Patient-Level Adverse Event Patterns in a Single-Institution Study of the Multi-Kinase Inhibitor Sorafenib.

Novel characterization of patterns of adverse events (AEs) of kinase inhibitors (KIs) could reveal new insights on human molecular physiology and methods to improve the therapeutic index of KIs. Incidence and severity of AEs for each of 157 patients enrolled in sorafenib clinical trials were determined for three clinically relevant treatment intervals: weeks 0-3, weeks 3-7, and after 7 weeks. The most common within patient co-occurrences were mucositis with dermatologic events: hand-foot syndrome (HFS; odds ratio [OR] = 4.36; p = 0.0017) and rash (OR = 5.32; p < 0.001). Prevalence of severe: alopecia (p = 0.02), diarrhea (p < 0.001), and fatigue (p = 0.005) increased over the course of therapy. Incidence of HFS (60%) and diarrhea (25%) increased up to a minimum steady-state concentration (approximately 5 mcg mL-1 ) and plateaued thereafter. Common AEs of sorafenib occur in distinct temporal and tissue distribution patterns and this analysis identified unrecognized relationships among mechanism-dependent and independent effects of a KI.

Comparative Effects of CT Imaging Measurement on RECIST End Points and Tumor Growth Kinetics Modeling.

Quantitative assessments of tumor burden and modeling of longitudinal growth could improve phase II oncology trials. To identify obstacles to wider use of quantitative measures we obtained recorded linear tumor measurements from three published lung cancer trials. Model-based parameters of tumor burden change were estimated and compared with similarly sized samples from separate trials. Time-to-tumor growth (TTG) was computed from measurements recorded on case report forms and a second radiologist blinded to the form data. Response Evaluation Criteria in Solid Tumors (RECIST)-based progression-free survival (PFS) measures were perfectly concordant between the original forms data and the blinded radiologist re-evaluation (intraclass correlation coefficient = 1), but these routine interrater differences in the identification and measurement of target lesions were associated with an average 18-week delay (range, -20 to 55 weeks) in TTG (intraclass correlation coefficient = 0.32). To exploit computational metrics for improving statistical power in small clinical trials will require increased precision of tumor burden assessments.

Sorafenib dose escalation is not uniformly associated with blood pressure elevations in normotensive patients with advanced malignancies.

Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12-h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose-escalation study. After 7 days' treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12-h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady-state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP-elevating effects.