Introduction
In this case report we describe two patients with 5-fluorouracil (5-FU) overdose due to an unintentional increased infusion rate in which treatment with uridine triacetate was ...considered. Where previous case reports focus on the use of uridine triacetate in case of toxicity, this case report shows why it should be considered to abstain from the use of uridine triacetate.
Case reports
The first patient is a 71-year-old woman who received 1200 mg/m2 5-FU in 2 h instead of 23 h. The second patient is a 74-year-old woman who received 2600 mg/m2 5-FU in 13 h instead of 24 h. The DPYD genotype of both patients was tested before the start of therapy and was found to be normal.
Management & Outcome
Both patients received best supportive care and were admitted to the intensive care unit for monitoring of acute manifestations of toxicity. The first patient did not develop toxicity. The second patient did develop toxicity, but recovered completely.
Discussion
The rationale for abstaining from the use of uridine triacetate was the inadequacy of evidence backing its clinical and cost-effectiveness and the fact that uridine triacetate is not registered for the use in the European Union. Comparison of clinical outcomes of the already published open-label cohort with clinical outcomes of a comparable, well-described, best supportive care cohort is required before the added value of uridine triacetate can be determined. In addition, there is a need for a valid predictor of toxicity after fluoropyrimidine overdose.
Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly ...caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A rs3918290, c.1905+1G>A, IVS14+1G>A, c.2846A>T rs67376798, D949V, c.1679T>G rs55886062, DPYD*13, I560S, and c.1236G>A rs56038477, E412E, in haplotype B3) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care.
In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (≥18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete.
Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 39% of 85 patients) than in wild-type patients (231 23% of 1018 patients; p=0·0013). The RR for severe fluoropyrimidine-related toxicity was 1·31 (95% CI 0·63–2·73) for genotype-guided dosing compared with 2·87 (2·14–3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10–8·80) in c.1679T>G carriers, 2·00 (1·19–3·34) compared with 3·11 (2·25–4·28) for c.2846A>T carriers, and 1·69 (1·18–2·42) compared with 1·72 (1·22–2·42) for c.1236G>A carriers.
Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care.
Dutch Cancer Society.
Background
Methotrexate in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) has limited progression‐free survival (PFS) benefit. We hypothesized that adding ...cetuximab to methotrexate improves PFS.
Methods
In the phase‐Ib‐study, patients with R/M SCCHN received methotrexate and cetuximab as first‐line treatment. The primary objective was feasibility. In the phase‐II‐study patients were randomized to this combination or methotrexate alone (2:1). The primary endpoint was PFS. Secondary endpoints were overall survival (OS), toxicity, and quality of life (QoL).
Results
In six patients in the phase‐Ib‐study, no dose limiting toxicities were observed. In the phase II study, 30 patients received the combination and 15 patients methotrexate. In the phase‐II‐study median PFS was 4.5 months in the combination group vs 2.0 months in the methotrexate group (HR 0.37; P = .002). OS, toxicity, and QoL were not significantly different.
Conclusion
Cetuximab with methotrexate improved PFS without increased toxicity in R/M SCCHN‐patients.
Fluoropyrimidine therapy including capecitabine or 5-fluorouracil can result in severe treatment-related toxicity in up to 30% of patients. Toxicity is often related to reduced activity of ...dihydropyrimidine dehydrogenase, the main metabolic fluoropyrimidine enzyme, primarily caused by genetic DPYD polymorphisms. In a large prospective study, it was concluded that upfront DPYD-guided dose individualisation is able to improve safety of fluoropyrimidine-based therapy. In our current analysis, we evaluated whether this strategy is cost saving.
A cost-minimisation analysis from a health-care payer perspective was performed as part of the prospective clinical trial (NCT02324452) in which patients prior to start of fluoropyrimidine-based therapy were screened for the DPYD variants DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A and received an initial dose reduction of 25% (c.2846A>T, c.1236G>A) or 50% (DPYD*2A, c.1679T>G). Data on treatment, toxicity, hospitalisation and other toxicity-related interventions were collected. The model compared prospective screening for these DPYD variants with no DPYD screening. One-way and probabilistic sensitivity analyses were also performed.
Expected total costs of the screening strategy were €2599 per patient compared with €2650 for non-screening, resulting in a net cost saving of €51 per patient. Results of the probabilistic sensitivity and one-way sensitivity analysis demonstrated that the screening strategy was very likely to be cost saving or worst case cost-neutral.
Upfront DPYD-guided dose individualisation, improving patient safety, is cost saving or cost-neutral but is not expected to yield additional costs. These results endorse implementing DPYD screening before start of fluoropyrimidine treatment as standard of care.
•DPYD-guided dose individualisation of fluoropyrimidines improves patient safety.•In our cost analysis, DPYD genotyping resulted in a cost saving of €51 per patient.•Results of this analysis endorse implementing DPYD genotyping as standard of care.
To investigate the toxicity of temozolomide (TMZ) in patients with brain tumors and appropriate nursing interventions.
Explorative analysis of prospective data.
A TMZ clinic led by a nurse ...practitioner (NP).
Group A (n = 71) received a standard dose of TMZ daily for five days 200 mg/m2 every four weeks; group B (n = 19) received a dose-intense schedule of TMZ daily for 21 days 75 mg/m2 every four weeks.
Toxicities were scored according to National Cancer Institute Common Terminology Criteria, and results in the two groups were compared.
Thrombopenia, neutropenia, and lymphopenia; nausea and vomiting; and NP interventions.
Of observed toxicities during six cycles, grade 3-4 thrombopenia was seen most frequently in group A. Neutropenia and subsequent interventions occurred more frequently in group A than in group B. Subsequent interventions consisted of dose delays and reductions. When patients were treated for a longer duration of time with TMZ, grade 3-4 lymphopenia occurred significantly more often in group B, necessitating Pneumocystis carinii pneumonia prophylaxis.
Degree of toxicity using a 5-day 200 mg/m2 or 21-day 75 mg/m2 schedule every four weeks was similar to that found in other studies.
Through awareness of toxicity in relation to knowledge of brain tumors, NPs can become more effective in active management of TMZ toxicity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Parathyroid carcinoma is an uncommon malignancy. Of the fewer than 400 cases reported, most have been cases of producing parathyroid carcinoma with accompanying hypercalcemia. Only 13 patients with ...nonproducing parathyroid carcinoma have been described. Nine of these 13 patients had metastatic disease. We report a patient with i.c. metastasis. Distal metastases of producing parathyroid carcinoma are treated surgically to prolong survival and prevent complications of hyperparathyroidism and hypercalcemia. One half of the patients with producing parathyroid carcinoma die within 5 years, mostly because of the complications of hypercalcemia. Nonproducing parathyroid carcinoma compares unfavorably with producing parathyroid carcinoma in terms of tumor progression and prognosis. Few data on choice of therapy in nonproducing parathyroid carcinoma are available. We treated our patient with a combination of radiotherapy and chemotherapy. Treatment was followed by an unexpectedly prolonged survival of 31 months after diagnosis of metastatic disease.
An on-line HPLC screening method for detection of inhibitors of human cytochrome P450 1A2 in extracts was developed. HPLC separation of extracts is connected to a continuous methoxyresorufin-
...O-demethylation (MROD) assay in which recombinant human P450 1A2 converts methoxyresorufin to its fluorescent metabolite resorufin. The system was tested with three P450 1A2 inhibitors, for which minimum detectable amounts (MDA) ranging from 0.7 to 9.5
ng were obtained. Analysis of a kava kava and a basil extract showed that the on-line system is applicable to complex mixtures, since in both extracts, peaks with P450 1A2 inhibiting activity were observed.
Natural products chemistry has witnessed many new developments in the last 5 years like extractions with subcritical water and ionic liquids, LC/HRMS and LC/SPE/cryo-NMR, UHPLC, TLC/MS, MS-based ...preparative HPLC, comprehensive chromatography (GC × GC, LC × LC), high-throughput screening, introduction of monolithic columns, miniaturisation, and automated structure identification. Nevertheless identifying bioactive constituents in complex plant extracts remains a tedious process. The classical approach of bioassay guided fractionation is time-consuming while off-line screening of extracts does not provide information on individual compounds and sometimes suffers from false positives or negatives. One way out of this is by coupling chromatography with chemical or biochemical assays, so called high resolution screening. An example is the development of HPLC on-line assays for antioxidants. By the post-column addition of a relatively stable coloured radical like DPPH
•
or ABTS
•+
, radical scavengers are detected as negative peaks because in a reaction coil they reduce the model radical to its reduced, non-coloured form. When combined with LC/DAD/MS and LC/SPE/NMR, reliable identification of active constituents becomes possible without the necessity of ever isolating them in a classical sense. Also for finding leads for new drugs, combining HPLC with biochemical assays is interesting but technically more difficult. Most enzymes do not work at the organic modifier concentrations commonly encountered in RP-HPLC and the reaction time is often longer requiring dilution and lengthy coils respectively. Therefore, new techniques have to be implemented to gain the required sensitivity for on-line enzyme assays. For stable analytes, high temperature LC offers a solution to the organic modifier problem. When enzymes are highly expensive, like those used in the screening for Cytochrome P450 inhibitors, miniaturisation to chip format may offer a way out. Microreactors (chips) are not only useful for miniaturising larger assays but also offer completely new prospects in phytochemical analysis. One such application is in the sample clean-up of acids and bases like alkaloids. In a lay-out of three parallel channels of 100 μm width with the middle one containing organic phase and the two outer ones water of high pH (feed phase) and low pH (trapping phase) such a chip replaces two classical LLE steps but is much faster and requires less solvents and less manpower input.
Abstract Introduction: The inability to predict treatment response results in unnecessary toxicity, decreased efficacy and survival. There is a clinical need for an effective biomarker to select ...patients for cancer treatment. A promising biomarker for treatment efficacy is response testing on patient-derived organoids (PDOs). For metastatic colorectal cancer (mCRC), larger prospective studies are needed to evaluate the predictive value of standardized PDO screens. Methods: OPTIC is an ongoing prospective multicenter trial (NL61668.041.17, started 2018) that will evaluate the value of tumor PDOs in therapy response prediction. We establish PDOs for mCRC patients from newly obtained biopsies, prior to the start of treatment. We compare PDO sensitivity (area under drug response curve) with patient response measured by changes in biopsied metastatic lesion size on CT scans. Secondary outcome measures are RECIST response and progression-free survival. We evaluate the feasibility of using PDOs as a biomarker by examining drug screen availability in a clinically relevant timeframe of 4 weeks. From 2020 onwards, we incorporated whole genome sequencing (WGS) on fresh-frozen biopsies to correlate drug response in vitro and in vivo, to genetic tumor characteristics. Additionally, PDO screens with experimental drugs based on genetic alterations identified by WGS could be performed. Trial inclusion will continue until 85 PDOs from clinically evaluable patients for standard of care (SOC) treatment are established, with expected completion in Q1 2024. Results: Currently, 206 patients were included in 5 hospitals and 180 biopsies were taken. PDO establishment success gradually increased from 22% in 2018-2020 to 75% in 2023, yielding an overall success rate of 50% (n=84 PDOs and 13 in culture). Critical factors in optimizing culture success were replacement of several growth factors in the culture medium, reducing time to processing and more frequent handling of biopsies. We have established PDOs for comparing with patient response for the following treatment categories: 5-fluorouracil (n=4), CAPOX/FOLFOX (n=23), irinotecan/FOLFIRI (n=11), FOLFOXIRI (n=12), trifluridine/tipiracil (n=14), panitumumab (n=14), encorafenib-cetuximab (n=2), non-SOC drugs (n=4). We have successfully screened the first 8 PDOs in consistent technical triplicates and biological duplicates (R<0.88, p<0.02). WGS succeeded in 76% (n=75), primarily failing when tumor percentage was <20%. Conclusion: We improved PDO establishment success to 75% which is essential to facilitate the implementation of PDOs in clinical treatment. OPTIC will enhance the clinical application of PDOs by defining thresholds for PDO sensitivity and analyzing the diagnostic power for different treatments. To enable personalized treatment in clinical practice, PDO screening should guide mCRC treatment and result in enhanced chance of response and reduced over- and mistreatment. Citation Format: Lidwien P. Smabers, Emerens Wensink, Carla S. Verissimo, Mayke Doorn, Tao Yang, Timo Voskuilen, Yasmine Abouleila, Maarten A. Huismans, Liselot Valkenburg-van Iersel, Geert A. Cirkel, Elske C. Gootjes, Frank J. Jeurissen, Guus M. Bol, Hilde H. Nienhuis, Manon M. Braat, Bas Penning de Vries, Sjoerd G. Elias, Edwin Cuppen, Robert G. Vries, Onno Kranenburg, Miriam Koopman, Sylvia F. Boj, Jeanine M. Roodhart. Organoids to predict treatment response in metastatic colorectal cancer (OPTIC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5174.
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