Transporter pumps and imatinib : a cause of pharmacokinetic resistance?

ABCB1, ATP-binding cassette sub-family B member 1; ABCG2, ATP-binding cassette sub-family G member 2; AGP, alpha 1 acid glycoprotein; Bcr-Abl, breakpoint cluster region of Abelson proto-oncogene; CAR, constitutive-androstane receptor; CML, chronic myeloid leukaemia; CYP3A4, cytochrome P450 3A4; GIST, gastrointestinal stromal tumours; OCT1, organic cation transporter 1; PK, pharmacokinetic; PXR, pregnane X receptor; TKI, tyrosine kinase inhibitor.3 page(s

Dose calculation of anticancer drugs

Background: Anticancer drugs are characterized by a narrow therapeutic window and significant inter-patient variability in therapeutic and toxic effects. Current body surface area (BSA)-based dosing fails to standardize systemic anticancer drug exposure and other alternative dosing strategies also have their limitations. Just as important as the initial dose selection is the subsequent dose revision to ensure the dose is correct. Objective: To provide an insight into the different dose individualization and dose adjustment methods, their feasibility and applicability in daily oncology practice and to suggest a practical framework for dose calculation and a basis for future research. Methods: Review of relevant literature related to dose calculation of anticancer drugs. Results: Strategies using clinical parameters, genotype and phenotype markers, and therapeutic drug monitoring all have potential and each has a role for specific drugs. However, no one method is a practical dose calculation strategy for many or all drugs. Conclusion: Given that BSA-dosing leads to significant underclosing it is not reasonable to use this as the sole method of dose calculation. Because of wide disparity in individual patient characteristics and elimination mechanisms, we are unlikely to find the 'Holy Grail' of a single individualized dosing strategy for every patient and anticancer drug in the near future. We propose a pragmatic, although invalidated system for initial dose calculation using dose clusters and structured subsequent dose revision based on treatment-related toxicities and therapeutic drug monitoring. These models need to be tested in clinical trials.13 page(s

Altered dihydropyrimidine dehydrogenase activity associated with mild toxicity in patients treated with 5-fluorouracil containing chemotherapy

Dihydropyrimidine dehydrogenase (DPD) plays a pivotal role in the metabolism of 5-fluorouracil (5FU). In patients treated with capecitabine or 5FU combined with other chemotherapeutic drugs, DPD activity in peripheral blood mononuclear cells was increased in patients experiencing grade I/II neutropenia. In contrast, decreased DPD activity proved to be associated with grade I/II dermatological toxicity, including hand-foot syndrome. Thus, patients with a low-normal or high-normal DPD activity proved to be at risk of developing mild toxicity upon treatment with 5FU-based chemotherapy, demonstrating the important role of DPD in the etiology of toxicity associated with 5FU and the catabolites of 5F

Treatment of Liver Metastases from Midgut Neuroendocrine Tumours: A Systematic Review and Meta-Analysis

Strong evidence comparing different treatment options for liver metastases (LM) arising from gastroenteropancreatic neuroendocrine tumours (GEP-NET) is lacking. The aim of this study was to determine which intervention for LMs from GEP-NETs shows the longest overall survival (OS). A systematic search was performed in MEDLINE, Embase and the Cochrane Library in February 2018. Studies reporting on patients with LMs of any grade of sporadic GEP-NET comparing two intervention groups were included for analysis. Meta-analyses were performed where possible. Eleven studies, with a total of 1108, patients were included; 662 patients had LM from pancreatic NETs (pNET), 164 patients from small-bowel NETs (SB-NET) and 282 patients of unknown origin. Improved 5-year OS was observed for surgery vs. chemotherapy (OR 0.05 95% CI [0.01, 0.21] p < 0.0001), for surgery vs. embolization (OR 0.18 95% CI [0.05, 0.61] p = 0.006) and for LM resection vs. no LM resection (OR 0.15 95% CI [0.05, 0.42] p = 0.0003). This is the largest meta-analysis performed comparing different interventions for LMs from GEP-NETs. Despite the high risk of bias and heterogeneity of data, surgical resection for all tumour grades results in the longest overall survival. Chemotherapy and embolization should be considered as an alternative in case surgery is not feasible