[89Zr]Zr-DFO-girentuximab and [18F]FDG PET/CT to Predict Watchful Waiting Duration in Patients with Metastatic Clear-cell Renal Cell Carcinoma.

PURPOSE: Watchful waiting (WW) can be considered for patients with metastatic clear-cell renal cell carcinoma (mccRCC) with good or intermediate prognosis, especially those with <2 International Metastatic RCC Database Consortium criteria and ≤2 metastatic sites [referred to as watch and wait ("W&W") criteria]. The IMaging PAtients for Cancer drug SelecTion-Renal Cell Carcinoma study objective was to assess the predictive value of [18F]FDG PET/CT and [89Zr]Zr-DFO-girentuximab PET/CT for WW duration in patients with mccRCC. EXPERIMENTAL DESIGN: Between February 2015 and March 2018, 48 patients were enrolled, including 40 evaluable patients with good (n = 14) and intermediate (n = 26) prognosis. Baseline contrast-enhanced CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab PET/CT were performed. Primary endpoint was the time to disease progression warranting systemic treatment. Maximum standardized uptake values (SUVmax) were measured using lesions on CT images coregistered to PET/CT. High and low uptake groups were defined on the basis of median geometric mean SUVmax of RECIST-measurable lesions across patients. RESULTS: The median WW time was 16.1 months [95% confidence interval (CI): 9.0-31.7]. The median WW period was shorter in patients with high [18F]FDG tumor uptake than those with low uptake (9.0 vs. 36.2 months; HR, 5.6; 95% CI: 2.4-14.7; P < 0.001). Patients with high [89Zr]Zr-DFO-girentuximab tumor uptake had a median WW period of 9.3 versus 21.3 months with low uptake (HR, 1.7; 95% CI: 0.9-3.3; P = 0.13). Patients with "W&W criteria" had a longer median WW period of 21.3 compared with patients without: 9.3 months (HR, 1.9; 95% CI: 0.9-3.9; Pone-sided = 0.034). Adding [18F]FDG uptake to the "W&W criteria" improved the prediction of WW duration (P < 0.001); whereas [89Zr]Zr-DFO-girentuximab did not (P = 0.53). CONCLUSIONS: In patients with good- or intermediate-risk mccRCC, low [18F]FDG uptake is associated with prolonged WW. This study shows the predictive value of the "W&W criteria" for WW duration and shows the potential of [18F]FDG-PET/CT to further improve this.

High-Dose Intermittent Treatment with the Multikinase Inhibitor Sunitinib Leads to High Intra-Tumor Drug Exposure in Patients with Advanced Solid Tumors.

Patients with advanced cancer refractory to standard treatment were treated with sunitinib at a dose of 300 mg once every week (Q1W) or 700 mg once every two weeks (Q2W). Tumor, skin and plasma concentrations were measured and immunohistochemical staining for tumor cell proliferation (TCP), microvessel density (MVD) and T-cell infiltration was performed on tumor biopsies before and after 17 days of treatment. Oral administration of 300 mg sunitinib Q1W or 700 mg Q2W resulted in 19-fold (range 5-35×) and 37-fold higher (range 10-88×) tumor drug concentrations compared to parallel maximum plasma drug concentrations, respectively. Patients with higher tumor sunitinib concentrations had favorable progression-free and overall survival than those with lower concentrations (p = 0.046 and 0.024, respectively). In addition, immunohistochemistry of tumor biopsies revealed an induction of T-cell infiltration upon treatment. These findings provide pharmacological and biological insights in the clinical benefit from high-dose intermittent sunitinib treatment. It emphasizes the potential benefit from reaching higher tumor drug concentrations and the value of measuring TKI tumor- over plasma-concentrations. The finding that reaching higher tumor drug concentrations provides most clinical benefit in patients with treatment refractory malignancies indicates that the inhibitory potency of sunitinib may be enforced by a high-dose intermittent treatment schedule. These results provide proof of concept for testing other clinically available multitargeted tyrosine kinase inhibitors in a high-dose intermittent treatment schedule.

High-dose administration of tyrosine kinase inhibitors to improve clinical benefit: A systematic review.

BACKGROUND: Innovative strategies to fully exploit the antitumor activity of multitargeted tyrosine kinase inhibitors (TKIs) are urgently needed. Higher concentrations of TKIs at their target site, i.e. intratumorally, may lead to broader kinase inhibition, which might be essential for the optimal suppression of tumor growth and induction of apoptosis. To reach these higher intratumoral concentrations, without encountering dose limiting toxicity, alternative TKI dosing strategies employing higher daily and high intermittent doses have been studied. In this systematic review, we evaluated the current clinical evidence to support (intermittent) high TKI dosing regimens. METHODS: A systematic review was conducted in the following databases: PubMed®, EMBASE® and Cochrane Library©, to evaluate efficacy of alternatively scheduled high-dosed regimen (a higher dose in a regular daily schedule than registered or a higher dose in an alternative intermittent schedule) of TKIs in (haemato-)oncology. Data were extracted independently by two authors according to predefined criteria. Extracted data were tabulated to summarize key findings. RESULTS: Out of twenty studies that met the inclusion criteria, thirteen investigated higher daily dose schedules of either afatinib, axitinib, erlotinib, gefitinib, imatinib, sorafenib, and sunitinib. Five of these studies included pharmacokinetic analyses, reporting marginal higher maximum drug concentrations (Cmax) in plasma (1.3-4-fold higher) compared to the standard dose schedules. Seven clinical trials investigated intermittent high-dose schedules requiring treatment breaks, with the following TKIs: afatinib, erlotinib, gefitinib, lapatinib, sorafenib, and sunitinib. Six of these included pharmacokinetic results, all reporting higher (2-21-fold) Cmax in plasma compared to the standard daily dose schedule, with manageable toxicity. No data on tumor concentrations were presented. Data on the efficacy outcomes were limited due to small sample size, study designs, phase 1 population and heterogeneous tumor types. CONCLUSIONS: Early phase clinical studies show that high-dose intermittent TKI-treatment schedules can lead to an increased Cmax compared to standard (low-dose) daily administration with manageable toxicity. These higher concentrations are assumed to reflect higher intratumoral concentrations. Further investigation of the potential improvement in clinical benefit of a high-dose intermittent strategy with multitargeting TKIs is warranted.

Phase I Dose-Escalation Study of Once Weekly or Once Every Two Weeks Administration of High-Dose Sunitinib in Patients With Refractory Solid Tumors.

PURPOSE: Dose and schedule optimization of treatment with tyrosine kinase inhibitors is of utmost importance. On the basis of preclinical data, a phase I clinical trial of once weekly or once every 2 weeks administration of high-dose sunitinib in patients with refractory solid malignancies was conducted. PATIENTS AND METHODS: Patients with advanced cancer refractory to standard treatment were eligible. With use of a standard 3 + 3 phase I design, patients received escalating doses of sunitinib, in 100 mg increments, starting at 200 mg once weekly. In both the once weekly and once every 2 weeks cohorts, 10 more patients were included at the maximum tolerated dose level. Primary end points were safety and tolerability. RESULTS: Sixty-nine patients with advanced cancer, predominantly colorectal cancer (42%), were treated with this alternative dosing regimen. Maximum tolerated dose was established at 300 mg once weekly and 700 mg once every 2 weeks, resulting in nine- and 18-fold higher maximum plasma concentrations compared with standard dose, respectively. Treatment was well tolerated, with fatigue (81%), nausea (48%), and anorexia (33%) being the most frequent adverse events. The only grade 3 or 4 treatment-related adverse event in 5% or more of patients was fatigue (6%). Sixty-three percent of patients had significant clinical benefit, with a 30% progression-free survival of 5 months or more. CONCLUSION: Sunitinib administered once weekly at 300 mg or once every 2 weeks at 700 mg is feasible, with comparable tolerability as daily administration. Administration of 700 mg once every 2 weeks can be considered as the most optimal schedule because of the highest maximum plasma concentration being reached. The promising preliminary antitumor activity of this alternative schedule in heavily pretreated patients warrants further clinical evaluation and might ultimately indicate a class characteristic of tyrosine kinase inhibitors.

The 'morning dip' in antimicrobial appropriateness: circumstances determining appropriateness of antimicrobial prescribing.

Objectives: Quality of care has been shown to vary depending on the time of day or day of the week and depending on caregivers' gender and experience. We aimed to study how these factors influence quality of antimicrobial prescribing. Methods: Prospective point-prevalence surveys were performed to determine the association between the above-mentioned prescription factors and antimicrobial appropriateness. Surveys included cases of patients admitted to a tertiary care hospital with a prescribed systemic antimicrobial drug and its prescribers. The main outcome was appropriateness of antimicrobial prescriptions. A post hoc qualitative survey among hospital physicians asked physicians to reflect on the results. Results: The study included 351 antimicrobial prescriptions by 150 physicians prescribed for 276 patients. Appropriateness of antimicrobial prescribing in the morning was significantly lower compared with the afternoon and evening/night [43% versus 68% versus 70%, crude OR afternoon versus morning = 3.00 (95% CI = 1.60-5.48), crude OR evening/night versus morning = 3.40 (95% CI = 1.64-6.69)]. First-year residents performed significantly worse than their more experienced colleagues [51% versus 69%, crude OR = 2.09 (95% CI = 1.26-3.38)]. Infectious disease expert consultation improved appropriateness [54% versus 81%, crude OR = 3.71 (95% CI = 2.05-6.23)]. No significant effects for gender or office hours versus non-office hours were found. Post hoc survey results suggest creating room to improve prescribing circumstances during mornings and for inexperienced physicians. Conclusions: Antimicrobial prescribing was less appropriate in the mornings and when prescribed by inexperienced physicians. Appropriateness may be increased by improving prescribing circumstances.

Trends in incidence, treatment and survival of small bowel adenocarcinomas between 1999 and 2013: a population-based study in The Netherlands.

BACKGROUND: We conducted a population-based study to establish the incidence, treatment and overall survival over time of patients with small bowel adenocarcinoma. MATERIAL AND METHODS: All patients diagnosed with small bowel adenocarcinoma in the Netherlands between 1999 and 2013 were included (n = 1775). Age-standardized incidence rates were calculated per 100 000 person-years using the European standardized population rate. The influence of patient and tumor characteristics on the administration of chemotherapy was analyzed by means of a multivariable logistic regression analysis. The Cochran-Armitage trend test was conducted to evaluate trends in treatment and survival and the Cox proportional hazards model was used to identify prognostic factors of overall survival. RESULTS: The incidence of small bowel adenocarcinomas increased, mainly due to an almost twofold increase of duodenal adenocarcinomas. Patients with locoregional duodenal tumors were less likely to undergo surgery (58%), towards 95% of the locoregional jejunal and ileal tumors (p < 0.0001). The use of chemotherapy doubled for adjuvant (7-15%) and palliative chemotherapy (19-37%). Median overall survival of patients with locoregional disease increased from 19 to 34 months (p = 0.0006), whereas median overall survival of patients with metastatic disease remained 4-5 months. Favorable prognostic factors for prolonged survival in locoregional disease, identified by multivariable survival analysis, included age <60 years, tumor stage I or II, diagnosis in 2009-2013, surgical treatment and chemotherapy. Favorable prognostic factors for prolonged survival in metastatic disease were age <50 years, jejunal tumors, surgical treatment and chemotherapy. CONCLUSION: Small bowel adenocarcinomas are rare tumors with an increasing incidence. The administration of adjuvant and palliative chemotherapy doubled, but median overall survival only increased for patients with locoregional disease. Given the rarity and dismal prognosis, it is important to develop international studies to determine the optimal treatment for these patients.