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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

Background The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). Materials and Methods To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network–Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. Results Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19–positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. Conclusion Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic.

Item does not contain fulltext BACKGROUND: Pazopanib and sunitinib are oral tyrosine kinase inhibitors (TKI) approved for the treatment of renal cell carcinoma. For both oncolytics, a clear target trough concentration level in plasma has been defined above which improved clinical efficacy can be expected. However, many factors can alter TKI exposure, including disease characteristics. CASE: A 79-year old male with metastatic papillary renal cell carcinoma and malignant ascites was treated with pazopanib. Initially, treatment with pazopanib at adequate trough concentrations resulted in regression of ascites. After a 6-month puncture-free interval, paracenteses were again required and the plasma trough concentration of pazopanib had decreased to 5 mg/L without any dose adjustments. Despite a dose increase, pazopanib levels remained subtherapeutic and could not prevent new paracenteses. Pazopanib concentrations in the drained ascites fluid were comparable to plasma concentrations and remained high also after treatment discontinuation. This observation suggests that the ascites compartment may act as a third space in which pazopanib accumulates. During subsequent treatment with sunitinib, a similar distribution over ascites fluid was observed. CONCLUSION: Presence of ascites or pleural effusion in patients treated with TKIs may lead to subtherapeutic plasma exposure, which may hamper treatment efficacy. Measuring TKIs plasma concentrations regularly during treatment is essential to identify patients with subtherapeutic exposure.

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 : 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.

BackgroundTesticular cancer (TC) survivors have an increased risk of various second primary malignancies. A recent cohort study detected an increased risk of colorectal cancer (CRC) in TC survivors treated with platinum-based chemotherapy with a hazard ratio of 3.9. CRC risk increased with higher cisplatin-dose. We know that colonoscopy surveillance in high-risk populations results in reduced incidence and mortality of CRC. TC survivors treated with platinum-based chemotherapy can potentially benefit from colonoscopy surveillance; however, to which extent is unknown. Furthermore, the pathogenesis of these secondary CRCs is unknown, and better insights into the carcinogenesis may affect surveillance decisions.MethodsThis prospective multicenter study will be performed in four Dutch hospitals. TC survivors are eligible if treated with ≥ 3 cycles of cisplatin before age 50. Colonoscopy will be performed ≥ 8 years after initial treatment (minimum and maximum ages at colonoscopy, 35 and 75 years, respectively). The primary aim of the study is the diagnostic yield of advanced neoplasia detected during colonoscopy. As secondary aim, we will evaluate the molecular profile of advanced colorectal neoplasia and will assess current platinum levels in blood and urine and correlate blood-platinum levels with prevalence of colorectal lesions. Furthermore, we will investigate effectiveness of fecal immunochemical testing (FIT) and burden of colonoscopy by two questionnaires. Demographic data, previous history, results of colonoscopy, hemoglobin level of FIT and results of molecular and platinum levels will be obtained. Yield of colonoscopy will be determined by detection rate of adenoma and serrated lesions, advanced adenoma detection rate and CRC detection rate. The MISCAN model will be used for cost-effectiveness analyses of CRC surveillance. With 234 participants undergoing colonoscopy, we can detect an absolute difference of 6% of advanced neoplasia with 80% power.DiscussionTC survivors treated with cisplatin-based chemotherapy can benefit from CRC surveillance. Evaluation of the diagnostic performance and patient acceptance of CRC surveillance is of importance to develop surveillance recommendations. Insight into the carcinogenesis of cisplatin-related advanced colorectal lesions will contribute to CRC prevention in the increasing number of TC survivors. The results may also be important for the many other cancer survivors treated with platinum-based chemotherapy.Trial registrationClinical Trials: NCT04180033, November 27, 2019,https://clinicaltrials.gov/ct2/show/NCT04180033.

Contains fulltext : 232106.pdf (Publisher’s version ) (Open Access) AIM: Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). Because of the large interpatient pharmacokinetic variability and established exposure-response and exposure-toxicity relationships in clinical trial patients, therapeutic drug monitoring (TDM) seems promising for optimizing sunitinib exposure. We aimed to investigate the relationship between sunitinib exposure and treatment outcome in a real-world patient cohort. METHODS: We performed a retrospective observational cohort study in 53 patients with metastatic RCC and 18 patients with metastatic GIST treated with sunitinib and receiving TDM-guided dosing. Time on treatment - as a surrogate for progression-free survival - in patients who achieved adequate sunitinib exposure was compared with patients who did not. Additionaly, the median sunitinib exposure was compared in patients with or without sunitinib-induced toxicity leading to dose reduction. RESULTS: The median time on treatment in patients with RCC who achieved adequate sunitinib exposure (n = 39) was 32 weeks, compared to 15 weeks in patients who did not achieve adequate sunitinib exposure (n = 12) (P = 0.244). In 29 patients (41%) with toxicity leading to dose reduction, sunitinib sum plasma trough concentration (C(trough) ) until dose reduction was significantly higher compared to patients without toxicity leading to dose reduction (median 60 ng/mL vs 44 ng/mL; P < 0.001) and reduced to comparable levels after dose reduction (44 ng/mL; P = 0.488). CONCLUSION: In our real-world patient cohort, patients with sunitinib-induced toxicity requiring dose reduction had significantly higher sunitinib exposure compared to patients without toxicity. The threshold for toxicity, however, was lower compared to that previously described in clinical trials.

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.

Contains fulltext : 218257.pdf (Publisher’s version ) (Open Access) BACKGROUND AND PURPOSE: The aim of this study was to assess the prevalence of cancer and its characteristics in patients with ischemic stroke and to compare this with cancer prevalence in the general population. METHODS: This was a multicenter cohort study with 2736 patients presenting with ischemic stroke or transient ischemic attack. The prevalence of cancer was assessed by interview and verified by reviewing all medical records. In stroke patients with a history of cancer, we studied the subtype of cancer and its treatment characteristics. We used the national database of The Netherlands Cancer Registry to calculate population-based age and sex cancer standardized prevalence ratios (SPRs) for patients with ischemic stroke. RESULTS: Cancer prevalence in ischemic stroke patients was 12%, corresponding to an SPR of 1.2 [95% confidence interval (CI), 1.0-1.3]. Increased SPRs were observed for cancer of the central nervous system (SPR, 18.2; 95% CI, 9.0-27.4), head and neck (SPR, 3.4; 95% CI, 2.3-4.6), lower respiratory tract (SPR, 2.4; 95% CI, 1.5-3.3) and urinary tract (SPR, 2.1; 95% CI, 1.4-2.9), but not for other cancer types. Cardiovascular risk factors, stroke etiology, treatment and outcome were not different between patients with or without a history of cancer. CONCLUSIONS: In stroke patients, the prevalence of cancer, most prominently cancer of the central nervous system, head and neck, lower respiratory and urinary tract, was higher than in the general population. Medical treatment for the prevention of stroke in cancer survivors deserves further study.

Background Cabozantinib is approved for treatment of renal cell cancer (RCC) in a starting dose of 60 mg. However, in the registration studies dose reductions were needed in 46-62% of patients due to toxicity. Improved clinical efficacy of cabozantinib was observed in RCC patients with an average exposure of > 750 ug/L. Data about cabozantinib pharmacokinetics in patients routinely treated with this drug is scarce, while treatment is challenging due to toxicity. Therefore, we explored the cabozantinib exposure in patients with two different tumour types in our clinic. Methods Clinical data and cabozantinib trough concentrations (Cmin) were collected from all patients treated with cabozantinib with at least one measured Cmin at steady state in our clinic between Jan 2018 - Aug 2020. We included salivary gland cancer (SGC) patients treated in a phase II study and RCC patients from our outpatient clinic. Geometric mean (GM) Cmin at the start dose, at 40 mg and at best tolerated dose (BTD) were compared between the two tumour types. Results In total 47 patients were included. All patients with SGC (n=22) started with 60 mg, while 13 of 25 patients with RCC started with 40 mg. GM Cmin level at the start dose was 1350 µg/L (95% CI 1182-1781) vs. 689 µg/L (95% CI 576-823) (P750 ug/L. Conclusion Unexpectedly, cabozantinib levels were significantly higher in patients with SGC compared to those with RCC at the dose of 40 mg. However, cabozantinib levels at BTD were comparable between patients with SGC and RCC. At BTD, the majority of patients did not reach the target of >750 µg/L. For most patients with RCC, the cabozantinib level at BTD corresponded to a dose of 40 mg. Therefore, 40 mg instead of 60 mg as a starting dose followed by dose-adjustment based on exposure and tolerability may be preferred in patients with RCC. Although cabozantinib is not registered for SGC, an even lower starting dose of 20 mg/day may be required in these patients based on cabozantinib levels at BTD. Future studies should focus on identifying an optimal and tolerable exposure-response target value for cabozantinib and elucidate factors that contribute to the differences in exposure, in order to individualise and improve treatment. Citation Format: Stefanie D. Krens, Wim van Boxtel, Maike J. Uijen, Frank G. Jansman, Ingrid M. Desar, Sasja F. Mulder, Carla M. van Herpen, Nielka P. van Erp. Exposure-toxicity analysis of cabozantinib in patients with salivary gland cancer and renal cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1363.

AIM Fixed dose oral tyrosine kinase inhibitors imatinib, sunitinib and pazopanib show a high interpatient variability in plasma exposure. A relationship between plasma exposure and treatment outcome has been established, which supports the rationale for dose optimization of these drugs. The aim of this study was to monitor how many patients reached adequate trough levels after therapeutic drug monitoring-based dose optimization in daily practice. METHODS A cohort study was performed in patients treated with imatinib, sunitinib or pazopanib of whom follow-up drug levels were measured between August 2012 and April 2016. Patients' characteristics were collected by reviewing electronic patient records. Drug levels were measured using high-performance liquid chromatography coupled with tandem mass spectrometry and trough levels were estimated using a predefined algorithm. Dose interventions were proposed based on trough levels. RESULTS In total, 396 trough levels were determined in 109 patients. Median sample frequency per patient was 3. During the first measurement only 38% of patients showed trough levels within the predefined target ranges despite standard dosing; 52% of the patients showed drug levels below and 10% above the target range. In 35 out of 41 patients (85%) dose interventions led to adequate trough levels. Eventually, 64% of the total cohort reached adequate trough levels. CONCLUSIONS Dose optimization proved an effective tool to reach adequate trough levels in patients treated with imatinib, sunitinib and pazopanib. The percentage of patients with adequate trough levels increased from 38 to 64%. Therapeutic drug monitoring may add to the improvement of efficacy and reduction of toxicity and costs of these treatments.

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.

Contains fulltext : 170106.pdf (Publisher’s version ) (Open Access) Background Diarrhea is a frequently occurring adverse event during treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and is mostly accompanied by abdominal cramps, flatulence and pyrosis. These complaints impair quality of life and lead to dose reductions and treatment interruptions. It is hypothesized that the diarrhea might be due to ischemia in bowel mucosa or inflammation, but the exact underlying pathophysiological mechanism of the diarrhea is still unknown. We aimed at exploring the mechanism for diarrhea in these patients by thorough endoscopic and histological assessment. Materials and methods Endoscopies of the upper and lower gastrointestinal (GI) tract in 10 patients with metastatic renal cell carcinoma (mRCC) who developed diarrhea during treatment with VEGFR TKIs were performed. Results Ten patients were included. The results showed endoscopically normal mucosa in the lower GI tract in seven patients without signs of ischemic colitis or inflammation. Gastroduodenoscopy revealed gastro-esophageal reflux disease, bulbitis and/or duodenitis with ulcers in eight patients. In three selected patients with bulbitis/duodenitis additional video capsule endoscopy was performed but revealed no additional intestinal abnormalities. Conclusion We observed frequent mucosal abnormalities in the upper GI tract in VEGFR TKI-treated mRCC patients with diarrhea. Although these abnormalities provide insufficient explanation for the occurrence of diarrhea, we suggest to perform routine upper GI endoscopy in VEGFR TKI-treated patients with GI complaints.

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.

Based on the high expression of carbonic anhydrase IX (CAIX) in 95% of clear cell renal cell carcinoma (ccRCC), the anti-CAIX monoclonal antibody girentuximab can be used for the detection of ccRCC. This clinical study explores the value of 89Zr-labeled girentuximab positron emission tomography/computed tomography (PET/CT) imaging in diagnostic challenges regarding ccRCC. PET/CT imaging was performed 4 or 5 d after injection of 89Zr-girentuximab in patients with a primary renal mass (n=16) or a history of ccRCC (n=14). Scans were used for decision making (surgery/active surveillance) in case of indistinct renal masses. All resected PET-positive primary lesions proved to be ccRCC, while no lesion progression was seen in PET-negative masses. In patients suspected of recurrent/metastatic ccRCC, PET/CT with 89Zr-girentuximab was useful to confirm or exclude ccRCC, evaluate the extent of the disease, and differentiate from other cancers. In this group, 89Zr-girentuximab PET/CT resulted in a major change in clinical management in five patients (36%), while in three patients (21%) repeat biopsies could be avoided. We conclude that 89Zr-girentuximab PET/CT is a valuable diagnostic tool that can guide clinical decision making in case of diagnostic dilemmas concerning ccRCC suspicion. Patient summary Positron emission tomography/computed tomography imaging with 89Zr-girentuximab can be a valuable diagnostic tool to identify clear cell renal cell carcinoma.

The aim of this study was to compare humoral and cellular immune responses to influenza vaccination in cancer survivors with and without severe symptoms of fatigue. Severely fatigued (n = 15) and non-fatigued (n = 12) disease-free cancer survivors were vaccinated against seasonal influenza. Humoral immunity was evaluated at baseline and post-vaccination by a hemagglutination inhibition assay. Cellular immunity was evaluated at baseline and post-vaccination by lymphocyte proliferation and activation assays. Regulatory T cells were measured at baseline by flow cytometry and heat-shock protein 90 alpha levels by ELISA. Comparable humoral immune responses were observed in fatigued and non-fatigued patients, both pre- and post-vaccination. At baseline, fatigued patients showed a significantly diminished cellular proliferation upon virus stimulation with strain H3N2 (1414 ± 1201 counts), and a trend in a similar direction with strain H1N1 (3025 ± 2339 counts), compared to non-fatigued patients (3099 ± 2401 and 5877 ± 4604 counts, respectively). The percentage of regulatory T lymphocytes was significantly increased (4.4 ± 2.1% versus 2.4 ± 0.8%) and significantly lower amounts of interleukin 2 were detected prior to vaccination in fatigued compared to non-fatigued patients (36.3 ± 44.3 pg/ml vs. 94.0 ± 45.4 pg/ml with strain H3N2 and 28.4 ± 44.0 pg/ml versus 74.5 ± 56.1 pg/ml with strain H1N1). Pre-vaccination heat-shock protein 90 alpha concentrations, post-vaccination cellular proliferation, and post-vaccination cytokine concentrations did not differ between both groups. In conclusion, influenza vaccination is favorable for severely fatigued cancer survivors and should be recommended when indicated. However, compared to non-fatigued cancer survivors, fatigued cancer survivors showed several significant differences in immunological reactivity at baseline, which warrants further investigation.

Contains fulltext : 136260.pdf (Publisher’s version ) (Closed access) Malignant ascites and pleural effusion are challenging clinical problems, with a major impact on quality of life. We conducted a randomized phase II trial to assess the palliative value of cediranib, an oral vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). After a baseline paracentesis or thoracentesis (on day 0), patients with symptomatic malignant ascites and/or pleural effusion were randomized between immediate treatment with cediranib (Immediate Cediranib) or delayed treatment with cediranib (Delayed Cediranib) on day 29, or after a new puncture was needed. The primary objective of the study was the puncture-free survival, defined as the time from study start (day 1) to the first need for paracentesis or thoracentesis, or time to death, whichever event occurred first. Twelve patients were enrolled. The median puncture-free survival was 45 days (range 10-368) in the Immediate Cediranib patients and 7 days (range 4-13) in the Delayed Cediranib patients (P = 0.011). The change in puncture-free interval (the puncture-free survival after study start minus the puncture-free interval before study start) increased with a median of 31 days in the Immediate Cediranib patients and shortened with a median of 3 days in the Delayed Cediranib patients (P = 0.015). The most common adverse events were fatigue and anorexia. In conclusion, cediranib increased the puncture-free survival and puncture-free interval with an acceptable toxicity profile. This is the first study in which an oral VEGFR TKI showed beneficial palliative effects in patients with malignant effusions.

1062Background: Treating breast cancer patients (BC pts) with everolimus and exemestane can be challenging due to toxicity and suboptimal treatment responses. We investigated whether everolimus exp...

Purpose Sunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen. Patients and Methods Eligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures. Results One hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM. Conclusion Sunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.

Item does not contain fulltext With the emergence of novel angiogenesis inhibitors, we are moving to a new era for patients with metastasized renal cell carcinoma. Since the results achieved reflect more a modification of the natural course of the disease than a cure, past achievements should not be neglected. Low-risk patients with clear cell histology, especially those with pulmonary metastasis only, should still be offered cytokine therapy. For intermediate-risk patients sunitinib is the treatment of choice. For high-risk patients, temsirolimus has to date provided the most convincing data, its availability is however limited. Data with sorafenib and sunitinib in the high-risk group are still anecdotal. The toxicity profiles of these 2 drugs are different and might particularly relate to patients with known cardiovascular co-morbidity. No sufficient data are available regarding sequential use. After cytokine failure, sorafinib is the treatment of choice. Patients should preferably be treated within clinical trials to answer unaddressed questions. It is well known that the strict entry criteria used within the clinical studies were applied very flexibly when drugs have been approved. These aspects require a careful follow-up to ascertain optimal use and to prevent misuse. Finally, the costs of prolonged treatment will be enormous, and only meaningful survival advantages will convince the health authorities to make these new treatments available for all patients.

Contains fulltext : 133887pub.pdf (Publisher’s version ) (Closed access) Sunitinib is a multiple tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor pathway and inhibits angiogenesis, cell proliferation, and tumor cell invasion, and stimulates apoptosis. Treatment with sunitinib in first-line metastatic renal cell carcinoma improves progression-free survival and overall survival compared with interferon-alpha. Crohn's disease is characterized by chronic immune-mediated intestinal inflammation. Although the exact pathogenesis of Crohn's disease remains unknown, the involvement of angiogenesis is acknowledged. It is unknown whether sunitinib interferes with the natural course of Crohn's disease. We describe a patient with metastatic renal cell carcinoma and a history of Crohn's disease who was treated with sunitinib and developed a severe exacerbation of Crohn's disease. After rechallenge with sunitinib, a second exacerbation occurred. We therefore conclude that angiogenesis inhibitors should be administered with care in patients with a history of Crohn's disease.

Contains fulltext : 134069.pdf (Publisher’s version ) (Open Access) Prostate cancer (PCa) is the most common cancer in men and the second most common cause of cancer-related death in men. In recent years, novel therapeutic options for PCa have been developed and studied extensively in clinical trials. Sipuleucel-T is the first cell-based immunotherapeutic vaccine for treatment of cancer. This vaccine consists of autologous mononuclear cells stimulated and loaded with an immunostimulatory fusion protein containing the prostate tumor antigen prostate acid posphatase. The choice of antigen might be key for the efficiency of cell-based immunotherapy. Depending on the treatment strategy, target antigens should be immunogenic, abundantly expressed by tumor cells, and preferably functionally important for the tumor to prevent loss of antigen expression. Autoimmune responses have been reported against several antigens expressed in the prostate, indicating that PCa is a suitable target for immunotherapy. In this review, we will discuss PCa antigens that exhibit immunogenic features and/or have been targeted in immunotherapeutic settings with promising results, and we highlight the hurdles and opportunities for cancer immunotherapy.

Contains fulltext : 125443.pdf (Publisher’s version ) (Open Access) BACKGROUND: Bleomycin has become an integral part of chemotherapy in patients with germ-cell tumors. One of the most feared side effects is bleomycin-induced pneumonitis. In patients with mild or moderate BIP, radiological signs disappear almost completely within nine months after discontinuation of bleomycin treatment. CASE PRESENTATION: We present a patient with a history of non seminoma of the testis and bleomycin-induced pneumonitis. During follow-up, regression of the hypothesis of eosinophilic migration to the liver after regression of bleomycin-induced pneumonitis is highly suspicious based on transient eosinophilia and focal eosinophilic liver disease. CONCLUSION: As follow up may consist of CT scanning in germ-line tumor patients, transient eosinophilic liver lesions reported during regressive bleomycin-induced pneumonitis should not be presumed automatically as metastatic tumor relapse and require further sequential imaging and pathological examination.

Contains fulltext : 134074.pdf (Publisher’s version ) (Open Access) Background: Impairment of cognitive functioning has been reported in several studies in patients treated with chemotherapy. So far, no studies have been published on the effects of the vascular endothelial growth factor receptor (VEGFR) inhibitors on cognitive functioning. We investigated the objective and subjective cognitive function of patients during treatment with VEGFR tyrosine kinase inhibitors (VEGFR TKI). Methods: Three groups of participants, matched on age, sex and education, were enrolled; 1. metastatic renal cell cancer (mRCC) or GIST patients treated with sunitinib or sorafenib (VEGFR TKI patients n = 30); 2. patients with mRCC not receiving systemic treatment (patient controls n = 20); 3. healthy controls (n = 30). Sixteen neuropsychological tests examining the main cognitive domains (intelligence, memory, attention and concentration, executive functions and abstract reasoning) were administered by a neuropsychologist. Four questionnaires were used to assess subjective cognitive complaints, mood, fatigue and psychological wellbeing. Results: No significant differences in mean age, sex distribution, education level or IQ were found between the three groups. Both patient groups performed significantly worse on the cognitive domains Learning & Memory and Executive Functions (Response Generation and Problem Solving) compared to healthy controls. However only the VEGFR TKI patients showed impairments on the Executive subdomain Response Generation. Effect sizes of cognitive dysfunction in patients using VEGFR TKI were larger on the domains Learning & Memory and Executive Functions, compared to patient controls. Both patients groups performed on the domain Attention & Concentration the same as the healthy controls. Longer duration of treatment on VEGFR TKI was associated with a worse score on Working Memory tasks. Conclusions: Our data suggest that treatment with VEGFR TKI has a negative impact on cognitive functioning, specifically on Learning & Memory, and Executive Functioning. We propose that patients who are treated with VEGFR TKI are monitored and informed for possible signs or symptoms associated with cognitive impairment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01246843. 10 p.

Item does not contain fulltext Weight loss, cachexia and sarcopenia are profound problems in the frail oncologic patients. With the development and increasing use of angiogenesis inhibitors in metastatic cancer patients, the question arises as to their influence on body weight and composition. Angiogenesis is not only important for the growth, development and metastatic potential of tumors but also for physiological processes in adipogenesis. A less known approach of angiogenesis inhibitors is their experimental use in obese models. This review focuses on the effects on the body weight and composition of angiogenesis inhibitors, especially of those targeting the vascular endothelial growth factor pathway. 01 februari 2012

Contains fulltext : 108175.pdf (Publisher’s version ) (Open Access) ABSTRACT: BACKGROUND: Chronic fatigue syndrome (CFS) is a clinical condition characterized by severe and disabling fatigue that is medically unexplained and lasts longer than 6 months. Although it is possible to effectively treat CFS, the nature of the underlying physiology remains unclear. Various studies have sought evidence for an underlying disturbance in immunity. The aim of this study was to compare the humoral and cellular immune responses upon influenza vaccination in CFS patients and healthy controls. RESULTS: Identical antibody titers were observed in CFS patients and healthy controls. Patients and controls demonstrated similar seroprotection rates against all three virus-strains of the influenza vaccine, both pre- and post-vaccination. Functional T cell reactivity was observed in both CFS patients and healthy controls. CFS patients showed a non-significant, numerically lower cellular proliferation at baseline compared to controls. Vaccination induced a significant increase in cellular proliferation in CFS patients, but not in healthy controls. Cytokine production and the number of regulatory T cells were comparable in patients and controls. CONCLUSIONS: The humoral and cellular immune responses upon influenza vaccination were comparable in CFS patients and healthy controls. Putative aberrations in immune responses in CFS patients were not evident for immunity towards influenza. Standard seasonal influenza vaccination is thus justified and, when indicated, should be recommended for patients suffering from CFS.

Purpose: The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib. Patients and Methods: Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines. Results: Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls. Conclusion: We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib. Clin Cancer Res; 17(13); 4541–9. ©2011 AACR.

The vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib is a first-line treatment in most patients with metastatic renal cell carcinoma. No psychiatric adverse events have previously been reported. We describe two patients with psychotic symptoms, during treatment with sunitinib. Possible mechanisms of sunitinib-induced psychosis are discussed.

The development of angiogenesis inhibitors introduced a new era in the treatment of metastatic renal cell carcinoma (mRCC). By now, sunitinib and sorafenib both multiple tyrosine kinase inhibitors ...

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.

e15596 Background: Diarrhea is a frequently occurring adverse event of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs). It impairs quality of life...

e14014 Background: Despite recent advances in treatment of metastatic clear cell renal cell carcinoma (ccRCC), the search for alternative treatment modalities, which can induce durable responses wi...

9070 Background: Postcancer fatigue (PCF) is a frequently occurring problem, impairing quality of life. Patients with chronic fatigue syndrome (CFS) also suffer from severe fatigue symptoms. We hypothesized that in fatigued patients (PCF and CFS) alterations in immune response could explain fatigue symptoms. Therefore, we examined whether the humoral and/or cellular immune response after influenza vaccination differed between fatigued patients and non-fatigued individuals and between PCF and CFS patients. Methods: PCF (n=15) and CFS patients (n=22) were vaccinated against influenza. Age and gender matched non-fatigued cancer survivors (n=12) and healthy controls (n=23) were included for comparison. Antibody responses were measured at baseline and at day 21 by a hemagglutination inhibition test. T cell responses were measured at baseline and at day 7 by a lymphocyte proliferation and activation assay. Results: Both patient groups developed seroprotection rates comparable to the accompanying control groups. Functional T cell reactivity was observed in all groups. Proliferation at baseline was significantly lower in fatigued patients compared to non-fatigued individuals. A significant increase in proliferation from baseline to day 7 was observed in fatigued patients, but not in controls. At day 7, proliferation was not significantly different between fatigued patients and non-fatigued individuals. CD4+CD127-FoxP3+ expression was significantly higher in PCF patients compared to non-fatigued cancer survivors. Conclusions: We observed a lower T cell proliferation at baseline in fatigued patients compared to non-fatigued individuals, suggesting a difference in the baseline state of the immune system between fatigued patients and non-fatigued individuals. Furthermore, the difference in CD4+CD127-FoxP3+ expression between PCF and CFS patients suggests subtle differences in immune state between these two fatigued patient groups. However, since humoral and cellular immune responses after vaccination did not differ significantly between fatigued patients and non-fatigued individuals, vaccination of fatigued patients (PCF and CFS) can be effective.

Angiomatoid fibrous histiocytoma is an uncommon soft-tissue tumor of intermediate malignancy that is often misdiagnosed initially. As there is not one immunohistochemical marker that consequently stains positive or negative for angiomatoid fibrous histiocytoma, molecular diagnostics are becoming more widely used. So far three translocations have been reported to arise in angiomatoid fibrous histiocytoma: FUS-ATF1, EWSR1-CREB1, or EWSR1-ATF1. We present a case of angiomatoid fibrous histiocytoma on the upper arm of a 40-year-old female, which was initially misdiagnosed as metastatic melanoma in a lymph node. Revision of the pathology revealed an angiomatoid fibrous histiocytoma, which was later confirmed by a EWSR1-CREB1 translocation with molecular diagnostics. Furthermore, we review the relevant literature and provide an overview of all available case reports in the past ten years. This case report illustrates the importance for pathologists of knowing the typical pathology features of AFH and integrating immunohistochemical and molecular findings in order to prevent overdiagnosis of lymph node metastasis of a malignancy.