Understanding how coping strategies and quality of life maintain hope in patients deliberating phase I trial participation.

Objective: This study aimed to understand how hope and motivation of patients considering phase I trial participation are affected by psychological factors such as coping strategies and locus of control (LoC) and general well-being as measured by the quality of life (QoL).

Methods: An exploratory cross-sectional study was performed in patients with incurable cancer (N = 135) referred to our phase I unit for the first time. Patients were potentially eligible for phase I trial participation and participated in our study while deliberating phase I trial participation.

Sorafenib-Induced Changes in Thyroid Hormone Levels in Patients Treated for Hepatocellular Carcinoma.

Context: The pathogenesis of tyrosine kinase inhibitor-induced thyroid hormone (TH) alterations are still a matter of debate.

Objective: The objective of this study was to determine the effects of sorafenib on TH levels in patients with hepatocellular carcinoma (HCC) and to evaluate possible mechanisms.

Design: We performed a prospective cohort study between 2009 and 2016.

Evaluation of KDR rs34231037 as a predictor of sunitinib efficacy in patients with metastatic renal cell carcinoma.

The identification of biomarkers able to predict clinical benefit from vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors is urgently needed. Recently, Maitland and colleagues described an association between KDR-rs34231037 and soluble VEGFR2 levels as well as pazopanib pharmacodynamics. We investigated in a well-characterized series of metastatic clear cell renal cell carcinoma patients whether rs34231037 could influence sunitinib response.

Imatinib treatment of poor prognosis mesenchymal-type primary colon cancer: a proof-of-concept study in the preoperative window period (ImPACCT).

Background: The identification of four Consensus Molecular Subtypes (CMS1-4) of colorectal cancer forms a new paradigm for the design and evaluation of subtype-directed therapeutic strategies. The most aggressive subtype - CMS4 - has the highest chance of disease recurrence. Novel adjuvant therapies for patients with CMS4 tumours are therefore urgently needed.

Towards better dose individualisation: metabolic phenotyping to predict cabazitaxel pharmacokinetics in men with prostate cancer.

Background: Cabazitaxel is approved for treatment of castration-resistant metastatic prostate cancer. The current dosing strategy of cabazitaxel is based on body surface area (BSA). Body surface area is known as a poor predictor for total systemic exposure to drugs, since it does not take into account variability in activity of metabolising enzymes, necessary for clearance of drugs.

Pharmacometric Modeling of Liver Metastases' Diameter, Volume, and Density and Their Relation to Clinical Outcome in Imatinib-Treated Patients With Gastrointestinal Stromal Tumors.

Three-dimensional and density-based tumor metrics have been suggested to better discriminate tumor response to treatment than unidimensional metrics, particularly for tumors exhibiting nonuniform size changes. In the developed pharmacometric modeling framework based on data from 77 imatinib-treated gastrointestinal patients, the time-courses of liver metastases' maximum transaxial diameters, software-calculated actual volumes (V ) and calculated ellipsoidal volumes were characterized by logistic growth models, in which imatinib induced a linear dose-dependent size reduction. An indirect response model best described the reduction in density.

Influence of OATP1B1 Function on the Disposition of Sorafenib-β-D-Glucuronide.

The oral multikinase inhibitor sorafenib undergoes extensive UGT1A9-mediated formation of sorafenib-β-D-glucuronide (SG). Using transporter-deficient mouse models, it was previously established that SG can be extruded into bile by ABCC2 or follow a liver-to-blood shuttling loop via ABCC3-mediated efflux into the systemic circulation, and subsequent uptake in neighboring hepatocytes by OATP1B-type transporters. Here we evaluated the possibility that this unusual process, called hepatocyte hopping, is also operational in humans and can be modulated through pharmacological inhibition.

Genetic polymorphisms as predictive biomarker of survival in patients with gastrointestinal stromal tumors treated with sunitinib.

This study aimed to identify single-nucleotide polymorphisms (SNPs) that are associated with outcome to treatment with sunitinib in patients with advanced gastrointestinal stromal tumors (GIST). Forty-nine SNPS involved in the pharmacokinetic and pharmacodynamic pathway of sunitinib were associated with progression-free survival (PFS) and overall survival (OS) in 127 patients with advanced GIST who have been treated with sunitinib. PFS was significantly longer in carriers of the TT genotype in POR rs1056878 (hazards ratio (HR) 4.

Tyrosine Kinase Inhibitors and Proton Pump Inhibitors: An Evaluation of Treatment Options.

Tyrosine kinase inhibitors (TKIs) have rapidly become an established factor in oncology, and have been shown to be effective in a wide variety of solid and hematologic malignancies. Use of the oral administration route of TKIs offers flexibility and is convenient for the patient; however, despite these advantages, the oral route of administration also causes a highly relevant new problem. Acid-inhibitory drugs, such as proton pump inhibitors (PPIs), increase the intragastric pH, which may subsequently decrease TKI solubility, bioavailability, and treatment efficacy.

Meta-analysis on the association of VEGFR1 genetic variants with sunitinib outcome in metastatic renal cell carcinoma patients.

VEGFR1 rs9582036 and rs9554320 were previously reported the association with sunitinib progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC). Hereafter, the association of both single nucleotide polymorphisms (SNPs) with PFS/OS was confirmed in two independent mRCC cohorts. The aim of the current study was to validate the associations of both SNPs with sunitinib outcome in three independent well-characterized cohorts (SUTOX, CCF and SOGUG) including 286 sunitinib-treated mRCC patients, as well as to perform a meta-analysis of current and published data combined.

A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients.

Background: Oral and subcutaneous morphine is widely used for the treatment of cancer-related pain; however, solid pharmacokinetic data on this practice are lacking. Furthermore, it is largely unknown which factors contribute to the variability in clearances of morphine and its metabolites and whether morphine clearance is related to treatment outcome.

Methods: Blood samples from 49 cancer patients treated with oral and/or subcutaneous morphine were prospectively collected and were used to develop a population pharmacokinetic model for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).

A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function.

Purpose: Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function.

Methods: Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.

A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients.

Fentanyl is a strong opioid that is available for various administration routes, and which is widely used to treat cancer-related pain. Many factors influence the fentanyl pharmacokinetics leading to a wide inter- and intrapatient variability. This systematic review summarizes multiple studied factors that potentially influence fentanyl pharmacokinetics with a focus on implications for cancer patients.

Effects of Budesonide on Cabazitaxel Pharmacokinetics and Cabazitaxel-Induced Diarrhea: A Randomized, Open-Label Multicenter Phase II Study.

Forty-seven percent of patients in the pivotal trial of cabazitaxel reported diarrhea of any grade. Aiming to reduce the incidence of diarrhea, we studied the effects of budesonide on the grade of cabazitaxel-induced diarrhea during the first two treatment cycles. Between December 2011 and October 2015, 246 metastatic castration-resistant prostate cancer patients were randomized to receive standard-of-care cabazitaxel 25 mg/m every 3 weeks plus prednisone 10 mg/day (group CABA) or same dose/schedule of cabazitaxel with concomitant budesonide 9 mg daily during the first two treatment cycles (group BUD).

Implementation of a Multicenter Biobanking Collaboration for Next-Generation Sequencing-Based Biomarker Discovery Based on Fresh Frozen Pretreatment Tumor Tissue Biopsies.

Background: The discovery of novel biomarkers that predict treatment response in advanced cancer patients requires acquisition of high-quality tumor samples. As cancer evolves over time, tissue is ideally obtained before the start of each treatment. Preferably, samples are freshly frozen to allow analysis by next-generation DNA/RNA sequencing (NGS) but also for making other emerging systematic techniques such as proteomics and metabolomics possible.

A European Spectrum of Pharmacogenomic Biomarkers: Implications for Clinical Pharmacogenomics.

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes.

Loss of SLCO1B3 drives taxane resistance in prostate cancer.

Background: Both taxanes, docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer.

Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients.

Background And Objective: Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients.

Methods: Pharmacokinetic data were available from 96 patients from three clinical studies.

Polymorphisms in SLCO1B1 and UGT1A1 are associated with sorafenib-induced toxicity.

Aim: Sorafenib-treated patients display a substantial variation in the incidence of toxicity. We aimed to investigate the association of genetic polymorphisms with observed toxicity on sorafenib.

Patients & Methods: We genotyped 114 patients that were treated with sorafenib at the Erasmus MC Cancer Institute, the Netherlands, for SLCO1B1, SLCO1B3, ABCC2, ABCG2, UGT1A1 and UGT1A9.

Opioid treatment failure in cancer patients: the role of clinical and genetic factors.

Aim: To identify clinical and genetic factors associated with outcome of opioid treatment.

Patients & Methods: We performed an exploratory analysis in a cohort of 353 patients treated with fentanyl, morphine, oxycodone and/or hydromorphone for cancer-related pain, exploring selected clinical and pharmacogenetic factors for a correlation with treatment failure for all and per type of opioid.

Results: Use of adjuvant pain medication, intensity of pain at rest and age were associated with treatment failure in the various cohorts.