Publications by authors named "Martin Boegemann"

39 Publications

Real-world outcomes in patients with metastatic renal cell carcinoma according to risk factors: the STAR-TOR registry.

Future Oncol 2021 Mar 16. Epub 2021 Mar 16.

University Hospital Muenster, 48149 Muenster, Germany.

Examine outcomes in sunitinib-treated patients by International Metastatic RCC Database Consortium (IMDC) or Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors. Patients enrolled in STAR-TOR registry (n = 327). End points included overall survival, progression-free survival and objective response rate. Overall survival was similar for IMDC 0 versus 1 (p = 0.238) or 2 versus ≥3 (p = 0.156), but different for MSKCC (0 vs 1, p = 0.037; 2 vs ≥3, p = 0.001). Progression-free survival was similar for IMDC 2 versus 3 (p = 0.306), but different for MSKCC (p = 0.009). Objective response rate was different for IMDC 1 (41.9%) and 2 (29.5%) and similar for MSKCC 1 (34.4%) and 2 (31.0%). Outcome data varied according to IMDC or MSKCC. MSKCC model accurately stratify patients into risk groups. Clinical trial registration: NCT00700258 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-1020DOI Listing
March 2021

Effect of comorbidities/comedications on sunitinib outcomes for metastatic renal cell carcinoma: the STAR-TOR registry.

Future Oncol 2020 Dec 6;16(35):2939-2948. Epub 2020 Oct 6.

Klinik für Urologie, Universitätsmedizin Göttingen, Göttingen, Germany.

Examine the effects of baseline hypertension (HTN) and statin or proton pump inhibitor (PPI) use on sunitinib treatment outcomes in STAR-TOR, a real-world registry. Presence or absence of HTN and use or nonuse of statins or PPIs were determined at registry entry. End points included overall survival (OS) and progression-free survival (PFS). Data were from 557 patients. Presence or absence of HTN did not affect OS or PFS. PFS (median [95% CI]) was longer in statin users (9.4 [6.5-13.6] months) versus nonusers (6.9 [5.7-8.2] months) (p = 0.0442). OS was shorter in PPI users (20.2 [14.9-28.3] months) versus nonusers (25.7 [22.7-33.0] months) (p = 0.0212). Comorbidities and comedications may affect real-world sunitinib treatment outcomes. Clinical Trial Registration: NCT00700258 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0548DOI Listing
December 2020

PSMA PET total tumor volume predicts outcome of patients with advanced prostate cancer receiving [Lu]Lu-PSMA-617 radioligand therapy in a bicentric analysis.

Eur J Nucl Med Mol Imaging 2021 Apr 24;48(4):1200-1210. Epub 2020 Sep 24.

Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany.

Introduction: [Lu]Lu-PSMA-617 (Lu-PSMA) radioligand therapy is an emerging treatment option for patients with end-stage prostate cancer. However, response to Lu-PSMA therapy is only achieved in approximately half of patients. It is clinically important to identify patients at risk of poor outcome. Therefore, the aim of this study was to evaluate pretherapeutic PSMA PET derived total tumor volume and related metrics as prognosticators of overall survival in patients receiving Lu-PSMA therapy.

Methods: A total number of 110 patients form the Departments of Nuclear Medicine Münster and Essen were included in this retrospective analysis. Baseline PSMA PET-CT was available for all patients. Employing a previously published approach, all tumor lesions were semi-automatically delineated in PSMA PET-CT acquisitions. Total lesion number, total tumor volume (PSMA-TV), total lesion uptake (PSMA-TLU = PSMA-TV * SUV), and total lesion quotient (PSMA-TLQ = PSMA-TV / SUV were quantified for each patient. Log2 transformation was used for regressions.

Results: Lesion number, PSMA-TV, and PSMA-TLQ were prognosticators of overall survival (HR = 1.255, p = 0.009; HR = 1.299, p = 0.005; HR = 1.326, p = 0.002). In a stepwise backward Cox regression including lesion number, PSMA-TV, PSA, LDH, and PSMA-TLQ, only the latter two remained independent and statistically significant negative prognosticators of overall survival (HR = 1.632, p = 0.011; HR = 1.239, p = 0.024). PSMA-TLQ and LDH were significant negative prognosticators in multivariate Cox regression in contrast to PSA value.

Conclusion: PSMA-TV was a statistically significant negative prognosticator of overall survival in patients receiving Lu-PSMA therapy. PSMA-TLQ was an independent and superior prognosticator of overall survival compared with PSMA-TV.
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http://dx.doi.org/10.1007/s00259-020-05040-1DOI Listing
April 2021

Consensus paper: current state of first- and second-line therapy in advanced clear-cell renal cell carcinoma.

Future Oncol 2020 Oct 23;16(29):2307-2328. Epub 2020 Sep 23.

Interdisciplinary GU Oncology, Clinic for Medical Oncology & Clinic for Urology, University Hospital Essen, D-45147, Essen, Germany.

The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.
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http://dx.doi.org/10.2217/fon-2020-0403DOI Listing
October 2020

Analysis of PSMA expression and outcome in patients with advanced Prostate Cancer receiving Lu-PSMA-617 Radioligand Therapy.

Theranostics 2020 19;10(17):7812-7820. Epub 2020 Jun 19.

Department of Nuclear Medicine, University Hospital Münster, Münster, Germany.

PSMA-PET-CT enables measuring molecular expression of prostate-specific membrane antigen (PSMA) , which is the target molecule of Lu-PSMA-617 (Lu-PSMA) therapy. However, the correlation of PSMA expression and overall survival (OS) in patients treated with Lu-PSMA therapy is currently unclear; especially with regard to coexistence of high and low PSMA expressing metastases. To this end, this retrospective single arm study elucidates the correlation of PSMA expression and overall survival in patients treated with Lu-PSMA therapy. Additionally, PET based criteria to define low PSMA expression were explored. Eighty-five patients referred to Lu-PSMA therapy were included in the analysis. Pretherapeutic Ga-PSMA-PET-CT scans were available for all patients. SUV of the highest PSMA expressing metastasis (PSMA), SUV of the lowest PSMA expressing metastasis (PSMA), and average SUV of all metastases (PSMA) amongst other PET parameters were measured for each patient. A log-rank cutoff-finder was used to determine low (lowPSMA) and high (highPSMA) average PSMA expression as well as low (lowPSMA) and high (highPSMA) minimal PSMA expression. PSMA was a significant prognosticator of overall survival in contrast to PSMA (HR: 0.959; p = 0.047 vs. HR: 0.992; p = 0.231). Optimal log rank cut-offs were: PSMA = 14.3; PSMA = 10.2. Patients with low average PSMA expression (lowPSMA) had significantly shorter survival compared to those with high average expression (highPSMA) (5.3 vs. 15.1 months; p < 0.001; HR: 3.738, 95%CI = 1.953-7.154; p < 0.001). Patients with low PSMA expressing metastases (lowPSMA) had shorter survival compared to those without a low PSMA expressing metastasis (highPSMA) (p = 0.003; 7.9 months vs. 21.3; HR: 4.303, 95%CI = 1.521-12.178; p = 0.006). Patients that were classified as highPSMA but with lowPSMA had an intermediate overall survival (11.4 months; longer compared to lowPSMA, 5.3 months, p = 0.002; but shorter compared to highPSMA, 21.3 months, p = 0.02). Low average PSMA expression is a negative prognosticator of overall survival. Absence of low PSMA expressing metastases is associated with best overall survival and the maximum PSMA expression seems not suited to prognosticate overall survival. Low PSMA expression might therefore be a negative prognosticator for the outcome of patients treated with Lu-PSMA therapy. Future studies are warranted to elucidate the degree of low PSMA expression tolerable for Lu-PSMA therapy.
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http://dx.doi.org/10.7150/thno.47251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359095PMC
June 2020

[Enzalutamide-new option in metastatic castration-sensitive prostate cancer? : Preliminary results of a randomized phase III trial (ENZAMET)].

Authors:
Martin Boegemann

Urologe A 2020 01;59(1):78-79

Klinik für Urologie und Kinderurologie, Universitätsklinik Münster, Albert-Schweitzer-Campus 1, GB A1, 48149, Münster, Deutschland.

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http://dx.doi.org/10.1007/s00120-019-01096-6DOI Listing
January 2020

[Knowledge of German-speaking urologists regarding the association between penile cancer and human papilloma virus: results of a survey of the European PROspective Penile Cancer Study (E-PROPS)].

Aktuelle Urol 2019 Nov 19. Epub 2019 Nov 19.

Urologische Klinik, St. Elisabeth-Klinikum Straubing, Deutschland.

Background:  A recent meta-analysis showed that penile cancer (PeC) is associated with the human papilloma virus (HPV) in 50 % of patients in Europe. It is unknown whether urologists are aware of the impact of viral carcinogenesis.

Methods:  A (German-language) survey comprising 14 items was created and sent to urologists of 45 clinical centres in Germany (n = 34), Austria (n = 8), Switzerland (n = 2) and Italy/South Tyrol (n = 1) once in Q3/2018. According to a predefined quality standard, a total of 557 surveys were eligible for final data analysis (response rate: 85.7 %). Among other questions, urologists were asked to state the frequency of HPV-associated PeC in Europe. 4 potential answers were provided: (A)-"< 25 %", (B)-"25 - 50 %", (C)-"> 50 - 75 %", (D)-"level of association unknown". For the final calculation, a tolerance of ± 50 % was considered acceptable, so B and C were deemed correct answers. Based on a bootstrap-adjusted multivariate logistic regression model, criteria independently predicting a correct answer were identified.

Results:  Categories A-D were selected in 19.2 % (n = 107), 48.8 % (n = 272), 12.9 % (n = 72) and 19 % (n = 106), respectively, representing a rate of 61.8 % of urologists (n = 344) reaching the endpoint (B + C). Autonomous performance of chemotherapy for PeC by urologists within the given centre (OR 1.55, p[Bootstrap] = 0.036) and the centre's number of urological beds (OR 1.02, p[Bootstrap] = 0.025) were the only parameters showing a significant independent impact on the endpoint. In contrast, the status of a university centre (p = 0.143), a leading position of the responding urologist (p = 0.375) and the number of PeC patients treated per year and centre (p = 0.571) did not significantly predict a correct answer.

Conclusions:  Our results demonstrate insufficient knowledge on the association of PeC and HPV among German-speaking urologists.
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http://dx.doi.org/10.1055/a-1032-8086DOI Listing
November 2019

Additional Local Therapy for Liver Metastases in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Systemic PSMA-Targeted Therapy.

J Nucl Med 2020 05 10;61(5):723-728. Epub 2019 Oct 10.

Department of Nuclear Medicine, University Hospital Münster, Münster, Germany

The aim of this study was to evaluate the efficacy of Lu-prostate-specific membrane antigen (PSMA)-617 (Lu-PSMA) and selective internal radiation therapy (SIRT) for the treatment of liver metastases of castration-resistant prostate cancer. Safety and survival of patients with metastatic castration-resistant prostate cancer and liver metastases assigned to Lu-PSMA alone ( = 31) or in combination with SIRT ( = 5) were retrospectively analyzed. Additionally, a subgroup ( = 10) was analyzed using morphologic and molecular response criteria. Median estimated survival was 5.7 mo for Lu-PSMA alone and 8.4 mo for combined sequential Lu-PSMA and SIRT. Lu-PSMA achieved discordant therapy responses with both regressive and progressive liver metastases in the same patient (best vs. worst responding metastases per patient: -35% vs. +63% diameter change; < 0.05). SIRT was superior to Lu-PSMA for the treatment of liver metastases (0% vs. 56% progression). The combination of Lu-PSMA and SIRT is efficient and feasible for the treatment of advanced prostate cancer. Lu-PSMA alone seems to have limited response rates in the treatment of liver metastases.
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http://dx.doi.org/10.2967/jnumed.119.233429DOI Listing
May 2020

A prognostic score for overall survival in patients treated with abiraterone in the pre- and post-chemotherapy setting.

Oncotarget 2019 Aug 20;10(49):5082-5091. Epub 2019 Aug 20.

Department of Urology, Stanford Medical School, Stanford, CA, USA.

Therapy resistance remains a serious dilemma in metastatic castration-resistant prostate cancer (mCRPC) with primary or secondary resistance frequently occurring against any given therapy. Available prognostic models for Abiraterone Acetate (AA) are specifically designed for either pre- or post-chemotherapy settings and mostly based on trial datasets not necessarily reflecting real-life. A score of 0-2 (low-risk) is associated with an OS-probability of 80.0% (95%CI: 71.3-90.6) and 50.5% (95%CI: 38.7-66.0) after 1 and 2 years while a score of 3-4 (high risk) is associated with an OS-probability of 35.3% (95%CI: 22.3-55.8) and 5.7% (95%CI: 1.5-21.8), respectively. The bootstrapping survival analysis of the scoring-system revealed a median c-index of 0.80 (IQR: 0.79-0.82). We developed a scoring-system using four real-life parameters 117 mCRPC patients treated with AA either pre- or post-chemotherapy. These parameters were evaluated using COX regression analysis. The scoring-system consists of binary-categorized parameters; when any of these exceeds the given cut-off, one point is added up to a final score ranging between 0-4 points. The final score was stratified by a median threshold of 2 into low- and high-risk groups. We evaluated the discriminative ability of our scoring-system using concordance probability (C-index) and Kaplan-Meier-analysis and applied a 100-times bootstrap for survival analysis. Our study introduces a novel prognostic scoring-system for OS of real-life mCRPC patients receiving AA treatment irrespective of the line of therapy. The scoring-system is simple and can be easily utilized based on PSA and LDH values, neutrophil to lymphocyte ratio, and ECOG performance status.
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http://dx.doi.org/10.18632/oncotarget.27133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707939PMC
August 2019

Second line chemotherapy and visceral metastases are associated with poor survival in patients with mCRPC receiving Lu-PSMA-617.

Theranostics 2019 9;9(17):4841-4848. Epub 2019 Jul 9.

Department of Nuclear Medicine, Münster University Hospital.

The purpose of this study was to identify previous treatments and biomarker profile features that prognosticate overall survival (OS) in patients with mCRPC receiving Lu-PSMA-617. 109 mCRPC patients treated with a median of 3 cycles of Lu-PSMA-617 were included. Data were analyzed according to OS as well as PSA response patterns with regard to prior therapies, laboratory biomarkers and metastatic extent in univariate as well as multivariate Cox's proportional hazards models. PSA decline was assessed using the lowest PSA levels after the first cycle of therapy (initial PSA response) and during the entire observation period (best PSA response). In total, 54 patients (49.5%) died during the observation period. First and second line chemotherapy were performed in 85% and 26%, and Abiraterone and Enzalutamide were administered in 83% and 85%, respectively. Any initial PSA decline occurred in 55% while 25% showed a PSA decline of ≥50%. The median estimated OS was 9.9 months (95% CI: 7.2-12.5) for all patients. Any initial decline of PSA was associated with significantly prolonged OS (15.5 vs. 5.7 months, 0.002). Second line cabazitaxel chemotherapy (6.7 15.7 months, 0.002) and presence of visceral metastases (5.9 16.4 months, <0.001) were associated with shorter OS. Only visceral metastases remained significant in a multivariate analysis. Lu-PSMA-617 is an effective therapy for patients with mCRPC. However, the present data indicate that its beneficial effects on OS are strongly influenced by pretreatment (history of second line chemotherapy with cabazitaxel) and the presence of visceral metastases at onset of Lu-PSMA-617 treatment.
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http://dx.doi.org/10.7150/thno.35759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691377PMC
August 2020

Combination possibility and deep learning model as clinical decision-aided approach for prostate cancer.

Health Informatics J 2020 06 26;26(2):945-962. Epub 2019 Jun 26.

University Hospital Muenster, Germany.

This study aims to introduce as proof of concept a combination model for classification of prostate cancer using deep learning approaches. We utilized patients with prostate cancer who underwent surgical treatment representing the various conditions of disease progression. All possible combinations of significant variables from logistic regression and correlation analyses were determined from study data sets. The combination possibility and deep learning model was developed to predict these combinations that represented clinically meaningful patient's subgroups. The observed relative frequencies of different tumor stages and Gleason score Gls changes from biopsy to prostatectomy were available for each group. Deep learning models and seven machine learning approaches were compared for the classification performance of Gleason score changes and pT2 stage. Deep models achieved the highest F1 scores by pT2 tumors (0.849) and Gls change (0.574). Combination possibility and deep learning model is a useful decision-aided tool for prostate cancer and to group patients with prostate cancer into clinically meaningful groups.
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http://dx.doi.org/10.1177/1460458219855884DOI Listing
June 2020

Comparative Analysis of AR Variant AR-V567es mRNA Detection Systems Reveals Eminent Variability and Questions the Role as a Clinical Biomarker in Prostate Cancer.

Clin Cancer Res 2019 07 16;25(13):3856-3864. Epub 2019 Apr 16.

Department of Urology, University Hospital Muenster, Muenster, Germany.

Purpose: Androgen receptor splice variants are known to facilitate resistance of prostate cancer cells toward antihormonal therapies. However, detection of the most prominent variant, AR-V7, on its own, is not sufficiently accurate for prediction of response. Thus, simultaneous detection of other variants might improve prediction. AR-V567es has been shown to be expressed in late stages of prostate cancer. Yet, there have been discrepant results regarding incidence of AR-V567es. We therefore aimed to perform a comprehensive comparison of different detection approaches for AR-V567es mRNA.

Experimental Design: We compared a custom-made, probe-based PCR assay with 6 published AR-V567es detection PCR assays in distinct samples, that is, cancer cell lines, LuCaP xenografts, primary and metastatic tumor samples, and circulating tumor cells (CTC).

Results: Using distinct approaches, we concordantly detected expression of AR-V567es in only three of 45 samples (LuCaP xenografts 86.2 and 136s2 as well as one CTC sample). We observed varying results in all other samples. Specificity analysis displayed nonspecific binding of 5 previously published PCR assays to AR full-length mRNA in the absence of AR-V567es.

Conclusions: Validation of biomarker detection approaches is one of the most critical steps before transfer into clinical application. By performing comparative analysis of different detection approaches, we revealed eminent variability among previously described systems. Furthermore, we demonstrate an overestimation of AR-V567es in prostate cancer, presumably due to nonspecific detection of AR-FL mRNA. Therefore, any correlation between AR-V567es expression and clinical responses is highly doubtful and does not reflect the biological nature of the disease.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4276DOI Listing
July 2019

Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Oncol 2019 03 6;20(3):408-419. Epub 2019 Feb 6.

University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Background: Abiraterone acetate plus prednisone or prednisolone improves progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. Radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases. We assessed concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 in such patients.

Methods: We did a randomised, double-blind, placebo-controlled, phase 3 trial at 165 oncology and urology centres in 19 countries. Eligible patients were aged 18 years or older, and had histologically confirmed, progressive, chemotherapy-naive, asymptomatic or mildly symptomatic castration-resistant prostate cancer and bone metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 6 months, and adequate haematological, renal, and liver function. Participants were randomly assigned (1:1) according to a permuted block design (block size 4) via interactive response technology to receive up to six intravenous injections of radium-223 (55 kBq/kg) or matching placebo once every 4 weeks. All patients were also scheduled to receive oral abiraterone acetate 1000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily during and after radium-223 or placebo treatment. The primary endpoint was symptomatic skeletal event-free survival, which was assessed in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, number NCT02043678. Enrolment has been completed, and follow-up is ongoing.

Findings: Between March 30, 2014, and Aug 12, 2016, 806 patients were randomly assigned to receive radium-223 (n=401) or placebo (n=405) in addition to abiraterone acetate plus prednisone or prednisolone. The study was unblinded prematurely, on Nov 17, 2017, after more fractures and deaths were noted in the radium-223 group than in the placebo group (in an unplanned ad-hoc analysis), but all patients had completed radium-223 or placebo before this date. At the primary analysis (data cutoff Feb 15, 2018), 196 (49%) of 401 patients in radium-223 group had had at least one symptomatic skeletal event or died, compared with 190 (47%) of 405 patients in the placebo group (median follow-up 21·2 months [IQR 17·0-25·8]). Median symptomatic skeletal event-free survival was 22·3 months (95% CI 20·4-24·8) in the radium-223 group and 26·0 months (21·8-28·3) in the placebo group (hazard ratio 1·122 [95% CI 0·917-1·374]; p=0·2636). Fractures (any grade) occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. The most common grade 3-4 treatment-emergent adverse events were hypertension (43 [11%] patients in the radium-223 group vs 52 [13%] patients in the placebo group), fractures (36 [9%] vs 12 [3%]) and increased alanine aminotransferase concentrations (34 [9%] vs 28 [7%]). Serious treatment-emergent adverse events occurred in 160 (41%) patients in the radium-223 group and 155 (39%) in the placebo group. Treatment-related deaths occurred in two (1%) patients in the radium-223 group (acute myocardial infarction and interstitial lung disease) and one (<1%) in the placebo group (arrhythmia).

Interpretation: The addition of radium-223 to abiraterone acetate plus prednisone or prednisolone did not improve symptomatic skeletal event-free survival in patients with castration-resistant prostate cancer and bone metastases, and was associated with an increased frequency of bone fractures compared with placebo. Thus, we do not recommend use of this combination.

Funding: Bayer.
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http://dx.doi.org/10.1016/S1470-2045(18)30860-XDOI Listing
March 2019

[Update Urooncology: News from major scientific meetings 2018].

Aktuelle Urol 2019 Feb 7;50(1):23-31. Epub 2019 Feb 7.

We are living in exciting times for urological oncology. The numbers of clinical trials are ever rising, a stream of new substances for tumour therapy is introduced. As it is more challenging than ever to obtain an overview as a clinician, this article aims to summarise the most important news with regard to the 3 most eminent urological tumour entities. Recent data from the most relevant urological and oncological conferences in 2018 on prostate cancer, renal cell carcinoma, and urothelial cancer are reported and their relevance for clinical practice is discussed.
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http://dx.doi.org/10.1055/a-0759-3664DOI Listing
February 2019

Abiraterone acetate plus prednisone for the Management of Metastatic Castration-Resistant Prostate Cancer (mCRPC) without prior use of chemotherapy: report from a large, international, real-world retrospective cohort study.

BMC Cancer 2019 Jan 14;19(1):60. Epub 2019 Jan 14.

The Christie Hospital, Manchester, UK.

Background: With the recent introduction of novel treatment options, real-world data from patients with metastatic castration-resistant prostate cancer (mCRPC) are required to better understand the impact on routine clinical practice. This study primarily aimed to describe the time to treatment failure (TTF) of mCRPC patients treated with abiraterone acetate plus prednisone or the corticosteroid of choice (AAP) in the pre-chemotherapy setting. Other relevant outcomes, clinical and treatment characteristics of these patients were also evaluated.

Methods: This retrospective, observational study collected data from chemotherapy-naïve mCRPC patients treated with AAP from four European countries. Kaplan-Meier curves were used to estimate TTF, progression-free survival (PFS), and time to first skeletal-related event. The impact of baseline characteristics on TTF and PFS was explored using univariate and multivariate Cox proportional hazard models. Log-rank test was used to assess the potential role of duration of response to ADT in predicting response to AAP treatment.

Results: Data from 481 eligible patients (Belgium: 68; France: 61; Germany: 150; UK: 202) were analysed. At AAP initiation, the median age of patients was 75.0 years (interquartile range [IQR]: 69.0-81.0), and the median PSA was 56.2 ng/mL (IQR: 22.2-133.1), with over 50% of patients presenting an ECOG score of 0 or 1. Visceral metastases were present in 7.5% of patients; an exclusion criterion in the COU-AA-302 clinical trial. The median TTF with AAP was 10.0 months (95%CI: 9.2-11.1) and the median PFS was 10.8 months (95%CI: 9.6-11.8). Shorter TTF was significantly associated with higher ALP (> 119 units/L), higher PSA (> 56.2 ng/mL), or poorer ECOG PS scores at AAP initiation (p < 0.05). Patients with longer duration of response to ADT (≥12 months) presented longer TTF and longer time to progression (p < 0.0001).

Conclusions: This European real-world study provides valuable insights into the characteristics, treatment, and outcomes of chemotherapy-naïve patients with mCRPC who received AAP in routine clinical practice. Treatment effectiveness of AAP in the real-world is maintained despite patients having poorer clinical features at initiation than those observed in the COU-AA-302 trial population.
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http://dx.doi.org/10.1186/s12885-019-5280-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332550PMC
January 2019

Sunitinib Treatment Modification in First-Line Metastatic Renal Cell Carcinoma: Analysis of the STAR-TOR Registry.

Anticancer Res 2018 Nov;38(11):6413-6422

Pfizer, Inc., New York, NY, U.S.A.

Background/aim: Sunitinib is the current standard of care for first-line (1L) treatment of metastatic renal cell carcinoma (mRCC). Previous studies suggest that a modified treatment schedule may benefit patients. Our aim was to evaluate efficacy and safety regarding sunitinib treatment modification in 1L treatment of mRCC.

Materials And Methods: Data were drawn from STAR-TOR, a German real-world registry to evaluate outcomes of patients with mRCC who received 1L sunitinib. Patients were divided into two groups: subsequent treatment modification (SM) or remaining on standard dose/schedule (SS). Time on treatment (TT), progression-free survival (PFS), and overall survival (OS) were estimated.

Results: Overall, 297 patients were analyzed; 33% underwent treatment modification. Significant baseline differences between groups were observed; SM patients were older and had a more favourable Karnofsky performance status. SM patients achieved better outcomes than SS patients for median TT (15.1 versus 3.9 months; p<0.0001), PFS (15.1 versus 6.0; p<0.0001), and OS (38.1 versus 13.7; p<0.0001). Diarrhoea (34%/17%), fatigue (30%/11%), hand-foot syndrome (28%/10%), and stomatitis (20%/6%) were more frequently reported in SM versus SS; incidence was reduced following schedule/dose modification (except diarrhoea).

Conclusion: In addition to AE mitigation, sunitinib treatment modification may help improve efficacy outcomes in mRCC by prolonging treatment duration.
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http://dx.doi.org/10.21873/anticanres.13002DOI Listing
November 2018

[Lu]-PSMA-617 radionuclide therapy in patients with metastatic castration-resistant prostate cancer.

Lancet Oncol 2018 08;19(8):e371

Department of Urology, University Hospital Muenster, 48149 Munster, Germany.

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http://dx.doi.org/10.1016/S1470-2045(18)30410-8DOI Listing
August 2018

Molecularly-driven precision medicine for advanced bladder cancer.

World J Urol 2018 Nov 8;36(11):1749-1757. Epub 2018 Jun 8.

Department of Urology, The University of Muenster Medical Center, Albert-Schweitzer, Campus 1, GB A1, 48149, Muenster, Germany.

Urothelial carcinoma of the bladder is a heterogeneous disease with many challenges for clinicians and patients alike. However, for the most part of the last three decades, treatment and outcomes for patients with this disease have not changed a lot. With recent advances in immunooncology leading to the approval of multiple agents for the metastatic setting, the treatment landscape started to change. With the emergent data from landmark multi-institutional sequencing projects as well as molecular data from recent trials, our understanding of the underlying disease biology, response patterns as well as definition of molecular subtypes has evolved tremendously. This review aims to summarize the currently available concepts of mutational profiles and molecular subtypes as well as their implications for management of urothelial carcinoma.
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http://dx.doi.org/10.1007/s00345-018-2354-zDOI Listing
November 2018

Discordant prostate specific antigen test results despite WHO assay standardization.

Int J Biol Markers 2018 Aug 8;33(3):275-282. Epub 2018 May 8.

1 Department of Urology, Prostate Center, University Hospital Münster, Muenster, Germany.

Introduction: Total PSA (tPSA) and free PSA (fPSA) are the most commonly used biomarkers for early detection of prostate cancer. Despite standardization efforts, many available PSA assays may still produce discordant results. In the present study, we compared four PSA assays calibrated to the WHO standards 96/670 and 96/668 for tPSA and fPSA, respectively.

Methods: Within the scope of the Prostate Cancer Early Detection Study Based on a ''Baseline'' PSA Value in Young Men (PROBASE), we tested tPSA and fPSA in serum samples from 50 patients in the four different PROBASE sites using four WHO-calibrated assays from Roche (Elecsys, Cobas), Beckman-Coulter (Access-II) and Siemens (ADVIA Centaur). The comparison was performed using the Passing-Bablok regression method.

Results: Compared to Access, the median tPSA levels for Centaur, Elecsys, and Cobas were +3%, +11%-20%, and +17%-23%, respectively, while for median fPSA levels the differences for Centaur, Elecsys, and Cobas were +49%, +29%-31%, and +22%, respectively.

Discussion: Despite all investigated assays being WHO-calibrated, the Elecsys and Cobas tPSA assays produced considerably higher results than the Access and Centaur assays. Differences in fPSA-recovery between all investigated assays were even more pronounced. When applying the tPSA cutoff of 3.1 μg/L recommended for WHO-calibrated assays, the use of higher calibrated assays may lead to unnecessary prostate biopsies. Conversely, if the historical threshold of 4 μg/L is applied when using WHO-calibrated assays, it could lead to falsely omitted prostate biopsies.
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http://dx.doi.org/10.1177/1724600818754750DOI Listing
August 2018

Das bewegt die Urologie – Aktuelles von den Kongressen 2017.

Aktuelle Urol 2018 Feb 1;49(1):25-36. Epub 2018 Feb 1.

Department of Urology und Pediatric Urology, Philipps University Marburg.

In 2017, many new and promising therapeutic innovations entered uro-oncology. Immunotherapy was highly topical and was intensively discussed at the annual meetings. This review summarises the news, together with future developments in the diagnosis and treatment of prostate, bladder and kidney cancer. Within the last year, there have been major developments in the treatment of hormone sensitive metastastic prostate cancer, metastatic transitional cell carcinoma and metastastic renal cell cancer. Many new drugs will be added to our therapeutic arsenal during the upcoming months.
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http://dx.doi.org/10.1055/s-0043-123706DOI Listing
February 2018

Lu-PSMA-617 radioligand therapy in mCRPC: ready for phase III trial?

Eur J Nucl Med Mol Imaging 2018 03 21;45(3):513-514. Epub 2017 Nov 21.

Department of Urology, University Hospital Muenster, Münster, Germany.

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http://dx.doi.org/10.1007/s00259-017-3892-0DOI Listing
March 2018

Prospects and progress of immunotherapy for bladder cancer.

Expert Opin Biol Ther 2017 11 23;17(11):1417-1431. Epub 2017 Aug 23.

a Department of Urology , University of Muenster Medical Center , Muenster , Germany.

Introduction: With recent advances in immunooncology and the introduction of checkpoint inhibitors into clinical practice for many cancers, the treatment landscape of urothelial carcinoma has changed dramatically and will continue to change further. Currently, a number of compounds and combinations are under investigation in numerous clinical trials and various clinical scenarios for bladder cancer. Areas covered: In this review, the authors provide an overview of the history and rationale for immunotherapy in bladder cancer. They also provide the currently available data evaluating checkpoint inhibitors for bladder cancer, and discuss ongoing trials and future perspectives for urothelial carcinoma treatment. Expert opinion: The introduction of checkpoint inhibitors into the management of bladder cancer marks a significant milestone for this disease. Checkpoint inhibitors have the potential to impact patients across multiple disease states from non-muscle-invasive disease to metastatic tumors refractory to conventional treatment. That being said, validated biomarkers, including genetic signatures, to accurately predict response, and the establishment of optimal sequencing and combination of these immunotherapeutic agents with chemo/radiotherapy are urgently needed.
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http://dx.doi.org/10.1080/14712598.2017.1366445DOI Listing
November 2017

Prognostic Value of PD-1 and PD-L1 Expression in Patients with High Grade Upper Tract Urothelial Carcinoma.

J Urol 2017 12 28;198(6):1253-1262. Epub 2017 Jun 28.

Department of Urology, University of Texas Medical Center, Dallas, Texas. Electronic address:

Purpose: We investigated the prognostic value of PD-1 and PD-L1 expression in patients with high grade upper tract urothelial carcinoma.

Materials And Methods: Tissue microarrays of 423 patients treated with extirpative surgery for high grade upper tract urothelial carcinoma from the International Upper Tract Urothelial Carcinoma collaboration were stained for PD-1 and PD-L1 using antibodies, including Cell Marque™ NAT105 diluted 1:250 and prediluted E1L3N® via immunohistochemistry. A 1% or greater staining rate of tumor infiltrating lymphocytes (PD-1) and tumor cells (PD-L1) was considered positive. Univariate and multivariate analyses were performed to assess independent prognosticators of survival outcomes.

Results: Median patient age was 70.0 years and median followup was 37.0 months. PD-1 and PD-L1 were positive in 37.2% and 26.2% of patients, respectively. PD-1 positivity was significantly associated with adverse pathological characteristics while PD-L1 positivity was associated with favorable pT stage. On univariate analysis PD-1 expression was associated with worse recurrence-free, cancer specific and overall survival. On multivariate analysis PD-1 expression was an independent prognosticator of cancer specific survival (HR 1.7, 95% CI 1.03-2.66, p = 0.039) and overall survival (HR 1.5, 95% CI 1.05-2.24, p = 0.029) but not recurrence-free survival (HR 1.4, 95% CI 0.9-2.16, p = 0.139). On univariate analysis PD-L1 expression was not significantly associated with survival outcomes. However, on multivariate analysis in patients with organ confined disease (pT2 or less, pN0/x and cM0), PD-L1 positivity was an independent prognosticator of recurrence-free survival (HR 0.2, 95% CI 0.06-0.98, p = 0.046) and overall survival (HR 0.3, 95% CI 0.11-0.63, p = 0.003).

Conclusions: PD-1 positivity of tumor-infiltrating lymphocytes was associated with adverse pathological criteria and independent prognostication of worse survival outcomes. PD-L1 positivity of tumor cells was an independent prognosticator of favorable survival outcomes in cases of organ confined disease.
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http://dx.doi.org/10.1016/j.juro.2017.06.086DOI Listing
December 2017

Why Targeting of PSMA Is a Valuable Addition to the Management of Castration-Resistant Prostate Cancer: The Urologist's Point of View.

J Nucl Med 2017 08 18;58(8):1207-1209. Epub 2017 May 18.

Department of Urology, University Hospital Münster, Münster, Germany.

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http://dx.doi.org/10.2967/jnumed.117.194753DOI Listing
August 2017

Spotlight on atezolizumab and its potential in the treatment of advanced urothelial bladder cancer.

Onco Targets Ther 2017 9;10:1487-1502. Epub 2017 Mar 9.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Urology, University of Münster Medical Center, Münster, Germany.

Metastatic urothelial carcinoma of the bladder is an aggressive malignancy with poor prognosis, reflecting a lack of effective systemic therapies. The current standard of care includes multiagent platinum-based chemotherapy; however a majority of patients do not respond to treatment and most eventually succumb to disease. Recently, renewed interest in immunotherapy in the form of immune-checkpoint inhibition has gained widespread attention for a number of malignancies. Atezolizumab, an anti-PDL1 antibody, has been shown to be effective in a subset of patients previously treated with or unfit for platinum-based chemotherapy, and has shown durable responses with a good tolerability profile. We review the mechanism of action and clinical evidence of atezolizumab for metastatic urothelial bladder cancer, and discuss this drug within the context of ongoing developments in this dynamic field of immunooncology.
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http://dx.doi.org/10.2147/OTT.S109453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352238PMC
March 2017

Novel AR-V7 detection in whole blood samples in patients with prostate cancer: not as simple as it seems.

World J Urol 2017 10 28;35(10):1625-1627. Epub 2017 Feb 28.

Clinic of Urology, University Hospital, Muenster, Germany.

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http://dx.doi.org/10.1007/s00345-017-2024-6DOI Listing
October 2017

The Role of the Neutrophil to Lymphocyte Ratio for Survival Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone.

Int J Mol Sci 2017 Feb 11;18(2). Epub 2017 Feb 11.

Department of Urology, Prostate Center, University Hospital Muenster, Albert-Schweitzer-Campus 1, GB A1, D-48149 Muenster, Germany.

The purpose of this study was to examine the prognostic capability of baseline neutrophil-to-lymphocyte-ratio (NLR) and NLR-change under Abiraterone in metastatic castration-resistant prostate cancer patients. The impact of baseline NLR and change after eight weeks of treatment on progression-free survival (PFS) and overall survival (OS) was analyzed using Kaplan-Meier-estimates and Cox-regression. 79 men with baseline NLR <5 and 17 with NLR >5 were analyzed. In baseline analysis of PFS NLR >5 was associated with non-significantly shorter median PFS (five versus 10 months) (HR: 1.6 (95%CI:0.9-2.8); = 0.11). After multivariate adjustment (MVA), ECOG > 0-1, baseline LDH>upper limit of normal (UNL) and presence of visceral metastases were independent prognosticators. For OS, NLR >5 was associated with shorter survival (seven versus 19 months) (HR: 2.3 (95%CI:1.3-4.0); < 0.01). In MVA, ECOG > 0-1 and baseline LDH > UNL remained independent prognosticators. After 8 weeks of Abiraterone NLR-change to <5 prognosticated worse PFS (five versus 12 months) (HR: 4.1 (95%CI:1.1-15.8); = 0.04). MVA showed a trend towards worse PFS for NLR-change to <5 ( = 0.11). NLR-change to <5 led to non-significant shorter median OS (seven versus 16 months) (HR: 2.3 (95%CI:0.7-7.1); = 0.15). MVA showed non-significant difference for OS. We concluded baseline NLR <5 is associated with improved survival. In contrast, in patients with baseline NLR >5, NLR-change to <5 after eight weeks of Abiraterone was associated with worse survival and should be interpreted carefully.
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http://dx.doi.org/10.3390/ijms18020380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343915PMC
February 2017

Variant histology in bladder cancer: how it should change the management in non-muscle invasive and muscle invasive disease?

Transl Androl Urol 2016 Oct;5(5):692-701

Department of Urology, University of Muenster Medical Center, Muenster, Germany; ; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Bladder cancer (BC) is a frequent type of carcinoma with an estimated incidence of approximately 100,000 men and women each year in the European Union (EU) with an associated mortality of 30,000 of these patients. In more than 70% the disease is diagnosed in a non-muscle invasive stage with the chance of minimally invasive, local treatment only, which might be required repetitively due to high rate of recurrence. In contrast, muscle invasive or metastatic stages need multimodal treatment strategies including surgical treatment and chemotherapy (CTX) in neoadjuvant (NAC), adjuvant, or palliative settings. Therapy recommendations and guidelines mainly refer to the most common histological type of BC, pure urothelial carcinoma (UC). However, BC can be classified as urothelial and non-UC. Non-urothelial BC and variants of UC account for up to 25% of all BCs. Further discrimination can be made into epithelial and non-epithelial non-UC. Most of the non-UCs are of epithelial origin (approximately 90%) including squamous-cell carcinoma, adenocarcinoma and small-cell carcinoma. Non-epithelial tumors are rare and include variants as sarcoma, carcinosarcoma, paraganglioma, melanoma and lymphoma. Even though it is unclear whether the prognosis of non-urothelial cancer truly differs from that of UC, there is evidence that additional variant histology might prognosticate an impaired prognosis. Accordingly, aggressive behavior and often advanced stages at primary presentation are frequently observed in non-UC arguing for radical and sometimes different treatment strategies as compared to pure UC. This review aims to summarize the available data for the most common histological variants of non-urothelial BC.
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http://dx.doi.org/10.21037/tau.2016.06.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071184PMC
October 2016

Early Prediction of Therapy Response to Abiraterone Acetate Using PSA Subforms in Patients with Castration Resistant Prostate Cancer.

Int J Mol Sci 2016 Sep 9;17(9). Epub 2016 Sep 9.

Department of Urology, Prostate Center, University Hospital Muenster, Albert-Schweitzer-Campus 1, GB A1, Muenster D-48149, Germany.

The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA), free PSA (fPSA), [-2]proPSA and the Prostate Health Index (PHI) following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC). In 25 patients, PSA-subforms were analyzed before and at 8-12 weeks under therapy as prognosticators of progression-free-survival (PFS) and overall survival (OS). Comparing patients with a PFS < vs. ≥12 months by using Mann-Whitney-Wilcoxon Tests, the relative-median-change of tPSA (-0.1% vs. -86.8%; p = 0.02), fPSA (12.1% vs. -55.3%; p = 0.03) and [-2]proPSA (8.1% vs. -59.3%; p = 0.05) differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. -46.3%; p = 0.06). In Kaplan-Meier analyses, declining fPSA and [-2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI): 9.6-16.4 vs. 10 months, 95% CI: 3.5-16.5; p = 0.11), respectively. Correspondingly, decreasing fPSA and [-2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR)) compared to 21 months in men with rising values (95% CI: 7.7-34.3; p = 0.14), respectively. We concluded that the addition of fPSA- and [-2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients.
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http://dx.doi.org/10.3390/ijms17091520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037797PMC
September 2016

Influence of Statins on Survival Outcome in Patients with Metastatic Castration Resistant Prostate Cancer Treated with Abiraterone Acetate.

PLoS One 2016 1;11(9):e0161959. Epub 2016 Sep 1.

Department of Urology, Muenster University Medical Center, Muenster, Germany.

Objective: Even though the exact mechanism is largely unknown until now, statins are supposed to improve survival outcomes in various malignancies. For prostate cancer however, statins are known to compete with dehydroepiandrosterone (DHEAS) for the transport into the cytosol both using the cell by the Solute Carrier Transporter and thus diminish the cellular uptake of DHEAS as a precursor of androgens. Abiraterone inhibits CYP17A1 and thus effectively decreases the production of all relevant androgens including DHEAS. In this study we examined whether statins still affect survival outcome in patients with metastatic castration resistant prostate cancer (mCRPC) when treated with Abiraterone.

Patients And Methods: 108 men with mCRPC treated with Abiraterone from 02/2010 to 07/2015 with (n = 21) or without (n = 87) concomitant treatment with statins were investigated. Progression free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier-estimates and univariate Cox-regression analysis. The influence on best clinical benefit under Abiraterone treatment was analyzed with bivariate and multivariate logistic regression analysis.

Results: PSA-decline ≥ 50% was not significantly different in both groups (57 vs. 53%; p = 0.73). The median PFS (9 vs. 10 months; p = 0.97) and OS (14 vs. 18 months; p = 0.77) did not differ significantly between those men treated with and without concomitant statin therapy, respectively. Accordingly, there was no improvement for best clinical benefit in patients using statins (odds ratio: 1.2 (CI: 0.4-4.2); p = 0.76).

Conclusion: Use of statins as concomitant medication did not improve survival outcomes or best clinical benefit in men with mCRPC treated with Abiraterone.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161959PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008748PMC
August 2017