Implementing Pharmacogenetic Testing in Gastrointestinal Cancers (IMPACT-GI): Study Protocol for a Pragmatic Implementation Trial for Establishing DPYD and UGT1A1 Screening to Guide Chemotherapy Dosing

Abstract

Background: Fluoropyrimidines (fluorouracil [5-FU], capecitabine) and irinotecan are commonly prescribed chemotherapy agents for gastrointestinal (GI) malignancies. Pharmacogenetic (PGx) testing for germline DPYD and UGT1A1 variants associated with reduced enzyme activity holds the potential to identify patients at high risk for severe chemotherapy-induced toxicity. Slow adoption of PGx testing in routine clinical care is due to implementation barriers, including long test turnaround times, lack of integration in the electronic health record (EHR), and ambiguity in test cost coverage. We sought to establish PGx testing in our health system following the Exploration, Preparation, Implementation, Sustainment (EPIS) framework as a guide. Our implementation study aims to address barriers to PGx testing.

Methods: The Implementing Pharmacogenetic Testing in Gastrointestinal Cancers (IMPACT-GI) study is a non-randomized, pragmatic, open-label implementation study at three sites within a major academic health system. Eligible patients with a GI malignancy indicated for treatment with 5-FU, capecitabine, or irinotecan will undergo PGx testing prior to chemotherapy initiation. Specimens will be sent to an academic clinical laboratory followed by return of results in the EHR with appropriate clinical decision support for the care team. We hypothesize that the availability of a rapid turnaround PGx test with specific dosing recommendations will increase PGx test utilization to guide pharmacotherapy decisions and improve patient safety outcomes. Primary implementation endpoints are feasibility, fidelity, and penetrance. Exploratory analyses for clinical effectiveness of genotyping will include assessing grade ≥3 treatment-related toxicity using available clinical data, patient-reported outcomes, and quality of life measures.

Conclusion: We describe the formative work conducted to prepare our health system for DPYD and UGT1A1 testing. Our prospective implementation study will evaluate the clinical implementation of this testing program and create the infrastructure necessary to ensure sustainability of PGx testing in our health system. The results of this study may help other institutions interested in implementing PGx testing in oncology care.

Clinical trial registration: https://ichgcp.net/clinical-trials-registry/NCT04736472, identifier [NCT04736472].

Keywords: DPYD; UGT1A1; cancer; chemotherapy; implementation science; pharmacogenetics; pragmatic trial; toxicity.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Varughese, Bhupathiraju, Hoffecker, Terek, Harr, Hakonarson, Cambareri, Marini, Landgraf, Chen, Kanter, Lau-Min, Massa, Damjanov, Reddy, Oyer, Teitelbaum and Tuteja.

Figures

Figure 1

Exploration, Preparation, Implementation, Sustainment (EPIS) framework used as a guide for implementing DPYD/UGT1A1 pharmacogenetic testing. EHR, electronic health record; PGx, pharmacogenomics; CDS, clinical decision support; QC/QI, quality control/quality improvement.

Figure 2

Discrete DPYD/UGT1A1 genotype results in a patient chart.

Figure 3

In-line warning at fluorouracil order entry informing provider of actionable DPYD results, clinical implication, and dose recommendation. © 2021 Epic Systems Corporation

Figure 4

Study schema for the IMPACT-GI study. (1) Patient provides informed consent at initial evaluation (baseline) visit in the gastrointestinal oncology clinic. (2) A laboratory order for pharmacogenetic testing is placed in the EHR. (3) A specimen is collected alongside routine laboratory collections by phlebotomy. (4) The specimen is sent to an external CLIA laboratory for genotyping and report generation. (5) Pharmacogenetic results are entered by the institutional lab into the precision medicine section of the EHR as discrete result components. (6a) When the care team signs and verifies chemotherapy orders, (6b) an alert indicating increased toxicity risk appears in the patient’s chart for individuals with actionable results. Clinical decision support provides recommendations for dose adjustments. (7) Following order verification, chemotherapy is prepared and dispensed to the patient in the oncology infusion suite. Fidelity is demonstrated when the prescriber adjusts dosing according to the patient’s genotype. Adverse event data is collected for the first six cycles of treatment. Patients complete a symptom questionnaire at each of these cycles and a one-time survey assessing attitudes towards pharmacogenetic testing after receiving at least two cycles. Tumor outcomes (progression-free survival, overall survival) are assessed at approximately six months following treatment initiation.