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Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Zielsetzung: Die Ergebnisse früherer Studien deuteten darauf hin, dass die Serumspiegel der microRNA (miR)-371a-3p (so genannter M371-Test) eine sehr viel höhere Sensitivität und Spezifität aufweisen als die klassischen Tumormarker für testikuläre Keimzelltumoren (germ cell tumors, GCTs) und sowohl für Seminome als auch für Nichtseminome anwendbar sind. Unser Ziel war es, den Nutzen dieses Tests als neuen Biomarker für GCTs zu bestätigen. Patienten und Methoden: Im Rahmen einer prospektiven Multicenter-Studie wurden die Serumspiegel von miRNA-371a-3p (miR-Spiegel) in Serumproben von 616 Patienten mit testikulären GCTs und 258 männlichen Kontrollen mittels quantitativer Polymerase-Kettenreaktion untersucht. Die GCT-Patientenpopulation umfasste 359 Patienten mit Seminom und 257 mit einem Nichtseminom; 371 hatten eine Erkrankung im klinischen Stadium I, 201 hatten eine systemische Erkrankung und 46 ein Rezidiv. Bei 424 Patienten erfolgten paarige Messungen vor und nach der Orchiektomie und bei 118 Patienten mit systemischer Erkrankung wurden serielle Messungen während der Behandlung durchgeführt. Die miR-Spiegel wurden mit denen von β-HCG (humanes Choriongonadotropin), α-Fetoprotein und Laktatdehydrogenase verglichen. Ergebnisse: Bei der GCT-Primärdiagnose betrug die Sensitivität des M371-Tests 90,1 %, die Spezifität 94,0 %, die Fläche unter der Kurve 0,966 in der Receiver-Operating-Characteristic-Analyse und der positive prädiktive Wert 97,2 %. Die Sensitivität von α-Fetoprotein, humanem β-Choriongonadotropin und Laktatdehydrogenase lag bei Seminomen bei weniger als 50 % und bei Nichtseminomen geringfügig höher. Es bestand eine signifikante Assoziation zwischen den miR-Spiegeln und dem klinischen Stadium, der Größe des Primärtumors und dem Ansprechen auf die Behandlung. Bei Rezidiven waren erhöhte miR-Spiegel zu beobachten, die anschließend bei einer Remission auf den Normalwert abfielen. Teratome exprimierten keine miR-371a-3p. Schlussfolgerung: Mit einer Sensitivität und Spezifität von mehr als 90 % schneidet der M371-Test besser ab als die klassischen GCT-Tumormarker. Alle histologischen Subgruppen mit Ausnahme des Teratoms exprimieren diesen Tumormarker. Nach weiterer Validierung könnte der Test für den klinischen Einsatz in Betracht kommen.

Abstract Preventing the ototoxicity caused by cisplatin is a major issue yet to be overcome. Useful preventive treatments will soon be available. Consequently, the next step is to filter out those patients who are more prone to develop ototoxicity. The aim of this study was to prospectively evaluate potential predictive markers of acute ototoxicity as determined by measures of distortion product otoacoustic emissions (DPOAEs). A total of 118 patients from our previous DPOAE analysis were put under evaluation. Ototoxic cases were divided according to unilateral (n = 45) or bilateral (n = 23) involvement. The clinicopathological characteristics, hearing test results, germline GSTT1, GSTM1, and GSTP1 polymorphisms, and common laboratory parameters were included in the new analysis. Univariate and multivariate statistical tests were applied. According to multivariate logistic regression, the only independent predictor of unilateral ototoxicity (vs. non-affected) was a GSTM1 null genotype (OR = 4.52; 95%CI = 1.3–16.3), while for bilateral damage, the GSTT1 null genotype (OR = 4.76; 1.4–16) was a predictor. The higher starting serum urea level was characteristic of bilateral ototoxicity; however, the only independent marker of bilateral (vs. unilateral) ototoxicity was the presence of GSTT1 null genotype (OR = 2.44; 1.23–4.85). Different processes, involving the GSTM1 and GSTT1 genotypes, respectively, govern the development of acute unilateral and bilateral ototoxicities. Further research is needed to clarify these processes. Based on the above findings, patients whom are at risk may be selected for otoprotective therapies. Key messages The acute ototoxicity was determined by DPOAE in 118 testicular cancer patients. GSTM1 null was the only marker of unilateral ototoxicity (vs. non-affected). The only marker of bilateral hearing loss (vs. non-affected) was the GSTT1 null. GSTT1 null was also the marker of bilateral vs. unilateral ototoxicity. A high-risk group may be selected for new, individualized otoprotective treatment.

Background Targeted therapies significantly improve clinical outcomes among patients with metastatic renal cell carcinoma (mRCC). Several new agents have been approved for first- and second-line use. However, there is a lack of compelling evidence comparing sequencing strategies, and available comparative data regarding the real-world effectiveness of different therapeutic sequences are limited. Materials and Methods We identified mRCC patients who initiated targeted therapy between January 1, 2008 and May 31, 2017 from the National Health Insurance Fund (NHIF) database of Hungary. Overall survival (OS) and duration of first-line treatment (DFT) were obtained for patients receiving sunitinib-everolimus, sunitinib-axitinib, or pazopanib-everolimus treatment sequences. OS of sunitinib-everolimus and sunitinib-axitinib sequences was also determined for patients having better or worse response to sunitinib first-line therapy. Results Median OS was significantly longer among patients treated with sunitinib-axitinib compared to those receiving sunitinib-everolimus. Median DFT was also significantly longer in the sunitinib-axitinib vs. sunitinib-everolimus group. Sunitinib-axitinib was associated with significantly longer median OS compared to sunitinib-everolimus in patients with better response to first-line sunitinib in the pooled sunitinib population. In patients with worse response to sunitinib, sunitinib-axitinib was associated with a trend towards greater OS compared to sunitinib-everolimus, but the difference did not reach statistical significance. Conclusions In this nationwide database analysis, mRCC patients treated with the sunitinib-axitinib sequence had significantly longer OS compared to those receiving sunitinib-everolimus therapy. The OS benefits of second-line axitinib were consistent among patients with better response to sunitinib defined by DFT values.

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.Findings Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7.4 months (IQR 3.5-13.9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4.1 months [95% CI 3.3-4.8] vs 2.8 months [2.6-2.9]; HR 0.696 [95% CI 0.573-0.845]; p=0.0002). Median overall survival was 9.4 months (95% CI 7.9-11.4) in the ramucirumab group versus 7.9 months (7.0-9.3) in the placebo group (stratified HR 0.887 [95% CI 0.724-1.086]; p=0.25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.Interpretation Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

BACKGROUND: The phase 3 RANGE trial found ramucirumab/docetaxel improved progression-free survival (PFS) versus placebo/docetaxel (median 4.1 vs 2.8 months; hazard ratio [HR] = 0.757, p = 0.0118) for treatment of platinum-refractory metastatic urothelial carcinoma (UC). Some patients received an immune checkpoint inhibitor (ICI) prior to RANGE. In other studies, unselected patients with platinum-refractory UC exhibited an overall response rate (ORR) of 15–31% to ICIs. OBJECTIVE: Efficacy and safety data from the subgroup of patients treated with prior ICI were examined using prespecified analyses to compare outcomes between RANGE treatment arms. METHODS: Randomized, double-blind RANGE study (n = 530) took place July 2015-April 2017 in 23 countries. Forty-five patients (8.5%) received prior ICI. PFS was evaluated using the Kaplan-Meier method and unstratified Cox proportional hazards model. RESULTS: 17 ramucirumab/docetaxel arm, 28 placebo/docetaxel arm patients were treated with an ICI. The prior-ICI ramucirumab subgroup had worse Bellmunt scores at baseline versus placebo (score of 2-3 : 70.6% vs 25%, respectively). Most patients (84.4%) received the ICI immediately following platinum and immediately prior to RANGE. ORR to prior ICI was 6.7% Responses were achieved by 5/17 (29.4%) on ramucirumab/docetaxel, compared to 2/28 (7.1%) on placebo/docetaxel. Median PFS was 3.15 months on ramucirumab/docetaxel versus 2.73 months on placebo/docetaxel (HR = 0.786, 95% CI = 0.404–1.528, p = 0.4877). The frequency of grade≥3 adverse events was similar between arms. Limitations include sample size and treatment setting of the analyzed population. CONCLUSIONS: Ramucirumab/docetaxel may provide a clinical benefit with acceptable safety in the third-line setting for metastatic UC patients whose disease has progressed on both prior platinum chemotherapy and ICI therapy.

Cisplatin containing chemotherapy has proven benefit for muscle-invasive locally advanced and metastatic urothelial cancer. The carboplatin based combinations are less effective in these settings. In most cases for the platinum based chemotherapy ineligible patients only the best supportive care could be given. The treatment options have expanded in the past few years with the introduction of systemic immunotherapy with checkpoint inhibitors. We review the relevant clinical trials' data which can completely transform the treatment landscape of locally advanced or metastatic urothelial cancer.

Introduction/Background* Immature teratomas are rare germ cell ovarian tumours occuring in about 1% of ovarian cancers. Growing Teratoma Syndrome (GTS) is a rare clinical situation where seemingly successful chemotherapy is followed by a rapid tumor progression, while tumour markers normalize. Despite radiological progression, the phenomenon is characterised by the maturation of the teratoma, and in most cases there is hardly any immature component left. In these rare cases radical surgical treatment is usually effective and can lead to complete recovery. Methodology case report Result(s)* A joint working group of the Department of Gynecology and Department of Genitourinary, Medical Oncology and Clinical Pharmacology of the National Institute of Oncology, Hungary diagnosed three immature ovarian teratoma cases with extended pelvic/abdominal tumor mass which showed progressive growth during and following chemotherapy. In all three cases, we had to perform multivisceral cytoreductive surgery with peritonectomy leading to complete cytoreduction. All patients are currently tumor-free. Postoperative histological findings showed 80-100% maturation, one of them operated 19 years after the primary treatment. Conclusion* By presenting these 3 patients, our goal is to raise awareness of the possibility of GTS and to emphasize the importance of adequate treatment.

Chemotherapy for the treatment of urothelial and bladder cancers has focused on renewed indications in light of clinical trials of modern therapies, which are described in our review. In stage T2-T4a N0-1 M0 cases, that are suitable for cisplatin, surgery is performed after neoadjuvant cisplatin- based chemotherapy. Less significant result is observed with adjuvant chemotherapy, especially in pT3-4 and/or N+ stage, if no neoadjuvant chemotherapy was administered. Cisplatin-based chemotherapy is the first-line treatment of cisplatin-eligible metastatic patients. First-line choice in chemo-fit cases with cisplatin ineligibility can be carboplatin- based chemotherapy. 4-6 cycles of cisplatin or carboplatin cause stable disease or regression, maintenance avelumab immunotherapy improves patient's survival. For those patients who progress during or after platinum-based chemotherapy, the effectiveness of chemotherapy in the second/multiple lines is less favourable in comparison with immunotherapy and targeted therapy. Modern antibody - cytotoxic drug conjugates have been discovered in the form of enfortumab vedotin and sacituzumab govitecan, and currently they seem to be effective in the third line after chemotherapy and immunotherapy.

Background The use of checkpoint inhibitors has become increasingly important in the treatment of different cancers, including advanced muscle-invasive urothelial cancer and even in basal cell carcinoma. We present the case of a patient with advanced basal cell carcinoma and metastatic muscle-invasive urothelial cancer, who was treated with the programmed death-ligand 1 inhibitor, atezolizumab for both cancers. Case presentation A 72-year-old Caucasian female patient, with a history of smoking without any comorbidities developed periocular basal cell carcinoma, which was surgically removed but relapsed 4 years later. Surgical excision was carried out twice, but with positive margins, therefore definitive radiotherapy was given. Subsequently, the patient developed non-muscle-invasive papillary urothelial carcinoma, which was removed by transurethral resection. Follow-up was irregular owing to the patient’s inadequate compliance, and within 2 years, the patient’s cancer relapsed and histology confirmed muscle-invasive urothelial carcinoma. Definitive radiochemotherapy was not accepted by the patient. Meanwhile, the patient’s basal cell carcinoma had also progressed, despite receiving vismodegib therapy. Therefore, the patient was administered epirubicin-cisplatin. Having reached the maximum cumulative dose of epirubicin, treatment with this chemotherapeutic agent could not be continued. The patient developed bladder cancer metastasis in her left suprainguinal lymph nodes. Owing to the presence of both types of tumors, programmed death-ligand 1 inhibitor atezolizumab treatment was chosen. In just over 1 year, the patient received 17 cycles of atezolizumab altogether, which was tolerated well without any adverse or side effects. Follow-up imaging scans indicated complete remission of the metastatic bladder cancer and stable disease of the basal cell carcinoma. The patient subsequently passed away in hospital due to a complication of COVID-19 infection. Conclusions Our patient attained stable disease in advanced basal cell carcinoma and complete remission in metastatic muscle-invasive urothelial cancer after receiving programmed death-ligand 1 inhibitor, atezolizumab, therapy. To our knowledge, this is the first paper to report the use of programmed death-ligand 1 inhibitor, atezolizumab, as treatment for advanced basal cell carcinoma. This case may also be of interest for clinicians when treating patients with two synchronous cancers.

Lessons Learned Background Endoglin is an angiogenic receptor expressed on proliferating tumor vessels and renal cell carcinoma (RCC) stem cells that is implicated as a mechanism of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors. This study evaluated an antiendoglin monoclonal antibody (carotuximab, TRC105) combined with axitinib in patients with advanced or metastatic clear cell renal cell carcinoma (mccRCC) who had progressed following one or more prior VEGF inhibitors. Methods TRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 Results A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. Conclusion The combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment.

Abstract: Current advances in molecular techniques and bioinformatics allowed the analysis of complex molecular patterns in various cancers including muscle-invasive bladder cancer. As a consequence, in the last few years numerous gene- and protein expression-based molecular classifications have been recommended. Recently a comprehensive consensus classification for muscle-invasive urothelial bladder cancer has been published, distinguishing 6 subgroups with a potential impact on clinical decision-making. At the same time, the therapeutic landscape of muscle-invasive bladder cancer becomes increasingly differentiated as novel checkpoint inhibitors have been available for cisplatin-ineligible and/or resistant patients. Furthermore, promising results have been obtained with FGFR targeting agents. Therefore, molecular subtyping will probably have a crucial role in individualized therapeutic decision-making in bladder cancer. In the present work, we summarize the evolution, recent advances and potential therapeutic relevance of molecular subclassifications in bladder cancer. Orv Hetil. 2019; 160(42): 1647–1654.

Background. In Hungary, the mortality rate for testicular germ cell cancer (TGCC) is 7.6% which is significantly higher than the EU average. We prospectively evaluated the effect of socioeconomic status on patient delay, doctor’s delay, and therapy outcomes.Methods: Questionnaires on subjective (MacArthur Subjective Status Scale), objective (wealth, education, and housing data) social status, and on patient’s and doctors’ delays were completed by newly diagnosed TGCC patients.Results: Patients belonged to a relatively high socioeconomic class, a university degree was double the Hungarian average, Cancer-specific mortality in the highest social quartile was 1.56% while in the lowest social quartile 13.09% (p=0.02). In terms of patient delay, 57.2% of deceased patients waited more than a year before seeking help, while this number for the surviving patients was 8.0% (p=0.0000). Longer patient delay was associated with a more advanced stage in non-seminoma but not in seminoma, the correlation coefficient for non-seminoma was 0.321 (pConclusions: Based on our result, we conclude that to improve survival, we should promote testicular cancer awareness, especially among the most deprived populations, and their health care providers.

Background In Hungary, the mortality rate for testicular germ cell cancer (TGCC) is 0,9/100000 which is significantly higher than the EU average. We prospectively evaluated the effect of socioeconomic position on patient delay and therapy outcomes. Methods Questionnaires on subjective social status (MacArthur Subjective Status Scale), objective socioeconomic position (wealth, education, and housing data), and on patient’s delay were completed by newly diagnosed TGCC patients. Results Patients belonged to a relatively high socioeconomic class, a university degree was double the Hungarian average, Cancer-specific mortality in the highest social quartile was 1.56% while in the lowest social quartile 13.09% (p = 0.02). In terms of patient delay, 57.2% of deceased patients waited more than a year before seeking help, while this number for the surviving patients was 8.0% (p = 0.0000). Longer patient delay was associated with a more advanced stage in non-seminoma but not in seminoma, the correlation coefficient for non-seminoma was 0.321 (p p = 0.0003, and r = − 0.20, p = 0.0005), respectively. Since the patient delay was correlated with the social quartile and resulted in a more advanced stage in non-seminoma, the lower social quartile resulted in higher mortality in non-seminoma patients (p = 0.005) but not in seminoma patients (p = 0.36) where the patient delay was not associated with a more advanced stage. Conclusions Based on our result, we conclude that to improve survival, we should promote testicular cancer awareness, especially among the most deprived populations, and their health care providers.

Importance The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P

The unprecedented development of prostate cancer therapy is a challenge for the proper sequential use of modern medicines. Patients' life expectancies improve when we use treatment lines, one after the other. There is no evidence- based guideline regarding the optimal sequence, but a number of data are available to help the physician selecting the best individualized therapeutic option. The basic treatment for advanced prostate cancer is still androgenic deprivation (ADT), to which we can add additional therapeutic agents. New types of hormonal (androgen receptor targeted, ARTA) agents are being used in an increasingly early line. Chemotherapy (CT) is the first choice in case of metastatic, hormone-sensitive disease especially in high volume cases that are causing symptoms or visceral crisis. CT is otherwise applied after ARTA. We have little but encouraging data about the early, sequential use of ARTAs with different mechanisms of action. In later lines, cross-resistance may develop between ARTA treatments, in which cases CT is the right decision. In this paper, we summarize the results of clinical trials that may help in therapeutic decision making, maximizing the benefits for patients.

The objective of our study was to assess the real-world safety and efficacy of nivolumab in the second- or later-line treatment of metastatic renal cell carcinoma (mRCC). We conducted a multicenter, retrospective, observational study of real-world data from patients who were treated with nivolumab under a patient expanded access program from 2015 to 2017 in Croatia, Hungary, and Malta. The primary safety endpoint was the discontinuation of therapy because of adverse events. The primary efficacy endpoint was overall survival (OS). We collected data from 87 patients with a median (interquartile range (IQR)) age of 63 (57-68) years, and 21% were females. The median (IQR) follow-up was 11 (5-31) months. Treatment was discontinued because of toxicity in 4 (5%) patients. Four (5%) patients experienced treatment-related adverse events of grade 3 or 4. The OS was 18.0 (95% CI: 11.0 to 28.6) months, and the PFS was 8.5 (95% CI: 4.9 to 12.1) months. Our study indicated a good safety and efficacy profile of nivolumab in the second- or later-line treatment of mRCC patients in a real-world clinical practice environment, which is comparable with the findings of the registrational trial.

Background. There is a lack of real-world data on the safety and efficacy of nivolumab in patients with previously treated advanced non-small-cell lung cancer (NSCLC) especially in South East Europe, a region with particularly high incidence and an unfavorable mortality-to-incidence ratio for lung cancer. Objectives. To evaluate the real-world safety and efficacy of nivolumab in patients with previously treated advanced squamous and nonsquamous NSCLC in South East Europe. Methods. This is a multicenter, retrospective cohort study on patients with stage IIIB or IV disease with at least one previous systemic treatment who received nivolumab through an expanded-access program between 2015 and 2017 in Croatia, Malta, and Hungary. The primary endpoint was the proportion of patients whose therapy was discontinued because of toxicity. Secondary endpoints were the incidence of adverse events (AEs), objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results. We analyzed data on 239 patients with a median (IQR) age of 62 (57–68), and 33% of them were women. Treatment was discontinued because of toxicity in 11.6% (95% CI 7.8% to 16.5%) of patients. The PFS was 6.4 (95% CI 5.2 to 8.6) months, and the median OS was 14.1 (10.6 to 18.0) months. Conclusions. The safety and efficacy of nivolumab in previously treated patients with advanced NSCLC in the real-world South East Europe clinical settings were consistent with the results of randomized clinical trials and comparable to the results from other countries.

Real-world evidence from clinical practices is fundamental for understanding the efficacy and tolerability of medicinal products. Patients with renal cell cancer were studied to gain data not represented by analyses conducted on highly selected patients participating in clinical trials. Our goal was to retrospectively collect data from patients with advanced renal tumours treated with pazopanib (PZ) to investigate the efficacy, frequency of side effects, and searching for predictive markers. Eighty-one patients who had received PZ therapy as first-line treatment were retrospectively evaluated. Overall survival (OS), progression-free survival (PFS) were assessed as endpoints. Median PFS and OS were 11.8 months (95% CI: 8.8–22.4); and 30.2 months (95% CI: 20.3–41.7) respectively. Severe side effects were only encountered in 11 (14%) patients. The presence of liver metastasis shortened the median PFS (5.5 vs. 14.8 months, p = 0.003). Median PFS for patients with or without side effects was 25.6 vs. 7.3 months, respectively (p = 0.0001). Patients younger than 65 years had a median OS of 41.7 months vs. 25.2 months for those over 65 years of age (p = 0.008). According to our results absence of liver metastases, younger age (

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Abstract: The treatment of metastatic prostate cancer can be divided into two pathophysiological phases: hormone-sensitive and castration-resistant phases. Huggins’ observation in the year 1941, which was awarded with the Nobel Prize in 1966, has a key role in treatment during the hormone-sensitive phase, stating that if the testicles are removed, the size of the prostate cancer decreases. Inducing androgen deprivation, i.e., testosterone depletion is the basic treatment of metastatic prostate cancer that patients have to receive life-long. In the past eight years, five new agents have been approved besides docetaxel in the treatment of metastatic castration-resistant prostate cancer: sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, and radium-223. With the sequential application of these agents, significant improvement can be achieved in survival. Besides the latest developments, the hormone-sensitive phase has become the focus of attention, especially in the treatment of patients with de novo metastases and poor prognosis. Many studies have proven the outstanding efficacy of adding early docetaxel and abiraterone to androgen deprivation therapy. The authors give a detailed overview of clinical studies leading to a paradigm change in treatment during the hormone-sensitive phase, and call attention to the difficulties encountered in Hungarian practice. Orv Hetil. 2018; 159(41): 1664–1671.

Everolimus is indicated for adults with metastatic renal cell carcinoma (mRCC) after failure of vascular endothelial growth factor receptor-tyrosine kinase inhibitors (TKI). Currently, the therapeutic applicability of EVE has been changing. Multicenter evaluation of efficacy and safety of everolimus in daily routine and definition of patient characteristics with favorable outcome. Data of 165 patients from 9 oncology institutes in Hungary were analyzed retrospectively. Everolimus therapy was used after one TKI in 10 mg starting dose. Physical and laboratory examinations and imaging tests were performed monthly and every 3 months, respectively. Median progression-free survival (PFS) was 5.4 months. Median overall survival (OS) was 16.2 months. PFS and OS results were more favorable in patients with ECOG 0–1 (pPFS = 0.033, pOS = 0.008) and after >9 months of TKI therapy (pPFS = 0.019, pOS = 0.045). Survival was longer in nonanemic patients with ECOG 0–1 than in anemic patients with ECOG 2–3, 30.9 and 7.7 months, respectively (p = 0.029). Dose reduction and treatment delay was required in 6.2% and 8.9% of patients, respectively. Common adverse events were exanthema, edema, stomatitis, anemia, and abnormal kidney functions and glucose levels. Results of this study show that everolimus is safe and efficacious in a real-world setting. Everyday practice showed that nonanemic patients with good performance status receiving TKI therapy for >9 months are favorable candidates for this treatment. Despite the efficiency of novel, registered drugs, everolimus still plays an important role during and after second-line therapy for mRCC when availability of modern remedies is limited.

Purpose Cabazitaxel 25 mg/m2 (C25) significantly improved overall survival (OS) versus mitoxantrone ( P < .001) in postdocetaxel patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase III TROPIC study. The phase III PROSELICA study ( ClinicalTrials.gov identifier: NCT01308580) assessed the noninferiority of cabazitaxel 20 mg/m2 (C20) versus C25 in postdocetaxel patients with mCRPC. Methods Patients were stratified by Eastern Cooperative Oncology Group performance status, measurability of disease per Response Evaluation Criteria in Solid Tumors (RECIST), and region, and randomly assigned to receive C20 or C25. To claim noninferiority of C20 (maintenance of ≥ 50% of the OS benefit of C25 v mitoxantrone in TROPIC) with 95% confidence level, the upper boundary of the CI of the hazard ratio (HR) for C20 versus C25 could not exceed 1.214 under a one-sided 98.89% CI after interim analyses. Secondary end points included progression-free survival, prostate-specific antigen (PSA), tumor and pain responses and progression, health-related quality of life, and safety. Results Overall, 1,200 patients were randomly assigned (C20, n = 598; C25, n = 602). Baseline characteristics were similar in both arms. Median OS was 13.4 months for C20 and 14.5 months for C25 (HR, 1.024). The upper boundary of the HR CI was 1.184 (less than the 1.214 noninferiority margin). Significant differences were observed in favor of C25 for PSA response (C20, 29.5%; C25, 42.9%; nominal P < .001) and time to PSA progression (median: C20, 5.7 months; C25, 6.8 months; HR for C20 v C25, 1.195; 95% CI, 1.025 to 1.393). Health-related quality of life did not differ between cohorts. Rates of grade 3 or 4 treatment-emergent adverse events were 39.7% for C20 and 54.5% for C25. Conclusion The efficacy of cabazitaxel in postdocetaxel patients with mCRPC was confirmed. The noninferiority end point was met; C20 maintained ≥ 50% of the OS benefit of C25 versus mitoxantrone in TROPIC. Secondary efficacy end points favored C25. Fewer adverse events were observed with C20.

Abstract: Until the past decade, therapeutic options for unresectable and/or metastatic renal cell carcinoma were limited. Renal cell carcinoma is generally resistant to conventional chemotherapy, and only a small percentage of patients with renal cell carcinoma benefit from cytokine treatment. Since 2005, the advances in target-based therapy and immunotherapy modalities have created a paradigm shift in the treatment of renal cell carcinoma. Herein, we review the most up-to-date practices and emerging therapies for the treatment of renal cell carcinoma and focus on the threrapy caused side-effects and side-effect management. Orv Hetil. 2017; 158(38): 1488–1502.

Abstract: In the past six years, five new drugs have been approved by the FDA for the treatment of metastatic castrate-resistant prostate cancer. While the disease itself still remains incurable, the sequential use of these drugs can significantly prolong survival while maintaining good quality of life. Research from the past decade made it clear that androgen receptor-mediated processes play a central part in the progression of the disease. Hormonal mechanisms related to androgen-receptors can remain active until late stages of the disease. A deeper understanding of these mechanisms has led to the introduction of new endocrine therapies, which resulted in a change of the nomenclature. The identification and remodelling of androgen receptor mutations that are responsible for primary and secondary resistance developing during the new therapies can pave the way to new and more efficient androgen receptor inhibitor treatments. The aim of the review is to present the pathophysiology of the androgen receptor signaling axis at the receptor level, to review FDA-approved drugs and to draw attention to the most promising developments in the treatment of this disease. Orv. Hetil., 2017, 158(2), 42–49.

Current advances in molecular techniques and bioinformatics allowed the analysis of complex molecular patterns in various cancers including muscle-invasive bladder cancer. As a consequence, in the last few years numerous gene- and protein expression-based molecular classifications have been recommended. Recently a comprehensive consensus classification for muscle-invasive urothelial bladder cancer has been published, distinguishing 6 subgroups with a potential impact on clinical decision-making. At the same time, the therapeutic landscape of muscle-invasive bladder cancer becomes increasingly differentiated as novel checkpoint inhibitors have been available for cisplatin-ineligible and/or resistant patients. Furthermore, promising results have been obtained with FGFR targeting agents. Therefore, molecular subtyping will probably have a crucial role in individualized therapeutic decision-making in bladder cancer. In the present work, we summarize the evolution, recent advances and potential therapeutic relevance of molecular subclassifications in bladder cancer. Orv Hetil. 2019; 160(42): 1647-1654.Absztrakt: A molekuláris biológia és a bioinformatika fejlődése által lehetőség nyílt a leggyakrabban előforduló daganatok – köztük az izominvazív húgyhólyagrákok – molekuláris hátterének teljes feltérképezésére. Ennek következtében az elmúlt évek során számos, a tumorok génexpressziós és fehérjemintázata alapján történő alcsoportbeosztás látott napvilágot az urothelialis húgyhólyagrákok molekuláris alapon történő elkülönítésére. A közelmúltban megszületett egy széles körű konszenzuson alapuló klasszifikáció, amely hat molekuláris alcsoportot különít el egymástól, és a jövőben jelentősen befolyásolhatja a terápiás döntéshozatalt is. Ezzel párhuzamosan az izominvazív húgyhólyagrák gyógyszeres terápiája is sokrétűbbé vált, hiszen a továbbra is az első vonalban alkalmazott perioperatív ciszplatinalapú kemoterápián túl a közelmúltban elérhetővé váltak új, checkpointgátló készítmények a kemoterápiára rezisztens, illetve alkalmatlan betegek számára. Továbbá ígéretes kezelési lehetőséget jelentenek az FGFR-támadáspontú szerek is. A terápiás fegyvertár bővülésével a molekuláris alcsoportok elkülönítése lényeges szerepet kaphat a legoptimálisabb kezelés kiválasztásában. Jelen munkánkban összefoglalást nyújtunk az izominvazív húgyhólyagrák molekuláris alcsoportbeosztásáról, valamint annak klinikai jelentőségéről. Orv Hetil. 2019; 160(42): 1647–1654.

Pathogenic sequence variants (PSV) in

Germ cell tumors of the testicle account for 1% of all tumors. Testicular cancer (TC) is the most common malignancy in men aged 15-35 years. Patients with TC have an excellent survival rate but often have not yet attempted to father children, and fertility is one of the main concerns of survivors, therefore it is important to preserve it. The most commonly used method is sperm banking. Retrospective analysis of the Hungarian data showed that in case of testicular cancer spermatogenesis is more impaired in the more advanced disease. No correlation was found among the histological types and the proportion of azoo- and oligozoospermia. The parameters of testicular cancer and non-Hodgkin lymphoma patients were worse compared to the normal population. Sperm cryopreservation prior to initiating life-saving cancer treatment offers men the best chance to father children and should be offered to all men with testicular cancer before chemotherapy, since cytostatic therapy may lead to infertility.

Background Atezolizumab, a humanised monoclonal antibody targeting PD-L1, is approved for locally advanced/metastatic urothelial carcinoma. SAUL evaluated atezolizumab in a broader, pretreated population, including patients ineligible for the pivotal IMvigor211 phase 3 trial of atezolizumab. Objective To determine the safety and efficacy of atezolizumab in an international real-world setting. Design, setting, and participants Between November 2016 and March 2018 (median follow-up 12.7mo), 1004 patients with locally advanced or metastatic urothelial or nonurothelial urinary tract carcinoma who experienced progression during or after one to three prior therapies for inoperable, locally advanced, or metastatic disease were enrolled. Patients with renal impairment, treated central nervous system metastases, or stable controlled autoimmune disease were eligible; 10% had Eastern Cooperative Oncology Group performance status (ECOG PS) 2 and 98% were platinum pretreated (Clinicaltrials.gov: NCT02928406). Intervention Atezolizumab 1200mg every 3wk until progression or unacceptable toxicity. Outcome measurements and statistical analysis The primary endpoint was safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Results and limitations The median treatment duration was 2.8mo (range 0–19); 22% remained on treatment and 8% discontinued because of toxicity. Grade ≥3 adverse events occurred in 45% of patients. The most common grade ≥3 treatment-related adverse events were fatigue, asthenia, colitis, and hypertension (each in 1%). Median OS was 8.7mo (95% confidence interval [CI] 7.8–9.9). The 6-mo OS rate was 60% (95% CI 57–63%), median PFS was 2.2mo (95% CI 2.1–2.4), and the ORR was 13% (95% CI 11–16%; 3% complete responses). Among IMvigor211-like patients (excluding ECOG PS 2 and other IMvigor211 exclusion criteria), median OS was 10.0mo (95% CI 8.8–11.9) and 6-mo OS was 65% (95% CI 61–69%). Conclusions SAUL confirms the tolerability of atezolizumab in a real-world pretreated population with urinary tract carcinoma. Efficacy overall and in the IMvigor211-like subgroup is consistent with previous pivotal anti-PD-L1/PD-1 urothelial carcinoma trials. These results support the use of atezolizumab in urinary tract carcinoma, including patients with limited treatment options. Patient summary In this international study we investigated the efficacy and safety of atezolizumab treatment for advanced urinary tract cancer in a large population of pretreated patients, including those who would not normally be candidates for clinical trials. Patients tolerated the treatment well, even if they had autoimmune disease, were being treated with corticosteroids, or had disease that had spread to their brain. Life expectancy in this study for patients typical of everyday clinical practice was similar to that seen in trials that enrolled only selected fitter patients.

Therapy with immune checkpoint inhibitors (ICPis) has become widespread in medical oncology, becoming part of the routine treatment for various malignancies. These antibodies induce an anti-cancer immune activation by blocking the natural immunosuppression, which is supposed to protect the human body's healthy cells from destruction by the immune system, caused also by cancers, and as a result, allow the immune system to take part in destroying malignant cells. However, the immune activation created by these molecules is not selective against cancer tissues, therefore adverse events associated to these therapies are similar to the signs and symptoms of autoimmune diseases. Common adverse events affect the skin, liver, lungs, gastrointestinal and endocrine systems, less frequently the heart and the nervous system, occasionally causing life-threatening complications. Therapy of these adverse events requires rapid diagnosis and adequate treatment in the form of various immunosuppressants.Napjainkban egyre inkább elérhetõ az immunellenõrzõpont-gátlókkal (immune checkpoint inhibitor, ICPi) végzett daganatellenes kezelés, mely több malignóma esetén is a rutinterápia részévé vált. E készítmények a daganatsejtek által is kiváltott, normális esetben csak a saját egészséges sejtek védelmére szolgáló természetes immunszuppressziót gátolva (a gátlás gátlásaként), daganatellenes immunaktivációt eredményeznek, melynek következtében az immunrendszer képes hatékonyan fellépni a daganatsejtek ellen, elpusztítva azokat. Mivel az immunrendszer e szerek által kiváltott aktivációja nem szelektíven, csak a daganatos szövetekre hat, a kialakuló mellékhatások a normális szövetek elleni autoimmun reakciók formájában jelennek meg leggyakrabban. Ezek között gyakoriságuk miatt kiemelt szerepe van a bõr, a tápcsatorna, a máj, a tüdõ és az endokrin szervek érintettségének. A szíveredetû, illetve neurológiai mellékhatások viszonylag ritkák, de jelentõsek az elõforduló súlyos, életveszélyes komplikációk szempontjából. Kezelésükben alapvetõ a korai felismerés és az immunszuppresszáns szerek megfelelõ dózisban történõ alkalmazása.

PURPOSE Previous studies suggested that serum levels of microRNA (miR)-371a-3p (so-called M371 test) have a much higher sensitivity and specificity than the classic markers of testicular germ cell tumors (GCTs) and are applicable toward both seminoma and nonseminoma. We sought to confirm the usefulness of this test as a novel biomarker for GCT. PATIENTS AND METHODS In a prospective, multicentric study, serum samples of 616 patients with testicular GCTs and 258 male controls were examined for serum levels of miRNA-371a-3p (miR levels) by quantitative polymerase chain reaction. The GCT population encompassed 359 patients with seminoma and 257 with nonseminoma; 371 had clinical stage I disease, 201 had systemic disease, and 46 had relapses. Paired measurements before and after orchiectomy were performed in 424 patients; 118 with systemic disease had serial measurements during treatment. miR levels were compared with those of β-human chorionic gonadotropin, α-fetoprotein, and lactate dehydrogenase. RESULTS For the primary diagnosis of GCT, the M371 test showed a sensitivity of 90.1%, a specificity of 94.0%, an area under the curve of 0.966 upon receiver operating characteristic analysis, and a positive predictive value of 97.2%. α-Fetoprotein, β-human chorionic gonadotropin, and lactate dehydrogenase had sensitivities of less than 50% in seminoma and slightly higher sensitivities in nonseminomas. miR levels were significantly associated with clinical stage, primary tumor size, and response to treatment. Relapses had elevated miR levels that subsequently dropped to normal upon remission. Teratoma did not express miR-371a-3p. CONCLUSION The M371 test outperforms the classic markers of GCT with both a sensitivity and a specificity greater than 90%. All histologic subgroups, except teratoma, express this marker. The test could be considered for clinical implementation after further validation.

During the last decades androgen deprivation therapy (ADT) was the standard treatment of prostate cancers. Survival of metastatic patients is 4 years if they receive ADT, but in case of poor prognosis survival rate is under 3 years. Since 2014 two prospective phase III studies have proven the survival advantage of early docetaxel therapy, administered together with ADT, for metastatic hormone-sensitive prostate cancer patients. Its advantage was even more considerable in case of high-volume metastatic cases. In two other studies the benefit of abiraterone-prednisone therapy combined with ADT was proven in comparison with ADT itself in case of newly diagnosed, metastatic, high-risk, hormone-naïve patients. One prospective study has proven the survival benefit of ADT administered together with radiotherapy of the prostate in case of low volume metastatic diseases. In our analysis we demonstrate these clinical studies and try to answer the contradictory questions about the occasionally overlapping therapeutic options.Az elmúlt évtizedekben az androgéndeprivációs terápia (ADT) volt a prosztatadaganatok standard kezelése. Az áttétes stádiumban felismert betegek túlélése 4 év az ADT mellett, azonban egyes, kedvezõtlen prognózisú betegcsoportok kimenetele nem éri el a 3 évet. 2014 óta két prospektív, fázis III-as vizsgálat bizonyította a docetaxel korai, ADT melletti alkalmazásának túlélést javító hatását áttétes hormonérzékeny betegeknél, kiemelt eredményt hozott a nagy volumenû áttétes daganatos esetekben. További két vizsgálatban az ADT-vel kombinált abirateron-prednizolon elõnyét igazolták, újonnan felismert, áttétes, magas rizikójú hormonnaiv betegeknél az ADT-vel összehasonlítva. A kis volumenû áttétes betegek esetén további egy prospektív vizsgálat igazolta az ADT mellett alkalmazott prosztatabesugárzás túlélésben mutatkozó hasznát. Munkánkban az említett klinikai vizsgálatokat mutatjuk be, valamint válaszokat keresünk az egymást alkalmanként átfedõ terápiás opciók kapcsán felmerülõ ellentmondásos kérdésekre.

As a result of the growing incidence of cancer as well as increased survival of patients, an increasing number of people are living longer with cancer. In recent years, research has shown that physical activity not only protects against a number of cancer types, but is also valuable for patients undergoing cancer treatment and during the rehabilitation phase, as well as for improving function and quality of life. Regular physical activity is an effective way to reduce the side effects of cancer, resulting in part from physical inactivity and in part from the disease itself. Too much rest can lead to a decrease in aerobic fitness, strength, mobility and unwanted weight gain in the patient. In prostate cancer patients, hormonal treatment especially accelerates this process. In this paper we summarize the available evidence concerning the role of exercise in prostate cancer prevention, treatment and rehabilitation.A magasabb daganatos incidencia és a javuló túlélés következtében a daganattal élõ betegek száma folyamatosan emelkedik. Az utóbbi években napvilágot látott vizsgálatok igazolták, hogy a mozgásnak fontos szerepe lehet a daganatos betegségek megelõzésében, a kezeléssel kapcsolatos mellékhatások csökkentésében, a rehabilitációban és az életminõség javításában. A betegség és a kezelés okozta tünetek miatt a betegek gyakran inaktívak, mely további állapotromlást okoz. A túl sok pihenés az állóképesség, az izomerõ és a mobilitás romlásához és elhízáshoz vezethet. A hormonkezelés prosztatarákban ezt a folyamatot különösen felgyorsítja. Dolgozatunkban összefoglaljuk a prosztatarákban jelenleg rendelkezésre álló evidenciákat a mozgás szerepével kapcsolatban, a megelõzésében, kezelésében, a mellékhatások kivédésében és a rehabilitációban.

The basic therapy of metastatic prostate carcinoma is androgen deprivation therapy. Unfortunately, almost all patients develop resistance to treatment that leads to castration-resistant prostate cancer. From 2010, 6 new active substances were registered for the treatment of metastatic castration-resistant prostate cancer, which dramatically improved the overall survival of patients. Two of these are treatments for the androgenic axis, the other drugs or therapeutic methods are immunotherapy, chemotherapy, isotope treatment and RANK-ligand inhibition. The year 2018 was a major success in the treatment of nonmetastatic castration-resistant prostate carcinoma, with the FDA authorizing both apalutamide and enzalutamide at this stage. The aim of this review is to present the standard of care of metastatic castration-resistant prostate cancer by disease stage, and to introduce the emerging treatment modalities presently assessed in clinical trials and discuss the open questions.A metasztatikus prosztatakarcinóma bázisterápiája az androgéndeprivációs terápia. Sajnos szinte minden betegnél rezisztencia alakul ki a kezelésre, mely kasztrációrezisztens prosztatarákhoz vezet. A metasztatikus kasztrációrezisztens prosztatarák kezelésében 2010-tõl 6 új hatóanyag került törzskönyvezésre, melyek drámaian javították a betegek teljes túlélését. Ezek közül kettõ az androgéntengelyt célzó kezelések közé tartozik, a többi hatóanyag, illetve terápiás eljárás: immunterápia, kemoterápia, izotópkezelés és RANK-ligandum-gátlás. A nem metasztatikus kasztrációrezisztens prosztatakarcinóma kezelésében a 2018-as év átütõ sikert hozott, az FDA engedélyezte mind az apalutamid, mind az enzalutamid használatát ebben a stádiumban. Közleményünk célja kasztrációrezisztens elõrehaladott prosztatadaganatban stádiumok szerint a már egyértelmû evidenciák ismertetése, az új fejlesztések bemutatása, nyitott kérdések megvitatása.

450 Background: 1L pembro is approved in advanced UC for cisplatin-ineligible pts with PD-L1 combined positive score (CPS) ≥10 and any platinum-ineligible pts regardless of CPS in the United States based on single-arm trial data. In the phase III KEYNOTE-361 study, 1L pembro + chemo did not statistically significantly improve PFS or OS vs chemo for pts with advanced UC; formal testing of 1L pembro vs chemo was not performed. We present an exploratory analysis of outcomes with pembro vs chemo for choice-of-carboplatin (carbo) pts in KEYNOTE-361 (NCT02853305). Methods: At randomization, choice of platinum agent (cisplatin or carbo) plus gemcitabine for each pt was selected based on investigator’s assessment of cisplatin ineligibility. ORR/DOR per RECIST v1.1 by blinded independent central review and OS were determined for all pts selected for carbo (“choice-of-carbo”) and also choice-of-carbo pts with CPS ≥10. Risk difference assessment for select AEs for pembro vs chemo was conducted in choice-of-carbo pts who received ≥1 dose study treatment. Results: As of Apr 29, 2020, the median (range) time from randomization to data cutoff in the full study cohort was 31.7 (22.0-42.3) mo. At randomization, renal impairment was the most common reason for choice of carbo by investigators (36% of all pts). 170 choice-of-carbo pts were randomized to the pembro arm, and 196 choice-of-carbo pts to the chemo arm. Median OS in this subgroup was 14.6 mo with pembro vs 12.3 mo with chemo (HR 0.83 [95% CI 0.65-1.06]). 18-mo OS rate was 42% with pembro vs 40% with chemo. ORR to pembro vs chemo was 27.6% vs 41.8%. Median (range) DOR with pembro vs chemo was not reached (NR) (3.2+-36.1+ mo) vs 6.3 (1.8+-33.8+) mo. 84/170 (49%) and 89/196 (45%) choice-of-carbo pts in the pembro and chemo arms, respectively, had CPS ≥10. In this subgroup, median OS was 15.6 mo with pembro vs 13.5 mo with chemo (HR 0.82 [95% CI 0.57-1.17]). 18-mo OS rate was 44% with pembro vs 43% with chemo. ORR to pembro vs chemo was 29.8% vs 46.1%. Median (range) DOR with pembro vs chemo was NR (4.2-36.1+ mo) vs 8.3 (2.1+-33.8+) mo. Among treated pts (N=166 for pembro, N=190 for chemo), 112 pts (68%) in the pembro arm and 163 pts (86%) in the chemo arm had grade 3-5 AEs of any cause. Pembro was associated with a higher risk of pruritus, while chemo was associated with a higher risk of decreased white blood cell, neutrophil, and platelet counts, nausea, thrombocytopenia, neutropenia, and anemia. Conclusions: Due to the trial design, this subset was not statistically tested and is exploratory. Median OS and 18-mo OS rates did not appear markedly different in the two arms; some parameters such as DOR favored pembro, although longer follow-up is needed to determine median DOR for pembro. The PD-L1 CPS ≥10 did not clearly enrich for responders to pembro in choice-of-carbo pts. Pembro was associated with a lower rate of grade 3-5 AEs of any cause than chemo. Clinical trial information: NCT02853305.

448 Background: 1L pembro + chemo did not show statistically superior PFS and OS vs chemo for pts with advanced UC in the phase III KEYNOTE-361 study; OS for pembro vs chemo was not formally tested. We analyzed PFS2 (time from randomization to progressive disease [PD] on first subsequent therapy, or death from any cause, whichever occurs first) by study treatment and subsequent therapy in KEYNOTE-361 (NCT02853305) to determine the effects, if any, of therapy sequence on PFS2. Methods: PFS2 was estimated for pts in each treatment arm, who received any subsequent therapy including any anti–PD-(L)1, any therapy other than anti–PD-(L)1, or no therapy. These were exploratory analyses; no formal comparisons were done. Results: 1010 pts were randomized: 351 pts to receive pembro + chemo, 307 to pembro, and 352 to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. Subsequent therapy was received by 124/351 (35%), 126/307 (41%), and 215/352 (61%) pts in the pembro + chemo, pembro, and chemo arms, respectively. Subsequent anti–PD-(L)1 therapy was received by 169/352 (48%) pts in the chemo arm vs 23/351 (7%) in the pembro + chemo arm and 14/307 (5%) in the pembro arm. Of pts in the pembro arm who received subsequent therapy, >90% received 2L cisplatin-based or carboplatin-based treatment. Median (m) PFS2 (95% CI) for all pts by treatment arm was 14.1 mo (12.6-16.2) with pembro + chemo, 10.9 mo (9.5-12.9) with pembro, and 10.4 mo (9.8-11.2) with chemo. Across treatment arms, pts in the pembro + chemo arm had the longest mPFS2 with any subsequent therapy (14.5 mo [95% CI 13.1-16.6]) (Table). Pts in the pembro arm who received no subsequent therapy had a longer mPFS2 (12.9 mo [95% CI 8.1-17.9]) vs pts in the chemo arm who received no subsequent therapy (9.4 mo [95% CI 7.6-10.6]). Finally, pts treated with 1L pembro in the trial followed by 2L therapy other than anti−PD-(L)1 had comparable mPFS2 (10.2 mo [95% CI 8.6-12.1]) to pts treated with 1L chemo in the trial followed by 2L anti−PD-(L)1 (11.1 mo [95% CI 10.2-12.9]). Conclusions: In this exploratory analysis, treatment sequence of chemo followed by anti−PD-(L)1 upon PD vs anti–PD-(L)1 followed by chemo upon PD did not appear to impact mPFS2. Among pts who did not receive 2L therapy, 1L pembro appeared to be associated with longer mPFS2 than chemo, potentially driven by long-term responders to pembro. Clinical trial information: NCT02853305 . [Table: see text]

439 Background: The phase III KEYNOTE-361 study examined the efficacy and safety of 1L pembro + chemo or pembro alone vs chemo for pts with advanced UC. The PFS and OS benefit of pembro + chemo vs chemo did not reach statistical significance; no further formal tesing was done. We present an exploratory analysis of OS by subsequent therapy in KEYNOTE-361 (NCT02853305) to assess how 1L and 2L therapy selection affected survival outcomes; no formal comparisons were conducted. Methods: OS was estimated for pts by whether they received subsequent therapy, and by whether subsequent therapy included an anti–PD-(L)1 agent. Results: 351 pts were randomized to pembro + chemo, 307 pts to pembro, and 352 pts to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. 124/351 pts (35%) in the pembro + chemo arm, 126/307 pts (41%) in the pembro arm, and 215/352 pts (61%) in the chemo arm received any subsequent therapy. Similar rates of subsequent therapy (pembro + chemo: 32%; pembro: 43%; chemo: 59%) were observed for pts who experienced progressive disease (PD) by blinded independent central review (BICR). A higher rate of pts (169/352 [48%]) in the chemo arm received subsequent anti–PD-(L)1 therapy than in either the pembro + chemo arm (23/351 [7%]) or pembro arm (14/307 [5%]). Due to the small pt numbers, pts in the pembro + chemo or pembro arms who received subsequent anti−PD-(L)1 were not considered further. This analysis included all pts who received 2L therapy (465/1010 pts [46%]); the rate of 2L therapy was similar in pts with PD by BICR (274/615 [45%]). Chemo agents alone or in combination, specifically carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, and paclitaxel, were the most commonly received subsequent therapies for pts who did not receive anti–PD-(L)1 in 2L. Pts who received 1L chemo followed by subsequent anti–PD-(L)1 had longer mOS (19.1 mo [95% CI 16.2-22.2]) than pts with 1L pembro followed by 2L therapy not including an anti−PD-(L)1 agent (16.0 mo [95% CI 11.8-19.2]) (Table). Conclusions: In this exploratory analysis, favorable survival outcomes were observed for pts who received 1L chemo followed by anti–PD-(L)1 compared with pts who received 1L pembro followed by 2L therapy not including an anti–PD-(L)1 agent. These data underline the continued importance of immunotherapy as 2L therapy for advanced UC. Clinical trial information: NCT02853305 . Research Sponsor: Merck & Co., Inc[Table: see text]

435 Background: The phase III KEYNOTE-361 study compared efficacy and safety of 1L pembro + chemo or pembro vs chemo in pts with advanced UC. The trial did not meet its primary endpoints of PFS or OS superiority for pembro + chemo vs chemo; formal testing for OS for pembro vs chemo was not performed. We present a post hoc landmark analysis to examine the durability of CR/PR/SD and long-term survival in pts with CR, PR, or SD to pembro vs chemo at week 9 in KEYNOTE-361 (NCT02853305). Methods: Landmark analyses of OS by CR/PR/SD at 9 weeks after randomization in the ITT population were performed. Pts were included if they had a best response of CR/PR/SD per RECIST v1.1 by blinded independent central review at the landmark date of week 9 (first imaging assessment per study protocol). Duration of CR/PR/SD and OS were estimated by the Kaplan-Meier method. No formal comparisons were performed. Results: 307 pts were randomized to receive pembro and 352 pts to receive chemo in the KEYNOTE-361 study. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 32.5 (22.0-42.4) mo for the pembo arm and 31.4 (22.1-41.6) mo for the chemo arm. In the landmark analysis, fewer pts had CR/PR/SD at week 9 with pembro (n=137 [45%]) than with chemo (n=253 [72%]). Median (range) duration of response for pembro vs chemo was 18.7 (4.4+-35.4+) vs 12.3 (0.0+-29.7+) mo for pts with CR, and 35.0 (1.1-36.1+) vs 6.1 (0.0+-36.3+) mo for pts with PR. Median (range) duration of SD was 4.8 mo (0.0-38.2+) with pembro and 4.6 mo (0.0-16.1+) with chemo. Median OS (95% CI) for pembro vs chemo was not reached (NR) (25.5-NR) vs NR (19.1-NR) for pts with CR; NR (NR-NR) vs 14.8 mo (12.1-21.0) for pts with PR; and 18.5 mo (13.8-28.8) vs 11.1 mo (8.1-14.6) for pts with SD, respectively. Long-term OS rates were higher with pembro vs chemo across all groups (CR/PR/SD) at week 9 (Table). Conclusions: In this post hoc landmark analysis, chemo was associated with more initial responses than pembro, whereas pembro was associated with longer median duration of CR and PR, and generally longer median OS than chemo. Among pts who achieved CR/PR/SD at week 9, the relative OS benefit for pembro vs chemo increased over time. Clinical trial information: NCT02853305. [Table: see text]

Objective To prospectively examine early hearing damage detectable with distortion product otoacoustic emission (DPOAE) after the first cycle of cisplatin treatment of patients with testicular tumor. Study Design Both ears of 137 consecutive patients were examined at 0.75 to 8 kHz before (B) and after (A) the first cycle of cisplatin (dose: 100 mg/m2/ 5 days). Methods The mean amplitudes (B vs. A) were compared with paired t test at each frequency. Ototoxic changes were considered when an individual amplitude difference (B-A) > 14 dB at 0.75 Hz or > 7 db at 1 to 8 kHz occurred. Results The mean amplitudes were statistically significantly lower after first cycle at 0.75, 6, and 8 kHz. The majority of patients (96%) presented positive differences (B-A) in one or both ears; in 85 (62%) cases, the positive difference reached the level of ototoxicity out of which 34 (40%) and 19 (22%) of patients suffered ototoxicity in one or both ears, respectively. The difference between right and left ears in distribution of ototoxic cases was nonsignificant. Forty-five (33%) and four (3%) patients showed ototoxicity at two or more frequencies in one or both ears, respectively. An increased proportion of ototoxic cases can be seen at 0.75 to 1 kHz and 6 to 8 kHz. Conclusion After the first cycle of cisplatin treatment, early ototoxicity occurs in close to two-thirds of patients, as identified by measuring DPOAE. Therefore, further research for biomarkers is required, which can predict patients at risk in order to avoid an irreversible hearing loss by personalized, preventive therapies. Level of Evidence 4. Laryngoscope, 127:1909–1915, 2017

The aim was to assess the relationship between treatment efficacy and adverse events (AEs) for patients with advanced renal cell carcinoma treated with first-line sunitinib.274 patients were treated with sunitinib (50 mg/d, 4-weeks-on and 2-weeks-off schedule). Physical and laboratory evaluations were done every sixth week. AEs were diagnosed at every visit. Clinical response was assessed every 3 months. The objective response rate (ORR), median progression-free (mPFS) and median overall survival (mOS) and AEs were evaluated. Besides χ(2) and log rank tests, multivariate Cox regression analysis and for synergism 1-sided t tests were used.The ORR was 25%. After a median follow-up of 32 months, the mPFS and mOS were 9 and 19 months, respectively. Hypertension, diarrhea, hypothyroidism, mucositis, hand-foot syndrome (HFS), skin toxicity, and leukopenia were the most frequent treatment-associated AEs. Significantly longer (P .01) mPFS and mOS were observed when hypertension, diarrhea, HFS, hypothyroidism, skin toxicity, or leukopenia occurred. A statistically significant synergistic effect of the listed AEs was observed for progression-free survival (P .001) and overall survival (P .001). Multivariate analysis revealed that besides the prognostic category, the higher number of AEs (3-6 vs. 0-2) was an independent marker of longer mPFS (24 vs. 5 months, respectively; P .001) and mOS (51 vs. 9 months, respectively; P .001).Results of this study provide evidence for the synergistically enhanced efficacy of sunitinib treatment in patients who present multiple AEs. These AEs are diagnosed routinely and their coexistence can help physicians to predict which group of patients would benefit the most from first-line sunitinib treatment.