Abstract
Background
Adjuvant fluoropyrimidine-based chemotherapy substantially reduces recurrence and
mortality after resection of stage 3 colon cancer. While standard doses of 5-fluorouracil
and capecitabine are safe for most patients, the risk of severe toxicity is increased
for the approximately 6% of patients with dihydropyimidine dehydrogenase (DPD) deficiency
caused by pathogenic DPYD gene variants. Pre-treatment screening for pathogenic DPYD gene variants reduces severe toxicity but has not been widely adopted in the United
States.
Methods
We conducted a cost-effectiveness analysis of DPYD genotyping prior to fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon
cancer, covering the c.1129-5923C>G (HapB3), c.1679T>G (*13), c.1905+1G>A (*2A), and
c.2846A>T gene variants. We used a Markov model with a 5-year horizon, taking a United
States healthcare perspective. Simulated patients with pathogenic DPYD gene variants received reduced-dose fluoropyrimidine chemotherapy. The primary outcome
was the incremental cost-effectiveness ratio (ICER) for DPYD genotyping.
Results
Compared with no screening for DPD deficiency, DPYD genotyping increased per-patient costs by $78 and improved survival by 0.0038 quality-adjusted
life years (QALYs), leading to an ICER of $20,506/QALY. In 1-way sensitivity analyses,
The ICER exceeded $50,000 per QALY when the cost of the DPYD genotyping assay was greater than $286. In probabilistic sensitivity analysis using
a willingness-to-pay threshold of $50,000/QALY DPYD genotyping was preferred to no screening in 96.2% of iterations.
Conclusion
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 and
sometimes fatal toxicities of fluoropyrimidine chemotherapy.
Keywords
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References
- Adjuvant chemotherapy for stage II and III colon cancer following complete resection: a cancer care ontario systematic review.Clin Oncol (R Coll Radiol). 2017; 29: 459-465
- All you need to know about DPYD genetic testing for patients treated with fluorouracil and capecitabine: a practitioner-friendly guide.JCO Oncol Pract. 2020; 16: 793-798
- Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.N Engl J Med. 2004; 350: 2343-2351
- Duration of adjuvant chemotherapy for stage III colon cancer.N Engl J Med. 2018; 378: 1177-1188
- DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147).J Natl Cancer Inst. 2014; 106
- DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis.Pharmacogenomics. 2013; 14: 1255-1272
- Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis.J Clin Oncol. 2014; 32: 1031-1039
- Upfront genotyping of DPYD*2A to individualize fluoropyrimidine therapy: a safety and cost analysis.J Clin Oncol. 2016; 34: 227-234
- Pathogenic DPYD variants and treatment-related mortality in patients receiving fluoropyrimidine chemotherapy: a systematic review and meta-analysis.Oncologist. 2021; 26: 1008-1016
- Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil.Eur J Cancer. 2004; 40: 939-950
- Increased prevalence of dihydropyrimidine dehydrogenase deficiency in African-Americans compared with Caucasians.Clin Cancer Res. 2006; 12: 5491-5495
- Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity.Br J Cancer. 2017; 116: 1415-1424
- DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis.Lancet Oncol. 2018; 19: 1459-1467
- Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: assessment of a multiparametric approach.Semin Oncol. 2017; 44: 13-23
- Prospective DPYD genotyping to reduce the risk of fluoropyrimidine-induced severe toxicity: ready for prime time.Eur J Cancer. 2016; 54: 40-48
- Consolidated Health Economic Evaluation Reporting Standards (CHEERS)–explanation and elaboration: a report of the ISPOR Health Economic Evaluation Publication Guidelines Good Reporting Practices Task Force.Value Health. 2013; 16: 231-250
- Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance).Pharmacogenet Genomics. 2016; 26: 133-137
ARUP Laboratories. Dihydropyrimidine Dehydrogenase (DPYD), 3 Variants. Vol 2021.
- The genotype for DPYD risk variants in patients with colorectal cancer and the related toxicity management costs in clinical practice.Clin Pharmacol Ther. 2019; 105: 994-1002
- SEER*Stat Database: Incidence - SEER 18 Regs Custom Data (with additional treatment fields), Nov 2018 Sub (2000-2016) <Katrina/Rita Population Adjustment>- Linked To County Attributes - Total U.S., 1969-2017 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released April 2019, based on the November 2018 submission.National Cancer Institute, Bethesda, MD2019
- Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators.Lancet. 1995; 345: 939-944
- Preference values associated with stage III colon cancer and adjuvant chemotherapy.Qual Life Res. 2010; 19: 391-400
- Quality of life in survivors of colorectal carcinoma.Cancer. 2000; 88: 1294-1303
CMS.gov: Clinical Laboratory Fee Schedule Files. Vol 2021.
- Inpatient hospitalization costs associated with nausea and vomiting among patients with cancer.J Clin Oncol. 2018; : 152
- Projections of the cost of cancer care in the United States: 2010-2020.J Natl Cancer Inst. 2011; 103: 117-128
- Adjusting health expenditures for inflation: a review of measures for health services research in the United States.Health Serv Res. 2018; 53: 175-196
- Cost-effectiveness of cetuximab as first-line treatment for metastatic colorectal cancer in the United States.Am J Clin Oncol. 2018; 41: 65-72
- Bevacizumab for metastatic colorectal cancer: a global cost-effectiveness analysis.Oncologist. 2017; 22: 694-699
- Cost-effectiveness of maintenance capecitabine and bevacizumab for metastatic colorectal cancer.JAMA Oncol. 2019; 5: 236-242
- A cost analysis of upfront DPYD genotype-guided dose individualisation in fluoropyrimidine-based anticancer therapy.Eur J Cancer. 2019; 107: 60-67
- Cost implications of reactive versus prospective testing for dihydropyrimidine dehydrogenase deficiency in patients with colorectal cancer: a single-institution experience.Dose Response. 2018; 161559325818803042
- DPYD genotyping in patients who have planned cancer treatment with fluoropyrimidines: a health technology assessment.Ont Health Technol Assess Ser. 2021; 21: 1-186
- Cost-effectiveness of screening for DPYD polymorphisms to prevent neutropenia in cancer patients treated with fluoropyrimidines.Pharmacogenomics. 2016; 17: 979-984
- Integrating somatic and germline next-generation sequencing into routine clinical oncology practice.JCO Precis Oncol. 2021; : 884-895
European Medicines Agency. 5-Fluorouracil (i.v.), capecitabine and tegafur containing products: Pre-treatment testing to identify DPD-deficient patients at increased risk of severe toxicity. Vol 2021.
- Potential Impact of DPYD Variation on Fluoropyrimidine Drug Response in sub-Saharan African Populations.Front Genet. 2021; 12626954
Article Info
Publication History
Published online: May 11, 2022
Accepted:
May 6,
2022
Received in revised form:
April 29,
2022
Received:
February 7,
2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
