Fluoropyrimidine-related toxicity in gastrointestinal cancer patients. Assessment of risk factors.

Background: Fluoropyrimidines (FPs) (5-fluorouracil and capecitabine) represent the backbone of many chemotherapy (CHT) regimens for the treatment (TX) of gastrointestinal (GI) cancers. However, a narrow therapeutic index characterizes these drugs. Major side effects are frequently observed, sometimes leading to patient (pt) death. Moreover, toxicity (tox) often implies TX discontinuation or delayed drug administration. A potential relationship between clinical and/or genetic (Gt) characteristics and the development of side effects during FP administration has been shown. The aim of our study was the identification of clinical, pathological and pharmacoGt factors related to the development of FP-related tox in a retrospective cohort. Patients and methods: 157 pts affected by GI neoplasms (colorectal and gastric cancers) treated with FP-based CHT (single agents or combinations mainly with platins) were included. FP-related tox was evaluated by NCI-CTCAE 4.03. Dihydropyrimidine dehydrogenase (DYPD) variants were analyzed by Sanger sequencing and TaqMan allelic discrimination assay. Statistical correlations were established by χ2 or Kruskall Wallis. All tests were performed by SPSS V.21 software. P < 0.05 was considered statistically significant. Results: The study of correlations between clinical, pathological factors and tox evidenced a relationship between development of tox (especially that occurring during the first three cycles) and gender (greater in females vs males), CHT regimen (greater in polyCHT vs monoCHT), and disease stage (greater in IV vs II-III stage). 83 pts (a cohort with baseline characteristics similar to the entire population) were genotyped for DYPD polymorphisms, including 3 nonfunctional DPYD variants related to FP tox (c.1905 + 1G > A, c.2846A > T and c.1679T > G) and the putative deleterious variant hapB3. A statistically significant association was observed between GI tox and DPYD c.1905 + 1G > A and c.2846A T polymorphisms. In particular, these polymorphisms were associated with grade ≥2 tox (p = 0.004 and p = 0.005, respectively). DPYD c.1905 + 1G> A was also correlated with asthenia (p = 0.001). Conclusions: Our results confirm the role of clinical and pathological factors (e.g. gender, CHT regimen, disease stage) in predicting the risk of tox. These factors in addition to the Gt analysis of DPYD variants (e.g. c.1905 + 1G > A, c.2846A > T and c.1679T > G), could help in the development of a predictive algorithm of tox in pts with GI cancer treated with FP-based CHT.