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BACKGROUND: This study aims to investigate the occurrence of unplanned hospitalizations in older patients with cancer and to determine predictive factors. METHODS: A prospective Belgian multicentre (n = 22), observational cohort study was performed. Patients ≥70 years with a malignant tumor were included. Patients underwent G8 screening followed by geriatric assessment (GA) if abnormal at baseline and were followed for unplanned hospitalizations at approximately three months. Uni- and multivariable regression models were performed to determine predictive factors associated with unplanned hospitalizations in older patients with an abnormal G8. RESULTS: In total, 7763 patients were included in the current analysis of which 2409 (31%) patients with a normal G8 score and 5354 (69%) with an abnormal G8 score. Patients with an abnormal G8 were hospitalized more frequently than patients with a normal G8 (22.9% versus 12.4%; p

BACKGROUND: Previously, we have shown a correlation between single nucleotide polymorphism (SNP) rs307826 in vascular endothelial growth factor receptor-3 (VEGFR3) and outcome in metastatic clear-cell renal cell carcinoma (m-ccRCC) patients treated with sunitinib. OBJECTIVE: We aimed to validate this finding in an independent patient series. METHODS: m-ccRCC patients receiving sunitinib as first-line targeted therapy were included in a validation cohort. Endpoints were response rate (RR), progression-free survival (PFS) and overall survival (OS). We also updated survival data of our discovery cohort as described previously. RESULTS: Eighty-four patients were included in the validation cohort. rs307826 AG/GG-carriers had a shorter PFS (8 versus 12 months, p = 0.04) and a trend towards a shorter OS (18 versus 27 months, p = 0.22) compared to AA-carriers. In the total series of 168 patients (from the discovery cohort, as described previously, and the validation cohort), rs307826 AG/GG-carriers had a poorer RR (29% versus 53%, p = 0.008), PFS (8 versus 15 months, p = 0.0002) and OS (22 versus 31 months, p = 0.004) compared to AA-carriers. rs307826 was independently associated with PFS and OS on multivariate analysis. CONCLUSION: VEGFR3 rs307826 seems to be associated with outcome on sunitinib in m-ccRCC. Its impact highlights the role of VEGFR3 in ccRCC pathogenesis and as a target of sunitinib.

Objectives: We aimed to determine the prognostic value of baseline Health-Related Quality Of Life (HRQOL) and geriatric assessment (GA) to predict three-month mortality in older patients with cancer undergoing treatment. Methods: Logistic regressions analysed HRQOL, as measured with the EORTC Global Health Status (GHS) scale, and geriatric information prognostic for early mortality controlling for oncology variables. The assessment was established with the odds ratio (OR), 95% confidence interval (CI) and level of significance set at p < 0.05. Discriminative power was evaluated with area under the curve (AUC). Results: In total, 6769 patients were included in the study, of whom 1259 (18.60%) died at three months. Our model showed higher odds of early death for patients with lower HRQOL (GHS, OR 0.98, 95% CI 0.98-0.99; p < 0.001), a geriatric risk profile (G8 Screening Tool, 1.94, 1.14-3.29; p = 0.014), cognitive decline (Mini Mental State Examination, 1.41, 1.15-1.72; p 0.001), being at risk for malnutrition (Mini Nutritional Assessment-Short Form, 1.54, 1.21-1.98; p = 0.001), fatigue (Visual Analogue Scale for Fatigue, 1.45, 1.16-1.82; p = 0.012) and comorbidities (Charlson Comorbidity index, 1.23, 1.02-1.49: p = 0.033). Additionally, older age, poor ECOG PS and being male increased the odds of early death, although the magnitude differed depending on tumor site and stage, and treatment (all p < 0.05). Predictive accuracy increased with 3.7% when including HRQOL and GA in the model. Conclusion: The results suggest that, in addition to traditional clinical measures, HRQOL and GA provide additional prognostic information for early death, but the odds differ by patient and tumor characteristics. (C) 2020 Elsevier Ltd. All rights reserved.

BACKGROUND: There are no validated markers that predict response or resistance in patients with metastatic clear-cell renal cell carcinoma (mccRCC) treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors such as sunitinib and pazopanib. Recently, single nucleotide polymorphism (SNP) rs2981582 in Fibroblast Growth Factor Receptor 2 (FGFR2) was found to be associated with clinical outcome in patients with mccRCC treated with pazopanib and sunitinib. We aimed to validate these findings in patients treated with sunitinib. MATERIALS AND METHODS: Germline DNA was collected in patients with mccRCC starting first-line systemic therapy with sunitinib. SNP rs2981582 in FGFR2 C>T was genotyped. Association of the genotype with response rate, tumor shrinkage, median progression-free survival (mPFS), and median overall survival (mOS) was studied. RESULTS: We collected clinical data from 154 patients with available germline DNA. Baseline prognostic markers were well-balanced between both subgroups. Patients with the TT genotype had a poorer outcome compared with patients with the CT/CC genotype. The median shrinkage of selected tumor target lesions during treatment with sunitinib was -16% versus -31% (P = .002), mPFS was 8 versus 15 months (P = .0007), and mOS was 22 versus 33 months (P = .04), respectively. On multivariate analysis, rs2981582 remained an independent predictor of PFS (hazard ratio, 2.858; 95% confidence interval, 1.659-4.923; P < .0001) and OS (hazard ratio, 1.795; 95% confidence interval, 1.003-3.212; P = .049). CONCLUSION: Polymorphism rs2981582 in FGFR2 is correlated to PFS and OS in patients with mccRCC treated with sunitinib. Prospective validation of the impact of this SNP is warranted. ispartof: CLINICAL GENITOURINARY CANCER vol:17 issue:2 pages:E235-E246 ispartof: location:United States status: published

BACKGROUND: Excessive activation of the PI3K/Akt/mTOR pathway is frequently observed in transitional cell carcinoma (TCC) due to a loss of PTEN and/or activating mutation of PIK3CA. Allosteric mTOR inhibition by everolimus resulted in modest efficacy in advanced TCC. In different TCC cell lines, it has been shown that PI3K inhibition enhanced the efficacy of mTOR inhibitors with a synergistic effect observed mainly in cells with PI3K/Akt/mTOR pathway alterations. OBJECTIVES: To assess in a multicenter phase II trial the safety and efficacy of BEZ235, an oral pan-class I PI3K and mTOR complex1/2 inhibitor, in locally advanced or metastatic TCC after failure of platinum-based therapy. PATIENTS AND METHODS: Patients with locally advanced or metastatic TCC progressing after platinum therapy were prospectively stratified by PI3K/Akt/mTOR pathway alterations, defined as PTEN loss and PIK3CA mutation. All received BEZ235 until progressive disease (PD) or unacceptable toxicity. The primary endpoint was the progression free survival (PFS) rate at 16 weeks. This study was, however, closed prematurely due to BEZ235 being withdrawn from further development. RESULTS: Twenty patients (18 without and two with PI3K/Akt/mTOR alterations) were enrolled and received BEZ235. One partial response (5%) and two cases of stable disease (10%) were observed, all in patients without PI3K/mTOR pathway alterations. The PFS rate at 8 and 16 weeks was 15% and 10%, respectively; the median PFS was 62 days (95% confidence interval (CI) 53 - 110 days; range 38 - 588 days) and the median OS was 127 days (95% CI 58 - 309 days; range 41 - 734 days). Among the 90% of patients who presented with any grade drug-related adverse events, 50% presented with grade 3 - 4 adverse events including stomatitis (15%), fatigue (5%), nausea (5%), diarrhea (5%), renal failure (5%), cutaneous rash (5%), hepatotoxicity (5%) and hypertension (5%), CONCLUSIONS: BEZ235 showed modest clinical activity and an unfavorable toxicity in patients with advanced and pretreated TCC. However, a minority of patients presented clinical benefit, suggesting that a complete blockade of the PI3K/ mTOR axis could improve outcome in some specific patients. Furthermore, this study showed that molecular stratification of patients for personalized medicine before treatment is feasible. This article is protected by copyright. All rights reserved.

Axitinib is a small molecule tyrosine kinase inhibitor with high affinity and specificity for the family of vascular endothelial growth factor receptors. It has previously demonstrated anti-tumor activity in a small cohort of patients with recurrent glioblastoma (rGB). We conducted a non-comparative randomized phase II clinical trial investigating axitinib monotherapy versus axitinib plus lomustine (LOM) in patients with rGB. Primary endpoint was 6 month progression-free survival (6mPFS). Patients who progressed on axitinib-monotherapy were allowed to cross-over. Between August 2011 and July 2015, 79 patients were randomized and initiated axitinib monotherapy (n = 50; AXI) or axitinib plus lomustine (n = 29; AXILOM). Median age was 55y [range 18-80], 50M/28F. Baseline characteristics were well balanced between study arms. Nineteen patients in the AXI-arm crossed-over at the time of progression. Treatment was generally well tolerated. AXILOM patients were at higher risk for grade 3/4 neutropenia (0 vs. 21%) and thrombocytopenia (4 vs. 29%). Best Overall Response Rate (BORR) in the AXI-arm was 28 vs. 38% in the AXILOM-arm. 6mPFS was 26% (95% CI 14-38) versus 17% (95% CI 2-32) for patients treated in the AXI versus AXILOM-arms, respectively. Median overall survival was 29 weeks (95% CI 20-38) in the AXI-arm and 27.4 weeks (95% CI 18.4-36.5) in the AXILOM-arm. MGMT-promoter hypermethylation and steroid treatment at baseline correlated significantly with PFS and OS. We conclude from these results that axitinib improves response rate and progression-free survival in patients with rGB compared to historical controls. There is no indication that upfront combination of axitinib with LOM improves results (European Clinical Trials Database (EudraCT) Study Number: 2011-000900-16).

Background: This phase II study assessed the safety and efficacy of everolimus, an oral mammalian target of rapamycin inhibitor in advanced transitional carcinoma cell (TCC) after failure of platinum-based therapy. Patients and methods: Thirty-seven patients with advanced TCC received everolimus 10 mg/day until progressive disease (PD) or unacceptable toxicity. The primary end point was the disease control rate (DCR), defined as either stable disease (SD), partial response (PR), or complete response at 8 weeks. Angiogenesis-related proteins were detected in plasma and changes during everolimus treatment were analyzed. PTEN expression and PIK3CA mutations were correlated to disease control. Results: Two confirmed PR and eight SD were observed, resulting in a DCR of 27% at 8 weeks. Everolimus was well tolerated. Compared with patients with noncontrolled disease, we observed in patients with controlled disease a significant higher baseline level of angiopoietin-1 and a significant early plasma decrease in angiopoietin-1, endoglin,and platelet-derived growth factor-AB. PTEN loss was observed only in patients with PD. Conclusions: Everolimus showed clinical activity in advanced TCC. The profile of the plasma angiogenesis-related proteins suggested a role of the everolimus antiangiogenic properties in disease control. PTEN loss might be associated with everolimus resistance.

10010Background: QoL is an important outcome parameter for older pts with cancer. This study aims to investigate baseline QoL and its evolution during treatment in older pts with cancer and to dete...

Objectives: The aim of this study is to describe a large-scale, Belgian implementation project about geriatric assessment (=GA) in daily oncology practice and to identify barriers and facilitators for implementing GA in this setting. Design / setting / participants: The principal investigator of every participating hospital (n=22) was invited to complete a newly developed questionnaire with closed-and open-ended questions. The closed-ended questions surveyed how GA was implemented. The open-ended questions identified barriers and facilitators for the implementation of GA in daily oncology practice. Descriptive statistics and conventional content analysis were performed as appropriate. Results: Qualifying criteria (e.g. disease status and cancer type) for GA varied substantially between hospitals. Thirteen hospitals (59.1%) succeeded to screen more than half of eligible patients. Most hospitals reported that GA data and follow-up data had been collected in almost all screened patients. Implementing geriatric recommendations and formulating new geriatric recommendations at the time of follow-up are important opportunities for improvement. The majority of identified barriers were organizational, with high workload, lack of time or financial/staffing problems as most cited. The most cited facilitators were all related to collaboration. Conclusion: Interventions to improve the implementation of GA in older patients with cancer need to address a wide range of factors, with organization and collaboration as key elements. All stakeholders, seeking to improve the implementation of GA in older patients with cancer, should consider and address the identified barriers and facilitators.

We conducted a randomized, non-comparative, multi center, phase II clinical trial in order to investigate the efficacy of axitinib, an oral small molecule tyrosine kinase inhibitor with high affinity and specificity for the vascular endothelial growth factor receptors, in patients with recurrent glioblastoma following prior treatment with radiation and temozolomide. Forty-four patients were randomly assigned to receive treatment with axitinib (5 mg BID starting dose; N = 22) or “physicians best alternative choice of therapy” that consisted of bevacizumab (N = 20) or lomustine (N = 2). Six-month progression-free survival served as the primary endpoint. The estimated 6-month progression-free survival rate was 34 % (95 % CI 14–54) for patients treated with axitinib and 28 % (95 % CI 8–48) with best alternative treatment; median overall survival was 29 and 17 weeks, respectively. Objective responses according to RANO criteria were documented in 28 % of patients treated with axitinib and 23 % of patients treated with best alternative therapy. A decrease in maximal uptake of 18F-fluoro-ethyl-tyrosine (18F-FET) by the glioblastoma on PET imaging was documented in 85 % of patients at the time of response on axitinib. Corticosteroid treatment could be stopped in four and tapered in seven out of the 15 patients who were treated with steroids at baseline in the axitinib cohort. Most frequent axitinib related grade ≥3 adverse events consisted of fatigue (9 %), diarrhea (9 %), and oral hyperesthesia (4.5 %). We conclude that axitinib has single-agent clinical activity and a manageable toxicity profile in patients with recurrent glioblastoma.

2038Background: vascular endothelial growth factor receptor (VEGFR) signal transduction mediates glioblastoma (GB) associated neo-angiogenesis. Axitinib, a small molecule TKI with high affinity and specificity for the VEGFRs, has demonstrated anti-tumor activity in patients with recurrent GB (J Clin Oncol 32:5s, 2014 [suppl; abstr 2018]). We investigated whether the combination of axitinib with lomustine (LOM) improves the outcome of pts with rGB as opposed to axitinib monotherapy. Methods: pts with rGB were randomized between single agent axitinib (AXI) vs. axitinib in combination with LOM (AXILOM) in an open label, randomized, phase II clinical trial. Pts in the AXI arm were allowed to cross over to AXILOM at progression. Six-month PFS served as the primary endpoint. Results: between February 2014 and July 2015, 56 pts were randomized 1:1 to AXI and AXILOM. Baseline characteristics were well balanced between both study arms (median age 56y [range 18-75]; 35M/21F; 15, 19, 11 and 11 pts had a WHO-PS of 0,...

Purpose To assess the efficacy and toxicity of the addition of estramustine to docetaxel (D) for the treatment of metastatic hormone-refractory prostate cancer. Patients and Methods One hundred fifty patients were randomly assigned to D alone (35 mg/m2 on days 2 and 9, every 3 weeks) or D in combination with estramustine (D/E; 280 mg orally three times a day on days 1 to 5 and 8 to 12, every 3 weeks). All patients received prednisone (10 mg/d). The primary end point was prostate-specific antigen (PSA) response rate, which was defined as a decrease in PSA ≥ 50% from baseline. The study was powered to test the hypothesis that D/E would improve the PSA response rate by 25%. Results The PSA response rate was not statistically different between the two groups. PSA of less than 4 ng/mL occurred in 29 (41%) of 71 patients receiving D/E and in 17 (25%) of 69 patients receiving D (P = .05). No significant differences were found for median time to PSA progression (D/E, 6.9 months; D, 7.3 months) or median overall survival time (D/E, 19.3 months; D, 21 months). More patients had at least one grade 3 or 4 toxicity with D/E (45%) compared with D (21%; P = .005), mainly as a result of grade 3 or 4 GI toxicity (P = .05). Serious adverse events were more frequent with D/E (n = 20) than with D (n = 9; P = .04). Conclusion The addition of estramustine to weekly D does not provide any clinically relevant advantage. Both regimens are well tolerated, although the toxicity profile favors D without estramustine.

e15535 Background: Excessive activation of the PI3K/Akt/mTOR pathway is frequently observed in TCC, due to loss of PTEN and/or activating mutation of PIK3CA.We previously showed in a phase II trial...

TPS134 Background: The overall survival (OS) of newly diagnosed glioblastoma (GB) patients (pts) treated with RT and TMZ is correlated with the methylation status of the MGMT-promoter. Pts with an ...