Page 83 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

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- 3 patients (1x *1/c.1236A>G and 2x *1/*2A) did not receive an initial dose reduction and developed toxicity grade 3-4 in cycle 1. For two of these patients, therapy was started before the genotype was known. For the third patient, the oncologist did not reduce the dose, because the dose in the chemotherapy regimen was already relatively low (capecitabine plus radiotherapy). For 1 patient with genotype *1/*2A, the dose was subsequently reduced to 50% of the normal dose and the patient did not develop toxicity grade 3-4 anymore. The other 2 patients quitted fluoropyrimidine therapy.
- For the carrier of both *2A and c.2846A>T, there was no dose recommendation, because it was not known whether the variants were on different alleles or on the same allele. Because therapy had to be started before the DPD-activity would have been determined, the physician decided to use a 50% dose reduction, taking into account the results of genotyping and that this patient had tolerated 5-FU containing regimens before. Fluoropyrimidine therapy was stopped in this patient after the first cycle due to toxicity (≤ grade 3).
- 2 patients (both with genotype *1/c.1236A>G)
did not start fluoropyrimidine therapy.
A subset of patients from Lee 2014 was reanalysed: 1953 patients, negative for *2A, *13 and c.2846A>T, and treated with 12 cycles of adjuvant FOLFOX therapy (5-FU, folinic acid and oxaliplatin) with or without cetuximab. 62.9% of patients had any grade ≥ 3 adverse event, with 32.7% having any grade ≥ 3 adverse event common to 5-FU treatment.
Adverse events classified as common to 5-FU treatment were fatigue, anorexia, dehydration, diarrhoea, stomatitis/mucositis, nausea/vomiting, leukopenia, neutropenia, febrile neutropenia, thrombocytopenia, and pain. Most frequent 5-FU adverse events included diarrhoea (12.5%), neutropenia (10.3%), pain (5.4%), fatigue (5.2%), nausea/vomiting (4.7%), and mucositis (4.1%).
Results were adjusted for clinicopathological factors like age, sex, treatment, total number of treatment cycles and dose modifications. The latter two outcomes (higher percentage of patients with premature continuation and with dose modification) might be results of 5-FU adverse events instead of causes.
Cetuximab increased the risk of 5-FU adverse events. Results were adjusted for this, but this indicates that adverse events common to 5-FU are not the same as 5-fluorouracil-induced adverse events.
Genotyping:
4
ref. 7 – FU, comb
Lee AM et al. Association between DPYD c.1129- 5923 C>G/hapB3 and severe toxicity to 5- fluorouracil- based chemotherap y in stage III colon cancer patients: NCCTG N0147 (Alliance). Pharmacogen et Genomics 2016;26:133- 7. PubMed PMID: 26658227.
Level of evidence score: 3
gene act. 1-1.5: CTC-AE 4
Authors’ conclusion: ‘No significant associations were identified between c.1129 -5923 C>G/hapB3 and overall grade≥3 adverse event rate. Our results suggest that c.1129-5923 C>G/hapB3 have limited predictive value for severe toxicity to 5-FU- based combination chemotherapy.’
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