Fluoropyrimidine Chemotherapy Research Articles

Upfront Oxaliplatin–Fluoropyrimidine Chemotherapy and Somatostatin Analogues in Advanced Well-Differentiated Gastro-Entero-Pancreatic Neuroendocrine Tumors

(1) Background: GEP-NETs are frequently diagnosed at advanced stage. For well-differentiated somatostatin receptor-positive (SSTR+) NETs, SSA are the preferred first-line therapy. However, in newly diagnosed patients with G2/G3 and a high tumor burden, SSA alone might not be enough; (2) Methods: We conducted a retrospective analysis to assess the effectiveness of combining oxaliplatin–fluoropyrimidine chemotherapy with SSA as an upfront strategy in newly diagnosed metastatic G2/G3 GEP-NET patients treated with oxaliplatin–fluoropyrimidine-based chemotherapy; (3) Results: Between March 2017 and October 2023, 32 pts (19 males, 13 females; M:F = 1.5:1; median age 54 years, range 31–82) were deemed eligible to receive oxaliplatin–fluoropyrimidine chemotherapy in addition to SSA; 14 received XELOX and 18 FOLFOX. After a median follow-up of 26 mo., each patient had completed at least two cycles of chemotherapy. The ORR was 25%, with a median DoR of 21.3 mo. The DCR was 87.5%. Notably, 28.1% of patients experienced tumor shrinkage sufficient for radical surgery on residual tumor lesions, encompassing both primary tumors and metastases; (4) Conclusions: Upfront treatment with the combination of oxaliplatin–fluoropyrimidine and SSA demonstrated effectiveness and safety. This approach may be considered to facilitate conversion surgery in eligible patients.

Oral probiotic supplementation to alleviate diarrhea induced by fluoropyrimidines or irinotecan-based chemotherapy: A systematic review and meta-analysis.

Oral probiotic supplementation to alleviate diarrhea induced by fluoropyrimidines or irinotecan-based chemotherapy: A systematic review and meta-analysis.

Implementation of mass pharmacogenetic testing: Dihydropyrimidine dehydrogenase testing prior to fluoropyrimidine treatment for patients.

Pharmacogenomics enables personalization of drug therapy improving effectiveness and/or safety. Dihydropyrimidine dehydrogenase [DPYD] testing prior to fluoropyrimidine chemotherapy was commissioned by NHS England in response to an update from the Medicines and Healthcare products Regulatory Agency. A questionnaire developed and approved by the National DPYD Working Group investigated processes of testing, receiving and responding to results. The survey was distributed to Genomics Medicine Service Alliance (GMSA) Clinical Directors and Pharmacy Senior Responsible Officers for dissemination in their geography. Data were collected June-September 2021. All hospitals delivering fluoropyrimidines across the UK were invited to participate. 131/138 (94.9%) organizations reported testing all patients receiving fluoropyrimidines. In England 76.7% of hospitals sent samples to centrally commissioned genomics laboratories. In the devolved nations, 73.9% sent samples to regional genomics laboratories. Multidisciplinary staff including oncologists, independent non-medical prescribers, clinical nurse specialists, screening pharmacists and chemotherapy nurses requested the test, checked and actioned the result. Self-reported turnaround times varied from <2days where a regional laboratory was colocated with a chemotherapy centre to >10days. Through multiprofessional, national collaboration, this is the first report studying the large-scale rollout of a nationally commissioned pharmacogenetic test. Whilst DPYD testing has been successfully implemented, there is a need to standardize and improve end-to-end turnaround times. This has led to the development of a best practice pathway. Critically, GMSAs must build on this implementation to deliver its priorities, in supporting equitable access to future pharmacogenomic testing across a wider cohort of therapies.

Implementing DPYD genotyping to predict chemotherapy toxicity in Australia: a feasibility study.

Implementing pharmacogenomic-guided management in cancer patients equitably and effectively in a large population presents challenges. DPYD genotyping determines clinically significant variants of patients at increased risk of developing grade3-5 fluoropyrimidine (FP) toxicity. FP chemotherapies are prescribed for ~16,000 Australians with a 10%-40% grade3-4 toxicity incidence and 1% mortality. Variant carriers can have FP dosing adjusted to improve treatment tolerance without compromising anticancer effect. This strategy has not been formally adopted within Australia, despite widespread international standardisation. This pilot study determined genotyping turnaround-times (TAT) for 4 DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/Haplotype B3) in Australian patients. Secondary objectives were identification of FP toxicities of DPYD variant carriers, and analysis of healthcare stakeholder perspectives, including enablers/barriers to implementation. Genotyping was determined by Real-Time Polymerase Chain Reaction. Qualitative data were determined through semi-structured questionnaire. 104 patients recruited over 24 months had a mean TAT of 7.2 days, 5.2 business days (range 1-30). Grade3-4 toxicity occurred in 9/16 DPYD variant carriers, including 2 ICU admissions and 1 death. Themes from 30 questionnaire respondents suggest that clinical environment and resources were fundamental barriers, and motivation to improve patient care was the predominant enabler of change. DPYD genotyping is feasible for improving precision-oncology for patients requiring FP chemotherapies. A TAT of 7 days is acceptable by both stakeholder respondents and national oncology clinician groups. This pilot study, although small, informs a large national project evaluating prospective DPYD genotyping and its impact on FP tolerability, patient safety and cost-effectiveness in Australia.

Fluoropyrimidine Chemotherapy and the Risk of Death and Cardiovascular Events in Patients With Gastrointestinal Cancer.

Fluoropyrimidine Chemotherapy and the Risk of Death and Cardiovascular Events in Patients With Gastrointestinal Cancer.

Blood TCTP as a potential biomarker associated with immunosuppressive features and poor clinical outcomes in metastatic gastric cancer

BackgroundNo established biomarker exists for specific myeloid cell populations or in gastric cancer. This study aimed to explore the prognostic and immunological relevance of plasma translationally controlled tumor protein (TCTP)...

Severe fluoropyrimidine toxicity in older adults with cancer with DPYD wild type.

Despite the implementation of DPYD genotype-guided dosing, approximately 1 in 3 patients receiving fluoropyrimidine-containing chemotherapy continues to experience severe toxicity. While clinical studies have demonstrated a favorable tolerance among highly selected fit older adults, real-world studies have shown an increased risk of toxicity. To identify predictors of severe toxicity or treatment deintensification in older DPYD wild-type adults receiving fluoropyrimidine-containing chemotherapy. Patients wild type for four tested DPYD variants, aged ≥65 years, who participated in a prospective clinical trial investigating genotype-guided individualized fluoropyrimidine dosing, were eligible for the study. The association between tumor-, treatment-, and patient-related characteristics and the occurrence of severe toxicity (grade ≥3, CTCAE v5.0) was analyzed in univariate and multivariate logistic regression analyses. The same analyses were performed for a composite endpoint of severe toxicity or treatment deintensification (including dose reduction, cycle delay, or discontinuation). A total of 311 patients were included. Median age was 71.2years and 58.8% were male. Grade ≥3 toxicity occurred in 23.2% of patients. In multivariate analysis, none of the characteristics studied were significantly associated with the occurrence of grade ≥3 toxicity. The composite endpoint occurred in 41.2% of patients and was associated with the use of full dose monotherapy in multivariate analysis. Despite DPYD genotype-based dosing, grade ≥3 toxicity and treatment deintensification frequently occur in older patients treated with fluoropyrimidine chemotherapy. No patient-related variables were found to be associated with grade ≥3 toxicity, but treatment with dose-reduced monotherapy resulted in fewer treatment deintensification or severe toxicity events.

Retrospective study of fluoropyrimidine chemotherapy dosing and toxicity in patients with screen-detected deleterious DPYD gene variants.

293 Background: Fluoropyrimidine chemotherapy agents are commonly used to treat solid tumors. Fluoropyrimidines are degraded by the enzyme dihydropyridine dehydrogenase (DPD), encoded by the DPYD gene. Deleterious variants in DPYD leads to functional DPD deficiency and increased toxicity risk. Methods: We conducted a retrospective study of patients with screen-detected deleterious DPYD variants who were treated with fluoropyrimidine chemotherapy between 01/01/15-04/15/23. Outcomes of interest were initial fluoropyrimidine dosing, dose adjustments (cycles 2-6), and early toxicities. Results: We identified 12 patients with heterozygous DPYD variants, including *2A (n=5), c.2846A&gt;T (3), c.1129-5923C&gt;G (2) and *13 (2). Initial chemotherapy regimens included FOLFOX (7), mFOLFIRINOX (3) and CAPEOX (1). Of 11 patients receiving FOLFOX/mFOLFIRINOX, nine began treatment with a 50-60% reduction of the 5-FU infusion dose, one received a 25% reduction, and one received a standard dose (due to treatment initiation prior to return of the genotype result). Seven patients tolerated the initial 5-FU infusion dose without further dose reductions, including three who tolerated limited dose-escalation. Four patients required further dose reduction from the cycle 1 dose, due to toxicity. The patient who received a standard 5-FU infusion dose in cycle 1 experienced grade 3 toxicity, but tolerated subsequent treatment after 50% dose reduction. The patient treated with CAPEOX tolerated 4 planned cycles with a 50% capecitabine dose reduction. Conclusions: Most patients who screened positive for deleterious DPYD gene variants tolerated fluoropyrimidine chemotherapy with a 50% dose reduction. However, 3 of 12 patients experienced toxicity requiring treatment discontinuation or dose reduction to less than 50% of the standard 5-FU dose.

Blood TCTP as a biomarker associated with immunosuppressive features and resistance to immunotherapy in metastatic gastric cancer.

474 Background: Cancer biomarkers are essential for determining the prognosis of the disease and/or predicting its response to specific treatments. However, established biomarkers representing specific myeloid cell populations and representative biomarkers in gastric cancer remain unavailable. Therefore, this study aimed to explore the prognostic and immunological relevance of plasma translationally controlled tumor protein (TCTP) in patients with advanced gastric cancer treated with immune checkpoint inhibitor (ICI) and cytotoxic chemotherapy. Methods: Plasma samples were prospectively collected from the cohorts of patients with gastric cancer who were treated with 1 st line fluoropyrimidine plus platinum chemotherapy (n = 143, cohort 1) and 3 rd line nivolumab (n = 165, cohort 2). Plasma TCTP levels were quantified using ELISA, and multiplex proteomic analysis (Olink) was conducted to assess expression levels of immune-related proteins. An external single-cell RNA sequencing (scRNA-seq) dataset was employed to validate the findings. Results: Patients with high plasma TCTP levels (TCTP-high group) exhibited poor survival outcomes with 1 st line chemotherapy compared to those with low levels (TCTP-low group) in cohort 1. In the TCTP-high group, proteins associated with immunosuppressive myeloid cells, angiogenesis, and immune exclusion of T/NK cell function were upregulated, whereas proteins involved in T-cell activation/exhaustion were significantly upregulated in the TCTP-low group. The scRNA-seq analyses of myeloid cells revealed that TCTP pathway-associated genes (i.e., TLR2 , CXCL1, and CXCL2 ) were specifically expressed in immunosuppressive APOE + macrophages, THBS1 + macrophages, and CD1C + conventional type 2 dendritic cells. In the TCTP-high group, patients treated with nivolumab (cohort 2) also experienced poor survival outcomes. Conclusions: Plasma TCTP is a readily measurable prognostic biomarker, reflecting immunosuppressive signals of myeloid cells in patients with gastric cancer treated with ICI and chemotherapy.

Zolbetuximab for Unresectable and Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma: A Review of Literature.

This article comprehensively reviews the working, efficacy, and safety profile of zolbetuximab. Zolbetuximab is a pioneering chimeric monoclonal antibody designed to target Claudin 18.2 (CLDN18.2), a tight junction protein frequently overexpressed in various gastrointestinal cancers, including gastric (G) and gastroesophageal junction (GEJ) adenocarcinomas. This drug has captured attention in the treatment of unresectable and metastatic G/GEJ cancer, especially in HER2-negative patients whose tumours express CLDN18.2.Zolbetuximab is a drug that binds to CLDN18.2, and its binding initiates an immune response that attacks and kills the cancer cells. It is typically co-prescribed with fluoropyrimidine and platinum-containing chemotherapy. The drug (formerly IMAB362), brand name Vyloy, was developed by Astellas Pharma, Tokyo, Japan. After multiple rounds of clinical trials, it was approved by the U.S. Food and Drug Administration (FDA) as a first-line treatment for locally advanced, unresectable cancer, establishing itself as a promising option for advanced G/GEJ cancers. Studies reveal that it targets CLDN18.2 for the selective killing of cancer cells while sparing most healthy tissues. Zolbetuximab has demonstrated a significant improvement in progression-free survival (PFS) when combined with chemotherapy (like mFOLFOX6 or CAPOX). Also, it showed prolonged PFS compared to chemotherapy alone in previously untreated, CLDN18.2-positive, HER2-negative patients. Zolbetuximab has also shown improvements in overall survival (OS), regardless of whether the cancer progresses. This is a crucial benefit for patients with advanced G/GEJ adenocarcinomas. Additionally, zolbetuximab's dual action triggers antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).This enhances the immune system's ability to destroy cancerous cells and results in highly potent tumour destruction compared with chemotherapy alone. Zolbetuximab is a relatively safe drug with a few adverse effects. The most frequently reported side effects were gastrointestinal, namely nausea, fatigue, vomiting, decreased appetite, diarrhea, neutropenia, anemia, and thrombocytopenia, potentially due to specific CLDN18.2 expression in the gastric mucosa. Its side effects are generally manageable, with no unexpected toxicity beyond those typically seen in patients receiving chemotherapy.

Reply to: "Give Patients the Choice to Test for DPD Deficiency Before Fluoropyrimidine Chemotherapy," "Large-Scale DPD Testing Should Be More Than an Option," and "A Big Problem With a Feasible Solution, Not a Small Problem With a Complex Solution".

Reply to: "Give Patients the Choice to Test for DPD Deficiency Before Fluoropyrimidine Chemotherapy," "Large-Scale DPD Testing Should Be More Than an Option," and "A Big Problem With a Feasible Solution, Not a Small Problem With a Complex Solution".

Long-Term Outcomes of 5-Fluorouracil-Related Early-Onset Toxicities: A Retrospective Cohort Study.

We aimed to determine whether the occurrence of early-onset toxicities due to 5-fluorouracil (5-FU) in treatment-naive patients undergoing their first cycle of FOLFOX/FOLFIRINOX was associated with decreased overall survival, increased risk of treatment cessation, and hospitalization. This was a retrospective cohort study using patient information from community oncology practices. Patients who received their first dose of 5-FU from 1 January 2015 through 1 August 2023 were included. The occurrence of an early-onset 5-FU-related toxicity (during 5-FU infusion or up to 96 h after infusion completion) in the first cycle of FOLFOX/FOLFIRINOX was the explanatory variable. The primary endpoint was overall survival (OS); secondary endpoints included early treatment cessation and early hospital admission. In total, 3988 patients were included; the median age was 62.9 years and 57.5% were male. Early-onset toxicities were observed in 19.1%, with vomiting, thrombocytopenia, and diarrhea being most common. Patients with early-onset toxicities had a median OS of 2.5 years [95% CI 2.2 to 2.9] compared with 5.3 years [95% CI 4.7 to 5.8] in patients without early-onset toxicities (p < 0.001). The occurrence of early-onset toxicities was associated with an adjusted hazard ratio of 1.61 [95% CI 1.44 to 1.80] and was also significantly associated with early treatment cessation (odds ratio [OR] 1.53, 95% CI 1.30 to 1.80) and early hospital admission (OR 8.69, 95% CI 3.45 to 24.18). Early-onset toxicities related to 5-FU during the first cycle of FOLFOX/FOLFIRINOX treatment were associated with poor outcomes. Early recognition and prompt intervention are pertinent to improve outcomes in patients receiving fluoropyrimidine chemotherapy.

Clinicopathological and prognostic significance of HER2-low expression in advanced gastric cancer: a retrospective observational study.

Human epidermal growth factor receptor 2 (HER2) status is a critical biomarker in advanced gastric cancer (AGC). While the role of HER2-positive tumors in guiding targeted therapies is well-established, the clinical implications of HER2-low expression, defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization-negative (ISH-negative), remain undetermined. The aim of this study was to investigate the prognostic significance and clinicopathological features of HER2-low AGC. This retrospective analysis involved patients with AGC treated with first-line fluoropyrimidine and platinum-based chemotherapy from 2011 to 2020. Patients were categorized into HER2-zero (HER2 IHC 0), HER2-low (IHC 1+ or 2+/ISH-negative), and HER2-positive (IHC 2+/ISH-positive or 3+) groups. Among 548 patients analyzed, 33.0%, 45.1%, and 21.8% were classified as HER2-zero, HER2-low, and HER2-positive, respectively. The proportions of male patients, intestinal-type histology, esophagogastric junction/cardia involvement, metastatic disease status, ≥2 metastatic sites, liver metastasis, lymph node metastasis, and high serum carcinoembryonic antigen levels were gradually elevated in the HER2-zero, HER2-low, and HER2-positive groups. Overall survival (median) was 13.8, 13.6, and 23.0 months, respectively, with a non-significant trend favoring HER2-positive over HER2-low (adjusted hazard ratio: 0.80; P = .0672). A delayed separation of Kaplan-Meier curves for overall survival between the HER2-zero and HER2-low groups was observed, without reaching statistical significance (adjusted hazard ratio: 1.12; P = .2568). Patients with HER2-low status exhibited intermediate and specific clinicopathological features within the HER2-negative category. In terms of prognosis, HER2-low patients showed a worsening trend compared with HER2-positive patients. This evidence implies that HER2-low status represents a distinct clinical subset, bridging the gap between the HER2-zero and HER2-positive profiles.

Review of the fluoropyrimidine antidote uridine triacetate.

In 2015, the United States Food and Drug Administration (FDA) approved uridine triacetate to treat overdose and severe toxicity of the fluoropyrimidine chemotherapy agents 5-fluorouracil (5-FU) and its oral prodrug capecitabine. Uridine triacetate is as an oral prodrug of uridine that competes with cytotoxic fluoropyrimidine metabolites for incorporation into nucleotides. Two million people worldwide start fluoropyrimidine chemotherapy each year, with 20-30% developing severe or life-threatening adverse effects, often attributable to a genetic predisposition such as dihydropyrimidine dehydrogenase deficiency. Whilst genetic prescreening is recommended prior to starting fluoropyrimidine agents, this only prevents 20-30% of early-onset life-threatening toxicity and so does not obviate the need for an antidote. Initial in-human studies established that uridine triacetate more than doubles the maximum tolerated weekly 5-FU bolus dose. A lack of clinical equipoise meant a placebo-controlled phase III trial was not ethical and so the phase III trials used historical controls. These found that uridine triacetate improved survival in those with fluoropyrimidine overdose and severe toxicity from 16% to 94%, with 34% able to resume chemotherapy within 30 days. Five case reports of delayed fluoropyrimidine toxicity demonstrate improvement following uridine triacetate treatment 120-504 h after last fluoropyrimidine administration, suggesting efficacy beyond the FDA licencing indications. Mechanistically uridine triacetate would be expected to be effective for overdose and severe toxicity of tegafur (a 5-FU prodrug), but there are no published case reports describing this. Uridine triacetate is available internationally through an expanded access scheme and has been available in the UK since 2019 on a named patient basis.

Improving dihydropyrimidine dehydrogenase genotyping (DPYD) prior to initiation of fluoropyrimidine-based chemotherapy at a community-based hospital: A quality improvement initiative.

347 Background: Dihydropyrimidine dehydrogenase gene (DPYD) testing is crucial in preventing toxicities from fluoropyrimidine chemotherapy. Despite benefits and established guidelines, its adoption within healthcare organizations remains inconsistent and suboptimal. We implemented a quality improvement project to improve DPYD testing prior to fluoropyrimidine chemotherapy at a community-based hospital. We aimed to increase DPYD testing for patients receiving fluoropyrimidine-based chemotherapy from 65% to 95% between July 2023 to July 2024. Balancing measures included DPYD testing turnaround time. Methods: For baseline diagnostics, manual chart review was performed on 126 patients to identify frequency of DPYD testing, and turnaround time (TAT) between May 1, 2023 to August 4, 2023. Patients were excluded if they received fluoropyrimidine-based chemotherapy prior to May 1, 2023. A multidisciplinary team including medical oncology residents and staff, pharmacists, nurses, and clinical informatics specialists worked jointly to identify and address barriers to implementation. Barriers identified included lack of established workflows and awareness of the importance of testing. Diagnostic tools utilized included Ishikawa diagrams and process mapping. The team used Plan-Do-Study-Act (PDSA) cycles to address barriers. A p-chart was used to analyze the results. Results: The baseline DPYD testing rate was 65%. Barriers identified via multidisciplinary sessions included lack of established workflow, awareness and importance of testing. PDSA cycles included education sessions to breast medical oncologists and medical oncology nurses, and development of a best-practice advisory in the electronic medical record. The percentage of eligible patients receiving DPYD testing increased from 65% to 95.8% in the total population. For breast cancer patients, the rate increased from 16.7% to 100%. For gastrointestinal cancer patients, the rate increased from 56.1% to 94.2%. Sustainability was demonstrated two months post-intervention with TAT stable between 7-8 days. Conclusions: Through PDSA cycles, we improved the frequency of DPYD testing for patients receiving fluoropyrimidine chemotherapy from 65% to 95.8%. Future work will assess changes in chemotherapy prescribing behavior in the setting of variant DPYD results, and outcomes of patients with variant DPYD testing.

Pharmacogenetics of DPYD and treatment-related mortality on fluoropyrimidine chemotherapy for cancer patients: a meta-analysis and trial sequential analysis

BackgroundFluoropyrimidines are chemotherapy drugs utilized to treat a variety of solid tumors. These drugs predominantly rely on the enzyme dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene, for their metabolism. Genetic mutations affecting this gene can cause DPYD deficiency, disrupting pyrimidine metabolism and increasing the risk of toxicity in cancer patients treated with 5-fluorouracil. The severity and type of toxic reactions are influenced by genetic and demographic factors and, in certain instances, can result in patient mortality. Among the more than 50 identified variants of DPYD, only a subset has clinical significance, leading to the production of enzymes that are either non-functional or impaired. The study aims to examine treatment-related mortality in cancer patients undergoing fluoropyrimidine chemotherapy, comparing those with and without DPD deficiency.MethodsThe meta-analysis selected and evaluated 9685 studies from Pubmed, Cochrane, Embase and Web of Science databases. Only studies examining the main DPYD variants (DPYD*2A, DPYD p.D949V, DPYD*13 and DPYD HapB3) were included. Statistical Analysis was performed using R, version 4.2.3. Data were examined using the Mantel-Haenszel method and 95% CIs. Heterogeneity was assessed with I2 statistics.ResultsThere were 36 prospective and retrospective studies included, accounting for 16,005 patients. Most studies assessed colorectal cancer, representing 86.49% of patients. Other gastrointestinal cancers were evaluated by 11 studies, breast cancer by nine studies and head and neck cancers by five studies. Four DPYD variants were identified as predictors of severe fluoropyrimidines toxicity in literature review: DPYD*2A (rs3918290), DPYD p.D949V (rs67376798), DPYD*13 (rs55886062) and DPYD Hap23 (rs56038477). All 36 studies assessed the DPYD*2A variant, while 20 assessed DPYD p.D949V, 7 assessed DPYD*13, and 9 assessed DPYDHap23. Among the 587 patients who tested positive for at least one DPYD variant, 13 died from fluoropyrimidine toxicity. Conversely, in the non-carrier group there were 14 treatment-related deaths. Carriers of DPYD variants was found to be significantly correlated with treatment-related mortality (OR = 34.86, 95% CI 13.96–87.05; p < 0.05).ConclusionsThis study improves our comprehension of how the DPYD gene impacts cancer patients receiving fluoropyrimidine chemotherapy. Identifying mutations associated with dihydropyrimidine dehydrogenase deficiency may help predict the likelihood of serious side effects and fatalities. This knowledge can be applied to adjust medication doses before starting treatment, thus reducing the occurrence of these critical outcomes.Graphical abstract

Association of pre-existing cardiovascular disease with administration of fluoropyrimidine chemotherapy in patients with gastrointestinal malignancies

ObjectiveFluoropyrimidine chemotherapy is a first-line treatment for many gastrointestinal (GI) cancers, however, cardiotoxicity concerns may limit administration in patients with pre-existing cardiovascular disease (CVD). This study investigated the association of...

Pembrolizumab (Keytruda)

CADTH recommends that Keytruda should be reimbursed by public drug plans for the treatment of locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2) positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumours express programmed cell death-ligand 1 (PD-L1) if certain conditions are met. Keytruda should only be covered to treat adult patients who have not received previous treatment for advanced or metastatic esophageal or GEJ cancer and have good performance status. Keytruda should only be reimbursed if prescribed in combination with trastuzumab, fluoropyrimidine, and platinum-containing chemotherapy by a clinician with expertise and experience in treating gastric and GEJ cancer.

Strategies for DPYD testing prior to fluoropyrimidine chemotherapy in the US.

Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at high risk for severe and fatal toxicity from fluoropyrimidine (FP) chemotherapy. Pre-treatment DPYD testing is standard of care in many countries, but not the United States (US). This survey assessed pre-treatment DPYD testing approaches in the US to identify best practices for broader adoption. From August to October 2023, a 22-item QualtricsXM survey was sent to institutions and clinicians known to conduct pre-treatment DPYD testing and broadly distributed through relevant organizations and social networks. Responses were analyzed using descriptive analysis. Responses from 24 unique US sites that have implemented pre-treatment DPYD testing or have a detailed implementation plan in place were analyzed. Only 33% of sites ordered DPYD testing for all FP-treated patients; at the remaining sites, patients were tested depending on disease characteristics or clinician preference. Almost 50% of sites depend on individual clinicians to remember to order testing without the assistance of electronic alerts or workflow reminders. DPYD testing was most often conducted by commercial laboratories that tested for at least the four or five DPYD variants considered clinically actionable. Approximately 90% of sites reported receiving results within 10days of ordering. Implementing DPYD testing into routine clinical practice is feasible and requires a coordinated effort among the healthcare team. These results will be used to develop best practices for the clinical adoption of DPYD testing to prevent severe and fatal toxicity in cancer patients receiving FP chemotherapy.

Predicting cardiovascular events with fluoropyrimidine chemotherapy using a standard cardiovascular risk calculator.

Fluoropyrimidine chemotherapy is important for treatment of many solid tumours but is associated with cardiotoxicity. The relationship of fluoropyrimidine-associated cardiotoxicity (FAC) with conventional cardiovascular (CV) risk factors is poorly understood, and standard cardiovascular risk scores are not validated in this context. Single-centre retrospective study of patients treated with fluoropyrimidine chemotherapy using electronic health records for cardiovascular risk factors (and calculation of QRISK3 score), cancer treatment, and clinical outcomes. FAC was defined by cardiovascular events during or within 3months of fluoropyrimidine treatment, and Cox regression was used to assess associations of CV risk and cancer treatment with FAC. One thousand eight hundred ninety-eight patients were included (45% male; median age 64years), with median follow up 24.5 (11.5-48.3months); 52.7% of patients were at moderate or high baseline CV risk (QRISK3 score >10%) Cardiovascular events occurred in 3.1% (59/1898)-most commonly angina (64.4%, 38/59) and atrial fibrillation (13.6%, 8/59), with 39% events during cycle one of treatment. In univariable analysis, QRISK3 score >20% was significantly associated with incident FAC (HR 2.25, 95% CI 1.11-4.93, P=0.03). On multivariable analysis, beta-blocker use (HR 1.04, 95% CI 1.00-1.08, P=0.04) and higher BMI (HR 2.33, 95% CI 1.04-5.19, P=0.04) were independently associated with incident CV events. Thirty-two of the 59 patients with FAC were subsequently rechallenged with fluoropyrimidine chemotherapy, with repeat CV events in 6% (2/32). Incident FAC did not affect overall survival (P=0.50). High BMI and use of beta-blockers are associated with risk of CV events during fluoropyrimidine chemotherapy. QRISK3 score may also play a role in identifying patients at high risk of CV events during fluoropyrimidine chemotherapy. Re-challenge with further fluoropyrimidine chemotherapy can be considered in patients following CV events during prior treatment.