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

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.

The PAZOREAL noninterventional study to assess effectiveness and safety of pazopanib and everolimus in the changing metastatic renal cell carcinoma treatment landscape.

VEGFR and mTOR inhibitors are broadly used in metastatic renal cell carcinoma (mRCC) therapy, and sequential first-line pazopanib (VEGFR inhibitor) and second-line everolimus (mTOR inhibitor) is a standard treatment option. Nivolumab and lenvatinib/everolimus combination was recently approved in Europe for use in mRCC after previous therapy. Prospective routine data on sequential therapy including nivolumab and/or lenvatinib are missing. This is a prospective, noninterventional study, which evaluates the effectiveness, tolerability, safety and quality of life following 450 patients with mRCC starting either on pazopanib as first-line therapy or third-line everolimus plus/minus lenvatinib following nivolumab. Adults with histologically confirmed mRCC of any subtype, who have a life expectancy of at least 6 months, are eligible.

Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study.

BACKGROUND: Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings. METHODS: Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed. RESULTS: In the total population (N = 334), median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211), median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%), anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered. CONCLUSIONS: This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC. Novartis study code, CRAD001LD27: VFA registry for noninterventional studies ( http://www.vfa.de/de/forschung/nisdb/).

Everolimus in metastatic renal cell carcinoma after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy: results of an interim analysis of a non-interventional study.

BACKGROUND: Everolimus is approved for treatment of anti-vascular endothelial growth factor (VEGF)-refractory patients with metastatic renal cell carcinoma (mRCC). Clinical trials rarely mirror treatment reality. Thus, a broader evaluation of everolimus is valuable for routine use. PATIENTS AND METHODS: A German multicenter non-interventional study documented mRCC patients starting everolimus after failure of initial VEGF-targeted therapy. Primary endpoint was effectiveness, defined as time to progression (TTP) according to investigator assessment (time from first dose to progression). RESULTS: Of 382 documented patients, 196 were included in this interim analysis. In the efficacy population (n = 165), median TTP was 7.0 months (95% confidence interval (CI) 5.1-9.0). Among patients with < or ≥ 6 months of previous VEGF-targeted therapy, median TTP was 6.6 months (95% CI 3.8-not estimable) and 7.4 months (95% CI 4.6-9.6), respectively. Most common adverse events were anemia (13%) and dyspnea (14%). Physicians assessed high tolerance and documented high adherence to everolimus therapy (approximately 97%). CONCLUSION: In routine clinical practice, everolimus is effective, as measured by median TTP (longer than median progression-free survival in RECORD-1 trial), and well tolerated. Our results support everolimus use in anti-VEGF-refractory patients with mRCC.

[The cancer registry notification seen from the perspective of the German Society of Uro-Oncologists (d-uo)]. / Die Krebsregistermeldung aus der Sicht der Deutschen Uro-Onkologen (d-uo).

The current cancer registry notification, which was introduced in Germany as a mandatory institution in 2015, has its starting point in the National Cancer Plan of 2008. Other milestones include the Federal Cancer Registry Data Act (2009), the Cancer Early Detection and Registry Act (2013), the Uniform Oncological Basic Data Set (2014/2021) with its modules (e.g. the module prostate carcinoma 2017) as well as the Cancer Registry Data Merger Act (2021). At the beginning of 2017, the German Society of Uro-Oncologists (d-uo) had the idea of designing a documentation platform that would enable d-uo members to report to the cancer registry and transfer data to d-uo's own database - without a double effort. The cancer registry reimburses the first notification of a tumour with € 18. As the only provider, d-uo reimburses its members for the documentation effort associated with the additional notification to d-uo with a further € 18. In addition to the basic oncological data set, further parameters were defined by d-uo. This data is collected, evaluated and interpreted as part of the VERSUS study. The realisation that the parameters of the basic data set are limited in their informative value led d-uo to establish the two national registries for urothelial carcinoma (UroNAT) and prostate carcinoma (ProNAT). This underscores d-uo's leading position in uro-oncological healthcare research in Germany.

[Real-world data on prostate cancer: the VERSUS trial by d-uo]. / Ergebnisse aus der VERSUS-Studie von d-uo am Beispiel des Prostatakarzinoms.

At the beginning of 2017, the German Society of Uro-Oncologists (d-uo) had the idea of designing a documentation platform that would enable d-uo members to report cancer cases to the cancer registry and transfer data to d-uo's own database - without a double effort. The cancer registry reimburses the first notification of a tumour with €18. As the only provider, d-uo reimburses its members for the documentation effort associated with the additional notification to d-uo with a further €18. In addition to the basic oncological data set, further parameters were defined by d-uo. This data is collected, evaluated and interpreted as part of the VERSUS study. At the end of 2022, 14,834 patients with a newly diagnosed urological tumour were included in the VERSUS study. Almost two thirds of all patients had prostate cancer. About half of all patients with prostate cancer were diagnosed as part of an early detection measure. These patients then also had more favourable tumour stages. Overall, almost every eighth patient already had metastases at the time of initial diagnosis. Data from the VERSUS study are available for 2,167 operations on prostate cancer with tumour category T2 or T3. There were 1,360 operations in patients with a T2 tumour (62.8%) and 807 operations in patients with T3 tumours (37.2%). A positive margin was present in 25.5% of all operated-on patients. In relation to tumour categories T2 and T3, the proportion of a positive resection margin was 14.3% and 44.2%, respectively. The VERSUS study will continue to provide answers to many questions from the uro-oncological field with reference to the "real world" situation in Germany.

[National Registries for Urothelial Cancer (UroNAT) and Prostate Cancer (ProNAT) by d-uo]. / Nationale Register Urothelkarzinom (UroNAT) und Prostatakarzinom (ProNAT) von d-uo.

The German Society of Uro-Oncologists ("Deutsche Uro-Onkologen e.V.", d-uo) provides a national registry for urothelial cancer (UroNat) and a national registry for prostate cancer (ProNAT). These registries aim to evaluate the standard of care for urothelial cancer of the bladder and the upper urinary tract as well as prostate cancer by office-based urologists, oncologists and outpatient hospital departments in Germany. This includes, but is not limited to, adherence to guidelines during the treatment of patients with urothelial cancer and prostate cancer. The registries aim to capture and analyse scientifically how patients with these two most frequent urological tumours are treated and how quality assurance is implemented to improve the quality of their outpatient treatment in Germany. Both registries may share basic patient data supplied by the non-interventional, prospective, multicentre VERSUS registry by d-uo, which has been ongoing since 2018 and today includes more than 15,000 patients with different urological malignancies. In the UroNAT and ProNAT registries, additional items and parameters are included to allow for more detailed analyses of outcomes of outpatient treatments in Germany, which have so far been unavailable from the German Cancer Registry. By documenting the current treatment landscape of urothelial and prostate cancer in the outpatient setting, the registries intend to identify potential improvements of patient care and to initiate their implementation into clinical practice. These non-interventional prospective registries only document daily routine diagnostics, clinical courses and procedures.

[Interdisciplinary recommendations for the treatment of advanced renal cell carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des fortgeschrittenen Nierenzellkarzinoms.

In the treatment of advanced renal cell carcinoma, anti-VEGFR tyrosine kinase inhibitors (TKI) have been replaced mostly by immunotherapy combinations with checkpoint inhibitors (CPI), especially in first line therapy. Due to these novel therapies, the prognosis of patients has been improved further. In pivotal studies a median overall survival of 3-4 years has been achieved. TKI monotherapy remains important for patients with low risk, a contraindication against immunotherapy and with regard to the SARS-CoV-2 pandemic.Selection of the correct first line therapy is difficult to answer because there are two CPI-TKI combinations and one CPI-combination. Temsirolimus and the combination bevacizumab + interferon alfa have become less important. In second line therapy, nivolumab and cabozantinib have demonstrated superior overall survival compared to everolimus. Furthermore, the combination of lenvatinib + everolimus and axitinib are approved treatment options in the second line and further settings. TKI are an option as well, but they have lower supporting evidence. Everolimus has been replaced in the second line setting by these new options. Biomarkers are not available. The German S3 guideline has been updated recently to give better orientation in clinical practice.The question of the optimal sequence is still unanswered. Most second line options were evaluated after failure of anti-VEGF-TKI, but these are only applicable for a minority of patients.The purpose of an interdisciplinary expert meeting in november 2020 was to debate which criteria should influence the therapy. The members discussed several aspects of treating patients with advanced or metastatic RCC, including the SARS-CoV-2 pandemic. As in previous years, the experts intended to provide recommendations for clinical practice. The results are presented in this publication.

The Non-Interventional PAZOREAL Study to Assess the Effectiveness and Safety of Pazopanib in a Real-Life Setting: Reflecting a Changing mRCC Treatment Landscape.

The approval of tyrosine kinase inhibitors and checkpoint inhibitors represented a remarkable progression in the therapeutic landscape for the treatment of metastatic renal cell carcinoma (mRCC). Yet, in the ever-evolving landscape of mRCC treatment, real-world data on these agents, including pazopanib, are scarce. The non-interventional PAZOREAL study investigated the effectiveness and safety of pazopanib (first-line), nivolumab (second-line), and everolimus (second- and third-line) in a real-life setting. The multicentric study included 376 mRCC patients who received first-line treatment with pazopanib and assessed time on the drug (primary endpoint), overall survival, best responses, disease control rates, as well as safety signals and health-related quality of life. The median overall time on the drug was 10.0 months, with first-line pazopanib having a median time on drug of 6.3 months. The median overall survival was 35.9 months. The disease control rate for first-line pazopanib was 56.9%. No new safety signals were detected. PAZOREAL provides valuable real-world data for first-line treatment with pazopanib.

[Osteoprotection in patients with non-metastatic hormone-sensitive prostate cancer (mHSPC) receiving androgen-deprivation therapy (ADT): Real-world data from Germany, presented by d-uo]. / Osteoprotektion beim nichtmetastasierten hormonsensitiven Prostatakarzinom (nmHSPC) unter androgendeprivativer Therapie (ADT): Aktuelle Daten aus Deutschland, vorgelegt von d-uo.

INTRODUCTION: Patients with prostate cancer often present with reduced bone mineral density. We herein present real-world data (RWD) regarding osteoprotection in patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC) receiving androgen deprivation therapy (ADT) treated by German urologists in private practice. MATERIAL AND METHODS: This is a questionnaire-based study including members of d-uo ("Deutsche Uro-Onkologen", German uro-oncologists). Patients with nmHSPC between July 2019 and June 2020 were included. They were asked about start, type and duration of osteoprotection as well as supplementation with calcium and vitamin D. RESULTS: Between July 2019 and June 2020, a total of 3,692 patients with prostate cancer were seen at least once in one of the private practices of 15 urologists (all d-uo members). There were 844 patients (22.9%) with nmHSPC treated with ADT. Osteoprotection using denosumab or a bisphosphonate to prevent skeletal-related events (SRE) was applied in 183/844 patients (21.7%) with nmHSPC. In patients receiving osteoprotection, denosumab was chosen in 73.2% of patients and a bisphosphonate was chosen in 26.8% of patients. Supplementation with calcium and vitamin D was given in 84.7% of patients. CONCLUSION: Patients with nmHSPC received osteoprotection in 1/5 of patients. Of these, 3/4 received denosumab and 1/4 received a bisphosphonate. The majority of patients were additionally treated with calcium and vitamin D. In our study, osteoprotection in patients with nmHSPC was rather an exception.

[Osteoprotection in patients with bone metastatic castration-resistant prostate cancer (mCRPC): real-world data from Germany, presented by d-uo]. / Osteoprotektion beim ossär metastasierten kastrationsresistenten Prostatakarzinom (mCRPC): Aktuelle Daten aus Deutschland, vorgelegt von d-uo.

INTRODUCTION: Patients with bone metastasis due to prostate cancer often present allover reduced bone mineral density. Additionally, patients with bone metastatic castration-resistant prostate cancer (mCRPC) have a relevant risk for skeletal-related events (SRE). We herein present real-world data (RWD) regarding osteoprotection in mCRPC patients with bone metastasis treated by German urologists in private practice. MATERIAL AND METHODS: This is a questionnaire-based study including members of d-uo ("Deutsche Uro-Onkologen", German uro-oncologists). All patients with histologically confirmed prostate cancer seen at least once in the surveyed urology practice between July 2019 and June 2020 were included. Questions included start, type and duration of osteoprotection as well as supplementation with calcium and vitamin D. RESULTS: Between July 2019 and June 2020, a total of 3,692 patients with prostate cancer were seen at least once in 15 urology practices. There were 410 mCRPC patients (11.1%) with bone metastasis. Osteoprotection with denosumab or a bisphosphonate to prevent SRE was applied in 274/410 mCRPC patients (66.4%) with bone metastasis. In patients receiving osteoprotection, denosumab was chosen for 67.9% of patients and a bisphosphonate was chosen for 32.1%. Supplementation with calcium and vitamin D was performed in 93.4% of the patients. The median duration of treatment was 25.3 months for denosumab compared with 39.6 months for bisphosphonates. CONCLUSIONS: Patients with mCRPC with bone metastasis received osteoprotection in 2/3 of cases. Of these, 2/3 received denosumab and 1/3 received a bisphosphonate. The majority of patients were also treated with calcium and vitamin D. According to guideline recommendations regarding osteoprotection in mCRPC patients with bone metastasis, our RWD data showed some lack of guideline adherence.

[Retrospective practice-related care research study on therapy of mCPRC with radium-223 dichloride]. / Retrospektive Versorgungsstudie von d-uo zur Therapie des mCRPC mit Radium-223-dichlorid.

During phase III study ERA-223, patients under combination therapy with radium-223 and abiraterone showed an increased risk of bone fractures and a possible higher risk of death. This observation led to a change in the German therapeutic guidelines in 2018. Radium-223 is now only allowed as a third-line monotherapy (besides ADT) in patients with metastatic castration resistant prostate cancer (mCRPC) with symptomatic bone lesions without known visceral metastases or for patients with mCRPC, for whom no other available systematic therapy is suitable. Since almost no data on practice-related care research on the use of radium-223 exist, we consulted members of d-uo (German Uro-Oncologists) over their therapy algorithms. This study analysed data of patients treated with radium-223 between 2014 and 2019. It could be shown that 50% of mCRPC-patients had received radium-223 in the past as third-line therapy. Half of these were treated in combination with new androgen receptor targeted therapies (ARTA) and no increase in bone fractures was observed. This was most likely due to the additional use of bone protecting agents. Despite the late cancer stage, treatment response was seen in almost half of the patients.

Laparoscopic adrenalectomy in urological centres - the experience of the German Laparoscopic Working Group.

OBJECTIVE: To evaluate the safety and feasibility of laparoscopic adrenalectomy (LA) performed in several German centres with different laparoscopic experience, as LA has become the gold-standard approach for benign surgical adrenal disorders; however, for solitary metastasis or primary adrenal cancer its precise role is uncertain. PATIENTS AND METHODS: The data of 363 patients who underwent a LA were prospectively collected in 23 centres. All centres were stratified into three groups according to their experience: group A (<10 LAs/year), group B (10-20 LAs/year) and group C (>20 LAs/year). In all, 15 centres used a transperitoneal approach, four a retroperitoneal approach and four both approaches. Demographic data, perioperative and postoperative variables, including operating time, surgical approach, tumour size, estimated blood loss, complications, hospital stay and histological tumour staging, were collected and analysed. RESULTS: The transperitoneal approach was used in 281 cases (77.4%) and the retroperitoneal approach was used in 82 patients (22.6%). In all, 263 of 363 lesions (72.5%) were benign and 100 (27.5%) were malignant. The mean (sd) operating time was 127.22 (55.56) min and 130.16 (49.88) min after transperitoneal and retroperitoneal LA, respectively. The mean complication rates for transperitoneal and retroperitoneal LA were 5% and 10.9%, respectively. CONCLUSION: LAs performed by urologists experienced in laparoscopy is safe for the removal of benign and malignant adrenal masses. LA for malignant adrenal tumours should be performed only in high-volume centres by a surgeon performing at least >10 LAs/year.

Comparison between a 1.92-µm fiber laser and a standard HF-dissection device for nephron-sparing kidney resection in a porcine in vivo study.

Nephron-sparing surgery was performed in a porcine model with a 1.92-µm fiber laser dissection device in comparison to a standard high-frequency dissection device. In nine pigs, general anesthesia and a median laparotomy were performed to expose both kidneys. On six kidneys (three HF and three laser) a partial renal parenchyma resection of the lower pole without opening of the renal pelvis was performed (group A). On 12 kidneys (four HF and eight laser), a hemi nephrectomy with opening of the renal pelvis was performed (group B). Total resection time including hemostasis of the remaining tissue was 501 ± 394 s in group "A-laser " vs. 176 ± 139 s in group "A-HF". For the group "B", the total resection time was 1174 ± 501 s (B laser) vs. 960 ± 407 s (B-HF). Blood loss was 28 ± 22 ml in group "A laser " vs. 15 ± 15 ml in group "A-HF". In group "B", the blood loss was 98 ± 73 ml (B laser) vs. 137 ± 118 ml (B-HF). No ischemic time for the kidneys was needed in group "A" for both dissection devices. In group "B", ischemia of the kidneys was performed three times during the eight laser procedures (420 ± 60 s) and only once at the four HF procedures (1,260 s). Healing process was observed over 4-6 weeks, survival rate was 100%, and no renal fistulas were found after the survival period. In conclusion, no significant differences were found between the compared dissection devices. However, the laser system with the flexible transmission fiber may have an advantage for a laparoscopic approach by steerable instruments.

SATB1, genomic instability and Gleason grading constitute a novel risk score for prostate cancer.

Current prostate cancer risk classifications rely on clinicopathological parameters resulting in uncertainties for prognostication. To improve individual risk stratification, we examined the predictive value of selected proteins with respect to tumor heterogeneity and genomic instability. We assessed the degree of genomic instability in 50 radical prostatectomy specimens by DNA-Image-Cytometry and evaluated protein expression in related 199 tissue-microarray (TMA) cores. Immunohistochemical data of SATB1, SPIN1, TPM4, VIME and TBB5 were correlated with the degree of genomic instability, established clinical risk factors and overall survival. Genomic instability was associated with a GS ≥ 7 (p = 0.001) and worse overall survival (p = 0.008). A positive SATB1 expression was associated with a GS ≤ 6 (p = 0.040), genomic stability (p = 0.027), and was a predictor for increased overall survival (p = 0.023). High expression of SPIN1 was also associated with longer overall survival (p = 0.048) and lower preoperative PSA-values (p = 0.047). The combination of SATB1 expression, genomic instability, and GS lead to a novel Prostate Cancer Prediction Score (PCP-Score) which outperforms the current D'Amico et al. stratification for predicting overall survival. Low SATB1 expression, genomic instability and GS ≥ 7 were identified as markers for poor prognosis. Their combination overcomes current clinical risk stratification regimes.

Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma: Final Overall Survival Analysis of the Phase 3 PROTECT Trial.

Most studies indicate no benefit of adjuvant therapy with VEGFR tyrosine kinase inhibitors in advanced renal cell carcinoma (RCC). PROTECT (NCT01235962) was a randomized, double-blind, placebo-controlled phase 3 study to evaluate adjuvant pazopanib in patients with locally advanced RCC at high risk of relapse after nephrectomy (pazopanib, n = 769; placebo, n = 769). The results of the primary analysis showed no difference in disease-free survival between pazopanib 600 mg and placebo. Here we report the final overall survival (OS) analysis (median follow-up: pazopanib, 76 mo, interquartile range [IQR] 66-84; placebo, 77 mo, IQR 69-85). There was no significant difference in OS between the pazopanib and placebo arms (hazard ratio 1.0, 95% confidence interval 0.80-1.26; nominal p > 0.9). OS was worse for patients with T4 disease compared to those with less advanced disease and was better for patients with body mass index (BMI) ≥30 kg/m2 compared to those with lower BMI. OS was significantly better for patients who remained diseasefree at 2 yr after treatment compared with those who relapsed within 2 yr. These findings are consistent with the primary outcomes from PROTECT, indicating that adjuvant pazopanib does not confer a benefit in terms of OS for patients following resection of locally advanced RCC. PATIENT SUMMARY: In the randomized, double-blind, placebo-controlled phase 3 PROTECT study, overall survival was similar for patients with locally advanced renal cell carcinoma (RCC) at high risk of relapse after nephrectomy who received adjuvant therapy with pazopanib or placebo. Pazopanib is not recommended as adjuvant therapy following resection of locally advanced RCC. This trial is registered at Clinicaltrials.gov as NCT01235962.

[Interdisciplinary recommendations for the treatment of advanced metastatic renal cell carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des fortgeschrittenen Nierenzellkarzinoms.

Due to novel therapies, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has improved. A median overall survival of more than two years is a realistic goal. Immunotherapy combinations with checkpoint inhibitors or checkpoint inhibitors and the tyrosine kinase inhibitor axitinib are new first-line options.Sunitinib, pazopanib, tivozanib and the combination of bevacizumab + interferon alpha are approved for first-line therapy regardless of the progression risk score. The use of both the combination of nivolumab + ipilimumab and cabozantinib is restricted to intermediate and high-risk patients. In this subgroup, the immunotherapy combination was more effective in terms of overall survival compared with sunitinib. Temsirolimus is only approved for high-risk patients.Sunitinib and pazopanib can also be applied as second-line options - for pazopanib the use is restricted to the event of cytokine failure. Nivolumab and cabozantinib demonstrated superior overall survival compared with everolimus. Furthermore, the combination of lenvatinib + everolimus and axitinib are approved treatment options in the second-line and further settings. Everolimus has been replaced in the second-line setting by these new options.The question regarding the optimal sequence is still unanswered.The purpose of an interdisciplinary expert meeting was to debate which criteria should influence treatment. The members discussed several aspects of treating patients with advanced or metastatic RCC. As in previous years, the experts intended to provide recommendations for clinical practice. The results are presented in this publication.

Radiological Monitoring of Modern Immunotherapy: A Novel Challenge for Interdisciplinary Patient Care. / Radiologisches Monitoring von modernen Immuntherapien: Neue Herausforderung für die interdisziplinäre Zusammenarbeit.

BACKGROUND: Immunotherapy represents an effective therapeutic approach for many malignant diseases that were previously difficult to treat. However, since immunotherapy can lead to atypical therapy response patterns in the form of pseudo-progression or mixed responses and comprise an altered spectrum of adverse reactions, they present a new challenge for oncologic imaging. Detailed knowledge in this area is essential for oncologic clinical radiologists, since the radiological report is a cornerstone of response assessment, and increasingly influences therapy regimens and coverage by health insurances. METHOD: This white paper is based on an expert meeting in Frankfurt am Main and subsequent discussions between the authors. Based on the iRECIST criteria, it is intended to provide orientation for a response assessment of oncologic patients undergoing immunotherapy that can be applied in the clinical routine. RESULTS: Radiological therapy monitoring outside clinical studies is subject to inherent limitations, but should be performed based on iRECIST criteria, according to the opinion of the expert panel. It should be taken into account that immunotherapies can in principle lead to pseudo-progression and autoimmunological side effects. Since radiological follow-up is currently the only method to accurately distinguish real progressive disease from pseudo-progression, clinically stable patients with disease progression under immunotherapy should undergo additional short-term follow-up imaging according to the suspected diagnosis. Biopsy should be used cautiously and predominately in curative settings. CONCLUSION: For response assessment of immunotherapy in clinical studies, the new iRECIST criteria were published in 2017. Outside studies, the application of iRECIST criteria in the clinical routine is subject to several limitations. The recommendations implied in these criteria can, however, be used in conjunction with the current literature as a guideline in clinical practice and outside studies. KEY POINTS: · Novel immunotherapies can cause atypical response patterns like pseudo-progression. · Compared to real progressive disease, pseudo-progression occurs rather rarely, yet can influence therapy. · Short-term follow-up according to iRECIST can help to distinguish pseudo-progression from real progression. · Hence, radiological follow-up outside clinical studies should be oriented towards iRECIST criteria. CITATION FORMAT: · Lennartz S, Diederich S, Doehn C et al. Radiological Monitoring of Modern Immunotherapy: A Novel Challenge for Interdisciplinary Patient Care. Fortschr Röntgenstr 2020; 192: 235 - 244.

In vivo studies on the availability and toxicity of antisense oligonucleotides in bladder cancer.

BACKGROUND: The urinary bladder is an ideal organ for topical treatment. A substantial number of bladder cancer patients are resistant to conventional intravesical therapy. In search of new agents, antisense oligonucleotides (AS-ON) may be interesting candidates. The availability and toxicity as well as the effectivity of AS-ON after intravesical instillation in different rodent models were examined. MATERIALS AND METHODS: Acute toxicity of AS-ON was tested by intravenous application (215-1,000 mg/kg body weight (bw)) in NMRI mice (n=30). The uptake and distribution of isotope-labelled AS-ON in bladder tissue was determined in Sprague Dawley rats (n=12) by radioactivity after intravesical application (2.5 mg/kg bw 3H-labelled AS-ON). Additionally, uptake and effectivity studies of AS-ON in tumors were performed in MB-49 bladder cancer-bearing C57/B16 mice (n=6) by immunohistochemistry and fluorescence microscopy. RESULTS: No systematic side-effects were noticed after intravenous application of physiological doses of AS-ON in NMRI mice. The mortality rate was 20% at the highest dose of 1,000 mg/kg bw. The highest AS-ON availability after intravesical application in rats was noticed in the bladder wall (12.3 microg/g), while the systemic concentration was low (1.1 microg/g). In fluorescence microscopy analysis, AS-ON were detected in the outer cells of the bladder wall and around vessels. AS-ON accumulated in the cytoplasm and in the nuclei. Immunohistochemical analysis demonstrated a reduction of the Ki-67 positivity after treatment with AS-ON (43%) compared to the untreated controls (58%). CONCLUSION: These preclinical experiments have shown that intravesical antisense oligonucleotides are safe and accumulate in the bladder and in bladder tumors, whereas systemic concentrations remain low. These data are the basis of a first clinical phase I study with intravesical instillation of Ki-67 antisense oligonucleotides.

[50 years of renal cell carcinoma]. / 50 Jahre Nierenzellkarzinom.

In the past 50 years, many knowledge gaps regarding renal cell carcinoma (RCC) have been closed. A pathological tumour classification has been developed and different histological subtypes are known today. In clear cell RCC, the (mutated) von Hippel-Lindau gene located on chromosome 3 is highly important. Operative therapy of non-metastatic RCC has evolved from radical nephrectomy to less radical techniques including procedures sparing the adrenal gland as well as nephron-sparing surgery. Surgical procedures are increasingly performed using laparoscopic or robot-assisted approaches. Even less invasive techniques such as cryoablation, radiofrequency ablation or active surveillance are applied for small renal masses, if indicated. Metastatic RCC is most commonly treated by systemic therapy. Chemotherapy has no effect in RCC. For more than 20 years, cytokine therapy was the standard of care for metastatic RCC. Mutations of the von Hippel-Lindau gene associated with accumulation of hypoxia-inducible factor, followed by increased transcription of vascular endothelial growth factor, provided the scientific rationale for the successful use of tyrosine kinase inhibitors, mTOR inhibitors, and anti-VEGF antibodies introduced in 2006. The development of checkpoint inhibitors has changed the systemic treatment of RCC in yet another relevant manner.