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J Clin Oncol. 2016 Jan 20;34(3):227-34. doi: 10.1200/JCO.2015.63.1325. Epub 2015 Nov 16.

Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis.

Author information

1
Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands.
2
Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands. j.schellens@nki.nl.

Abstract

PURPOSE:

Fluoropyrimidines are frequently prescribed anticancer drugs. A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase (DPD; ie, DPYD*2A) is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. This study determined the feasibility, safety, and cost of DPYD*2A genotype-guided dosing.

PATIENTS AND METHODS:

Patients intended to be treated with fluoropyrimidine-based chemotherapy were prospectively genotyped for DPYD*2A before start of therapy. Variant allele carriers received an initial dose reduction of ≥ 50% followed by dose titration based on tolerance. Toxicity was the primary end point and was compared with historical controls (ie, DPYD*2A variant allele carriers receiving standard dose described in literature) and with DPYD*2A wild-type patients treated with the standard dose in this study. Secondary end points included a model-based cost analysis, as well as pharmacokinetic and DPD enzyme activity analyses.

RESULTS:

A total of 2,038 patients were prospectively screened for DPYD*2A, of whom 22 (1.1%) were heterozygous polymorphic. DPYD*2A variant allele carriers were treated with a median dose-intensity of 48% (range, 17% to 91%). The risk of grade ≥ 3 toxicity was thereby significantly reduced from 73% (95% CI, 58% to 85%) in historical controls (n = 48) to 28% (95% CI, 10% to 53%) by genotype-guided dosing (P < .001); drug-induced death was reduced from 10% to 0%. Adequate treatment of genotype-guided dosing was further demonstrated by a similar incidence of grade ≥ 3 toxicity compared with wild-type patients receiving the standard dose (23%; P = .64) and by similar systemic fluorouracil (active drug) exposure. Furthermore, average total treatment cost per patient was lower for screening (€2,772 [$3,767]) than for nonscreening (€2,817 [$3,828]), outweighing screening costs.

CONCLUSION:

DPYD*2A is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. DPYD*2A genotype-guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient. On a population level, upfront genotyping seemed cost saving.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00838370.

PMID:
26573078
DOI:
10.1200/JCO.2015.63.1325
[Indexed for MEDLINE]

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