Gastrointestinal (GI) malignancies are among the most commonly diagnosed cancers worldwide. Despite the introduction of targeted and immunotherapy agents in the treatment landscape, cytotoxic agents, such as fluoropyrimidines and irinotecan, remain as the cornerstone of chemotherapy for many of these tumors. Pharmacogenetics (PGx) is a rapidly evolving field that accounts for interpatient variability in drug metabolism to predict therapeutic response and toxicity. Given the significant incidence of severe treatment-related adverse events associated with cytotoxic agents, utilizing PGx can allow clinicians to better anticipate drug tolerability while minimizing treatment interruptions or delays. In this review, the PGx profiles of drug-gene pairs with potential impact in GI malignancy therapy-DPYD-5-fluorouracil/capecitabine and UGT1A1-irinotecanand the available clinical evidence of their roles in reducing severe adverse events are discussed. Considerations for clinical implementation, such as optimal laboratory workflows, electronic health record integration, and stakeholder engagement, as well as provider education, are addressed. Last, exploratory PGx markers in GI malignancy treatment are described. As the PGx knowledge base rapidly evolves, pharmacists will be vital in leveraging their pharmacology knowledge and clinical skills to implement PGx testing in the clinic.

Background Pharmacogenetic (PGx) testing for germline variants in the DPYD and UGT1A1 genes can be used to guide fluoropyrimidine and irinotecan dosing, respectively. Despite the known association between PGx variants and chemotherapy toxicity, preemptive testing prior to chemotherapy initiation is rarely performed in routine practice. Methods We conducted a qualitative study of oncology clinicians to identify barriers to using preemptive PGx testing to guide chemotherapy dosing in patients with gastrointestinal malignancies. Each participant completed a semi-structured interview informed by the Consolidated Framework for Implementation Research (CFIR). Interviews were analyzed using an inductive content analysis approach. Results Participants included sixteen medical oncologists and nine oncology pharmacists from one academic medical center and two community hospitals in Pennsylvania. Barriers to the use of preemptive PGx testing to guide chemotherapy dosing mapped to four CFIR domains: intervention characteristics, outer setting, inner setting, and characteristics of individuals. The most prominent themes included 1) a limited evidence base, 2) a cumbersome and lengthy testing process, and 3) a lack of insurance coverage for preemptive PGx testing. Additional barriers included clinician lack of knowledge, difficulty remembering to order PGx testing for eligible patients, challenges with PGx test interpretation, a questionable impact of preemptive PGx testing on clinical care, and a lack of alternative therapeutic options for some patients found to have actionable PGx variants. Conclusions Successful adoption of preemptive PGx-guided chemotherapy dosing in patients with gastrointestinal malignancies will require a multifaceted effort to demonstrate clinical effectiveness while addressing the contextual factors identified in this study.

BackgroundFluoropyrimidines (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.MethodsThe 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.ConclusionWe 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 Registrationhttps://clinicaltrials.gov/ct2/show/NCT04736472, identifier [NCT04736472].

Background: Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer, second to death caused by cancer itself. Guidelines from the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) support the use of low molecular weight heparin (LMWH) and vitamin K antagonists (VKA) for treatment of VTE in cancer patients. The novel oral anticoagulants (NOACs) are increasingly being used for all types of VTE, but their safety and efficacy in cancer-associated VTE has not been established. In the CLOT trial of LMWH in cancer-associated VTE, the rate of recurrent VTE was 9.0%, compared to 5.1% among the subgroup of cancer patients who received rivaroxaban in the EINSTEIN trial; bleeding rates among cancer patients in the CLOT and EINSTEIN trials were 14% and 15.2%, respectively. Due to a paucity of data, at this point neither the NCCN nor ASCO supports the use of NOACs for treatment of cancer-associated VTE. Objective: Evaluate the efficacy and safety of NOACs in cancer-associated VTE. Methods: We performed a retrospective chart review of all patients with a diagnosis of active malignancy who received a prescription for a NOAC for treatment of VTE at Yale Cancer Center between February 1, 2012, and December 31, 2014. Patients with a heritable thrombophilia or bleeding disorder were excluded. Data collected included patient demographics, body mass index (BMI), cancer type and stage, type of VTE event (deep venous thrombosis (DVT), pulmonary embolism (PE), or both), type of NOAC, compliance with NOAC therapy, appropriate NOAC dose, and potential drug-drug interactions (DDI) with NOACs. Primary outcomes were recurrent VTE, defined as the finding of new or progressive DVT or PE on imaging with or without symptoms, and clinically relevant bleeding (CRB), defined as a decrease in hemoglobin of at least 2 g/dL in a 24-hour period, a requirement for red blood cell transfusion, any critical site bleeding event, or any type of bleeding event requiring increased physician monitoring. Fisher's exact test was used to calculate p-values where appropriate. Results: 75 patients met inclusion criteria; rivaroxaban was the only NOAC used in all cases. The incidence of recurrent VTE and CRB was 7.0% (n = 5) and 25.3% (n = 19), respectively. There were two fatal events, one due to recurrent VTE and one due to major gastrointestinal bleed; in neither case was NOAC compliance, dosing, or DDIs implicated in the fatality. Over half (n = 39) of all study patients were on a concomitant medication with a known DDI with NOAC therapy; the most common such agents were ciprofloxacin, fluconazole, azithromycin and voriconazole. In only one of the 80 DDI cases was anticoagulation therapy changed. NOAC dosing was inappropriate in 20 instances, mostly due to patients not receiving the recommended loading dose prior to beginning maintenance dosing. Among the 19 occurrences of CRB, advanced stage solid tumor emerged as a statistically significant (p = 0.0151) risk factor for bleeding while on rivaroxaban. Conclusion: Treatment of cancer-associated VTE with NOAC therapy is effective, but the risk of bleeding in our cohort was higher than in other published studies. Patients with advanced stage solid tumors may be at a particularly high risk of bleeding. Prescriber practices with NOACs may require modification based on high utilization of concomitant medications with DDIs and failure to prescribe appropriate loading doses of NOACs in treatment of VTE. Disclosures No relevant conflicts of interest to declare.

Chemotherapy, and now targeted therapies and immunotherapies, are widely used for the management of patients with all stages of lung cancer. Some challenges present when patients are receiving concomitant hemodialysis for various comorbid conditions. However, this should not immediately rule out a patient for treatment. Many drugs may be safely given to patients who are receiving hemodialysis with the proper dosing schedule and careful monitoring. This article will outline the current literature surrounding the use of these drugs in patients undergoing active hemodialysis while being treated for lung cancer.