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Contains fulltext : 249093.pdf (Publisher’s version ) (Open Access) Cabozantinib is registered in fixed 60 mg dose. However, 46% to 62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure greater than 750 μg/L. In our study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured C(min) at steady-state. The geometric mean (GM) C(min) at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM C(min) at the start dose was 1456 μg/L (95% CI: 1185-1789) vs 682 μg/L (95% CI: 572-812) (P

Contains fulltext : 208839.pdf (Publisher’s version ) (Closed access) Pazopanib is taken fasted in a fixed oral daily dose of 800 mg. We hypothesized that ingesting pazopanib with food may improve patients' comfort and reduce gastrointestinal (GI) adverse events. Therefore, we investigated the bioequivalent dose of pazopanib when taken with food compared with 800 mg pazopanib taken fasted. In addition, we investigated the differences in GI toxicity, patient satisfaction, and patient's preference for either intake. The intake of 600 mg pazopanib with food resulted in a bioequivalent exposure and was preferred over a standard pazopanib dose without food. No differences were seen in GI toxicities under both intake regimens. Patients seem to be more positive about their feelings about side effects and satisfaction with their therapy when pazopanib was taken with food. Forty-one of the patients (68%) preferred the intake with a continental breakfast.

Nivolumab has been approved as second-line treatment for advanced renal cell carcinoma in Europe. We performed a real-world analysis to validate this practice. The study included 264 patients from 24 hospitals in the Netherlands. We found that toxicity and efficacy of nivolumab are comparable with previous results. Increase in eosinophil count was the strongest predictor of improved survival. Results can be used to improve personalized therapy.Background: Nivolumab, a programmed death 1 inhibitor, has been approved as secondline treatment for advanced renal cell carcinoma (RCC) in Europe since 2016. We investigated the toxicity and efficacy of nivolumab as well as potential predictive biomarkers in the Dutch population. Patients and Methods: This was a retrospective, multicenter study of the Dutch national registry of nivolumab for the treatment of advanced RCC. The main outcome parameters included toxicity, objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and time to treatment failure (TTF). In addition, potential predictive and prognostic biomarkers for outcomes were evaluated. Results: Data on 264 patients were available, of whom 42% were International Metastatic RCC Database Consortium (IMDC) poor risk at start of nivolumab, 16% had >= 3 lines of previous therapy, 7% had noneclear-cell RCC, 11% had brain metastases, and 20% were previously treated with everolimus. Grade 3/4 immune-related adverse events occurred in 15% of patients. The median OS was 18.7 months (95% confidence interval, 13.7-23.7 months). Progression occurred in 170 (64.4%) of 264 patients, with a 6-and 12months TTP of 49.8% and 31.1%, respectively. The ORR was 18.6% (49 of 264; 95% confidence interval, 14%-23%). Elevated baseline lymphocytes were associated with improved PFS (P=.038) and elevated baseline lactate dehydrogenase with poor OS, PFS, and TTF (P=.000). On-treatment increase in eosinophils by week 8 predicted improved OS (P=.003), PFS (P=.000), and TTF (P=.014), whereas a decrease of neutrophils was associated with significantly better TTF (P=.023). Conclusions: The toxicity and efficacy of nivolumab for metastatic RCC after previous lines of therapy are comparable with the results in the pivotal phase III trial and other real-world data. On-treatment increase in eosinophil count is a potential biomarker for efficacy and warrants further investigation. (C) 2020 Elsevier Inc. All rights reserved.

Contains fulltext : 229162.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Radical cystectomies (RCs) are increasingly centralized, but bladder cancer can be diagnosed in every hospital The aim of this study is to assess the variation between hospitals of diagnosis in a patient's chance to undergo a RC before and after the volume criteria for RCs, to identify factors associated with this variation and to assess its effect on survival. METHODS AND MATERIALS: Patients diagnosed with muscle-invasive bladder cancer (cT2-4a,N0/X,M0/X) without nodal or distant metastases between 2008 and 2016 were identified through the Netherlands Cancer Registry. Multilevel logistic regression analysis was used to investigate the hospital specific probability of undergoing a cystectomy. Cox proportional hazard regression analysis was used to assess the case-mix adjusted effect of hospital-specific probabilities on survival. RESULTS: Of the 9,215 included patients, 4,513 (49%) underwent a RC. The percentage of RCs varied between 7% and 83% by hospital of diagnosis before the introduction of the first volume criteria (i.e., 2008-2009; minimum of 10 RCs). This variation decreased slightly to 17%-77% after establishment of the second volume criteria (i.e., 2015-2016; minimum of 20 RCs). Age, cT-stage and comorbidity were inversely and socioeconomic status was positively associated with RC. Both being diagnosed in a community hospital and/or being diagnosed in a hospital fulfilling the RC volume criteria were associated with increased use of RC compared to academic hospitals and hospitals not fulfilling the volume criteria. For each 10% increase in the percentage of RC in the hospital of diagnosis, 2-year case-mix adjusted survival increased 4% (hazard ratio 0.96, 95% confidence interval 0.94-0.98). CONCLUSION: Probability of RC varied between hospitals of diagnosis and affected 2-year overall survival. Undergoing a RC was associated with age, cT-stage, socioeconomic status, type of hospital, and whether the hospital of diagnosis fulfilled the RC volume criteria. Future research is needed to identify patient, tumor, and hospital characteristics affecting utilization of curative treatment as this may benefit overall survival.

4564 Background: Pazopanib has been licensed for advanced soft tissue sarcoma and metastatic renal cell carcinoma in a fixed oral daily dose of 800mg taken fasted. We hypothesized that ingesting pazopanib with food may improve patients’ comfort and reduce gastro-intestinal adverse events. Moreover, a food intervention, resulting in a better absorption, can lead to a lower dose, which could significantly reduce treatment costs. Methods: Part 1 of the study was performed to determine whether 600mg pazopanib taken with a continental breakfast was bioequivalent to 800mg pazopanib taken fasted. In part 2, differences in GI-toxicity and patient satisfaction were assessed by the cancer-therapy-satisfaction-questionnaire after both intake regimens. Finally, patient’s preference for either intake regimen was asked. Results: 16 patients were included in the bioequivalence study. The geometric mean ratio (fed/fasted) of the area under the plasma concentration time curve was 1.10 (90% CI 1.00-1.19), maximum peak concentration was 1.12 (90% CI 1.02-1.22) and pazopanib trough concentration was 1.10 (90% CI 1.02-1.18). In part 2, 60 patients were included. No differences were seen in the occurrence of GI-toxicities under both intake regimens. Patients seem to be more positive about their feelings about side effects (72.3(95% CI 68.1-76.5) vs 68·2 (62.7-73.6); p=.092) and satisfaction with therapy scores were higher (84.7(95% CI 81.4-87.9) vs 81.9 (78.7-85.2); p= .059) when pazopanib was taken with food. 41 (68%) of the patients preferred the intake with continental breakfast. Conclusions: Intake of 600mg pazopanib with food results in bioequivalent exposure and was preferred over a standard pazopanib dose without food. Moreover, with this simple food intervention a large cost reduction can be realized in patients treated with pazopanib. Clinical trial information: NCT02138526.

Background: Treating breast cancer patients with everolimus and exemestane can be challenging due to toxicity and suboptimal treatment responses. Objective: We investigated whether everolimus exposure and early metabolic response are predictors for toxicity and effectiveness in these patients. Patients and Methods: We performed pharmacokinetic assessments 14 and 35 days after starting treatment. [18F]fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) was performed at baseline, and 14 and 35 days after the start of the therapy. We recorded toxicity, defined as dose interventions within 3 months, and progression-free survival (PFS). Results: Among 44 evaluable patients, the geometric mean (GM) Ctrough was higher in patients with toxicity compared to patients without (17.4 versus 12.3 μg/L (p = 0.02)). The optimal cut-off value to predict toxicity was Ctrough > 19.2 μg/L. GM Ctrough of patients with and without progressive disease (PD) within 3 months was not significantly different (12.0 versus 15.2 μg/L (p = 0.118)). In 28 evaluable patients, PD within 3 months could best be predicted using the percentage decrease in peak standardized uptake value normalized by lean body mass of the lesion with highest FDG uptake (SULpeak high) at day 14. Patients with 11% decrease in SULpeak high at day 14 had a median PFS of 90 days versus 411 days, respectively (p = 0.0013) and more frequently had PD within 3 months: 70 vs 11%, respectively. Conclusions: Our results show that everolimus toxicity is related to everolimus Ctrough. No relation was observed between everolimus exposure and treatment effectiveness. An early FDG-PET can identify patients at high risk of nonresponse. These results warrant further validation. Clinicaltrials.gov identifier: NCT01948960.

Contains fulltext : 80319.pdf (Publisher’s version ) (Closed access) Residents report that they received inadequate teaching in palliative care and low levels of comfort and skills when taking care of dying patients. This study describes the effects of a problem-based palliative care course on perceived competence and knowledge in a representative Dutch cohort of residents in internal medicine. Before and after the course, we carried out a questionnaire survey and knowledge test in 91 residents. The results show that many residents felt they had limited competence or were incompetent when taking care of patients in the palliative care phase. This was particularly true with respect to communication concerning euthanasia and physician-assisted suicide or hastened death (86% and 85% respectively reported limited competence or incompetence). Participants reported that they received inadequate training in palliative care and believed that specific education would make them feel more competent. The number of times that residents were engaged in palliative care situations and the years of clinical experience had a positive influence on perceived competence. Participating in the course improved perceived competence and knowledge in palliative care. No correlation was found between perceived competence and knowledge of palliative care.