BACKGROUND: Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes. METHODS: In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone (comparison group). Event-free survival was one of two primary end points. Overall survival was the key secondary end point. RESULTS: In total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI, 55.4 to 64.0) in the comparison group (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001 by stratified log-rank test). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI, 71.3 to 78.8) in the comparison group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P = 0.01 by stratified log-rank test). Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6% in each group. Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group. CONCLUSIONS: Perioperative durvalumab plus neoadjuvant chemotherapy led to significant improvements in event-free survival and overall survival as compared with neoadjuvant chemotherapy alone. (Funded by AstraZeneca; NIAGARA ClinicalTrials.gov number, NCT03732677; EudraCT number, 2018-001811-59.).
- MeSH
- adjuvantní chemoterapie škodlivé účinky metody MeSH
- analýza přežití MeSH
- cisplatina aplikace a dávkování škodlivé účinky MeSH
- cystektomie * MeSH
- deoxycytidin * aplikace a dávkování škodlivé účinky analogy a deriváty MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- gemcitabin MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- monoklonální protilátky * aplikace a dávkování škodlivé účinky MeSH
- nádory močového měchýře * mortalita patologie terapie MeSH
- neoadjuvantní terapie škodlivé účinky metody MeSH
- protinádorové látky imunologicky aktivní * aplikace a dávkování škodlivé účinky MeSH
- protokoly antitumorózní kombinované chemoterapie * aplikace a dávkování škodlivé účinky MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
PURPOSE: There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across disease settings in UC, the Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary, international consensus panel. METHODS: Through open communication and scientific debate in small- and whole-group settings, surveying, and responses to clinical questionnaires, the consensus panel developed recommendations on optimal definitions of the disease state, end points, trial design, evaluations, sample size calculations, and pathology considerations for definitive studies in low- and intermediate-risk nonmuscle-invasive bladder cancer (NMIBC), high-risk NMIBC, muscle-invasive bladder cancer in the neoadjuvant and adjuvant settings, and metastatic UC. The expert panel also solicited input on the recommendations through presentations and public discussion during an open session at the 2021 Bladder Cancer Advocacy Network (BCAN) Think Tank (held virtually). RESULTS: The consensus panel developed a set of stage-specific bladder cancer clinical trial design recommendations, which are summarized in the table that accompanies this text. CONCLUSION: These recommendations developed by the SITC-IBCG Bladder Cancer Clinical Trial Design consensus panel will encourage uniformity among studies and facilitate drug development in this disease.
WHAT IS THIS SUMMARY ABOUT?: This is a summary of a paper published in a medical journal that describes the results of a study called CheckMate 274. This study looked at a new treatment for muscle-invasive urothelial cancer, a type of cancer found in the urinary tract that has spread from the inner lining of the urinary tract or bladder and into the surrounding muscle wall where it can then spread to other parts of the body. The standard treatment for muscle-invasive urothelial cancer is surgery to remove affected parts of the urinary tract. However, cancer returns in more than half of people after this surgery. Adjuvant therapy is given to people after surgery with muscle-invasive urothelial cancer with a goal to reduce the risk of the cancer coming back; however, at the time this study started, there was no standard adjuvant treatment. WHAT HAPPENED IN THE STUDY?: In the CheckMate 274 study, researchers compared nivolumab with a placebo as an adjuvant treatment for people with muscle-invasive urothelial cancer. The aim of the study was to understand how well nivolumab worked to reduce the chance of the cancer returning after surgery. The study also looked at what side effects (unwanted or unexpected results or conditions that are possibly related to the use of a medication) people had with treatment. WHAT DO THE RESULTS MEAN?: The results showed that people who received nivolumab versus placebo: Survived longer before the cancer was detected again, including people who had programmed death ligand-1 (shortened to PD-L1) on their cancer cells. Survived longer before a secondary cancer outside of the urinary tract was detected. Experienced no differences in health-related quality of life (the impact of the treatment on a person's mental and physical health). Had similar side effects to the people who received nivolumab in other studies. Clinical Trial Registration: NCT02632409 (ClinicalTrials.gov).
- MeSH
- imunoterapie metody MeSH
- kvalita života MeSH
- lidé MeSH
- nádory močového měchýře * farmakoterapie MeSH
- nádory svalů * farmakoterapie MeSH
- nivolumab terapeutické užití MeSH
- svaly MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
INTRODUCTION: The only phase III trial that evaluated the role of adjuvant chemotherapy following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) was terminated early. Thus, eventual overall survival (OS) surrogacy, as per Prentice, cannot be assessed in this setting. We aimed to identify an intermediate clinical endpoint (ICE) that could serve as an OS surrogate after RNU for UTUC. PATIENTS AND METHODS: We retrospectively analyzed 823 high-grade UTUC patients treated with RNU at 8 tertiary referral centers. We explored the role of any recurrence (aR), defined as recurrence in the urinary tract or in the resection bed as well the presence of distant metastasis (DM), defined as metastatic disease outside the urinary tract and regional lymph nodes, on OS through a time-varying Cox regression analyses fitted at the landmark points of 1, 2, 3, and 4 years from RNU. Models' discrimination was assessed using Harrell's c index, after internal validation. RESULTS: Median follow-up for survivors was 5.6 years (interquartile range: 2.0-8.8). Overall, 391 and 212 patients experienced aR and DM, respectively. In a time-varying model, aR and DM were predictors of OS: hazard ratio [HR]:1.20, 95% confidence interval [CI]: 1.13-1.28 (P < .001) and HR:1.26, 95% CI: 1.18-1.34 (P < .001), respectively. Progression to DM within 3 years from RNU was the most informative ICE for predicting OS (c index: 0.81; HR: 4.40; 95%CI: 2.45-7.92; P < .001), compared to DM within 1, 2, and 4 years (c indexes: 0.74, 0.76, and 0.78, respectively). Progression to DM within 3 years from RNU was further found superior for predicting OS compared to aR at any landmark points. CONCLUSIONS: Progression to DM within 3 years represents a potential OS surrogate for surgically-treated UTUC. This information could help in patient counseling, future study design and expedite results release of ongoing randomized controlled trials.
BACKGROUND: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group. CONCLUSIONS: In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).
- MeSH
- adjuvantní chemoterapie MeSH
- analýza podle původního léčebného záměru MeSH
- antigeny CD274 metabolismus MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- invazivní růst nádoru MeSH
- karcinom z přechodných buněk farmakoterapie patologie chirurgie MeSH
- kvalita života MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory močového měchýře farmakoterapie patologie chirurgie MeSH
- nivolumab škodlivé účinky terapeutické užití MeSH
- placeba terapeutické užití MeSH
- přežití po terapii bez příznaků nemoci MeSH
- protinádorové látky imunologicky aktivní škodlivé účinky terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- staging nádorů MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Research Support, N.I.H., Extramural MeSH
- srovnávací studie MeSH
CONTEXT: Urothelial carcinoma can exhibit a wide range of variant morphologies. Many variants present diagnostic challenges and carry clinical implications that inform prognosis and treatment decisions. OBJECTIVE: To provide an overview of the diagnostic, therapeutic, and prognostic significance of histological variants of urothelial carcinoma. EVIDENCE ACQUISITION: A PubMed/MEDLINE-based literature search was conducted using the key terms "urothelial carcinoma", "variant histology", "nested", "micropapillary", "microcystic", "sarcomatoid", "squamous differentiation", "glandular differentiation", "clear cell", "plasmacytoid", "lymphoepithelioma-like carcinoma", "squamous cell carcinoma", "small cell carcinoma", "adenocarcinoma", "radiotherapy", "neoadjuvant chemotherapy", and "adjuvant chemotherapy". EVIDENCE SYNTHESIS: The incidence of variant histology is increasing due to improved recognition. Nonetheless, diagnosis can pose challenges due to sampling limitations and interobserver variability. Although associated with advanced disease at presentation, survival outcomes for most variants do not differ significantly compared with pure urothelial carcinoma of the same stage. Controversy exists regarding optimal management due to the low quality of available evidence. For most cases, radical cystectomy with pelvic lymph node dissection (with neoadjuvant chemotherapy when appropriate) represents the standard of care. Small cell carcinoma and lymphoepithelioma-like carcinoma appear to be particularly chemosensitive. CONCLUSIONS: Accurate identification of variant histological subtypes is an important part of risk stratification, as these variants exhibit aggressive biological behaviour. Variant histology tumours are associated with advanced disease at presentation, which must be considered when counselling patients regarding survival outcomes. Optimal management remains to be defined but in most cases; neoadjuvant chemotherapy and radical cystectomy with pelvic lymph node dissection remains the mainstay of treatment. PATIENT SUMMARY: It is important to recognise histological variants of urothelial carcinoma as they indicate aggressive disease. When compared with patients with pure urothelial carcinoma of the same disease stage, survival does not appear to be significantly worse. In most cases, patients with invasive variant histology should be treated with neoadjuvant chemotherapy and radical cystectomy. Take Home Messages Accurate identification of variant histology is important as it exhibits aggressive biological behaviour and affects treatment. Although associated with advanced disease at presentation, with appropriate treatment, survival outcomes are not significantly different compared with pure urothelial carcinoma of the same stage.
- MeSH
- karcinom z přechodných buněk klasifikace diagnóza patologie terapie MeSH
- lidé MeSH
- prognóza MeSH
- urologické nádory klasifikace diagnóza patologie terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Cieľ Na základe výsledkov niekoľkých publikácií existuje predpoklad o spojitosti medzi cisplatinou a zvýšeným rizikom tromboembolizmu. Avšak keďže zvýšené riziko venóznych tromboembolických príhod (VTE) spojených s chemoterapiou založenou na cisplatine nie je doposiaľ dostatočne preskúmané, uskutočnili sme systematický prehľad a metaanalýzu randomizovaných klinických štúdií zisťujúcich incidenciu a riziko VTE asociovaných s chemoterapiou založenou na cisplatine. Metódy V databáze PubMed sme vyhľadali články publikované od 1. januára 1990 do 31. decembra 2010. Vhodnými štúdiami boli prospektívne randomizované štúdie fázy II a III, ktoré porovnávali chemoterapiu založenú na cisplatine oproti necisplatinovej chemoterapii u pacientov so solídnymi nádormi. Zisťovali sme údaje o všetkých stupňoch VTE. Kvalita každej štúdie bola vypočítaná na základe Jadadových skóre. Stupne incidencie, relatívne riziká (RR) a 95% CI boli vypočítané s použitím modelu náhodných vplyvov. Výsledky Celkove bolo do štúdie zahrnutých 8 216 pacientov s rozličnými pokročilými solídnymi nádormi z 38 randomizovaných kontrolovaných štúdií. Incidencia VTE bola 1,92% (95% CI 1,07–2,76) u pacientov s chemoterapiou založenou na cisplatine a 0,79% (95% CI 0,45–1,13) u pacientov s chemoterapiou bez cisplatiny. Pacienti, ktorí dostávali cisplatinovú chemoterapiu, mali signifi kant ne vyššie riziko VTE (RR 1,67; 95% CI 1,25–2,23; p = 0,01). Najvyššie RR VTE bolo na základe exploratívnej podskupinovanej analýzy zistené u pacientov dostávajúcich týždňovú ekvivalentní dávku cisplatiny > 30 mg/m2 (2,71; 95% Cl 1,17–6,30; p = 0,02) a v štúdiách, ktoré boli publikované od roku 2000 do 2010 (1,72; 95% CI 1,27–2,34; p = 0‚01). Záver Cisplatina je asociovaná so signifikantne zvýšeným rizikom VTE u pacientov s pokročilými solídnymi nádormi pri porovnaní s chemoterapiou bez cisplatiny.
- MeSH
- cisplatina * škodlivé účinky terapeutické užití MeSH
- hodnocení rizik metody statistika a číselné údaje MeSH
- incidence * MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory farmakoterapie krev MeSH
- randomizované kontrolované studie jako téma MeSH
- rizikové faktory MeSH
- žilní tromboembolie * epidemiologie chemicky indukované MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- Publikační typ
- metaanalýza MeSH
- práce podpořená grantem MeSH
