Cost effectiveness of DPYD genotyping to screen for dihydropyrimidine dehydrogenase (DPD) deficiency prior to adjuvant chemotherapy for colon cancer.

Abstract

55 Background: Fluoropyrimidine chemotherapy agents, including 5-fluorouracil and capecitabine, are the backbone of adjuvant treatment for colon cancer, and adjuvant chemotherapy substantially reduces recurrence and mortality after surgical resection of stage 3 colon cancer. While fluoropyrimidine chemotherapy is generally safe, the risk of severe, potentially fatal chemotherapy toxicity is substantially increased for the 2-3% of U.S. patients with DPD deficiency caused by pathogenic variants in the DPYD gene. DPYD genotype testing is readily available in the U.S. but has not been widely adopted. We evaluated the cost effectiveness of DPYD genotyping prior to adjuvant chemotherapy for colon cancer in the U.S. Methods: We constructed a Markov model to simulate screening for DPD deficiency with DPYD genotyping (versus no screening) among patients receiving fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer. Screen-positive patients were modeled to receive dose-reduced fluoropyrimidine chemotherapy. Model transition probabilities for treatment-related toxicities were derived from published clinical trial data with annotation of DPYD genotype and chemotherapy dosing strategy. Our analysis is from the healthcare perspective, with a time horizon of five years and an annual discount rate of 3% for future costs and benefits. Direct healthcare costs and health utilities were estimated from published sources and converted to 2020 US dollars, and post-treatment survival was modeled from SEER data. The primary outcome was the incremental cost-effectiveness ratio (ICER), defined as dollars per quality-adjusted life year (QALY). We used a value of $100,000/QALY as the cost-effectiveness threshold. One-way sensitivity analyses were used to examine model uncertainty. Results: Compared with no screening, screening for DPD deficiency with DPYD genotyping increased per-patient costs by $106 and improved quality-adjusted survival by 0.0028 QALYs, leading to an ICER of $37,300/QALY. In one-way sensitivity analyses, the ICER exceeded $100,000/QALY when the carrier frequency of pathogenic DPYD gene variants was less than 1.17%, and when the specificity of DPYD genotyping was less than 98.9%. Cost-effectiveness estimates were not sensitive to the cost of DPYD genotyping, the cost of toxicity-related hospitalizations, or the health utility associated with grade 3-4 toxicity. Conclusions: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe, sometimes fatal toxicities of fluoropyrimidine chemotherapy.

Impact of Granulocyte Colony-Stimulating Factor (G-CSF) on the Outcomes of Patients With Metastatic Pancreatic Adenocarcinoma (MPA) During First-Line Treatment With FOLFIRINOX: A Single-Center Retrospective Analysis

“…Patients with dihydropyrimidine dehydrogenase (DYPD) deficiency are at higher risk of hematological toxicities from FOLFIRINOX, including neutropenia. 38 Importantly, recent data suggest that the search for DPD deficiency in the setting of adjuvant treatment in colon cancer is cost-effective, 39 raising the question as to whether this would apply to other treatment scenarios. Likewise, patients with polymorphisms affecting the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) present increased toxicity when treated with FOLFIRINOX 38 and recent data suggest that irinotecan dose optimization based on UGT 1A1 genotyping might improve FOLFIRINOX safety profile.…”

Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation

“…Cost analyses of the two prospective trials on preemptive DPYD -guided fluoropyrimidine dosing in Europe showed that this strategy was at least cost-neutral after accounting for decreased healthcare utilization for chemotherapy-related toxicities [ 4 , 28 ]. Subsequent modeling studies using United States-based cost data demonstrated preemptive DPYD and UGT1A1 testing to be cost-effective in both the metastatic and adjuvant settings [ 29 , 30 ]. The United States Centers for Medicare and Medicaid Services recently posted a Local Coverage Determination to cover PGx testing for medications with known drug-gene interactions, and commercial insurers are beginning to follow suit [ 31 , 32 ].…”