPD), the rate limiting enzyme of
fluoropyrimidines, is an important risk factor for fluoropyrimidine associated
severe toxicity. About 5-8% of the population has a deficiency in DPD activity,
often as a result of single nucleotide polymorphisms (SNPs) in the gene
encoding for DPD, DPYD. Recently, it was shown by Henricks et al. that DPYD
genotype-based dose reductions improved patient safety of fluoropyrimidine
treatment. A prospective, multicentre safety analysis was performed to assess
the effect of prospective screening for the four most relevant DPYD variants
(DPYD*2A, DPYD*7, c.2846A>T, c.1236G>A/HapB3, c.1679T>G) on patient safety and
subsequent DPYD genotype-guided dose individualization in daily clinical care.
For DPYD*2A and c.1679T>G carriers, a decreased risk of severe (>= grade 3)
toxicity was shown after a 50% reduction. For c.2846A>T and c.1236G>A carriers
a 25% dose reduction was not enough to decrease severe treatment-related
toxicity. A larger initial dose reduction of 50%, with subsequent individual
dose titrations, should therefore be considered.
Despite the first case of a DPD-deficient patient who developed
life-threatening toxicity after treatment with topical 5-FU was described in
1999, similar research has never been performed in patients treated with 5-FU
cream. Another patient developed severe neutropenia after initiating topical
5-FU treatment. Although DPD deficiency was suspected, genotyping for the
clinically relevant DPYD SNPs could not be performed. To provide more clarity,
our primary aim is to prospectively study the incidence of severe 5-FU
cream-related toxicity in patients with and without a clinically relevant DPYD
variants, eventually to determine the most optimal dosing regime in patients
treated with 5-FU cream.

To study if patients who carry clinically relevant DPYD variants (DPYD*2A,
DPYD*7, c.2846A>T, c.1236G>A/HapB3, c.1679T>G) are at a higher risk for
developing severe 5-FU cream-related toxicity.

This is a prospective, observational clinical trial. The number of patients
needed for this study is between 350-550, with the expectation that 27 of them
carry one of the clinically relevant DPYD variants (DPYD*2A, DPYD*7, c.2846A>T,
c.1236G>A/HapB3, c.1679T>G). From patients treated with 5-FU cream, one blood
sample will be withdrawn before or during therapy with 5-FU cream for DPYD
genotyping. Genotyping will be performed after treatment. Therefore, the
genotype does not influence the treatment regime. On five time points (1, 2 and
3 weeks after start therapy, with stop therapy and 3 months after start)
toxicity will be evaluated using photos of the treatment area. In addition,
patients will be asked to complete diaries to obtain information about
toxicity. If obtained informed consent, pharmacokinetic data will be assessed
to determine if there is a difference in clearance in patients with a
clinically relevant DPYD variant.

In order to determine the DPYD genotype, a total of 4 mL EDTA blood will be
drawn from the patients intended to be treated with 5-FU cream, or patients who
recently started with application of 5-FU cream.
If additive consent is provided, an additional blood sample will be withdrawn
to determine the pharmacokinetic profile of 5-FU and its metabolites.
Both samples can be withdrawn at the same time.
Patients will be asked to complete diaries to obtain information about toxicity
and a questionnaire about sun exposition in the past and their skin type. In
addition, on five time points (1, 2 and 3 weeks after start therapy, with stop
therapy and 3 months after start therapy) toxicity will be evaluated using
photos of the treatment area. Photos of the treatment area will be sent by
email to the study email address. These proceedings take some extra time for
the patients.