DPYD Genotyping in Patients Who Have Planned Cancer Treatment With Fluoropyrimidines: A Health Technology Assessment.

Abstract

Background: Fluoropyrimidine drugs (such as 5-fluorouracil and capecitabine) are used to treat different types of cancer. However, these drugs may cause severe toxicity in about 10% to 40% of patients. A deficiency in the dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by the DPYD gene, increases the risk of severe toxicity. DPYD genotyping aims to identify variants that lead to DPD deficiency and may help to identify people who are at higher risk of developing severe toxicity, allowing their treatment to be modified before it begins. Recommendations for fluoropyrimidine treatment modification are available for four DPYD variants, which are the focus of this review: DPYD∗2A, DPYD∗13, c.2846A>T, and c.1236G>A. We conducted a health technology assessment of DPYD genotyping for patients who have planned cancer treatment with fluoropyrimidines, which included an evaluation of clinical validity, clinical utility, the effectiveness of treatment with a reduced fluoropyrimidine dose, cost-effectiveness, the budget impact of publicly funding DPYD genotyping, and patient preferences and values.

Methods: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included systematic review and primary study using the Risk of Bias in Systematic Reviews (ROBIS) tool and the Newcastle-Ottawa Scale, respectively, and we assessed the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature review and conducted cost-effectiveness and cost-utility analyses with a half-year time horizon from a public payer perspective. We also analyzed the budget impact of publicly funding pre-treatment DPYD genotyping in patients with planned fluoropyrimidine treatment in Ontario. To contextualize the potential value of DPYD testing, we spoke with people who had planned cancer treatment with fluoropyrimidines.

Results: We included 29 observational studies in the clinical evidence review, 25 of which compared the risk of severe toxicity in carriers of a DPYD variant treated with a standard fluoropyrimidine dose with the risk in wild-type patients (i.e., non-carriers of the variants under assessment). Heterozygous carriers of a DPYD variant treated with a standard fluoropyrimidine dose may have a higher risk of severe toxicity, dose reduction, treatment discontinuation, and hospitalization compared to wild-type patients (GRADE: Low). Six studies evaluated the risk of severe toxicity in DPYD carriers treated with a genotype-guided reduced fluoropyrimidine dose versus the risk in wild-type patients; one study also included a second comparator group of DPYD carriers treated with a standard dose. The evidence was uncertain, because the results of most of these studies were imprecise (GRADE: Very low). The length of hospital stay was shorter in DPYD carriers treated with a reduced dose than in DPYD carriers treated with a standard dose, but the evidence was uncertain (GRADE: Very low). One study assessed the effectiveness of a genotype-guided reduced fluoropyrimidine dose in DPYD∗2A carriers versus wild-type patients, but the results were imprecise (GRADE: Very low).We found two cost-minimization analyses that compared the costs of the DPYD genotyping strategy with usual care (no testing) in the economic literature review. Both studies found that DPYD genotyping was cost-saving compared to usual care. Our primary economic evaluation, a cost-utility analysis, found that DPYD genotyping might be slightly more effective (incremental quality-adjusted life years of 0.0011) and less costly than usual care (a savings of $144.88 per patient), with some uncertainty. The probability of DPYD genotyping being cost-effective compared to usual care was 91% and 96% at the commonly used willingness-to-pay values of $50,000 and $100,000 per quality-adjusted life-year gained, respectively. Assuming a slow uptake, we estimated that publicly funding pre-treatment DPYD genotyping in Ontario would lead to a savings of $714,963 over the next 5 years.The participants we spoke to had been diagnosed with cancer and treated with fluoropyrimidines. They reported on the negative side effects of their treatment, which affected their day-to-day activities, employment, and mental health. Participants viewed DPYD testing as a beneficial addition to their treatment journey; they noted the importance of having all available information possible so they could make informed decisions to avoid adverse reactions. Barriers to DPYD testing include lack of awareness of the test and the fact that the test is being offered in only one hospital in Ontario.

Conclusions: Studies found that carriers of a DPYD variant who were treated with a standard fluoropyrimidine dose may have a higher risk of severe toxicity than wild-type patients treated with a standard dose. DPYD genotyping led to fluoropyrimidine treatment modifications. It is uncertain whether genotype-guided dose reduction in heterozygous DPYD carriers resulted in a risk of severe toxicity comparable to that of wild-type patients. It is also uncertain if the reduced dose resulted in a lower risk of severe toxicity compared to DPYD carriers treated with a standard dose. It is also uncertain whether the treatment effectiveness of a reduced dose in carriers was comparable to the effectiveness of a standard dose in wild-type patients.For patients with planned cancer treatment with fluoropyrimidines, DPYD genotyping is likely cost-effective compared to usual care. We estimate that publicly funding DPYD genotyping in Ontario may be cost-saving, with an estimated total of $714,963 over the next 5 years, provided that the implementation, service delivery, and program coordination costs do not exceed this amount.For people treated with fluoropyrimidines, cancer and treatment side effects had a substantial negative effect on their quality of life and mental health. Most saw the value of DPYD testing as a way of reducing the risk of serious adverse events. Barriers to receipt of DPYD genotyping included lack of awareness and limited access to DPYD testing.