Thesis Format
Integrated Article
Degree
Master of Science
Program
Epidemiology and Biostatistics
Supervisor
Sarma, Sisira K.
2nd Supervisor
Schwarz, Ute I.
Co-Supervisor
Abstract
Colorectal cancer patients receiving fluoropyrimidine-based chemotherapy are at risk of experiencing treatment-related adverse events (AEs), and mortality. The risk is increased for patients with reduced dihydropyrimidine dehydrogenase activity due to impaired-function variants in the DPYD gene. DPYD genotype-guided treatment has been shown to reduce treatment-related AEs and corresponding costs through the administration of lower doses for DPYD variant carriers. This thesis compared clinical and economic outcomes between DPYD genotype-guided patients and standard-of-care patients derived from historic and contemporaneous control groups using health administrative data from Ontario, Canada. There were no differences in toxicity prevalence, or cancer-related mortality between the DPYD genotype-guided group and most control groups following inverse probability weighting. The DPYD genotype-guided group had a $5,241 reduction in per-patient cancer costs when compared with the historic control, but a $1,401 - $1,530 increase when compared with the contemporaneous controls. Future research is suggested to better understand the mixed results.
Summary for Lay Audience
Colorectal cancer was the fourth most common cancer in Canada and the second leading cause of cancer-related death among Canadians in 2024. Fluoropyrimidines are commonly used chemotherapy drugs for the treatment of colorectal cancer, including 5-fluorouracil and capecitabine. The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for breaking down 5-fluorouracil.
Published international guidelines identified four rare differences or variants in the DPYD gene that decrease DPD activity, leading to the accumulation of 5-fluorouracil in the body. This buildup can cause severe adverse events (AEs) or deaths. To reduce this risk, adjusting fluoropyrimidine dosages based on an individual’s DPYD variant is recommended. Recent Canadian and international studies have demonstrated both the clinical effectiveness and economic benefits of adopting DPYD genotype-guided treatment over the standard-of-care. However, it remains uncertain whether DPYD genotype-guided treatment offers similar benefits at the population level in Ontario, Canada.
This thesis assessed differences in the clinical (e.g., frequency of AEs) and economic (e.g., AE-related costs) outcomes of colorectal cancer patients who received DPYD genotype-guided treatment compared with those who received standard-of-care treatment between 2012-2019. The standard-of-care patients consisted of one historical control group (i.e., patients from London, Ontario between 2012-2013) and two contemporaneous control groups (i.e., patients from the rest of Ontario between 2014-2019). Differences between the treatment and control groups were analyzed using doubly robust inverse probability treatment weighting estimators.
The results revealed no significant difference in the number or frequency of AEs or in cancer-related death between the DPYD genotype-guided treatment group and the control groups, except in a few specific cases. Compared with the historical control group, patients who received the DPYD genotype-guided treatment had a $5,241 reduction in per-patient cancer costs. However, compared with the contemporaneous control groups, the DPYD genotype-guided patients had $2,571 - $3,346 higher per-patient total healthcare costs. Most of this increase came from a $1,401 - $1,530 increase in per-patient cancer costs among the DPYD genotype-guided group when compared with the contemporaneous control groups. Differences in toxicity reporting, patient and clinician treatment adherence, and potential unmeasured confounders are likely to account for the mixed results.
Recommended Citation
Vasa, Tanmay H., "Quantifying the Clinical and Economic Consequences of DPYD Genotype-Guided Fluoropyrimidine Dosing in Colorectal Cancer Patients: A Case Study from Ontario, Canada" (2025). Electronic Thesis and Dissertation Repository. 10888.
https://ir.lib.uwo.ca/etd/10888
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