This overview presents the updated European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC).
To provide practical evidence-based recommendations and ...consensus statements on the clinical management of MMIBC with a focus on diagnosis and treatment.
A broad and comprehensive scoping exercise covering all areas of the MMIBC guideline has been performed annually since its 2017 publication (based on the 2016 guideline). Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries, resulting in yearly guideline updates. A level of evidence and a grade of recommendation were assigned. Additionally, the results of a collaborative multistakeholder consensus project on advanced bladder cancer (BC) have been incorporated in the 2020 guidelines, addressing those areas where it is unlikely that prospective comparative studies will be conducted.
Variant histologies are increasingly reported in invasive BC and are relevant for treatment and prognosis. Staging is preferably done with (enhanced) computerised tomography scanning. Treatment decisions are still largely based on clinical factors. Radical cystectomy (RC) with lymph node dissection remains the recommended treatment in highest-risk non–muscle-invasive and muscle-invasive nonmetastatic BC, preceded by cisplatin-based neoadjuvant chemotherapy (NAC) for invasive tumours in “fit” patients. Selected men and women benefit from sexuality sparing RC, although this is not recommended as standard therapy. Open and robotic RC show comparable outcomes, provided the procedure is performed in experienced centres. For open RC 10, the minimum selected case load is 10 procedures per year. If bladder preservation is considered, chemoradiation is an alternative in well-selected patients without carcinoma in situ and after maximal resection. Adjuvant chemotherapy should be considered if no NAC was given. Perioperative immunotherapy can be offered in clinical trial setting. For fit metastatic patients, cisplatin-based chemotherapy remains the first choice. In cisplatin-ineligible patients, immunotherapy in Programmed Death Ligand 1 (PD-L1)-positive patients or carboplatin in PD-L1–negative patients is recommended. For second-line treatment in metastatic disease, pembrolizumab is recommended. Postchemotherapy surgery may prolong survival in responders. Quality of life should be monitored in all phases of treatment and follow-up. The extended version of the guidelines is available at the EAU website: https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/.
This summary of the 2020 EAU MMIBC guideline provides updated information on the diagnosis and treatment of MMIBC for incorporation into clinical practice.
The European Association of Urology Muscle-invasive and Metastatic Bladder Cancer (MMIBC) Panel has released an updated version of their guideline, which contains information on histology, staging, prognostic factors, and treatment of MMIBC. The recommendations are based on the current literature (until the end of 2019), with emphasis on high-level data from randomised clinical trials and meta-analyses and on the findings of an international consensus meeting. Surgical removal of the bladder and bladder preservation are discussed, as well as the use of chemotherapy and immunotherapy in localised and metastatic disease.
Radical cystectomy with urinary diversion remains the mainstay of managing muscle-invasive bladder cancer (MIBC). The use of neoadjuvant chemotherapy (NAC) has improved overall survival rates, but selection of patients who will benefit most from NAC remains challenging. In case bladder-preserving strategies are considered, patient stratification according to their risk profile is imperative and management should be discussed in a multidisciplinary team. As yet, there are no validated prognostic molecular markers to guide the clinical management of MIBC. In a metastatic setting, cisplatin-based chemotherapy remains the first choice in fit patients. In unfit patients, based on interim results from two on-going clinical trials, first-line treatment with pembrolizumab or atezolizumab for urothelial cancer is restricted to Programmed Death Ligand 1-positive patients only.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Patients with treatment-naïve metastatic urothelial carcinoma are grouped according to platinum eligibility based on clear definitions. In general, first-line treatment consists of platinum-based ...chemotherapy in which cisplatin is to be preferred to carboplatin. Patients who are cisplatin ineligible but carboplatin eligible should receive carboplatin-gemcitabine combination chemotherapy. In case of positive programmed death ligand 1 (PD-L1) status, treatment with checkpoint inhibitors (atezolizumab or pembrolizumab) could be an alternative option.
Patients unfit for both cisplatin and carboplatin (platinum unfit) can be considered for immunotherapy (U.S. Food and Drug Administration approved irrespective of PD-L1 status and European Medicines Agency approved only for PD-L1 positive) or can receive best supportive care.
Treatment of metastatic urothelial carcinoma is currently undergoing a rapid evolution.
This overview presents the updated European Association of Urology (EAU) guidelines for metastatic urothelial carcinoma.
A comprehensive scoping exercise covering the topic of metastatic urothelial carcinoma is performed annually by the Guidelines Panel. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries, resulting in yearly guideline updates.
Platinum-based chemotherapy is the recommended first-line standard therapy for all patients fit to receive either cisplatin or carboplatin. Patients positive for programmed death ligand 1 (PD-L1) and ineligible for cisplatin may receive immunotherapy (atezolizumab or pembrolizumab). In case of nonprogressive disease on platinum-based chemotherapy, subsequent maintenance immunotherapy (avelumab) is recommended. For patients without maintenance therapy, the recommended second-line regimen is immunotherapy (pembrolizumab). Later-line treatment has undergone recent advances: the antibody-drug conjugate enfortumab vedotin demonstrated improved overall survival and the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib appears active in case of FGFR3 alterations.
This 2021 update of the EAU guideline provides detailed and contemporary information on the treatment of metastatic urothelial carcinoma for incorporation into clinical practice.
In recent years, several new treatment options have been introduced for patients with metastatic urothelial cancer (including bladder cancer and cancer of the upper urinary tract and urethra). These include immunotherapy and targeted treatments. This updated guideline informs clinicians and patients about optimal tailoring of treatment of affected patients.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The upregulation of PPARγ/RXRα transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPARγ-dependent and modulates the tumor microenvironment to ...favor escape from immuno-surveillance. The activation of the pathway has been linked to PPARG gains/amplifications resulting in PPARγ overexpression and to recurrent activating point mutations of RXRα. Here, we report recurrent mutations of PPARγ that also activate the PPARγ/RXRα pathway, conferring PPARγ-dependency and supporting a crucial role of PPARγ in luminal bladder cancer. These mutations are found throughout the protein-including N-terminal, DNA-binding and ligand-binding domains-and most of them enhance protein activity. Structure-function studies of PPARγ variants with mutations in the ligand-binding domain allow identifying structural elements that underpin their gain-of-function. Our study reveals genomic alterations of PPARG that lead to pro-tumorigenic PPARγ/RXRα pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment.
Summary Background The likelihood of tumour recurrence after nephrectomy in localised clear cell renal cell carcinoma is well characterised by clinical and pathological parameters. However, these ...assessments can be improved and personalised by the addition of molecular characteristics of each patient's tumour. We aimed to develop and validate a prognostic multigene signature to improve prediction of recurrence risk in clear cell renal cell carcinoma. Methods In the development stage, we investigated the association between expression of 732 genes, measured by reverse-transcription PCR, and clinical outcome in 942 patients with stage I–III clear cell renal cell carcinoma who had undergone a nephrectomy at the Cleveland Clinic (OH, USA). 516 genes were associated with recurrence-free interval. 11 of these genes were selected by further statistical analyses, and were combined with five reference genes (ie, 16 genes in total), from which a recurrence score algorithm was developed. The recurrence score was then validated in an independent cohort of 626 patients from France with stage I–III clear cell renal cell carcinoma who had also undergone nephrectomy. The association between the recurrence score and the risk of recurrence and cancer-specific survival in the first 5 years after surgery was assessed using Cox proportional hazard regression, stratified by tumour stage (stage I vs stage II vs III). Findings In our primary univariate analysis, the continuous recurrence score (median 37, IQR 31–45) was significantly associated with recurrence-free interval (hazard ratio 3·91 95% CI 2·63–5·79 for a 25-unit increase in score, p<0·0001). In multivariable analyses, the recurrence score was significantly associated with the risk of tumour recurrence (hazard ratio per 25-unit increase in the score 3·37 95% CI 2·23–5·08, p<0·0001) after stratification by stage and adjustment for tumour size, grade, or Leibovich score. The recurrence score was able to identify a clinically significant number of both high-risk stage I and low-risk stage II–III patients. A heterogeneity study on separate samples showed little to no intratumoural variability among the 16 genes. Interpretation Our findings validate the recurrence score as a predictor of clinical outcome in patients with stage I–III clear cell renal cell carcinoma, providing a more accurate and individualised risk assessment beyond existing clinical and pathological parameters. Funding Genomic Health Inc and Pfizer Inc.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Muscle-invasive bladder carcinoma (MIBC) constitutes a heterogeneous group of tumors with a poor outcome. Molecular stratification of MIBC may identify clinically relevant tumor subgroups and help to ...provide effective targeted therapies. From seven series of large-scale transcriptomic data (383 tumors), we identified an MIBC subgroup accounting for 23.5% of MIBC, associated with shorter survival and displaying a basal-like phenotype, as shown by the expression of epithelial basal cell markers. Basal-like tumors presented an activation of the epidermal growth factor receptor (EGFR) pathway linked to frequent EGFR gains and activation of an EGFR autocrine loop. We used a 40-gene expression classifier derived from human tumors to identify human bladder cancer cell lines and a chemically induced mouse model of bladder cancer corresponding to human basal-like bladder cancer. We showed, in both models, that tumor cells were sensitive to anti-EGFR therapy. Our findings provide preclinical proof of concept that anti-EGFR therapy can be used to target a subset of particularly aggressive MIBC tumors expressing basal cell markers and provide diagnostic tools for identifying these tumors.
Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer (BC). FGFR3 mutations are common in noninvasive BC and associated with favorable BC prognosis. Overexpression was ...reported in up to 40% of FGFR3 wild-type muscle-invasive BC. We analyzed FGFR3 mutations, FGFR3, and p53 protein expression and assessed their prognostic value in a cohort of 1000 chemotherapy-naive radical cystectomy specimens. FGFR3 mutations were found in 11%, FGFR3 overexpression was found in 28%, and p53 overexpression was found in 69% of tumors. Among FGFR3 mutant tumors, 73% had FGFR3 overexpression versus 22% among FGFR3 wild-type tumors. FGFR3 mutations were significantly associated with lower pT stage, tumor grade, absence of carcinoma in situ, pN0, low-level p53, and longer disease-specific survival (DSS). FGFR3 overexpression was associated only with lower pT stage and tumor grade. Moreover, FGFR3 overexpression was not associated with DSS in patients with FGFR3 wild-type tumors. In conclusion, FGFR3 mutations identified patients with favorable BC at cystectomy. Our results suggest that FGFR3 mutations have a driver role and are functionally distinct from FGFR3 overexpression. Hence, patients with FGFR3 mutations would be more likely to benefit from anti-FGFR3 therapy. Ideally, further research is needed to test this hypothesis.
Oncogenic fibroblast growth factor receptor 3 (FGFR3) mutations are very common in bladder cancer. In this report, we found that these FGFR3 mutations were associated with favorable features and prognosis of bladder cancer compared with patients with FGFR3 overexpressed tumors only. As a consequence, patients with FGFR3 mutant tumors would be more likely to benefit from anti-FGFR3 therapy than patients with FGFR3 protein overexpression only.
Oncogenic fibroblast growth factor receptor 3 (FGFR3) mutations were associated with favorable bladder cancer in a series of 1000 radical cystectomy cases. Moreover, patients with FGFR3 mutant tumors would be more likely to benefit from anti-FGFR3 therapy than patients with overexpression only.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A great number of DNA-damage repair (DDR) pathways have been recognized to be frequently dysregulated in advanced stages of prostate cancer. DNA-repair defects in prostate cancer represents a ...clinically relevant disease subset. Tumors whose ability to repair double-strand DNA breaks by homologous recombination is compromised, are highly sensitive to blockade of the repair of DNA single-strand breaks via the inhibition of the enzyme poly(ADP) ribose polymerase (PARP).
A systematic review of the literature has been conducted in January 2020 using PubMed Medline database in line with the recommendations from the PRISMA guidelines. The following string terms were used for searching clinical trial articles: castration resistant OR castrate resistance OR castration refractory AND prostate cancer AND PARP OR poly(ADP-ribose) polymerase inhibitor OR DNA-repair OR homologous recombination repair. On-going clinical trials with olaparib, niraparib, talazoparib, veliparib, and rucaparib in mCRPC were searched on the clinicalTrials.gov website.
From this research 176 articles were identified. After title screening and abstract reading, five papers and four abstract were considered for the systematic review. Thirty-two clinical trials were also identified: from these 16 trials which did not include mCRPC patients or only prostate cancer patients, trials not yet recruiting and trials including radio-metabolic treatments were excluded. Sixteen trials were included and discussed in the paper.
Olaparib has been the first agent showing a benefit in terms of rPFS and ORR alone or in combination with abiraterone plus prednisone in patients with DDR deficiency prostate cancer. Also rucaparib showed a benefit in terms of PSA response rate and ORR in patients with BRCA2 and BRCA1 mutation in a phase-II study. Other phase-III clinical trials are evaluating niraparib and talazoparib, alone or in combination with AR signaling inhibitors.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Introduction and hypothesis
Tapes for stress urinary incontinence (SUI) and meshes for pelvic organ prolapse can result in postoperative complications, such as urethral (UP) or bladder (BP) ...perforations. Martius fat pad (MFP) is an historic procedure, widely used to treat lower urinary tract (LUT) fistulae. We report our experience with the insertion of the biological small intestinal submucosa (SIS) xenograft as an alternative to MFP in these prosthetic complications.
Methods
We conducted a retrospective, monocentric study which included all patients who underwent SIS insertion during surgical removal of tape/vaginal mesh for UP or BP from 2011 to 2019. Preoperative assessment was based on history, symptoms, physical examination and urethrocystoscopy. Primary outcome was successful repair defined as absence of any LUT defect. Secondary outcomes were complications, LUT symptoms, pain and additional SUI surgical procedures.
Results
Thirty-eight patients were included. Twenty-six had a UP and eight a BP. In four cases, perforation involved both the bladder neck and urethra. All LUT defects were cured. Six postoperative complications were reported (five of grade ≤ 2 and one of grade 3b according to the Clavien-Dindo classification). At the mean follow-up of 37.2 (range 6–98) months, 14 patients (36.8%) presenting a postoperative SUI underwent a SUI surgical procedure and 1 patient had a laparoscopic sacrocolpopexy for cystocele recurrence.
Conclusion
Absorbable SIS xenograft is an effective and safe graft for the management of lower urinary tract tape and mesh perforations. The cost has to be balanced with the good results, short operative time and no fat pad complications as in MFP.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Precise determination of glomerular filtration rate (GFR) is essential for the management of patients with muscle-invasive bladder cancer (MIBC). We aim to describe the early evolution of measured ...GFR (mGFR) after radical cystectomy and urinary diversion (RCUD) and to identify risk factors for GFR decline. GFR measurement using
Cr-EDTA continuous infusion, estimated GFR (eGFR) from five published equations and renal scintigraphy with split renal function determination were performed before and 6 months after RCUD. Chronic Kidney Disease (mGFR < 60 mL/min/1.73 m
) and GFR stages were defined according to the KDIGO guidelines using mGFR. Twenty-seven patients (men 85%, median age 65, IQR 59; 68 years) were included. A total of 20 (74%) patients experienced significant mGFR decline at 6 months postoperatively. Median mGFR decreased from 84.1 pre-operatively (IQR 65.3; 97.2) to 69.9 mL/min/1.73 m
(IQR 55.0; 77.9) 6 months after surgery (p < 0.001). Thirteen (48%) patients had a progression to a worse GFR stage. Of the 22 patients without pre-operative CKD, 5 (23%) developed post-operative CKD. Diabetes mellitus was more frequent in patients in the highest tertile of relative mGFR decline (44% vs. 11%, p = 0.02) and platinum-based adjuvant chemotherapy tended to be more frequently used in these patients (44% vs. 17%, p = 0.06). Importantly, pre-operative weight was independently and negatively associated with post-operative mGFR and with mGFR slope in multivariable analyses. In this prospective series, we demonstrated that early and significant mGFR decline occurred after RCUD and perioperative platinum-based chemotherapy, especially in patients with diabetes mellitus and overweight.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Prostate cancer among black men is known to have specific molecular characteristics, especially the androgen receptor or enzymes related to the androgen metabolism. These targets are keys to the ...action of new hormonal therapies. Nevertheless, literature has a lack of data regarding black men. We aimed to gather the available literature data on new hormonal therapies among black populations.
We conducted a literature review from the PubMed / MEDLINE database until October 2020. All clinical studies of new hormonal therapies and black populations, regardless of methodology, were included.
Four studies provided data on new hormonal therapies in black populations. Three studies reported a PSA decline in black patients treated with Abiraterone, higher in black men than in white men. Overall survival also appears to be higher in black patients treated with Abiraterone only or first.
Few articles have evaluated the effectiveness and safety of use of these treatments among black populations. The first results seem to show that Abiraterone can provide a benefit in overall survival in black populations. Prospective studies are needed to answer these questions in the future.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
