Impact of Clinical and Pharmacogenetic Variables on the Risk of Fluoropyrimidine-Related Adverse Events within Ontario
Abstract
Severe life-threatening adverse events are a major limitation of fluoropyrimidine chemotherapy, these events are disastrous for patients and costly to the healthcare system. Identifying patients at high risk for developing adverse events would allow for preventive dose reduction, improving patient outcomes and reducing healthcare cost. This thesis uses data pulled from provincial databases to quantify the adverse event burden of fluoropyrimidines in Ontario. We found that 31% of Ontario patients treated with fluoropyrimidine systemic chemotherapy developed a severe adverse event that requires acute medical care. Patients that required acute medical therapy were significantly costlier to the public system averaging an increased cost of $16,754 (CAD). Therefore, there is a substantial potential to reduce cost to the health care system and pay for preventive screening strategies. A known risk factor for fluoropyrimidine adverse events is Dihydropyrimidine dehydrogenase (DPD, gene DPYD) deficiency. We demonstrate that screening for DPD deficiency through targeted genetic testing and genotype-guided dosing reduces the risk of adverse events in genetically deficient patients. Unfortunately, 31% of wildtype patients still experience a severe adverse event, requiring further research into predictors of adverse event risk. Following up on genetic variants, we tested for a recently described intrageneric DPYD deletion through a nested case-control study. We found the deletion associated with toxicity, however the variant was too rare to decide on the overall relevancy to clinical testing at this time. Next, we looked beyond genetics and tested the impact of plasma folate level on adverse event risk. Despite previous literature suggesting an association we found that plasma folate levels were not predictive of fluoropyrimidine adverse event risk. Therefore, there remains a significant number of unexplained fluoropyrimidine-related adverse events. In conclusion, while folate level did not show a predictive value, pharmacogenetic testing was found to be feasible and effective at reducing adverse events. To this end, we worked with Health Quality Ontario to translate these findings, pretreatment DPYD testing is now recommended to be a publicly funded test in Ontario.