Page 197 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Fluoropyrimidine dosages in chemoradiation therapy
is used, and there are no cycles; therefore, the highest toxicity grade over the entire treatment period was used. Gastrointestinal toxicity included diarrhoea, mucositis, nausea and vomiting (nausea or vomiting were not scored by all databases). Haematological toxicity included leukopenia, thrombocytopenia and neutropenia.
Statistics
To study the association between study groups and severe gastrointestinal or haematological toxicity multivariable logistic regression models with grouped diagnosis as covariate were estimated. Gastrointestinal and haematological toxicity outcomes were dichotomised (grades 0─2 versus grades 3─5). Diagnoses were grouped according to tumour location, either pelvic or non-pelvic region (grouped diagnosis). Differences in baseline characteristics between study groups were tested using Pearson Chi-square or Kruskal Wallis tests. Owing to the retrospective character of this study, there was no protocol on how to deal with additional dose adjustments during treatment in the analysis. A Mann–Whitney U test was applied to compare duration of hospitalisation between DPYD variant allele carriers who received dose reductions or standard dosages. P-values of <0.05 were considered statistically significant. Statistical analyses were performed using SPSS (v23, Chicago, IL, USA).
Results
Study population
The combined database of 828 patients was divided into three study groups. Seven hundred seventy-one patients were wild-types, 34 patients were DPYD variant allele carriers who received standard fluoropyrimidine dosages in CRT and 23 patients were DPYD variant allele carriers who received upfront reduced (50 or 75%) fluoropyrimidine dosages in CRT. Baseline characteristics per database and study group are shown in Tables 1 and 2. Each original database included patients in each study group, described in Table 2. Cancer of the rectum was the most present in 71.7% of the patients. 86.6% of the patients received capecitabine. Baseline characteristics between study groups showed no significant differences.
In one DPYD *2A carrier, dose reductions were applied during treatment but not at the first drug administration. In three DPYD*2A carriers initial reduced dosages were increased during treatment. Three out of four patients had a total dose intensity of approximately 50% (according to current dosing guidelines). The fourth patient was excluded from statistical analyses. These four patients were described in Table 2.
Toxicity
Toxicity of patients from this study treated with comparable treatment schedules was similar to toxicity of rectal cancer patients described in literature (Supplementary Table 1). Differences in toxicity between databases were observed. Grade 2 radiation dermatitis and grade 2 ‘other toxicity’ were very high in the LUMC and CRO database, respectively, resulting in a high overall toxicity percentage in these databases (Supplementary Table 2). Toxicity separated per study group is shown in Table 3.
Percentages of severe gastrointestinal and haematological toxicity were 8 and 2.9% for wild-types, 17.6 and 11.8% for DPYD variant allele carriers treated with a standard dose,
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