Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial.

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.

Clinical Results and Biomarker Analyses of Axitinib and TRC105 versus Axitinib Alone in Patients with Advanced or Metastatic Renal Cell Carcinoma (TRAXAR).

LESSONS LEARNED: The combination of carotuximab with axitinib did not provide a benefit over axitinib monotherapy in patients with metastatic clear cell renal cell carcinoma who had previously progressed on one or more vascular endothelial growth factor (VEGF)-targeted therapies. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. 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.

Real-world safety and efficacy of nivolumab for ≥ 2nd line treatment of metastatic renal cell carcinoma: A retrospective cohort study in Croatia, Hungary, and Malta.

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.

Low socioeconomic position is a risk factor for delay to treatment and mortality of testicular cancer patients in Hungary, a prospective study.

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 < 0.001). For patient delay, the most important variables were the mother's and patient's education levels (r = - 0.21, 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.

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial.

BACKGROUND: Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonist-plus 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/m2 (60 mg/m2 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. FUNDING: Eli Lilly and Company.

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial.

BACKGROUND: Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population. 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 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. FINDINGS: Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96-4·47] vs 2·76 months [2·60-2·96]; hazard ratio [HR] 0·757, 95% CI 0·607-0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8-30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4-18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1-2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. INTERPRETATION: To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. FUNDING: Eli Lilly and Company.

Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma.

BACKGROUND: Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. METHODS: We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate. RESULTS: Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus. CONCLUSIONS: Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).

[Modern treatment of metastatic hormone-sensitive prostate cancer]. / Metasztatikus hormonérzékeny prosztatadaganat korszeru kezelése.

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.

[Targeted treatment of renal cell carcinoma, treatment caused side-effects and side-effect management]. / A vesesejtes daganatok célzott terápiás kezelése, a terápia okozta mellékhatások és ellátásuk.

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.

[Androgen receptor-mediated processes in castrate-resistant metastatic prostate cancer]. / Androgénreceptor mediálta folyamatok metasztatikus kasztrációrezisztens prosztatadaganatban.

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.

[The role of steroids in oncological practice]. / Szteroidok szerepe az onkológiai gyakorlatban.

Corticosteroids are a class of steroid hormones that are produced and disengage in the adrenal cortex. Traditionally natural and synthetic corticosteroids are used for diagnosing and treating dysfunctions of the adrenal cortex and treating inflammatory and immunological diseases. Their use is also widespread in oncological practice. Corticosteroids are indispensable in palliative care, in certain urgent oncological cases, as premedication of some chemotherapies and last but not least they have a key role in the secondary hormonal manipulations of metastatic castrate-resistant prostate cancer. The purpose of our review is to describe and compare the effects of different agents in oncological practice, to give a detailed account of the above mentioned indications and would also like to draw attention to the possible side effects of a long-term steroid treatment. Orv Hetil. 2017; 158(42): 1651-1657.

[The role of immunotherapy in the modern treatment of urothelial carcinoma]. / Az immunterápia szerepe az uroteliális daganatok modern kezelésében.

By the emergence of modern immunotherapies with active agents like PD-1 (nivolumab, pembrolizumab) and PD-L1 immune checkpoint blockers (atezolizumab, avelumab, durvalumab), new therapeutic options have become available for the treatment of patients with locally advanced and metastatic urothelial carcinoma. According to the recent publications, they have been effective in case of progression after platinum therapy, in or after second-line and in firstline therapies for cisplatin ineligible patients, respectively. Patient survival and tumor response data are very promising; in particular stages, they seem to be more effective than the previously administered chemotherapies. Their toxicity profiles also appear to be more favorable. Immunological side effects are rare; their identification and management require preparedness and multidisciplinary thinking. Current and ongoing trials are investigating the combinations of new remedies with other immunotherapeutic agents (e.g., CTLA-4 inhibitor ipilimumab, tremelimumab) or chemotherapies as well as trying to identify biomarkers in order to further increase effectiveness. In our review, we summarize the recently published data about urothelial carcinoma therapy and give a brief overview of the ongoing clinical trials.

[Immunotherapy of renal cell cancer]. / Immunterápia a vesedaganatok kezelésében.

The authors briefly highlight the results of targeted therapy and present new solutions in kidney cancer immunotherapy. The important checkpoint inhibitors (anti-CTLA-4, -PD-1 and -PD-L1/2) and their combinations, together with the combinations of targeted drugs and immunotherapy are discussed. The newest checkpoint agents, vaccination and pegylated interleukin-2 are also presented. The most promising clinical trials (CheckMate-025, AGS-003, IMA 901) and the on-going first line phase III trials are shown in metastatic clear cell renal carcinoma.

[Immunotherapy in the treatment of genitourinary cancers]. / Immunterápia az urológiai daganatok kezelésében.

In this clinical review we provide information regarding advance and main achievements in the immunotherapy of genitourinary, particularly renal cell and prostate cancer. Nivolumab treatment became the new standard of care in locally advanced or metastatic renal cell cancer after failure on tyrosine kinase inhibitor treatment. Sipuleucel-T prolonged survival in patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer but had no effect on progression-free survival. Based on the results of phase I/II trials anti-PD-1/PD-L1 monoclonal antibodies are a new hope in the treatment of urothelial bladder cancer. Regarding germ cell tumors basic research is ongoing.

[Treatment strategies for advanced prostate cancer]. / Kezelési stratégiák elorehaladott prosztatadaganatban.

There has been dramatic improvement in the diagnosis and treatment of prostate cancer recently. The treatment of localized disease became more successful with the application of new, sophisticated techniques available for urologic surgeons and radiotherapists. Nevertheless a significant proportion of patients relapses after the initial local treatment or is diagnosed with metastatic disease at the beginning. In the past five years, six new drugs became registered for the treatment of metastatic, castration-resistant prostate cancer, such as sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, the α-emitting radionuclide alpharadin and the receptor activator of nuclear factor kappa-B (RANK) ligand inhibitor denosumab. The availability of these new treatment options raises numerous questions. In this review we present the standard of care of metastatic prostate cancer by disease stage (hormone naive/ hormone sensitive metastatic prostate cancer, non-metastatic castration-resistant prostate cancer, oligometastatic/multimetastatic castration-resistant prostate cancer) and the emerging treatment modalities presently assessed in clinical trials. We would also like to give advice on debatable aspects of the management of metastatic prostate cancer.

Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy: final analysis of a multicentre, open-label, early-access protocol trial.

BACKGROUND: In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. METHODS: We did a multicentre, open-label, early-access protocol trial in 23 countries. We enrolled patients who had metastatic castration-resistant prostate cancer progressing after taxane chemotherapy. Participants received oral doses of abiraterone acetate (1000 mg daily) and prednisone (5 mg twice a day) in 28-day cycles until disease progression, development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time to clinical progression) were gathered to guide treatment decisions. We included in our analysis all patients who received at least one dose of abiraterone acetate. This study is registered with ClinicalTrials.gov, number NCT01217697. FINDINGS: Between Nov 17, 2010, and Sept 30, 2013, 2314 patients were enrolled into the early-access protocol trial. Median follow-up was 5·7 months (IQR 3·5-10·6). 952 (41%) patients had a grade 3 or 4 treatment-related adverse event, and grade 3 or 4 serious adverse events were recorded in 585 (25%) people. The most common grade 3 and 4 adverse events were hepatotoxicity (188 [8%]), hypertension (99 [4%]), cardiac disorders (52 [2%]), osteoporosis (31 [1%]), hypokalaemia (28 [1%]), and fluid retention or oedema (23 [1%]). 172 (7%) patients discontinued the study because of adverse events (64 [3%] were drug-related), as assessed by the investigator, and 171 (7%) people died. The funder assessed causes of death, which were due to disease progression (85 [4%]), an unrelated adverse experience (72 [3%]), and unknown reasons (14 [1%]). Of the 86 deaths not attributable to disease progression, 18 (<1%) were caused by a drug-related adverse event, as assessed by the investigator. Median time to PSA progression was 8·5 months (95% CI 8·3-9·7) and median time to clinical progression was 12·7 months (11·8-13·8). INTERPRETATION: No new safety signals or unexpected adverse events were found in this early-access protocol trial to assess abiraterone acetate for patients with metastatic castration-resistant prostate cancer who progressed after chemotherapy. Future work is needed to ascertain the most effective regimen of abiraterone acetate to optimise patients' outcomes. FUNDING: Janssen Research & Development.

[Bone-targeted treatment in prostate cancer]. / Csontáttétek célzott kezelése prosztatarákban.

Prostate cancer is one of the most common cancers in men. In case of metastatic disease, bone manifestation is presented in 85-90% of the patients. The new targeted treatments are the denosumab RANK-ligand monoclonal antibody and Ra-223-chloride radioisotope therapy. This paper summarizes the treatment possibilities of bone metastasis and presents the results of phase III trials of denosumab and Ra-223-chloride. The upcoming change in financial support underlines the actuality of this paper.

[Successful treatment of metastatic testicular tumor of extreme size]. / Extrém méretû metasztatikus heretumor sikeres kezelése.

Testicular cancer is the most common cancer in young males. Testicular cancer has one of the highest cure rates of all cancers: with modern chemotherapy treatment five-year survival rate exceeds 90 percent overall, and reaches almost 100 percent in early stages. However, these favorable results can only be achieved if these patients are transferred to a reference center, because better outcome was reported for patients who had been treated in a high volume center. Strict adherence to therapeutic protocol is vital for good results. We present a case of a testicular cancer patient with very advanced disease and poor performance status, who was deemed incurable by another oncological center. We achieved complete remission by strictly adhering to the protocol, and using all the available supportive measures. We would like to demonstrate the difficulties we were facing while treating this poor prognostic patient.

[Successful sunitinib treatment of a patient with Stauffer's syndrome]. / Stauffer-szindrómában szenvedõ beteg sikeres sunitinibkezelése.

Several potential biomarkers of response to targeted therapies are being evaluated in metastatic renal cell carcinoma (RCC) to improve drug development and to determine which patient may benefit the most from the different treatment options. Stauffer's syndrome is a paraneoplastic syndrome that presents with the elevation of hepatic enzymes without hepatic metastases in patients with renal cell carcinoma. Hereby we report the case of our patient who suffered from multiple peritoneal metastases of renal cell cancer accompanied by Stauffer's syndrome. During his course of disease, the change in the serum gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) levels correlated well with the extent of metastatic spread. Hypertension, grade 2 hand-foot syndrome and hypothyreosis also developed in relation to the successful sunitinib treatment. These side effects are predictive biomarkers in patients responding well to sunitinib. As other potential causes of increased GGT and ALP were excluded, the elevation of these enzymes were attributed to Stauffer's syndrome. During treatment, magnetic resonance imaging (MRI) follow-up showed complete regression, while the serum GGT and ALP levels halved. In this case, besides the known biomarkers, changes in serum GGT and ALP levels correlated well with the regression of metastatic renal cell carcinoma. To our knowledge, this is the first case published in the medical literature to show GGT and ALP levels in Stauffer's syndrome as potential biomarkers.

[Experience with everolimus therapy for patients with metastatic renal cancer in Hungary]. / Áttétes vesedaganatos betegek everolimusterápiájával szerzett hazai tapasztalatok.

Everolimus is indicated for the therapy of adults with advanced renal cell carcinoma after failure of treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). The aim of the study was a multicenter evaluation of efficiency and toxicity of everolimus in patients with metastatic renal carcinoma who received one line of VEGFR-TKI therapy. Data of one hundred and one patients were analyzed retrospectively. Patients received everolimus therapy between January 2010 and July 2013. Data were collected in 7 different oncology institutes in Hungary. Starting daily dose of everolimus was 10 mg in 28-day cycles. Physical and laboratory examinations were done monthly. Imaging tests were performed every 3 months. Tumor response and toxicity were evaluated according to RECIST 1.0 and NCI CTCAE 3.0, respectively. Statistical analysis was performed with SPPS version 20.0 for Windows. Currently 26 (27%) patients are being treated, 52 (54.1%) patients are alive. Median progression-free survival (PFS) was 5.7 months (95% CI 4.07-7.33). Partial remission, stable disease and progression occurred in 6 (6%), 71 (74%) and 19 (20%) patients, respectively. Median overall survival (OS) was 14.3 months (95% CI 6.99-19.81). PFS and OS results were more favorable in patients with ECOG 0-1. Survival was poorer in case of anemia, while better if PFS was longer than 12 months. In anemic patients with ECOG 0-1 and ECOG 2-3 OS was 30.9 and 7.7 months, respectively (p=0.031). Dose reduction and treatment delay happened in 8 (7.9%) and 12 (11.9%) cases, respectively. The most common side effects were the following: exanthema, edema, stomatitis, pneumonitis, anemia and abnormal kidney-, liver functions, blood sugar and cholesterol levels. According to the Hungarian experience, everolimus can safely be administered. PFS and OS results representing the centers' everyday practice, are similar to the results of the respective subgroups in the registration study.