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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Kim, Richard B.

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.

Summary for Lay Audience

Fluoropyrimidines are a class of widely used chemotherapy drugs; however, they cause significant side effects which can be lethal and occur in up to one in three patients. This thesis discusses the use of fluoropyrimidines in Ontario and investigates methods to reduce the number of severe side effects experienced by patients. A known risk factor for fluoropyrimidine side effects is deficiency of the key enzyme that degrades the drug; patients with the deficiency are exposed to higher drug levels and more side effects. In chapter 2 we found targeted screening for this genetic deficiency is an effective way to protect some patients from experiencing toxic outcomes. Chapter 3 tested for the presence of a newly described deficiency causing variant. We found that a patient carrying the novel variant experienced severe side-effects and required a reduced dose of fluoropyrimidines. However, the variant was rare and the overall utility at the provincial level remains uncertain. Chapter 4 investigated whether the environmental risk factor of dietary folate intake could improve the prediction of fluoropyrimidine side effect risk. We measured plasma folate levels in a sample of genetically competent patients and tested for an association between plasma folate level and fluoropyrimidine side effects. We found that plasma folate level had no impact on the risk for severe side effects, but did notice that other clinical characteristics such as the patients’ sex were predictive of their risk. Finally, Chapter 5 places the previous work into the larger context by directly assessing the health care burden of fluoropyrimidine use in Ontario. We found that 31% of fluoropyrimidine treated patients require emergency medical care due to severe side effects. Patients that were forced to receive fluoropyrimidine-related emergency medical treatment were significantly costlier to the health care system than those patients that did not. Combining the results of chapters 2 and 5 allowed for a convincing argument for knowledge translation at the policy level. Our work has now been used to support recommendations that Ontario publicly fund genetic testing prior to fluoropyrimidine chemotherapy. This is a significant advancement for the field and patient safety.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Available for download on Tuesday, August 01, 2023

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