Immunotherapy for advanced or metastatic urothelial carcinoma: an abridged Cochrane review.

OBJECTIVES: To assess the effects of immunotherapy compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma. METHODS: Based on a published protocol, we performed a systematic search of multiple databases. Two review authors independently performed the literature selection, identified relevant studies, assessed the eligibility of studies for inclusion, and extracted data. We performed statistical analyses using a random-effects model and assessed the quality of the evidence on a per-outcome basis according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We included five randomised controlled trials and also identified seven single-arm studies. When used as first-line therapy, immunotherapy probably has little to no effect on the risk of death from any cause compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87-1.07; moderate-certainty evidence). immunotherapy probably has little to no effect on health-related quality of life (mean difference [MD] 4.10, 95% CI 3.83-4.37; moderate). Immunotherapy probably reduces grade 3-5 adverse events (risk ratio [RR] 0.47, 95% CI 0.29-0.75; moderate). In the second-line setting immunotherapy may reduce the risk of death from any cause (HR 0.72, 95% CI 0.63-0.81; low). Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; low). Immunotherapy may reduce grade 3-5 adverse events (RR 0.89, 95% CI 0.81-0.97; low). CONCLUSIONS: Compared to chemotherapy, immunotherapy has little to no effect on the risk of death from any cause in a first-line setting. Nevertheless, it may reduce the risk of death from any cause when used as second-line therapy. The health-related quality of life of participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce grade 3-5 adverse events when used as first- and second-line therapy, respectively.

Immunotherapy for advanced or metastatic urothelial carcinoma.

BACKGROUND: Immune checkpoint inhibitors are increasingly important in the treatment algorithm for locally advanced and metastatic bladder cancer. Numerous ongoing studies are investigating these agents as first- and second-line therapies, both alone and in combination with chemotherapy or in a maintenance therapy setting. OBJECTIVES: To assess the effects of immune checkpoint inhibitors compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma. SEARCH METHODS: We performed a comprehensive search including the Cochrane Library, MEDLINE, Embase, three other databases, several trial registers, other sources of gray literature, and conference proceedings, with no restrictions on language of publication. We limited the search period to run from 2000 until August 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) using immunotherapy versus chemotherapy and would have considered non-randomized trials in the absence of randomized trial data. Participants had locally advanced inoperable (cT4b or N+, or both) or metastatic (M1) (or both) urothelial carcinoma of the bladder or upper urinary tract. We excluded studies of people in whom immunotherapy was used in combination with chemotherapy or in a surveillance setting. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies for inclusion and abstracted data from included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence on a per-outcome basis. MAIN RESULTS: We included five RCTs and identified seven single-armed studies. The RCTs included 3572 participants comparing immunotherapy versus chemotherapy for the treatment of locally advanced and metastatic bladder cancer. First-line therapy Immunotherapy probably has little to no effect on the risk of death from any cause when used as first-line therapy compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87 to 1.07; I2 = 0%; 3 studies, 2068 participants; moderate-certainty evidence). This corresponds to 750 deaths per 1000 participants with chemotherapy and 11 fewer (45 fewer to 26 more) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy probably has little to no effect on health-related quality of life (mean difference (MD) 4.10, 95% CI 3.83 to 4.37; 1 study, 393 participants; moderate-certainty evidence), when assuming a minimal clinically important difference (MCID) of at least 6 points (using the Functional Assessment of Cancer Therapy - Bladder [FACT-BL] tool; scale 0 to 156 with higher scores representing better quality of life). Immunotherapy probably reduces adverse events grade 3 to 5 (RR 0.47, 95% CI 0.29 to 0.75; I2 = 97%; 3 studies, 2046 participants; moderate-certainty evidence). This corresponds to 908 grade 3 to 5 adverse events per 1000 participants with chemotherapy, with 481 fewer (644 fewer to 227 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy. We found no evidence for the outcome time to death from bladder cancer. Immunotherapy probably increases the risk of time to disease progression (HR 1.33, 95% CI 1.17 to 1.50; I2 = 0%; 2 studies, 1349 participants; moderate-certainty evidence). This corresponds to 660 events per 1000 participants with chemotherapy and 102 more (57 more to 152 more) events per 1000 participants with immunotherapy at 36 months. Immunotherapy may reduce discontinuations due to adverse effects (RR 0.47, 95% CI 0.20 to 1.10; I2 = 94%; 3 studies, 2046 participants; low-certainty evidence). This corresponds to 338 discontinuations per 1000 participants with chemotherapy and 179 fewer (271 fewer to 34 more) discontinuations per 1000 participants with immunotherapy. Second-line therapy Immunotherapy may reduce the risk of death from any cause when used as second-line therapy (HR 0.72, 95% CI 0.63 to 0.81; I2 = 0%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 920 deaths per 1000 participants with chemotherapy (vinflunine, paclitaxel, docetaxel) and 59 fewer (95 fewer to 28 fewer) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; I2 = 85%; 2 studies, 727 participants; low-certainty evidence), assuming an MCID of at least 10 points (using the EORTC QLQ tool; scale 0 to 100 with higher scores representing better quality of life). Immunotherapy may reduce adverse events grade 3 to 5 in participants undergoing second-line therapy (RR 0.89, 95% CI 0.81 to 0.97; I2 = 9%; 2 studies, 1423 participants; low-certainty evidence). This corresponds to 630 grade 3 to 5 adverse events per 1000 participants with chemotherapy and 76 fewer (126 fewer to 25 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy. We found no evidence for the outcome of time to death from bladder cancer. We are very uncertain if immunotherapy reduces the risk of disease progression (HR 0.99, 95% CI 0.84 to 1.16; I2 = 0%; 2 studies, 1473 participants; very low-certainty evidence). Immunotherapy may reduce discontinuations due to adverse events in participants undergoing second-line therapy (RR 0.35, 95% CI 0.17 to 0.72; I2 = 69%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 110 discontinuations per 1000 participants with chemotherapy and 72 fewer (91 fewer to 31 fewer) discontinuations per 1000 participants with immunotherapy. AUTHORS' CONCLUSIONS: Compared to chemotherapy, immunotherapy for treating advanced or metastatic urothelial carcinoma probably has little to no effect on the risk of death from any cause when used as first-line therapy. Still, it may reduce the risk of death from any cause when used as second-line therapy. Health-related quality of life for participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce adverse events grade 3 to 5 when used as first- and second-line therapy, respectively.

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

BACKGROUND: Since the approval of tyrosine kinase inhibitors, angiogenesis inhibitors and immune checkpoint inhibitors, the treatment landscape for advanced renal cell carcinoma (RCC) has changed fundamentally. Today, combined therapies from different drug categories have a firm place in a complex first-line therapy. Due to the large number of drugs available, it is necessary to identify the most effective therapies, whilst considering their side effects and impact on quality of life (QoL). OBJECTIVES: To evaluate and compare the benefits and harms of first-line therapies for adults with advanced RCC, and to produce a clinically relevant ranking of therapies. Secondary objectives were to maintain the currency of the evidence by conducting continuous update searches, using a living systematic review approach, and to incorporate data from clinical study reports (CSRs). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings and relevant trial registries up until 9 February 2022. We searched several data platforms to identify CSRs. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating at least one targeted therapy or immunotherapy for first-line treatment of adults with advanced RCC. We excluded trials evaluating only interleukin-2 versus interferon-alpha as well as trials with an adjuvant treatment setting. We also excluded trials with adults who received prior systemic anticancer therapy if more than 10% of participants were previously treated, or if data for untreated participants were not separately extractable. DATA COLLECTION AND ANALYSIS: All necessary review steps (i.e. screening and study selection, data extraction, risk of bias and certainty assessments) were conducted independently by at least two review authors. Our outcomes were overall survival (OS), QoL, serious adverse events (SAEs), progression-free survival (PFS), adverse events (AEs), the number of participants who discontinued study treatment due to an AE, and the time to initiation of first subsequent therapy. Where possible, analyses were conducted for the different risk groups (favourable, intermediate, poor) according to the International Metastatic Renal-Cell Carcinoma Database Consortium Score (IMDC) or the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Our main comparator was sunitinib (SUN). A hazard ratio (HR) or risk ratio (RR) lower than 1.0 is in favour of the experimental arm. MAIN RESULTS: We included 36 RCTs and 15,177 participants (11,061 males and 4116 females). Risk of bias was predominantly judged as being 'high' or 'some concerns' across most trials and outcomes. This was mainly due to a lack of information about the randomisation process, the blinding of outcome assessors, and methods for outcome measurements and analyses. Additionally, study protocols and statistical analysis plans were rarely available. Here we present the results for our primary outcomes OS, QoL, and SAEs, and for all risk groups combined for contemporary treatments: pembrolizumab + axitinib (PEM+AXI), avelumab + axitinib (AVE+AXI), nivolumab + cabozantinib (NIV+CAB), lenvatinib + pembrolizumab (LEN+PEM), nivolumab + ipilimumab (NIV+IPI), CAB, and pazopanib (PAZ). Results per risk group and results for our secondary outcomes are reported in the summary of findings tables and in the full text of this review. The evidence on other treatments and comparisons can also be found in the full text. Overall survival (OS) Across risk groups, PEM+AXI (HR 0.73, 95% confidence interval (CI) 0.50 to 1.07, moderate certainty) and NIV+IPI (HR 0.69, 95% CI 0.69 to 1.00, moderate certainty) probably improve OS, compared to SUN, respectively. LEN+PEM may improve OS (HR 0.66, 95% CI 0.42 to 1.03, low certainty), compared to SUN. There is probably little or no difference in OS between PAZ and SUN (HR 0.91, 95% CI 0.64 to 1.32, moderate certainty), and we are uncertain whether CAB improves OS when compared to SUN (HR 0.84, 95% CI 0.43 to 1.64, very low certainty). The median survival is 28 months when treated with SUN. Survival may improve to 43 months with LEN+PEM, and probably improves to: 41 months with NIV+IPI, 39 months with PEM+AXI, and 31 months with PAZ. We are uncertain whether survival improves to 34 months with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. Quality of life (QoL) One RCT measured QoL using FACIT-F (score range 0 to 52; higher scores mean better QoL) and reported that the mean post-score was 9.00 points higher (9.86 lower to 27.86 higher, very low certainty) with PAZ than with SUN. Comparison data were not available for PEM+AXI, AVE+AXI, NIV+CAB, LEN+PEM, NIV+IPI, and CAB. Serious adverse events (SAEs) Across risk groups, PEM+AXI probably increases slightly the risk for SAEs (RR 1.29, 95% CI 0.90 to 1.85, moderate certainty) compared to SUN. LEN+PEM (RR 1.52, 95% CI 1.06 to 2.19, moderate certainty) and NIV+IPI (RR 1.40, 95% CI 1.00 to 1.97, moderate certainty) probably increase the risk for SAEs, compared to SUN, respectively. There is probably little or no difference in the risk for SAEs between PAZ and SUN (RR 0.99, 95% CI 0.75 to 1.31, moderate certainty). We are uncertain whether CAB reduces or increases the risk for SAEs (RR 0.92, 95% CI 0.60 to 1.43, very low certainty) when compared to SUN. People have a mean risk of 40% for experiencing SAEs when treated with SUN. The risk increases probably to: 61% with LEN+PEM, 57% with NIV+IPI, and 52% with PEM+AXI. It probably remains at 40% with PAZ. We are uncertain whether the risk reduces to 37% with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. AUTHORS' CONCLUSIONS: Findings concerning the main treatments of interest comes from direct evidence of one trial only, thus results should be interpreted with caution. More trials are needed where these interventions and combinations are compared head-to-head, rather than just to SUN. Moreover, assessing the effect of immunotherapies and targeted therapies on different subgroups is essential and studies should focus on assessing and reporting relevant subgroup data. The evidence in this review mostly applies to advanced clear cell RCC.

Combination of radiation and immunotherapy in the treatment of genitourinary malignancies: A systematic review and meta-analysis.

BACKGROUND: Due to possible synergistic effects, the combination of radiation therapy (RT) and immune checkpoint inhibitors (ICI) represents an interesting therapeutic option. An increasing number of clinical trials are ongoing to investigate this combination in genitourinary malignancies and the first results are available. OBJECTIVES: To review and summarize available data on the combination of RT and ICI in genitourinary malignancies and update the evidence for this potential therapeutic approach. EVIDENCE ACQUISITION: A study protocol was registered in the PROSPERO-Database. Terms of search were prostate cancer, bladder cancer, renal cell carcinoma, penile cancer, testicular cancer, radiotherapy, and immunotherapy in multiple literature databases and study registers. Clinical studies reporting on the combination treatment of RT and ICI were included. A systematic review of ongoing trials according to the PRISMA statement and a meta-analysis of available trials were performed. EVIDENCE SYNTHESIS: Overall, 43 studies met the inclusion criteria examining the therapeutic effect of combined RT and ICI. For bladder cancer, renal cell carcinoma, prostate cancer, and penile cancer 28, 9, 5, and 1 trial could be identified, respectively. No study was found for testicular cancer. Three phases III trials were identified, all other trials were phase I or II. Twelve studies have been completed so far. The meta-analysis of available data indicates comparable toxicity of RT plus ICI vs. ICI alone for grade 3/4 AEs. Mature efficacy data is limited with interesting early results. CONCLUSION: This article reviews the clinical trial landscape investigating RT and ICI in genitourinary malignancies. It provides an overview of ongoing trials and discusses available results. Actual data regarding efficacy is limited, while toxicities seem comparable to ICI alone. Especially in bladder and kidney cancer, further trial results might impact on the clinical use of the combination therapy.

[Organoids as a milestone on the way to personalized treatment of urothelial carcinoma: a systematic review]. / Organoide als Meilenstein auf dem Weg zur personalisierten Therapie des Urothelkarzinoms: ein systematischer Review.

BACKGROUND: The treatment options for locally advanced and metastatic urothelial carcinoma (UC) are currently limited to established chemotherapy and immunotherapy protocols. Targeted treatment is so far restricted to a small subgroup of patients. Urothelial organoid systems could make a decisive contribution in establishing effective personalized treatment options by enabling drug response prediction through testing the sensitivity of individual patients. The aim of this article is to describe the state of the science of clinically applicable organoid systems for UC. METHODOLOGY: A systematic literature search was conducted in several medical databases (Medline, Cochrane Library) and study registers (ClinicalTrials.gov, the EU Clinical Trials Register and the WHO International Clinical Trials Registry). The search terms and the search strategy were adapted to the databases used. RESULTS: Overall, 7 studies met the inclusion criteria on the topic of UC organoids. These studies describe the fundamental workflow in establishing organoid systems in patients with tumors of the urinary bladder or the renal pelvis. The success rates in generating organoids from non-muscle-invasive bladder cancer were 70-77% and for muscle-invasive bladder cancer 42%. For patient organoids systematic drug testing was carried out. CONCLUSION: The generation of UC organoids is feasible and the ex vivo testing of individual treatment forms is possible. Due to the lack of a standardized methodology, their implementation remains experimental at the moment. The methodology has a high potential to provide a personalized treatment concept to patients with urothelial cancer.

Narrow band imaging versus white light cystoscopy alone for transurethral resection of non-muscle invasive bladder cancer.

BACKGROUND: Disease recurrence and progression remain major challenges for the treatment of non-muscle invasive bladder cancer. Narrow band imaging (NBI) is an optical enhancement technique that may improve resection of non-muscle invasive bladder cancer and thereby lead to better outcomes for people undergoing the procedure.  OBJECTIVES: To assess the effects of NBI- and white light cystoscopy (WLC)-guided transurethral resection of bladder tumor (TURBT) compared to WLC-guided TURBT in the treatment of non-muscle invasive bladder cancer. SEARCH METHODS: We performed a comprehensive literature search of 10 databases, including the Cochrane Library, the Cochrane Database of Systematic Reviews, MEDLINE, Embase, several clinical trial registries, and grey literature for published and unpublished studies, irrespective of language. The search was performed per an a priori protocol on 3 December 2021. SELECTION CRITERIA: We included randomized controlled trials of participants with suspected or confirmed non-muscle invasive bladder cancer. Participants in the control group must have received WLC-guided TURBT alone (hereinafter simply referred to as 'WLC TURBT'). Participants in the intervention group had to have received NBI- and WLC-guided TURBT (hereinafter simply referred to as 'NBI + WLC TURBT'). DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion/exclusion, performed data extraction, and assessed risk of bias. We conducted meta-analysis on time-to-event and dichotomous data using a random-effects model in RevMan, according to Cochrane methods. We rated the certainty of evidence for each outcome according to the GRADE approach. Primary outcomes were time to recurrence, time to progression, and the occurrence of a major adverse event, defined as a Clavien-Dindo III, IV, or V complication. Secondary outcomes included time to death from bladder cancer and the occurrence of a minor adverse event, defined as a Clavien-Dindo I or II complication.  MAIN RESULTS: We included eight studies with a total of 2152 participants randomized to the standard WLC TURBT or to NBI + WLC TURBT. A total of 1847 participants were included for analysis.  Based on limited confidence in the time-to-event data, we found that participants who underwent NBI + WLC TURBT had a lower risk of disease recurrence over time compared to participants who underwent WLC TURBT (hazard ratio 0.63, 95% CI 0.45 to 0.89; I2 = 53%; 6 studies, 1244 participants; low certainty of evidence). No studies examined disease progression as a time-to-event outcome or a dichotomous outcome. There was likely no difference in the risk of a major adverse event between participants who underwent NBI + WLC TURBT and those who underwent WLC TURBT (risk ratio 1.77, 95% CI 0.79 to 3.96; 4 studies, 1385 participants; low certainty of evidence). No studies examined death from bladder cancer as a time-to-event outcome or a dichotomous outcome. There was likely no difference in the risk of a minor adverse event between participants who underwent NBI + WLC TURBT and those who underwent WLC TURBT (risk ratio 0.88, 95% CI 0.49 to 1.56; I2 = 61%; 4 studies, 1385 participants; low certainty of evidence).  AUTHORS' CONCLUSIONS: Compared to WLC TURBT alone, NBI + WLC TURBT may lower the risk of disease recurrence over time while having little or no effect on the risks of major or minor adverse events.

Blue vs white light for transurethral resection of non-muscle-invasive bladder cancer: an abridged Cochrane Review.

OBJECTIVES: To assess the effects of blue-light (BL)-enhanced transurethral resection of bladder tumour (TURBT) compared to white-light (WL)-based TURBT in the treatment of non-muscle-invasive bladder cancer (NMIBC). METHODS: Based on a published protocol, we performed a systematic search of multiple databases from their inception to March 2021. We included randomized controlled trials (RCTs) comparing blue-light (BL) TURBT to white-light (WL) TURBT. Our meta-analysis was based on a random-effects model. We assessed the quality of evidence on a per-outcome basis according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. RESULTS: We included 16 RCTs involving a total of 4325 participants in this review. BL TURBT may reduce the risk of disease recurrence over time (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54-0.81; low-certainty evidence) depending on baseline risk. For participants with low-, intermediate- and high-risk NMIBC, this corresponded to 48 (66 fewer to 27 fewer), 109 (152 fewer to 59 fewer) and 147 (211 fewer to 76 fewer) fewer recurrences per 1000 participants when compared to WL TURBT, respectively. BL TURBT may also reduce the risk of disease progression over time (HR 0.65, 95% CI 0.50-0.84; low-certainty evidence) depending on baseline risk. For participants with low-, intermediate- and high-risk NMIBC, this corresponded to 1 (1 fewer to 0 fewer), 17 (25 fewer to 8 fewer), and 56 (81 fewer to 25 fewer) fewer progressions per 1000 participants when compared to WL TURBT, respectively. CONCLUSIONS: Our findings suggest a favourable impact of BL TURBT on the risk of disease recurrence and progression; however, whether this risk reduction is clinically relevant greatly depends on the baseline risk of patients. We did not find an increase in severe surgical complications with BL cystoscopy, and we did not find any trial evidence on other, non-surgical adverse events.

Evaluation of Pre-operative Biopsy, Surgical Procedures and Oncologic Outcomes in Upper Tract Urothelial Carcinoma (UTUC).

Purpose: Discordance between pre-operative biopsy and final pathology for Upper Tract Urothelial Carcinoma (UTUC) is high and optimal management remains controversial. The aim of this study is to evaluate the accuracy of pre-operative biopsy, to identify prognostic factors and to evaluate the effect of adjuvant chemotherapy on survival and oncologic outcome in UTUC. Methods: We analyzed records of patients receiving surgical treatment for UTUC. Pathology of pre-operative biopsy was compared to surgical specimen. We used Kaplan-Meier method to estimate survival probabilities and Cox's proportional hazards models to estimate the association between covariates and event times. Primary endpoint was overall survival (OS). A matched-pair analysis was performed to evaluate the effect of adjuvant chemotherapy. Results: 151 patients underwent surgical treatment (28% open, 36% laparoscopic, 17% robotic radical nephroureterectomy; 14% segmental ureteral resections and 5% palliative nephrectomy) for UTUC and were included in the analysis. Upstaging from

Blue versus white light for transurethral resection of non-muscle invasive bladder cancer.

BACKGROUND: Disease recurrence and progression remain major challenges in the treatment of non-muscle invasive bladder cancer (NMIBC). Blue light-enhanced transurethral resection of bladder cancer (TURBT) is an approach to improve staging and achieve a complete resection of NMIBC. OBJECTIVES: To assess the effects of blue light-enhanced TURBT compared to white light-based TURBT in the treatment of NMIBC. SEARCH METHODS: We searched several medical literature databases, including the Cochrane Library, MEDLINE, and Embase, as well as trial registers, including ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We performed a comprehensive search with no restrictions on language of publication or publication status until March 2021. SELECTION CRITERIA: We included randomized controlled trials using blue light versus white light TURBT. Included participants had a high level of suspicion based on imaging or 'visible diagnosis' for primary urothelial carcinoma of the bladder or recurrent urothelial carcinoma of the bladder upon cytoscopy. We excluded studies in which blue light was used in a surveillance setting.  DATA COLLECTION AND ANALYSIS: Two review authors independently performed data extraction and risk of bias assessment. Our primary outcomes were time to disease recurrence, time to disease progression, and serious surgical complications. Secondary outcomes were time to death from bladder cancer, any adverse events, and non-serious complications. We rated the certainty of evidence using the GRADE approach. MAIN RESULTS: We included 16 randomized controlled trials involving a total of 4325 participants in the review. The studies compared blue light versus white light TURBT for treatment of NMIBC.  Primary outcomes Blue light TURBT may reduce the risk of disease recurrence over time (hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.54 to 0.81; low-certainty evidence) depending on baseline risk. For participants with low-, intermediate-, and high-risk NMIBC, this corresponded to 48 (66 fewer to 27 fewer), 109 (152 fewer to 59 fewer), and 147 (211 fewer to 76 fewer) fewer recurrences per 1000 participants when compared to white light TURBT, respectively.  Blue light TURBT may also reduce the risk of disease progression over time (HR 0.65, 95% CI 0.50 to 0.84; low-certainty evidence) depending on baseline risk. For participants with low-, intermediate-, and high-risk NMIBC, this corresponded to 1 (1 fewer to 0 fewer), 17 (25 fewer to 8 fewer), and 56 (81 fewer to 25 fewer) fewer progressions per 1000 participants when compared to white light TURBT, respectively. Blue light TURBT may have little or no effect on serious surgical complications (risk ratio (RR) 0.54, 95% CI 0.14 to 2.14; low-certainty evidence). This corresponded to 10 fewer (19 fewer to 25 more) surgical complications per 1000 participants with blue light TURBT.  Secondary outcomes Blue light TURBT may have little or no effect on the risk of death from bladder cancer over time (HR 0.55, 95% CI 0.19 to 1.61; low-certainty evidence). This corresponded to 22 deaths per 1000 participants with white light TURBT and 10 fewer (17 fewer to 13 more) deaths per 1000 participants with blue light TURBT.   We are very uncertain how blue light TURBT affects the outcome adverse events of any grade (RR 1.09, 95% CI 0.88 to 1.33; low-certainty evidence).  No analysis was possible for the outcome non-serious surgical complications, as it was not reported by any of the included studies. AUTHORS' CONCLUSIONS: Blue light-enhanced TURBT for the treatment of non-muscle invasive bladder cancer compared to white light-based TURBT may reduce the risk of disease recurrence and disease progression over time depending on baseline risk. There may be little or no effect on serious surgical complications. The certainty of evidence for our findings was low, meaning that future studies are likely change to the reported estimates of effect. Frequent issues that led to downgrading of the certainty of the evidence were study limitations, inconsistency, and imprecision.

Intravesical gemcitabine for non-muscle invasive bladder cancer: An abridged Cochrane Review.

PURPOSE: To assess the comparative effectiveness and toxicity of intravesical gemcitabine instillation for non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: We performed a comprehensive literature search on 11 September 2020. We included RCTs in which participants received intravesical gemcitabine for primary or recurrent NMIBC. Two review authors independently assessed the included studies and extracted data for the primary outcomes (time to recurrence, time to progression, grade III to V adverse events) and the secondary outcomes (time to death from bladder cancer, time to death from any cause, grade I or II adverse events, and disease-specific quality of life). We performed statistical analyses using a random-effects model and rated the certainty of the evidence using GRADE. RESULTS: We found seven studies with 1,222 participants. Gemcitabine may reduce the risk of recurrence over time, but may have a similar effect on progression and grade III to V adverse events compared to saline. Gemcitabine may reduce recurrence and progression compared to mitomycin. We are uncertain about the effect of gemcitabine on the grade III to V adverse events compared to mitomycin. Gemcitabine may reduce recurrence and progression compared to giving BCG again in recurrent high-risk NMIBC after BCG treatment. CONCLUSIONS: Based on the findings of this review, gemcitabine may have a favorable impact on recurrence and progression-free survival than saline and mitomycin but we are uncertain about how major adverse events compare. The same is true when comparing gemcitabine to BCG in individuals with high-risk diseases who have previously failed BCG.

Intravesical gemcitabine for non-muscle invasive bladder cancer.

BACKGROUND: It remains unclear whether people with non-muscle invasive bladder cancer (NMIBC) benefit from intravesical gemcitabine compared to other agents in the primary or recurrent setting following transurethral resection of a bladder tumor. This is an update of a Cochrane Review first published in 2012. Since that time, several randomized controlled trials (RCTs) have been reported, making this update relevant.  OBJECTIVES: To assess the comparative effectiveness and toxicity of intravesical gemcitabine instillation for NMIBC. SEARCH METHODS: We performed a comprehensive literature search of the Cochrane Library, MEDLINE, Embase, four other databases, trial registries, and conference proceedings to 11 September 2020, with no restrictions on the language or status of publication. SELECTION CRITERIA: We included RCTs in which participants received intravesical gemcitabine for primary or recurrent NMIBC. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the included studies and extracted data for the primary outcomes: time to recurrence, time to progression, grade III to V adverse events determined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0), and the secondary outcomes: time to death from bladder cancer, time to death from any cause, grade I or II adverse events determined by the CTCAE v5.0 and disease-specific quality of life. We performed statistical analyses using a random-effects model and rated the certainty of the evidence using GRADE. MAIN RESULTS: We included seven studies with 1222 participants with NMIBC across five comparisons. This abstract focuses on the primary outcomes of the three most clinically relevant comparisons. 1. Gemcitabine versus saline: based on two years' to four years' follow-up, gemcitabine may reduce the risk of recurrence over time compared to saline (39% versus 47% recurrence rate, hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.54 to 1.09; studies = 2, participants = 734; I2 = 49%; low-certainty evidence), but the CI included the possibility of no effect.  Gemcitabine may result in little to no difference in the risk of progression over time compared to saline (4.6% versus 4.8% progression rate, HR 0.96, 95% CI 0.19 to 4.71; studies = 2, participants = 654; I2 = 53%; low-certainty evidence).  Gemcitabine may result in little to no difference in the CTCAE grade III to V adverse events compared to saline (5.9% versus 4.7% adverse events rate, risk ratio [RR] 1.26, 95% CI 0.58 to 2.75; studies = 2, participants = 668; I2 = 24%; low-certainty evidence).  2. Gemcitabine versus mitomycin: based on three years' follow-up (studies = 1, participants = 109), gemcitabine may reduce the risk of recurrence over time compared to mitomycin (17% versus 40% recurrence rate, HR 0.36, 95% CI 0.19 to 0.69; low-certainty evidence). Gemcitabine may reduce the risk of progression over time compared to mitomycin (11% versus  18% progression rate, HR 0.57, 95% CI 0.32 to 1.01; low-certainty evidence), but the CI included the possibility of no effect.  We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to mitomycin (RR 0.51, 95% CI 0.13 to 1.93; very low-certainty evidence). The analysis was only based on recurrent NMIBC. 3. Gemcitabine versus Bacillus Calmette-Guérin (BCG) for recurrent (one-course BCG failure) high-risk NMIBC: based on 6 months' to 22 months' follow-up (studies = 1, participants = 80), gemcitabine may reduce the risk of recurrence compared to BCG (41% versus 97% recurrence rate, HR 0.15, 95% CI 0.09 to 0.26; low-certainty evidence) and progression over time (16% versus 33% progression rate, HR 0.45, 95% CI 0.27 to 0.76; low-certainty evidence). We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to BCG (RR 1.00, 95% CI 0.21 to 4.66; very low-certainty evidence).  In addition, the review provides information on  the comparison of gemcitabine versus BCG and gemcitabine versus one-third dose BCG.  AUTHORS' CONCLUSIONS: Based on findings of this review, gemcitabine may have a more favorable impact on recurrence and progression-free survival than mitomycin but we are very uncertain as to how major adverse events compare. The same is true when comparing gemcitabine to BCG in individuals with high risk disease who have previously failed BCG. The underlying low- to very low-certainty evidence indicates that our confidence in these results is limited; the true effects may be substantially different from these findings; therefore, better quality studies are needed.

Clinical Practice Guidelines for Bladder Cancer: A Systematic Review and Meta-Analysis Using the AGREE II Instrument.

CONTEXT: Numerous health care organizations have established guidelines on diagnosis and treatment of bladder cancer. However, the lack of a standardized guideline development approach results in considerable differences of the guidelines' methodological quality. OBJECTIVE: To assess the methodological quality of all relevant clinical practice guidelines (CPGs) for urinary bladder cancer and provide a reference for clinicians in choosing guidelines of high methodological quality. EVIDENCE ACQUISITION: A systematic literature search was conducted in Medline via PubMed, 4 CPG databases, and 7 databases of interdisciplinary organizations. CPGs for non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) with the topics screening, pathology, diagnosis, treatment, and aftercare published in English language between 2012 and 2018 were included. The CPG quality was analyzed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. EVIDENCE SYNTHESIS: A total of 16 CPGs were included for the quality appraisal. Because of predefined criteria, 5 CPGs were "strongly recommended" (American Urological Association NMIBC, European Association of Urology [EAU] NMIBC, EAU MIBC, National Institute for Health and Care Excellence, and National Comprehensive Cancer Network), 4 CPGs were "weakly recommended" and 7 CPGs were "not recommended." CONCLUSIONS: The methodological quality of bladder cancer guidelines is diverse. Considering the rapid development of new therapies (e.g., immune checkpoint inhibitors), "living guidelines" of high methodological quality, such as the EAU NMIBC or MIBC guideline, will become more relevant in the future guideline's landscape.

Radiation therapy before radical cystectomy combined with immunotherapy in locally advanced bladder cancer - study protocol of a prospective, single arm, multicenter phase II trial (RACE IT).

BACKGROUND: Patients with locally advanced bladder cancer (cT3/4 cN0/N+ cM0) have a poor prognosis despite radical surgical therapy and perioperative chemotherapy. Preliminary data suggest that the combination of radiation and immunotherapy does not lead to excess toxicity and may have synergistic (abscopal) anti-tumor effects. We hypothesize that the combined preoperative application of the PD-1 checkpoint-inhibitor Nivolumab with concomitant radiation therapy of the bladder and pelvic region followed by radical cystectomy with standardized lymphadenectomy is safe and feasible and might improve outcome for patients with locally advanced bladder cancer. METHODS: Study design: "RACE IT" (AUO AB 65/18) is an investigator initiated, prospective, multicenter, open, single arm phase II trial sponsored by Technical University Munich. Study drug and funding are provided by the company Bristol-Myers Squibb. Study treatment: Patients will receive Nivolumab 240 mg i.v. every 2 weeks for 4 cycles preoperatively with concomitant radiation therapy of bladder and pelvic region (max. 50.4 Gy). Radical cystectomy with standardized bilateral pelvic lymphadenectomy will be performed between week 11-15. Primary endpoint: Rate of patients with completed treatment consisting of radio-immunotherapy and radical cystectomy at the end of week 15. Secondary endpoints: Acute and late toxicity, therapy response and survival (1 year follow up). Main inclusion criteria: Patients with histologically confirmed, locally advanced bladder cancer (cT3/4, cN0/N+), who are ineligible for neoadjuvant, cisplatin-based chemotherapy or who refuse neoadjuvant chemotherapy. Main exclusion criteria: Patients with metastatic disease (lymph node metastasis outside pelvis or distant metastasis) or previous chemo-, immune- or radiation therapy. Planned sample size: 33 patients, interim analysis after 11 patients. DISCUSSION: This trial aims to evaluate the safety and feasibility of the combined approach of preoperative PD-1 checkpoint-inhibitor therapy with concomitant radiation of bladder and pelvic region followed by radical cystectomy. The secondary objectives of therapy response and survival are thought to provide preliminary data for further clinical evaluation after successful completion of this trial. Recruitment has started in February 2019. TRIAL REGISTRATION: Protocol Code RACE IT: AB 65/18; EudraCT: 2018-001823-38; Clinicaltrials.gov: NCT03529890; Date of registration: 27 June 2018.

[50 years of systemic therapy of urinary bladder cancer]. / 50 Jahre Systemtherapie des Harnblasenkarzinoms.

This review summarises the treatment strategies of the last five decades for metastatic urothelial cancer. The introduction of combination chemotherapy in the mid-1980s led to clinically significant response rates and prolonged survival. Two years ago, the results of a phase-3 clinical trial with the PD1 inhibitor pembrolizumab for second-line treatment of metastatic urothelial carcinoma were published. These data were the first to show an overall survival benefit in comparison with a conventional chemotherapy with vinflunine, docetaxel or paclitaxel. Currently, PD1/PD-L1 inhibitors are also tested within randomized phase-3-trials for first-line treatment using different approaches either as a monotherapy or a combination with conventional chemotherapy or CTLA-4 inhibitors. Whereas data from single-arm phase-2 clinical trials have already been published, first phase-3 data are expected in 2019.

Fully Printed Infrared Photodetectors from PbS Nanocrystals with Perovskite Ligands.

Colloidal nanocrystals from PbS are successfully applied in highly sensitive infrared photodetectors with various device architectures. Here, we demonstrate all-printed devices with high detectivity (∼1012 cm Hz1/2/W) and a cut-off frequency of >3 kHz. The low material consumption (<0.3 mg per detector) and short processing time (14 s per detector) enabled by the automated printing promises extremely low device costs. To enable all-printed devices, an ink formulation was developed based on nanocrystals stabilized by perovskite-like methylammonium iodobismuthate ligands, which are dispersed in a ternary solvent. Fully inkjet printed devices based on this solvent were achieved with printed silver electrodes and a ZnO interlayer. Considerable improvements were obtained by the addition of small amounts of the polymer poly(vinylpyrrolidone) to the ink. The polymer improved the colloidal stability of the ink and its film-formation properties and thus enabled the scalable printing of single detectors and detector arrays. While photoconductors were shown here, the developed ink will certainly find application in a series of further electronic devices based on nanocrystals from a broad range of materials.

Classification of additives for organic photovoltaic devices.

The use of additives to improve the performance of organic photovoltaic cells has been intensely researched in recent years. However, so far, no system has been reported for the classification of additives and their functions. In this report, a system for classifying additives according to the fundamental mechanism by which they influence microstructure formation for P3HT:PCBM is suggested. The major parameters used for their classification are solubility and drying kinetics. Both are discussed in detail and their consequences on processing are analyzed. Furthermore, a general mechanism to classify the impact of additives on structure formation is suggested and discussed for different materials relevant to organic photovoltaic devices.

Transparent cellulose sheets as synthesis matrices for inorganic functional particles.

Transparent cellulose sheets were prepared through tape-casting a solution of cellulose. Flexible, luminescent sheets were produced by adding europium trichloride to the casting solution and treating the sheets with an aqueous solution of ammonium fluoride. Scanning electron micrographs of the resulting sheets showed europium trifluoride particles with diameters from 200nm to 500nm. These were found by transmission electron microscopy to be agglomerates of crystallites in the size range of 10-20nm. The structure of supercritically dried sheets was further assessed by small-angle X-ray scattering and suggests a preferred orientation of slightly elongated pores of roughly 12nm in diameter. Evaluation of the emission characteristics of the sheets showed the band pattern between 580nm and 700nm typical for Eu3+ phosphors. Our developed process is a versatile tool for the fabrication of transparent cellulose structures with different shapes and various embedded functional particles.