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Background/aim Per literature, patients with epidermal growth factor receptor (EGFR) exon-20 insertions respond poorly to tyrosine kinase inhibitors (TKIs). This study analyzed real-world data to examine the prognostic and predictive value of these mutations. Patients and methods We conducted a retrospective cohort study using Czech TULUNG Registry data, with data on multiple mutation types, collected in 2011-2020. Results We analyzed 554 (95.85%) patients with EGFR exon-19 deletions or exon-21 L858R substitutions and 24 (4.15%) patients with exon-20 insertions who received first-line high-value therapies. We summarized clinical characteristics and outcomes in all patients and by cohort. The risk of progression was statistically significantly higher (86%) in the exon-20 insertion cohort compared to the cohort with other mutations. Although not statistically significant, the risk of death was 44% higher in patients with exon-20 insertions. Conclusion Advanced NSCLC patients with rare EGFR exon-20 insertions have a high risk of progression.

Background/aim Platinum-based chemotherapy with pemetrexed or paclitaxel/bevacizumab are regimens used in combination with checkpoint inhibitors in non-squamous non-small cell lung cancer (NSCLC) treatment. We conducted a real-world study to compare the outcomes of these chemotherapeutic regimens. Patients and methods We investigated 1,534 patients with advanced non-squamous NSCLC treated with platin/pemetrexed (n=1212) or platin/paclitaxel/bevacizumab (n=322) in 9 cancer centres in the Czech Republic. Results The regimen containing platin/paclitaxel/bevacizumab showed significantly better overall response rate (ORR) compared to the platin/pemetrexed [40.8% vs. 32.7% (p=0.008)] in the overall population and [55.0% vs. 38.8% (p=0.002)] in the Eastern Cooperative Oncology Group performance status 0 group. There was no significant improvement in progression-free survival (PFS) and overall survival (OS) in either of these two groups of patients. Conclusion In our real-world data analysis, patients treated with platin/paclitaxel/bevacizumab had better overall response rate (ORR), but not PFS or OS. Thus, both treatment regimens are similarly effective. Their selection should therefore be based on the potential side effects.

Background/Aim: We investigated efficacy differences for afatinib versus gefitinib in non-small-cell lung cancer (NSCLC) according to epidermal growth factor receptor (EGFR) mutations. Patients and Methods: We retrospectively analysed data for 343 patients with NSCLC with performance status 1 having EGFR mutations treated with gefitinib or afatinib. Overall response rate (ORR) was tested by Fisher & rsquo;s exact test. Overall (OS) and progression free (PFS) survival were estimated by Kaplan & ndash;Meier method. Results: ORR did not differ in any group or subgroup. Among all patients, we observed significantly longer PFS for those treated with afatinib vs. gefitinib (median 13.4 vs. 9.5 months, p=0.026), but only a nonsignificant trend was observed for OS. We showed nonsignificant trends of better PFS and OS using afatinib for exon 19 deletion and L858R subgroups. We observed no significant PFS differences for other EGFR mutations but a nonsignificant trend towards better OS for those treated with afatinib. Conclusion: Afatinib led to longer PFS for patients with common EGFR mutations but not for those with rare mutations.

We prospectively investigated whether metabolic response assessed by 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (PET/CT) early in the course of neoadjuvant chemotherapy is predictive of survival in patients with adenocarcinoma of the esophagus and esophagogastric junction. PET/CT was performed before and in the third week after the initiation of the first cycle of neoadjuvant chemotherapy, which consisted of epirubicin, cisplatin, and 5-fluorouracil or capecitabine. The metabolic response was defined as a relative decrease in the peak standardized uptake value (SUL) of the tumor by ≥ 35% or total lesion glycolysis (TLG) by ≥ 66%. The associations of metabolic response with overall survival (OS) and disease-free survival (DFS) were investigated using Kaplan-Meier curves and multivariable Cox regression analysis. Among 126 recruited patients, the early metabolic response was assessed in 107 patients (90 of them underwent surgical resection). The five-year OS and DFS rates of all patients were 28% and 27%, respectively. No difference was found in OS (p = 0.10 for SUL, p = 0.08 for TLG) or DFS (p = 0.50 for SUL, p = 0.20 for TLG) between metabolic responders and non-responders. Post hoc analysis of the patients with a follow-up PET/CT within 16 days showed that metabolic response reflected by SUL predicted OS (p = 0.03). We concluded that metabolic response assessed by PET/CT after the first cycle of neoadjuvant chemotherapy does not predict survival in patients with adenocarcinoma of the esophagus and esophagogastric junction. However, proper timing of the follow-up PET/CT may affect the prognostic ability of the early metabolic response.

Background: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum–etoposide) showed a significant improvement in overall survival versus platinum–etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide alone. Methods: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum–etoposide, durvalumab plus platinum–etoposide, or platinum–etoposide alone. In all groups, patients received etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL/min or cisplatin 75–80 mg/m2 on day 1 of each cycle. Patients in the platinum–etoposide group received up to six cycles of platinum–etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum–etoposide versus platinum–etoposide and for durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. Findings: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum–etoposide, 268 to durvalumab plus platinum–etoposide, and 269 to platinum–etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3–27·9). Durvalumab plus tremelimumab plus platinum–etoposide was not associated with a significant improvement in overall survival versus platinum–etoposide (hazard ratio [HR] 0·82 [95% CI 0·68–1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6–12·0) versus 10·5 months (9·3–11·2). Durvalumab plus platinum–etoposide showed sustained improvement in overall survival versus platinum–etoposide (HR 0·75 [95% CI 0·62–0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3–14·7) versus 10·5 months (9·3–11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum–etoposide group, and 88 [33%] of 266 patients in the platinum–etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 85 (32%) in the durvalumab plus platinum–etoposide group, and 97 (36%) in the platinum–etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum–etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum–etoposide group (pancytopenia and thrombocytopenia [n=1 each]). Interpretation: First-line durvalumab plus platinum–etoposide showed sustained overall survival improvement versus platinum–etoposide but the addition of tremelimumab to durvalumab plus platinum–etoposide did not significantly improve outcomes versus platinum–etoposide. These results support the use of durvalumab plus platinum–etoposide as a new standard of care for the first-line treatment of ES-SCLC. Funding: AstraZeneca.

Background Data regarding real‐life effectiveness of any treatment may improve clinical decision‐making. The aim of this study was to evaluate real‐life effectiveness of tyrosin‐kinase inhibitors, bevacizumab and pemetrexed as first‐line treatments in patients with advanced/metastatic non‐small cell lung cancer (NSCLC). Methods We analyzed data of 2157 patients of the Czech TULUNG Registry of patients with advanced/metastatic NSCLC who received modern‐era treatments between 2011 and 2018. Patients treated with gefitinib, erlotinib, afatinib, bevacizumab (+ maintenance), pemetrexed (+ maintenance) as first‐line therapy were included in the study. A systematic literature search separately identified clinical trials suitable for calculation of comparator pooled OS and PFS for each regimen. For each subgroup, basic characteristics and survival data (Kaplan‐Meier estimates) are shown. We propose the “index of real‐life effectiveness” (IRE), a ratio of real‐life OS/PFS and comparator pooled OS/PFS. Univariate and multivariate logistic regression identified factors were associated with longer OS (ie, IRE>1.1). Results Survival analysis showed median OS of 23 months for erlotinib, 29.3 months for afatinib, 19.6 months for gefitinib, 12.2 months for pemetrexed, 17.5 months for pemetrexed maintenance, 15.8 months for bevacizumab and 15.8 months for bevacizumab maintenance. Calculated IREs for OS for the regimens were: erlotinib 1.013, afatinib 1.184, gefitinib 0.736, pemetrexed 1.188, pemetrexed maintenance 1.294, bevacizumab 1.178, and bevacizumab maintenance 1.189. Multivariate regression analysis showed that these factors were associated with longer OS: lower PS for afatinib; lower PS, absence of adverse events and female sex for bevacizumab; and lower PS and female sex for pemetrexed. Conclusions This study clearly demonstrated that real‐life effectiveness of certain treatment regimens may strongly differ in various populations/health care systems, and comparison between TULUNG data and pooled survival data from trials showed higher real‐life effectiveness for most of the studied first‐line regimens. Lower ECOG PS, younger age, female sex and adverse events were associated with longer survival in most regimens. Key points Significant findings of the study Comparison between TULUNG data and pooled survival data from trials showed higher real‐life effectiveness for most of the studied first‐line regimens; for most regimens, lower ECOG PS, younger age, female sex and adverse events were associated with longer survival. What this study adds Real‐life effectiveness of certain treatment regimens may strongly differ in various populations/health care systems., Comparison between our TULUNG data and pooled survival data from clinical trials showed higher real‐life effectiveness for most of the studied first‐line regimens. We found that lower ECOG PS, younger age, female sex and adverse events were associated with longer survival. We demonstrated that real‐life effectiveness of certain treatments may strongly differ in various populations and health care systems.

Background The aim of this project was to collect real-world evidence and describe treatment patterns for stage III non-small cell lung cancer in Central and Eastern Europe. Based on real-world evidence, an expert opinion was developed, and the unmet needs and quality indicators were identified. Patients and methods A systematic literature search and a multidisciplinary expert panel of 10 physicians from 7 countries used a modified Delphi process to identify quality indicators and unmet needs in patients with stage III non-small cell lung cancer. The profound questionnaire was used to characterize treatment patterns used for stage III non-small cell lung cancer, and a systematic review identified patterns in Central and Eastern Europe. The first questionnaire was completed by a group of medical oncologists, radiation oncologists and pneumologists. The panel of experts attended an in-person meeting to review the results of the questionnaire and to process a second round Delphi. An additional survey was then compiled and completed by the panel. Results A complete consensus was reached by the panel of experts on a set of evidence-based clinical recommendations. The experience-based questionnaire generated a highly variable map of treatment patterns within the region. A list of unmet needs and barriers to quality care were developed with near-unanimous consent of the panel of experts. Conclusions The current landscape of diagnostic and therapeutic approaches in Central and Eastern European countries is highly variable. We identified several significant barriers, mainly related to the availability of diagnostic and imaging methods and low rates of chemoradiotherapy with curative intention as initial treatment for unresectable stage III NSCLC.

Background Management of non-small-cell lung cancer (NSCLC) is affected by regional specificities. The present study aimed at determining diagnostic and therapeutic procedures including outcome of patients with NSCLC stage III in the real-world setting in Central European countries to define areas for improvements . Patients and methods This multicentre, prospective and non-interventional study collected data of patients with NSCLC stage III in a web-based registry and analysed them centrally. Results Between March 2014 and March 2017, patients (n=583) with the following characteristics were entered: 32% females, 7% never-smokers; ECOG performance status (PS) 0, 1, 2 and 3 in 25%, 58%, 12% and 5%, respectively; 21% prior weight loss; 53% squamous carcinoma, 38% adenocarcinoma; 10% EGFR mutations. Staging procedures included chest X-ray (97% of patients), chest CT (96%), PET-CT (27%), brain imaging (20%), bronchoscopy (89%), endobronchial ultrasound (EBUS) (13%) and CT-guided biopsy (9%). Stages IIIA/IIIB were diagnosed in 55%/45% of patients, respectively. N2/N3 nodes were diagnosed in 60%/23% and pathologically confirmed in 29% of patients. Most patients (56%) were treated by combined modalities. Surgery plus chemotherapy was administered to 20%, definitive chemoradiotherapy to 34%, chemotherapy only to 26%, radiotherapy only to 12% and best supportive care (BSC) to 5% of patients. Median survival and progression-free survival times were 16.8 (15.3;18.5) and 11.2 (10.2;12.2) months, respectively. Stage IIIA, female gender, no weight loss, pathological mediastinal lymph node verification, surgery and combined modality therapy were associated with longer survival. Conclusions The real-world study demonstrated a broad heterogeneity in the management o f stage III NSCLC in Central European countries and suggested to increase the rates of PET-CT imaging, brain imaging and invasive mediastinal staging.

To investigate potential association between administration of corticosteroids, antibiotics, probiotics, proton pump inhibitors, non-steroidal anti-inflammatory drugs (NSAID), statins and metformin and outcome in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Patients and Methods: A total of 224 patients with advanced NSCLC treated at nine comprehensive cancer centers were analyzed in this national retrospective study. Survival statistics were evaluated using Kaplan-Meier method and Cox analysis. Results: Only corticosteroid use had a significant negative effect on the objective response rate. In the univariate analysis, there was no significant effect of the studied concomitant medications on the efficacy of nivolumab. In a subsequent multifactorial analysis, a possible positive effect of the concomitant use of NSAID at the initiation of nivolumab treatment was revealed. Conclusion: The results of the present retrospective exploratory analysis underscore the importance of knowing the exact type of concomitant medication, the route of administration, the dose of medication, and the region of the ongoing study. The present data indicated a significantly higher rate of progression in patients treated with corticosteroids and the possible positive effect of NSAID use at the initiation of nivolumab treatment. © 2020 International Institute of Anticancer Research. All rights reserved.

Background: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum–etoposide) in treatment-naive patients with ES-SCLC. Methods: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum–etoposide; durvalumab plus tremelimumab plus platinum–etoposide; or platinum–etoposide alone. All drugs were administered intravenously. Platinum–etoposide consisted of etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL per min or cisplatin 75–80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum–etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum–etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum–etoposide group versus the platinum–etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing. Findings: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum–etoposide group and 269 to the platinum–etoposide group. Durvalumab plus platinum–etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59–0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5–14·8) in the durvalumab plus platinum–etoposide group versus 10·3 months (9·3–11·2) in the platinum–etoposide group, with 34% (26·9–41·0) versus 25% (18·4–31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum–etoposide group and 166 (62%) of 266 in the platinum–etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. Interpretation: First-line durvalumab plus platinum–etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. Funding: AstraZeneca.

Most studies indicate no benefit of adjuvant therapy with VEGFR tyrosine kinase inhibitors in advanced renal cell carcinoma (RCC). PROTECT (NCT01235962) was a randomized, double-blind, placebo-controlled phase 3 study to evaluate adjuvant pazopanib in patients with locally advanced RCC at high risk of relapse after nephrectomy (pazopanib, n = 769; placebo, n = 769). The results of the primary analysis showed no difference in disease-free survival between pazopanib 600 mg and placebo. Here we report the final overall survival (OS) analysis (median follow-up: pazopanib, 76 mo, interquartile range [IQR] 66-84; placebo, 77 mo, IQR 69-85). There was no significant difference in OS between the pazopanib and placebo arms (hazard ratio 1.0, 95% confidence interval 0.80-1.26; nominal p > 0.9). OS was worse for patients with T4 disease compared to those with less advanced disease and was better for patients with body mass index (BMI) >= 30 kg/m(2) compared to those with lower BMI. OS was significantly better for patients who remained diseasefree at 2 yr after treatment compared with those who relapsed within 2 yr. These findings are consistent with the primary outcomes from PROTECT, indicating that adjuvant pazopanib does not confer a benefit in terms of OS for patients following resection of locally advanced RCC.Patient summary: In the randomized, double-blind, placebo-controlled phase 3 PROTECT study, overall survival was similar for patients with locally advanced renal cell carcinoma (RCC) at high risk of relapse after nephrectomy who received adjuvant therapy with pazopanib or placebo. Pazopanib is not recommended as adjuvant therapy following resection of locally advanced RCC. (C) 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.

The role of cytoreductive nephrectomy (CN) in treatment of locally advanced or metastatic renal cell carcinoma (mRCC) in the era of targeted therapies (TT) is still not clearly defined. The study population consisted of 730 patients with synchronous mRCC. The RenIS (Renal carcinoma Information System) registry was used as the data source. The CN/TT cohort included patients having CN within 3 months from the mRCC diagnosis and subsequently being treated with TT, while the TT cohort included patients receiving TT upfront. Median progression-free survival from the first intervention was 6.7 months in the TT arm and 9.3 months in the CN/TT patients (p &lt, 0.001). Median overall survival was 14.2 and 27.2 months, respectively (p &lt, 0.001). Liver metastasis, high-grade tumor, absence of CN, non-clear cell histology, and MSKCC (Memorial Sloan-Kettering Cancer Center) poor prognosis status were associated with adverse treatment outcomes. According to the results of this retrospective study, patients who underwent CN and subsequently were treated with TT had better outcomes compared to patients treated with upfront TT. The results of the study support the use of CN in the treatment algorithm for mRCC.

Background Treatment of non‐small cell lung cancer (NSCLC) improved substantially in the last decades. Novel targeted and immune‐oncologic drugs were introduced into routine treatment. Despite accelerated development and subsequent drug registrations by the European Medicinal Agency (EMA), novel drugs for NSCLC are poorly accessible in Central and Eastern European (CEE) countries. Material and Methods The Central European Cooperative Oncology Group conducted a survey among experts from 10 CEE countries to provide an overview on the availability of novel drugs for NSCLC and time from registration to reimbursement decision in their countries. Results Although first‐generation epidermal growth factor receptor tyrosine kinase inhibitors were reimbursed and available in all countries, for other registered therapies—even for ALK inhibitors and checkpoint inhibitors in first‐line—there were apparent gaps in availability and/or reimbursement. There was a trend for better availability of drugs with longer time from EMA marketing authorization. Substantial differences in access to novel drugs among CEE countries were observed. In general, the availability of drugs is not in accordance with the Magnitude of Clinical Benefit Scale (MCBS), as defined by the European Society for Medical Oncology (ESMO). Time spans between drug registrations and national decisions on reimbursement vary greatly, from less than 3 months in one country to more than 1 year in the majority of countries. Conclusion The access to novel drugs for NSCLC in CEE countries is suboptimal. To enable access to the most effective compounds within the shortest possible time, reimbursement decisions should be faster and ESMO MCBS should be incorporated into decision making., Access to novel therapies is a factor contributing to disparities in cancer care. Limited drug availability is a challenge in Central and Eastern European countries, where financial and organizational shortages exist. This article reports a survey that investigated access to novel anti‐cancer drugs for non‐small cell lung cancer.

Background: The Memorial Sloan&ndash, Kettering Cancer Center (MSKCC) prognostic model has been widely used for the prediction of the outcome of metastatic renal cell carcinoma (mRCC) patients treated with systemic therapies, however, data from large studies are limited. This study aimed at the evaluation of the impact of the MSKCC score on the outcomes in mRCC patients treated with first-line sunitinib, with a focus on the intermediate-risk group. Methods: Clinical data from 2390 mRCC patients were analysed retrospectively. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were analysed according to the MSKCC risk score. Results: ORR, median PFS, and OS for patients with one risk factor were 26.7%, 10.1, and 28.2 months versus 18.7%, 6.2, and 16.2 months, respectively, for those with two risk factors (ORR: p = 0.001, PFS: p &lt, 0.001, OS: p &lt, 0.001). ORR, median PFS, and OS were 33.0%, 17.0, and 44.7 months versus 24.1%, 9.0, and 24.1 months versus 13.4%, 4.5, and 9.5 months in the favourable-, intermediate-, and poor-risk groups, respectively (ORR: p &lt, 0.001, PFS: p &lt, 0.001). Conclusions: The results of the present retrospective study demonstrate the suitability of the MSKCC model in mRCC patients treated with first-line sunitinib and suggest different outcomes between patients with one or two risk factors.

Aim To investigate potential associations between clinical and standard peripheral blood biomarkers and clinical outcome in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Patients and methods A total of 120 patients with advanced NSCLC treated at seven comprehensive cancer care centers were analyzed in this national retrospective study. Survival statistics were evaluated using the Kaplan-Meier method and Cox analysis. Results Among clinical parameters, histology was significantly associated with progression-free survival. Univariate Cox-proportional hazards model indicated prognostic and predictive role of a panel of laboratory parameters reflecting chronic inflammatory pattern (elevated neutrophil count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, C-reactive protein and decrease in hemoglobin and albumin). Higher serum calcium concentration was also associated with nivolumab treatment effect. Conclusion Tumor histology was the only clinical parameter predicting the outcome of nivolumab treatment. Among the laboratory parameters, our analysis identified a laboratory panel reflecting chronic inflammation as a potential predictive marker of nivolumab treatment.

Background The aim of this prospective study was to assess whether [18F]fluorodeoxyglucose PET can be used to predict histopathological response early in the course of neoadjuvant chemotherapy in patients with adenocarcinoma of the oesophagus and oesophagogastric junction. Methods Following the PET response criteria in solid tumours (PERCIST 1.0) as a standardized method for semiquantitative assessment of metabolic response, FDG-PET/CT was performed before (PET1) and after (PET2) initiation of the first cycle of chemotherapy. The relative changes in the peak standardized uptake value (ΔSUL) and total lesion glycolysis (ΔTLG) between PET1 and PET2 were correlated with histopathological response, defined as less than 50 per cent viable tumour cells in the resection specimen. A receiver operating characteristic (ROC) curve analysis was used to identify the optimal cut-off value with the highest accuracy of histopathological response prediction. Results PET2 was performed a median of 16 (range 12–22) days after the start of chemotherapy. Some 27 of 90 patients who underwent surgery had a histopathological response. There was no association between the median ΔSUL or median ΔTLG and the histopathological response. A post hoc analysis in 47 patients with PET2 performed 16 days or less after the start of chemotherapy showed that ΔTLG, but not ΔSUL, was associated with the histopathological response (P = 0·009). The optimal cut-off value of ΔTLG was 66 per cent or more. Conclusion FDG-PET/CT after the first cycle of chemotherapy does not predict histopathological response in patients with adenocarcinoma of the oesophagus and oesophagogastric junction.

Background It is well known that patient characteristics and survival outcomes in randomized trials may not necessarily be similar to those in real-life clinical practice. The aim of the present study was to analyse second line treatment strategies in the real-world practice and to estimate the outcomes of patients treated with second-line targeted therapy for metastatic renal cell carcinoma (mRCC). Methods This is a retrospective, registry-based study using data from the national registry of targeted therapies for mRCC. The RENIS registry contains data on 3049 patients who started the therapy with at least one targeted agent before 31 December, 2014. Of these patients, 1029 had a record of at least two different targeted therapies and sufficient data for analysis. Survival analysis was carried out using the Kaplan-Meier method. Statistical significance of differences in survival between subgroups was assessed using the log-rank test. Results The median overall survival from the start of second-line treatment was 17.0 months (95% confidence interval [CI] 14.5–19.5 months), 17.1 months (95% CI 14.5–19.8), and 15.4 months (95% CI 11.0–19.7) for second-line everolimus, sorafenib, and sunitinib, respectively. Patients receiving second-line everolimus were older at the start of second-line treatment, more likely to have metachronous disease, and less likely to be previously treated with cytokines or to continue to third-line treatment than patients treated with second-line sunitinib or sorafenib. Progression-free survival (PFS) correlated with PFS on first-line treatment only for everolimus. Conclusions In this retrospective study, no significant differences in survival were observed between the cohorts treated with different second-line agents including everolimus, sorafenib, and sunitinib.

Background Although targeted therapies with inhibitors of the vascular endothelial growth factor (VEGF) are the mainstay of treatment for metastatic renal cell carcinoma, there are limited data on the outcome of patients with long-term response to this treatment. Patients and Methods In a retrospective, registry-based study, patients continuously treated with first-line anti-VEGF agents for at least 24 months were included. In total, 219 patients had evaluable data and were included in the outcome analysis. Results Median progression-free survival (PFS) after initiation of first-line targeted therapy was 39.7 months (95% confidence interval [CI], 35.9-43.5 months), with 5-year PFS of 34.2% (95% CI, 27.2%-41.2%). Median overall survival (OS) reached 79.1 months (95% CI, 65.2-93.0 months) with the 5-year OS of 62.1% (95% CI, 54.5%-69.7%). In this cohort, 28, 103, and 88 patients achieved complete response (CR), partial response (PR), or stable disease (SD) as the best response, respectively. Median PFS and OS were comparable in patients with PR and SD, but significantly longer in patients with CR (log rank test P value for PFS difference Conclusion There are marked differences in PFS and OS between patients who receive long-term anti-VEGF treatment, achieving CR and non-CR as the best clinical response. Patients with non-CR experienced a relatively high progression rate shortly after the landmark time point of 2 years.

Background Radiotherapy (RT) is a mainstay of oncology treatment in both curative and palliative situations. With respect to palliative and supportive care, RT improves local control of disease and relieves symptoms, particularly pain, compression of surrounding structures, and/or bleeding. The aim here was to evaluate the effects and toxicity of palliative RT in our department from April 2015 to April 2018. Patients and methods During this period, 338 cases received palliative RT, representing approximately one third of indications for this treatment method. We evaluated selected subgroups of patients: those with advanced lung cancer, bone metastases, or soft tissue metastases. Patients were irradiated by the IMRT (intensity modulated radiation therapy) technique using the TomoTherapy HD (Accuray, USA) platform. Results Palliative RT for primary lung cancer was performed for 29 patients. Of these, symptoms were relieved in 22 patients (76%) and local control (confirmed by imaging) was achieved in 19 patients (66%). Treatment-related toxicity was acceptable. Overall, 104 patients received irradiation for bone metastases; pain relief was achieved in more than 75% of cases. Another 71 patients were irradiated to treat soft tissue metastases; symptoms were relieved in 60% of cases. Treatment-related toxicity in our patients was lower than reported previously, suggesting improved quality of life for patients irradiated using modern RT technologies. Conclusion Palliative RT provided excellent symptom control in our patients, with minimal toxicity. Thus, RT is an effective and easy-to-use method for many palliative indications. Key words: palliative care - radiotherapy - lung neoplasms - neoplasm metastasis - bone metastases - pain management The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 28. 8. 2018 Accepted: 29. 10. 2018.

Purpose To investigate the efficacy and safety of an active cellular immunotherapy (DCVAC/LuCa) and chemotherapy in patients with stage IV non-small cell lung cancer (NSCLC). Patients and Methods SLU01 was a multicenter, open-label, parallel-group, randomized, phase I/II trial. NSCLC patients were randomized in a ratio of 1:1:1 to receive: DCVAC/LuCa and chemotherapy (carboplatin and paclitaxel; Group A); DCVAC/LuCa, chemotherapy, pegylated interferon-α2b, and hydroxychloroquine (Group B); or chemotherapy alone (Group C). DCVAC/LuCa was administered subcutaneously every 3–6 weeks (up to 15 doses). The primary endpoint was overall survival (OS). During the study, enrollment into Group B was discontinued for strategic reasons. Results Forty-five patients were randomized to Group A, 29 patients to Group B, and 38 patients to Group C. The median OS in the modified intention-to-treat (mITT) population was 3.7 months longer in Group A than in Group C (15.5 vs. 11.8 months; p = 0.0179; hazard ratio = 0.54; 95% confidence interval: 0.32–0.91). This OS effect was consistent across subgroups of the mITT population (females, males, current smokers, former smokers, and patients with non-squamous and squamous cell histology). The most common treatment-emergent adverse events of any grade reported in Groups A, B, and C, respectively, were neutropenia (50.0%, 29.6%, and 20.6%), fatigue (40.0%, 18.5%, and 20.6%), anemia (35.0%, 44.4%, and 32.4%), paresthesia (27.5%, 25.9%, and 17.6%), and alopecia (25.0%, 29.6%, and 41.2%). Conclusion DCVAC/LuCa in combination with carboplatin and paclitaxel extended OS and was well tolerated.

Background It is currently not known whether treatment with anti–vascular endothelial growth factor agents for metastatic renal cell carcinoma (mRCC) can be safely discontinued in patients achieving a complete response (CR). Objective To assess outcomes for patients with mRCC achieving CR on targeted therapy (TT) and the survival of patients discontinuing TT after CR. Design, setting, and participants A national registry was used to identify patients achieving CR during first-line TT using bevacizumab, sunitinib, sorafenib, or pazopanib. Outcome measurements and statistical analysis Relationships with outcomes were analysed using a log-rank test. Results and limitations A total of 100 patients achieving CR were identified out of 2803 patients. The median time to CR was 10.1 mo. Median progression-free survival (PFS) from TT initiation was 3.8 yr (95% confidence interval [CI] 2.9–4.6 yr) and the 5-yr overall survival (OS) was 80% (95% CI 70–91%). Patients discontinuing TT within 1 mo after achieving CR and those continuing TT beyond CR had similar OS (CI for difference in 2-yr post-CR OS –13% to 19%; p =0.3) and PFS (CI for difference in 2-yr post-CR PFS –29% to 17%; p =0.7). The limitations include the retrospective, registry-based data analysis. Conclusions Achievement of CR on TT for mRCC was associated with excellent long-term prognosis. No significant differences in post-CR survival were observed between patients discontinuing TT after the date of CR and those who continued on TT, although the wide CIs cannot exclude important differences between the groups. Patient summary According to this registry-based analysis, patients with metastatic renal cancer with no signs of disease (complete response) after treatment with targeted agents experience excellent long-term survival even if the treatment does not continue beyond the date of complete response.

Objectives The aim of the analysis was to assess the accuracy of various FDG-PET/CT parameters in staging lymph nodes after neoadjuvant chemotherapy. Methods In this prospective study, 74 patients with adenocarcinoma of the esophageal–gastric junction were examined by FDG-PET/CT in the course of their neoadjuvant chemotherapy given before surgical treatment. Data from the final FDG-PET/CT examinations were compared with the histology from the surgical specimens (gold standard). The accuracy was calculated for four FDG-PET/CT parameters: (1) hypermetabolic nodes, (2) large nodes, (3) large-and-medium large nodes, and (4) hypermetabolic or large nodes. Results In 74 patients, a total of 1540 lymph nodes were obtained by surgery, and these were grouped into 287 regions according to topographic origin. Five hundred and two nodes were imaged by FDG-PET/CT and were grouped into these same regions for comparison. In the analysis, (1) hypermetabolic nodes, (2) large nodes, (3) large-and-medium large nodes, and (4) hypermetabolic or large nodes identified metastases in particular regions with sensitivities of 11.6%, 2.9%, 21.7%, and 13.0%, respectively; specificity was 98.6%, 94.5%, 74.8%, and 93.6%, respectively. The best accuracy of 77.7% reached the parameter of hypermetabolic nodes. Accuracy decreased to 62.0% when also smaller nodes (medium-large) were taken for the parameter of metastases. Conclusions FDG-PET/CT proved low sensitivity and high specificity. Low sensitivity was based on low detection rate (32.6%) when compared nodes imaged by FDG-PET/CT to nodes found by surgery, and in inability to detect micrometastases. Sensitivity increased when also medium-large LNs were taken for positive, but specificity and accuracy decreased.

Esophageal cancer is a malignant disease with poor prognosis, increasing incidence, and ineffective treatment options. MicroRNAs are post-transcriptional regulators of gene expression involved in many biological processes including carcinogenesis. We determined miR-205 expression levels in tumor/non-tumor tissues of 45 esophageal cancer patients using qPCR and found that decreased level of miR-205 in tumor tissue correlates with poor overall survival in esophageal adenocarcinoma patients. Further, we observed significantly higher levels of miR-205 in tumor tissue of esophageal squamous cell carcinoma. Ectopic overexpression of miR-205 in adenocarcinoma cell line SK-GT-4 led to decreased cell proliferation, cell cycle arrest in G1, and decreased migration ability. Conversely, in squamous cell line KYSE-150, same effects like inhibition of proliferation, migration, and colony-forming potential and cell cycle arrest in G2 were observed after silencing of miR-205. We performed global gene expression profiling and revealed that suppressive functioning of miR-205 in adenocarcinoma could be realized through regulation of epithelial-mesenchymal transition (EMT), whereas oncogenic in squamous cell carcinoma by regulation of metalloproteinase 10. Our results suggest that miR-205 could serve as biomarker in esophageal cancer and acts as a tumor suppressor in esophageal adenocarcinoma and oncogene in esophageal squamous cell carcinoma.

Background and Aim: From October 2013 there is a possibility to treat patients with NSCLC and with activated epidermal growth factor receptor (EGFR) mutations with three TKI in the Czech Republic. We have tried to find differences among patient groups treated with single TKI in 1st line of treatment. Patients and methods: Only patients with EGFR mutation and in which 1st line treatment started in October 2013 until October 2017 were included in analysis. We analysed 347 patients (gefitinib - 164 patients, afatinib - 130 patients, erlotinib - 53 patients). Results: Between these three groups of patients there was no statistically significant difference in sex (p=0.988), in smoking habits (p=0.549), in type of EGFR mutation (p=0.200), in adenocarcinoma proportion (p=0.256). There was statistically significant difference according to age (p=0.001), PS ( Conclusion: We have not found any important difference in basic characteristic of patients treated in 1st line treatment with TKI (sex, smoking, histology and type of EGFR mutation) except for the age – patients treated with afatinib were younger. We have not found any important difference in response to treatment, in disease control and OS. We found a significant difference in PS segmentation, in occurrence of adverse events and PFS.

Background: Pazopanib is approved for the first-line treatment of patients with metastatic renal cell carcinoma (mRCC). The present study was a retrospective registry-based analysis of 426 patients with mRCC treated with pazopanib as first-line targeted therapy. Patients and Methods: The data were obtained from the Renal Cell Carcinoma Information system registry. Patient baseline parameters, treatment course and outcomes, and toxicity were analysed. Results: Median progression-free and overall survival were 12.9 (95% confidence interval(CI)=11.0-14.8) months and 33.2 (95% CI=29.9-36.4) months, respectively. Overall response rate and disease control rate were 25.1% and 57.4%, respectively. Adverse events led to discontinuation of treatment in 37 (12.1%) patients. Conclusion: The results confirm that pazopanib is an effective and safe first-line targeted treatment in patients with mRCC. Both the International mRCC Database Consortium and the Memorial Sloan Kettering models were valid predictors of prognosis and nephrectomy was associated with improved survival.

Purpose This phase III trial evaluated the efficacy and safety of pazopanib versus placebo in patients with locally advanced renal cell carcinoma (RCC) at high risk for relapse after nephrectomy. Patients and Methods A total of 1,538 patients with resected pT2 (high grade) or ≥ pT3, including N1, clear cell RCC were randomly assigned to pazopanib or placebo for 1 year; 403 patients received a starting dose of 800 mg or placebo. To address toxicity attrition, the 800-mg starting dose was lowered to 600 mg, and the primary end point analysis was changed to disease-free survival (DFS) for pazopanib 600 mg versus placebo (n = 1,135). Primary analysis was performed after 350 DFS events in the intent-to-treat (ITT) pazopanib 600 mg group (ITT600mg), and DFS follow-up analysis was performed 12 months later. Secondary end point analyses included DFS with ITT pazopanib 800 mg (ITT800mg) and safety. Results The primary analysis results of DFS ITT600mg favored pazopanib but did not show a significant improvement over placebo (hazard ratio [HR], 0.86; 95% CI, 0.70 to 1.06; P = .165). The secondary analysis of DFS in ITT800mg (n = 403) yielded an HR of 0.69 (95% CI, 0.51 to 0.94). Follow-up analysis in ITT600mg yielded an HR of 0.94 (95% CI, 0.77 to 1.14). Increased ALT and AST were common adverse events leading to treatment discontinuation in the pazopanib 600 mg (ALT, 16%; AST, 5%) and 800 mg (ALT, 18%; AST, 7%) groups. Conclusion The results of the primary DFS analysis of pazopanib 600 mg showed no benefit over placebo in the adjuvant setting. Purpose This phase III trial evaluated the efficacy and safety of pazopanib versus placebo in patients with locally advanced renal cell carcinoma (RCC) at high risk for relapse after nephrectomy. Patients and Methods A total of 1,538 patients with resected pT2 (high grade) or ≥ pT3, including N1, clear cell RCC were randomly assigned to pazopanib or placebo for 1 year; 403 patients received a starting dose of 800 mg or placebo. To address toxicity attrition, the 800-mg starting dose was lowered to 600 mg, and the primary end point analysis was changed to disease-free survival (DFS) for pazopanib 600 mg versus placebo (n = 1,135). Primary analysis was performed after 350 DFS events in the intent-to-treat (ITT) pazopanib 600 mg group (ITT600mg), and DFS follow-up analysis was performed 12 months later. Secondary end point analyses included DFS with ITT pazopanib 800 mg (ITT800mg) and safety. Results The primary analysis results of DFS ITT600mg favored pazopanib but did not show a significant improvement over placebo (hazard ratio [HR], 0.86; 95% CI, 0.70 to 1.06; P = .165). The secondary analysis of DFS in ITT800mg (n = 403) yielded an HR of 0.69 (95% CI, 0.51 to 0.94). Follow-up analysis in ITT600mg yielded an HR of 0.94 (95% CI, 0.77 to 1.14). Increased ALT and AST were common adverse events leading to treatment discontinuation in the pazopanib 600 mg (ALT, 16%; AST, 5%) and 800 mg (ALT, 18%; AST, 7%) groups. Conclusion The results of the primary DFS analysis of pazopanib 600 mg showed no benefit over placebo in the adjuvant setting.

Background and Aim: From October 2013 there is a possibility to treat patients with NSCLC and with activated epidermal growth factor receptor (EGFR) mutations with three TKI (afatinib, eriotinib, gefitinib) in the Czech Republic. We have tried to find differences among patient groups treated with single TKI in 1st line of treatment. Patients and methods: As data source we used the TULUNG registry, which is focused on the data collection of patients with NSCLC treated with target therapy in the Czech Republic. We analysed 232 patients (gefitinib - 115 patients, afatinib - 77 patients, eriotinib - 40 patients.). Statistical significance was assessed using the Fisher's exact test or Kruskal-Wallis test (a=0.05).

Objectives: The aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs). Patients and methods: A national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs. Results: Median progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013. Conclusion: PFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy.

Background The convergence of nutritional, genetic, and inflammatory factors plays a significant role in the pathophysiology of squamous cell esophageal cancer (SCEC). The parameters of inflammation, indices of nutritional status, and adipocyte-derived hormones such as leptin, adiponectin, and resistin have been shown to be prognostic factors in some gastrointestinal and pancreatic cancers. Material/Methods Forty-two patients with SCEC were subjected to a multimodal regimen of concurrent neoadjuvant chemoradiotherapy (CRT) followed by surgery. We retrospectively analyzed the impact of pretreatment values of serum leptin, adiponectin, resistin, soluble leptin receptor, C-reactive protein, TNF alpha, leukocytes, and indices of nutritional status (BMI, plasma total protein, albumin, cholesterol, and triacylglycerols) on overall survival (OS). Results Univariate analysis revealed significant a negative correlation between OS and serum adiponectin (p=0.027), and a positive relationship was found between serum albumin (p=0.002), cholesterol (p=0.049) level, and OS. In multivariate analysis, only the trend (p=0.086) for negative serum adiponectin association with the OS was observed. Conclusions In men with SCEC treated by neoadjuvant concurrent CRT and esophagectomy, high pretreatment level of serum adiponectin was associated with shorter OS while the serum albumin and cholesterol were associated with longer OS.

Background Data on the efficacy and safety of all targeted therapies for metastatic renal cell carcinoma (mRCC) including sunitinib are collected in the Czech RENIS patient registry. RENIS thus provides a uniquely large sample of long-term effectiveness and prognostic data of sunitinib according to adverse/risk factors measured by the Memorial Sloan Kettering Cancer Center (MSKCC) score. The aim of this study was to analyze the long-term overall (OS) and progression-free survival (PFS) of sunitinib, when used as 1st line treatment, based on MSKCC risk group scores including MSKCC scores for two intermediate subgroups. Methods Data from mRCC patients treated using sunitinib in the 1st line were collected in RENIS between 06/2007 and 02/2018. OS/PFS were then stratified based on MSKCC scores: a) favorable risk (0 adverse factors (AF)), b) intermediate risk (pooled 1–2 AFs), and c) poor risk (3+ AFs). The OS/PFS of the intermediate risk group was further stratified into two subgroups: i) 1 AF and ii) 2 AFs. All OS/PFS data were analyzed using Kaplan-Meier estimates. Differences in OS/PFS between risk groups were assessed using median survival, 95% confidence intervals (CI), and the log-rank test. Then we assessed the OS/PFS for 1-, 3-, and 5-year survival. Results Over the 11-year follow-up, 2390 patients were treated using sunitinib with 806, 1450, and 134 patients in the favorable, intermediate, and poor MSKCC risk groups. The more favorable MSKCC risk group was accompanied by an improved OS and PFS (p Table . 957P OS and PFS results for sunitinib treatment based on MSKCC risk groups MSKCC favorable MSKCC intermediate MSKCC poor MSKCC intermediate All patients 1 AF 2 AFs Overall survival Median survival (95% CI) 44.7months (40.9-50.5) 24.1months (21.9-26.0) 9.5months (7.2-14.1) 28.2months (25.9-30.7) 16.2months (14.5-20.2) 28.5months (26.3-30.5) 1-year survival (95% CI) 85.0% (82.4-87.6) 69.1% (66.6-71.7) 44.3% (35.0-53.7) 74.3% (71.4-77.2) 58.0% (53.1-62.9) 73.3% (71.4-75.2) 3-year survival (95 %CI) 57.3% (53.4-61.3) 37.1% (34.1-40.1) 9.6% (3.1-16.2) 42.0% (38.3-45.7) 26.3% (21.4-31.2) 42.9% (40.5-45.2) 5-year survival (95% CI) 35.6% (31.2-40.1) 23.4% (20.4-26.4) 3.2% (0.0-8.8) 26.5% (22.7-30.3) 16.5% (11.8-21.2) 26.8% (24.3-29.2) n 806 1450 134 969 481 2390 Log-rank p-value - Progression-free survival Median survival (95% CI) 17.0months (15.4-18.8) 9.0months (8.3-9.5) 4.5months (3.9-6.1) 10.1months (9.4-11.4) 6.2months (5.5-7.5) 10.6months (9.9-11.5) 1-year survival (95% CI) 61.8% (58.3-65.3) 40.7% (38.0-43.4) 20.8% (13.1-28.5) 45.1% (41.8-48.4) 31.6% (27.1-36.1) 46.9% (44.7-49.0) 3-year survival (95 %CI) 25.1% (21.7-28.5) 13.0% (11.0-15.1) 1.8% (0.0-5.1) 15.9% (13.2-18.6) 7.0% (4.2-9.7) 16.6% (14.9-18.4) 5-year survival (95% CI) 10.4% (7.7-13.2) 8.0% (6.2-9.8) 1.8% (0.0-5.1) 9.7 (7.3-12.0) 4.5% (2.1-6.9) 8.4% (7.0-9.9) n 806 1450 134 969 481 2390 Log-rank p-value - Conclusions Better MSKCC risk scores were associated with significantly longer OS and PFS. To our knowledge, this is the largest published sunitinib mRCC cohort described relative to MSKCC risk groups. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure J. Finek: Honoraria (self): Amgen; Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): Bayer; Honoraria (self): Teva; Honoraria (self): MSD; Honoraria (self): Merck; Honoraria (self): Sanofi; Honoraria (self): Pierre Fabre. A. Poprach: Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Ipsen; Honoraria (self): Novartis; Honoraria (self): BMS; Honoraria (self): Bayer. B. Melichar: Honoraria (self): BMS; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Astellas Pharma; Honoraria (self): Pfizer; Honoraria (self): Bayer. J. Kopecky: Honoraria (self): BMS; Honoraria (self): Novartis; Honoraria (self): Pfizer. M. Zemanova: Advisory / Consultancy: Novartis; Honoraria (self): Eli Lilly; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Boehringer Ingelheim. T. Buchler: Honoraria (self): Amgen; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: Janssen. K. Kopeckova: Honoraria (self): Novartis; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Pfizer. T. Mlcoch: Full / Part-time employment: Value Outcomes. T. Dolezal: Full / Part-time employment: Value Outcomes. All other authors have declared no conflicts of interest.

9039 Background: Immunotherapy aiming the induction of tumor cell specific immune responses controlling the tumor growth, has emerged as a promising treatment modality in lung cancer(LuCa). Autologous DCVAC can present tumor antigens to elicit a durable immune response. We hypothesized that adding DCVAC to the standard of care chemotherapy (ct) could prolong overall survival (OS) and progression-free survival (PFS). Methods: This study evaluated the efficacy and safety of DCVAC/LuCa (active cellular immunotherapy based on dendritic cells) concomitantly added to ct (carboplatin/paclitaxel) - Arm A (A) vs DCVAC/LuCa + immune modulators (IFN-α and hydroxychloroquine) - Arm B (B)+ct vs ct - Arm C (C) in NSCLC patients (pts). Randomization 1:1:1; pts in A and B received up to 15 doses of DCVAC, ct was given 4-6 cycles in A and C. Stage IV NSCLC was confirmed histologically or cytologically, ECOG 0-1 pts were eligible. Stratification was done by histology subtype and smoking history. Primary efficacy analysis compared A vs C only as enrollment to B was closed early based on Sponsor’s assessment of further clinical development potential, there were no safety concerns or signals. Results: 112 pts at 12 sites were randomized (A/45 B/29 C/38). Patients characteristics were comparable across the study groups with the exception of gender (m/f, %: 65/35 (A) and 74/26 (C) and smoking history (75 % of smokers in A, 97 % in C). Median follow up time was 25.8 months, range 0.1-41.8. Median OS was 15.5 months in A compared to 11.8 months in C, hazard ratio (HR) 0.55, p-value 0.0232, 95% CI [0.33, 0,93], data maturity 77%. Median PFS was 6.74 in A and 5.63 months in C, HR 0.59, p-value 0.0415, 95% CI [0.36, 0.99], data maturity 86%. Overall response rate was 45% in A vs 34% in C. Most TEAEs were related to ct (anemia [35%-A, 32%-C], neutropenia [48% in A, 21%-C], thrombocytopenia [25% in A, 27% in C]). There were no grade ≥ 3 TEAEs solely related to DCVAC. Most common leukapheresis (lp)-related AE was vomiting in 2 pts out of 67 pts undergone lp. Conclusions: Addition of DCVAC-based immunotherapy to the standard of care chemotherapy significantly improved OS in stage IV NSCLC. Clinical trial information: NCT02470468.

Background Nonclear cell renal cell carcinoma (nccRCC) is a heterogeneous group of primary kidney tumors. The aim of the present retrospective study was to analyze outcomes of patients with nccRCC treated with tyrosine-kinase inhibitors (TKIs) based on a national registry. Methods The registry contained evaluable data of 93 nccRCC patients treated with first-line TKIs, including 87 patients with papillary renal cell carcinoma (RCC) and 6 patients with chromophobe RCC. The control cohort consisted of 1,788 patients with clear-cell RCC treated with first-line TKIs. Multivariable Cox proportional hazard model was used to evaluate the effect of potential prognostic factors on the survival measures. Results Median progression-free survival was 11.8 and 6.5 months in the clear cell renal cell carcinoma and nccRCC patients, respectively (P = 0.018), and median overall survival was 33.2 and 22.0 months, respectively (P = 0.007). In the multivariate analysis, independent factors associated with inferior progression-free survival included high tumor grade, worse Memorial Sloan Kettering Cancer Center risk group, absence of nephrectomy, and sunitinib (as opposed to pazopanib) as first-line targeted therapy. Independent predictors of inferior overall survival included nonclear cell histology, tumor grade, worse Memorial Sloan Kettering Cancer Center risk group, absence of nephrectomy, older age, and sunitinib as first-line targeted therapy. Conclusions The present retrospective, registry-based study confirms that patients with nccRCC treated with TKIs have worse clinical outcomes compared to clear cell renal cell carcinoma patients with similar baseline characteristics.

The effectiveness of continuation maintenance therapy with pemetrexed versus the watch-and-wait approach was proved by a large randomised phase III trial. We focused on continuance maintenance therapy with pemetrexed in routine clinical practice in the Czech Republic.

Background Although a significant proportion of patients with metastatic renal cell carcinoma (mRCC) are elderly, the data on the outcomes of targeted therapies in this population are limited. The aim of the present retrospective registry-based study was to analyse efficacy and toxicity of sunitinib as the first-line targeted therapy of elderly mRCC patients. Patients and Methods The national RENal information system registry of mRCC patients treated with targeted agents in the Czech Republic was used as the data source. Of the 1315 patients treated with sunitinib as first-line targeted therapy, 1016 and 299 patients were aged < 70 and aeyen70 years, respectively. Results Elderly patients had a significantly longer interval from diagnosis to the initiation of therapy. Median progression-free survival was 10.8 months (95 % confidence interval 9.8-11.8) and 8.8 months (7.2-10.4) for patients aged < 70 and aeyen70 years, respectively (p = 0.321). Median overall survival was 31.9 months (27.9-35.9) and 26.3 months (21.3-31.2), respectively (p = 0.044). Significantly more elderly patients started on a reduced dose of sunitinib or discontinued the treatment prior to progression because of adverse events. Conclusions The differences in patient profile and dose-reduction rates point to a different approach in the management of older and younger patients in daily clinical practice. The lower dose intensity of sunitinib in the elderly population may have translated into inferior survival.

Combined modality treatment for esophageal carcinoma seems to improve survival over surgery alone. Different combinations of cytotoxic drugs have been studied to improve antitumor efficacy and limit the toxicity of chemoradiotherapy (CRT) with inconsistent results. We present a prospective study of neoadjuvant CRT with or without paclitaxel in chemotherapy schedule. One hundred seven patients (93 males, 14 females), median age 59 years (range 44-76), with operable esophageal cancer were enrolled. They received the following neoadjuvant therapy: Carboplatin, area under curve (AUC) = 6, intravenously on days 1 and 22, 5-fluorouracil (5-FU), 200 mg/m(2)/day, continuous infusion on days 1 to 42, radiation therapy 45 grays/25fractions/5 weeks beginning on day 1. Forty-four patients (41%) were furthermore non-randomly assigned to paclitaxel 200 mg/m(2)/3 h intravenously on days 1 and 22. Nutritional support from the beginning of the treatment was offered to all patients. Surgery was done within 4-8 weeks after completion of CRT, if feasible. All patients were evaluated for grade 3 plus 4 toxicities: leukopenia (28%), neutropenia (30%), anemia (6%), thrombocytopenia (31%), febrile neutropenia (6%), esophagitis (24%), nausea and vomiting (7%), pneumotoxicity (8%). Seventy-eight patients (73%) had surgery and 63 of them were completely resected. Twenty-two patients (20%) achieved pathological complete remission, and additional 20 (19%) had node-negative and esophageal wall-positive residual disease. There were 10 surgery-related deaths, mostly due to pulmonary insufficiency. Twenty-nine patients were not resected, 15 for early progression, 14 for medical reasons or patient refusal. After a median follow-up of 52 months (range 27-80), median survival of 18.0 months and 1-, 2-, 3- and 5-year survival of 56.7, 37.5, 27.0 and 21% was observed in the whole group of 107 patients. Addition of paclitaxel to carboplatin and continual infusion of FU significantly increased hematologic and non-hematologic toxicity, but treatment results as overall survival or time to progression did not differ significantly in groups with and without paclitaxel. Patients achieving pathological complete remission or nodes negativity after neoadjuvant therapy had favorable survival prognosis, whereas long-term prognosis of node positive patients was poor. Distant metastases prevailed as a cause of the treatment failure. Factors significant for survival prognosis in multivariate analysis were postoperative node negativity, performance status, and grade of dysphagia. Addition of paclitaxel to carboplatin and continual FU significantly increased hematologic and non-hematologic toxicity without influencing efficacy of the treatment. This study confirmed improved prognosis of patients after achieving negativity of nodes. Distant metastases prevailed as cause of the treatment failure. Prospectively, it is important to look for a therapeutic combination with better systemic effect.

Background Esophageal cancer is the malignant tumor with very poor prognosis and increasing incidence often diagnosed at very late stage, so the prognosis of affected patients is unsatisfactory, despite the development of therapeutic option such as surgery, chemotherapy and radiotherapy. Consequently, there is a great need for biomarkers to allow a tailored multimodality approach with increased efficiency. Altered expression of microRNAs has been reported in wide range of malignancies, including esophageal cancer. The aim of this study was to examine the expression levels of candidate microRNAs in esophageal cancer and evaluate their diagnostic and prognostic potential. Findings Using quantitative real-time PCR, expression levels of 9 candidate microRNAs were examined in 62 tissue samples, 23 esophageal adenocarcinomas, 22 esophageal squamous cell carcinomas and 17 adjacent esophageal mucosa samples. MicroRNA expression levels were further analyzed in regards to clinico-pathological features of esophageal cancer patients. We observed significantly decreased levels of miR-203 and increased levels of miR-21 in adenocarcinoma tissues when compared to normal mucosa. MiR-29c and miR-148 indicated good ability to distinguish between histological subtypes of esophageal cancer. MiR-203 and miR-148 were linked to disease-free survival and overall survival in esophageal adenocarcinoma patients, and miR-148 also in esophageal squamous cell carcinoma patients. Conclusions Our data suggest that altered expression of miR-21, miR-29c, miR-148 and miR-203 are related to neoplastic transformation and progression of the disease and these microRNAs could serve as a potential diagnostic and prognostic biomarkers in esophageal cancer. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4646922201567057

Characteristics of NSCLC Patients Treated in First Line Treatment with Tyrosine Kinase Inhibitors (TKI) - Real Data from the Czech Republic.

4507 Background: PROTECT (NCT01235962) evaluated the efficacy and safety of pazopanib (PAZ) versus placebo in patients (pts) with locally advanced renal cell carcinoma (RCC) post nephrectomy. Methods: 1538 pts with resected pT2 (high grade), pT3 or greater clear cell RCC were randomly assigned to PAZ or placebo for 1 year. The starting dose (800 mg) following treatment of 403 pts was lowered to 600 mg to improve tolerability and primary endpoint was changed to disease-free survival (DFS) with PAZ 600 (N = 1135). Primary analysis was performed after 350 DFS events in intent-to-treat (ITT) PAZ 600, and DFS follow-up analysis was performed after an additional 12 months. Secondary endpoints included DFS with ITT PAZ 800 and ITT ALL, and safety. Results: Disease characteristics were similar between arms. The primary analysis results of DFS ITT 600 were not significant [HR: 0.862; 95% CI, 0.699, 1.063; p = 0.165] (Table). The secondary endpoint of DFS in ITT PAZ 800 and ITT ALL yielded 31% and 20% risk reduction, respectively. Updated DFS analysis in ITT 600 showed a higher HR with longer follow up. Increased ALT and AST were the most common adverse events leading to treatment discontinuation in the PAZ 600 (ALT 16% and AST 5%) and PAZ 800 (ALT 18% and AST 7%) groups. Conclusions: The study did not meet the primary DFS endpoint in ITT 600; however, a 31% decrease in the risk of recurrence was observed in ITT 800. The safety profiles in the 600 mg and 800 mg groups were similar and consistent with PAZ prior experience. Clinical trial information: NCT01235962. [Table: see text]

Aim: The aim of this retrospective, registry-based study was to analyse treatment outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib and renal insufficiency (RI). Methods: The cohort included 790 patients treated with sunitinib between 2006 and 2013. At the start of sunitinib therapy 22, 234, and 534 patients had severe (glomerular filtration rate [GFR] 60 ml/min/1.73 m(2)), respectively. Results: For the three groups defined above, median progression-free survival (PFS) (95% confidence interval [CI]) was 5.3 months (0.1-18.5), 8.1 months (6.2-9.9) and 11.3 months (9.4-13.2) (p = 0.244), and median overall survival (OS) was 26.3 months (1.2-51.4), 21.2 months (13.2-29.1) and 26.3 months (22.6-29.9) (p = 0.443), respectively. The disease control rates were 45.5%, 56.4% and 59.2%, respectively (p = 0.374). No unexpected toxicity was reported in the patients with RI, but the treatment was more frequently discontinued because of adverse events and the duration of therapy was significantly shorter in these patients (p = 0.007). Conclusions: Duration of first-line targeted treatment for mRCC was significantly shorter for patients with RI, and may have translated into a trend to shorter PFS. These results highlight the need for optimal management of side-effects in patients with mRCC and RI.

e15545Background: There have been reports suggesting that histopathological responders, who markedly benefit from neoadjuvant chemotherapy (NeoCT), may be identified by 18-fluorodeoxyglucose positr...

Background When applying the PET Response Criteria in Solid Tumors protocol, a threshold value based on standardized uptake value corrected to lean body mass (SUL) in liver parenchyma, or in the blood pool, is used: to metabolically specify a measurable lesion; to calculate metabolic tumor volume (mTV) and its product total lesion glycolysis (TLG); and as a limit for response measurement. The problem with using changes in glucose metabolism as a marker for response to therapy is its reproducibility on test-retest examinations. Therefore, before the evaluation of tumor treatment response, we verified our diagnostic protocol for homogeneity using the PET Response Criteria in Solid Tumors quality parameters. In addition, we analyzed the effect of the time span between examinations on the average value of SUL (SUL MEAN) in liver parenchyma at three different points: first at baseline (BL), after the first course of chemotherapy (ChT1), and finally after finishing therapy (ChT3). We also analyzed the influence of SUL MEAN variation on mTV and TLG. Methods Eighty-four patients with esophageal cancer were prospectively examined at BL using 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG)-PET/CT; 53 of 84 patients were examined after ChT1, 47 of 84 after ChT3, and 41 of 84 underwent all three examinations. Coefficient of variance (CV) and relative differences (RDw) were assessed for test-retest liver SUL values. The influence of liver SUL MEAN to mTV and TLG was modeled on BL examinations by artificial changes in liver SUL MEAN by ± 20%. Results No significant differences were found in test-retest liver SUL MEAN values. Comparing BL with ChT1, BL with ChT3, and ChT1 with ChT3, the CV of the liver SUL MEAN was 10.4, 10.7, and 10.3%; nevertheless, in 34.0, 38.3, and 36.6% of these examinations, respectively, the liver average SUL MEAN values exceeded the limit for inclusion in the study; that is, the difference was less than ± 0.3 U and ± 20%. The corresponding CV of blood background was 14.9, 16.5, and 17.2%. The artificial decrease of -20% in the liver SUL MEAN resulted in an increase of +43.6% in mTV and of +20.4% in TLG, whereas an increase of +20% in the liver SUL MEAN resulted in a decrease of -20.6% in mTV and -11.9% in TLG. Conclusion SUL MEAN values in reference tissues (liver parenchyma or descending aorta) measured before chemotherapy did not differ significantly from those measured during chemotherapy. The CV of liver SUL MEAN was comparable to that seen in published data, but some patients had to be excluded from the study because of the individual variability of their mean liver SUL MEAN, which consequently hinders the clinical usage of mTV and TLG. Even in the standardized protocol, all potential sources of variability should be minimized.