ABSTRACT
PURPOSE: The primary objective of this study was to determine if dihydropyrimidine dehydrogenase (DPD) activity measured in peripheral blood mononuclear cells (PBMCs) is related to adverse events during fluoropyrimidine therapy. METHODS: A retrospective cohort study was conducted. The study population included 481 patients who received fluoropyrimidine treatment and for whom relevant patient characteristics were known and adverse events were noted in the electronic health records. Factors besides DPD phenotype that could affect the incidence of adverse events were corrected for using log regression. These log regression models were used to identify an association between the DPD phenotype measured in PBMCs and adverse events. RESULTS: Patients with a decreased DPD activity measured in PBMCs suffered more adverse events. Results from log regression data show that this effect remains significant after correcting for dosage, chemotherapy regimen and relevant patient characteristics. CONCLUSION: A significant correlation was found between reduced DPD enzyme activity in PBMCs and adverse events. The findings in this paper support further exploring DPD phenotyping as a method for preventing fluoropyrimidine-related adverse events. Further assessment of DPD phenotyping will require clinical validation in a prospective study.
Subject(s)
Antimetabolites, Antineoplastic , Dihydrouracil Dehydrogenase (NADP) , Humans , Dihydrouracil Dehydrogenase (NADP)/genetics , Retrospective Studies , Leukocytes, Mononuclear , Prospective Studies , Phenotype , Fluorouracil/therapeutic useABSTRACT
Locally advanced head and neck squamous cell carcinoma (LAHNSCC) treatment consists of radiotherapy (RT) alone or cisplatin-based concomitant chemoradiotherapy (CCRT). CCRT is accompanied by substantially more toxicity than RT alone. A previous retrospective cohort study found that LAHNSCC patients with tumors negative for nuclear expression of the signal transducer and activator of transcription 3 (STAT3) protein might not benefit from the addition of cisplatin to radiotherapy (RT) treatment. We set out to validate these results in a new cohort. We found that in patients with both STAT3 positive and negative tumors, disease-free survival (DFS) and overall survival (OS) did not differ significantly between treatment with cisplatin-based concomitant chemoradiotherapy (CCRT) and radiotherapy alone. Therefore, our validation study does not confirm that STAT3 is a potential biomarker to predict the effectiveness of the addition of cisplatin to RT in LAHNSCC patients.
Subject(s)
Biomarkers, Tumor/metabolism , Head and Neck Neoplasms/metabolism , STAT3 Transcription Factor/metabolism , Adult , Aged , Antineoplastic Agents/therapeutic use , Chemoradiotherapy , Cisplatin/therapeutic use , Female , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/therapy , Humans , Male , Middle Aged , Neoplasm Staging , Prognosis , Radiotherapy , Retrospective Studies , Survival Rate , Treatment OutcomeABSTRACT
PURPOSE: Everolimus treatment is seriously hampered by its toxicity profile. As a relationship between everolimus exposure and effectiveness and toxicity has been established, early and ongoing concentration measurement can be key to individualize the dose and optimize treatment outcomes. Dried blood spot (DBS) facilitates sampling at a patients' home and thereby eases dose individualization. The aim of this study is to determine the agreement and predictive performance of DBS compared to whole blood (WB) to measure everolimus concentrations in cancer patients. METHODS: Paired DBS and WB samples were collected in 22 cancer patients treated with everolimus and analyzed using UPLC-MS/MS. Bland-Altman and Passing-Bablok analysis were used to determine method agreement. Limits of clinical relevance were set at a difference of ± 25%, as this would lead to a different dosing advice. Using DBS concentration and Passing-Bablok regression analysis, WB concentrations were predicted. RESULTS: Samples of 20 patients were suitable for analysis. Bland-Altman analysis showed a mean ratio of everolimus WB to DBS concentrations of 0.90, with 95% of data points within limits of clinical relevance. Passing-Bablok regression of DBS compared to WB revealed no constant bias (intercept 0.02; 95% CI 0.93-1.35) and a small proportional bias (slope 0.89; 95% CI 0.76-0.99). Predicted concentrations showed low bias and imprecision and 90% of samples had an absolute percentage prediction error of < 20%. CONCLUSIONS: DBS is a valid method to determine everolimus concentrations in cancer patients. This can especially be of value for early recognition of over- or underexposure to enable dose adaptations.
