The European Association of Urology (EAU) guidelines panel on upper urinary tract urothelial carcinoma (UTUC) has updated the guidelines to aid clinicians in evidence-based management of UTUC.
To ...provide an overview of the EAU guidelines on UTUC as an aid to clinicians.
The recommendations provided in these guidelines are based on a review of the literature via a systematic search of the PubMed, Ovid, EMBASE, and Cochrane databases. Data were searched using the following keywords: urinary tract cancer, urothelial carcinomas, renal pelvis, ureter, bladder cancer, chemotherapy, ureteroscopy, nephroureterectomy, neoplasm, (neo)adjuvant treatment, instillation, recurrence, risk factors, metastatic, immunotherapy, and survival. The results were assessed by a panel of experts.
Even though data are accruing, for many areas there is still insufficient high-level evidence to provide strong recommendations. Patient stratification on the basis of histology and clinical examination (including imaging) and assessment of patients at risk of Lynch syndrome will aid management. Kidney-sparing management should be offered as a primary treatment option to patients with low-risk UTUC and two functional kidneys. In particular, for patients with high-risk or metastatic UTUC, new treatment options have become available. In high-risk UTUC, platinum-based chemotherapy after radical nephroureterectomy, and adjuvant nivolumab for unfit or patients who decline chemotherapy, are options. For metastatic disease, gemcitabine/carboplatin chemotherapy is recommended as first-line treatment for cisplatin-ineligible patients. Patients with PD-1/PD-L1–positive tumours should be offered a checkpoint inhibitor (pembrolizumab or atezolizumab).
These guidelines contain information on the management of individual patients according to the current best evidence. Urologists should take into account the specific clinical characteristics of each patient when determining the optimal treatment regimen according to the risk stratification of these tumours.
Cancer of the upper urinary tract is rare, but because 60% of these tumours are invasive at diagnosis, timely and appropriate diagnosis is most important. A number of known risk factors exist.
Purpose Urothelial carcinoma of the bladder is the 4th most common malignancy in men and the 8th most common cause of male cancer death in the United States. Conversely, upper tract urothelial ...carcinoma accounts for only 5% to 10% of all urothelial carcinoma. Due to the relative preponderance of urothelial carcinoma of the bladder, much of the clinical decision making regarding upper tract urothelial carcinoma is extrapolated from evidence that is based on urothelial carcinoma of the bladder cohorts. In fact, only 1 major urological organization has treatment guidelines specific for upper tract urothelial carcinoma. While significant similarities exist between these 2 diseases, ignoring the important differences may be preventing us from optimizing therapy in patients with upper tract urothelial carcinoma. Therefore, we explored these dissimilarities, including the differential importance of gender, anatomy, staging, intracavitary therapy, surgical lymphadenectomy and perioperative systemic chemotherapy on the behavior of urothelial carcinoma of the bladder and upper tract urothelial carcinoma. Materials and Methods A nonsystematic literature search using the MEDLINE/PubMed® database was conducted to identify original articles, review articles and editorials. Searches were limited to the English language and studies in humans and in adults, and used the key words urothelial carcinoma, upper tract urothelial carcinoma or transitional cell carcinoma combined with several different sets of key words to identify appropriate publications for each section of the manuscript. The key words, broken down by section, were 1) epidemiology, sex, gender; 2) location, tumor location; 3) staging, stage; 4) intracavitary, intravesical, topical therapy; 5) lymphadenectomy, lymph node, lymph node dissection and 6) adjuvant, neoadjuvant, chemotherapy. Results Women who present with urothelial carcinoma of the bladder do so with less favorable tumor characteristics and have worse survival than men. However, gender does not appear to be associated with survival outcomes in upper tract urothelial carcinoma. The prognostic effect that urothelial carcinoma tumor location has on outcomes prediction is a matter of debate, and the influence of tumor location may reflect our technical ability to accurately stage and treat the disease more than the actual tumor biology. Moreover, technical limitations of upper tract urothelial carcinoma sampling compared to transurethral resection for urothelial carcinoma of the bladder are the most important source of staging differences between the 2 diseases. Intravesical chemotherapy and immunotherapy are essential components of standard of care for most nonmuscle invasive bladder cancer, while adjuvant intracavitary therapy for patients with upper tract urothelial carcinoma treated endoscopically or percutaneously has been sparsely used and without any clear guidelines. The widespread adoption of the use of intracavitary therapy in the upper tract will likely not only require additional data to support its efficacy, but will also require a less cumbersome means of administration. Lymphadenectomy at the time of radical cystectomy is widely accepted while lymphadenectomy at the time of radical nephroureterectomy is performed largely at the discretion of the surgeon. Among other reasons, this may be due in part to the variable lymphatic drainage along the course of the ureter compared to the relatively confined lymphatic landing sites for the bladder. Level I evidence has demonstrated a clear survival benefit for systemic chemotherapy before radical surgery or radiation in patients with clinical T2-4N0M0 urothelial carcinoma of the bladder. Such data are not available in the population with upper tract urothelial carcinoma. However, the use of neoadjuvant chemotherapy may be even more important in upper tract urothelial carcinoma than in urothelial carcinoma of the bladder because of the obligatory kidney function loss that occurs at radical nephroureterectomy. Conclusions While urothelial carcinoma of the bladder and upper tract urothelial carcinoma share many characteristics, they represent 2 distinct diseases. There are practical, anatomical, biological and molecular differences that warrant consideration when risk stratifying and treating patients with these disparate twin diseases. To overcome the challenges that impede progress toward evidence-based medicine in upper tract urothelial carcinoma, we believe that focused collaborative efforts will best augment our understanding of this rare disease and ultimately improve the care we deliver to our patients.
Abstract Context This review focuses on risk assessment and prediction tools for bladder cancer (BCa). Objective To review the current knowledge on risk assessment and prediction tools to enhance ...clinical decision making and counseling of patients with BCa. Evidence acquisition A literature search in English was performed using PubMed in July 2013. Relevant risk assessment and prediction tools for BCa were selected. More than 1600 publications were retrieved. Special attention was given to studies that investigated the clinical benefit of a prediction tool. Evidence synthesis Most prediction tools for BCa focus on the prediction of disease recurrence and progression in non–muscle-invasive bladder cancer or disease recurrence and survival after radical cystectomy. Although these tools are helpful, recent prediction tools aim to address a specific clinical problem, such as the prediction of organ-confined disease and lymph node metastasis to help identify patients who might benefit from neoadjuvant chemotherapy. Although a large number of prediction tools have been reported in recent years, many of them lack external validation. Few studies have investigated the clinical utility of any given model as measured by its ability to improve clinical decision making. There is a need for novel biomarkers to improve the accuracy and utility of prediction tools for BCa. Conclusions Decision tools hold the promise of facilitating the shared decision process, potentially improving clinical outcomes for BCa patients. Prediction models need external validation and assessment of clinical utility before they can be incorporated into routine clinical care. Patient summary We looked at models that aim to predict outcomes for patients with bladder cancer (BCa). We found a large number of prediction models that hold the promise of facilitating treatment decisions for patients with BCa. However, many models are missing confirmation in a different patient cohort, and only a few studies have tested the clinical utility of any given model as measured by its ability to improve clinical decision making.
Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis ...of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies.
Introduction
Immunotherapy is changing the way we think about and treat urothelial carcinoma (UC). The PD-1/PD-L1 pathway inhibition has shown robust efficacy, associated with an acceptable toxicity ...profile, in patients with locally advanced and metastatic unresectable disease, addressing a high decades-old unmet medical need.
Material and methods
Using the Pubmed database, we conducted a literature review for English written published articles up to June 2020. The highest available evidence for the immunotherapy treatment of UC with ICIs were evaluated. The leading phase one, two and three clinical trials were considered for inclusion (n = 12). Patient’s data were extracted from studies depicting the UTUC subpopulation.
Results
Two monoclonal antibodies targeting PD-1 (pembrolizumab and nivolumab) and three to its ligand PD-L1 (atezolizumab, avelumab, and durvalumab) have obtained US FDA and EMA approval for the second-line treatment of platinum-pretreated patients, between 2016 and 2019. Atezolizumab and Pembrolizumab are even currently approved in the first-line setting for cisplatin ineligible patients, with PD-L1- positive tumor. The neoadjuvant scenario in localized high-risk disease is still evolving, with the first data available to date limited to the muscle-invasive bladder carcinoma. The management of patients with upper tract urothelial carcinoma (UTUC: renal pelvis and ureters) is complicated by the lack of specific high-level evidence, due to the rarity of the disease. No published studies addressing immunotherapy in UTUC patients only are available. The largest clinical trials aimed at UC patients, regardless of the upper or lower location of the primary tumor, have enrolled a minority of patients with UTUC, providing the data on which our current knowledge is based. However, targeted scientific efforts are needed to improve our level of care.
Conclusions
This review summarizes the main currently available evidence on the use of the PD-1/PD-L1 pathway inhibition with reference to patients presenting with UTUC.
Abstract Context and objective To present a summary of the 2nd International Consultation on Bladder Cancer recommendations on the screening, diagnosis, and markers of bladder cancer using an ...evidence-based strategy. Evidence acquisition A detailed Medline analysis was performed for original articles addressing bladder cancer with regard to screening, diagnosis, markers, and pathology. Proceedings from the last 5 yr of major conferences were also searched. Evidence synthesis The major findings are presented in an evidence-based fashion. Large retrospective and prospective data were analyzed. Conclusions Cystoscopy alone is the most cost-effective method to detect recurrence of bladder cancer. White-light cystoscopy is the gold standard for evaluation of the lower urinary tract; however, technology like fluorescence-aided cystoscopy and narrow-band imaging can aid in improving evaluations. Urine cytology is useful for the diagnosis of high-grade tumor recurrence. Molecular medicine holds the promise that clinical outcomes will be improved by directing therapy toward the mechanisms and targets associated with the growth of an individual patient's tumor. The challenge remains to optimize measurement of these targets, evaluate the impact of such targets for therapeutic drug development, and translate molecular markers into the improved clinical management of bladder cancer patients. Physicians and researchers eventually will have a robust set of molecular markers to guide prevention, diagnosis, and treatment decisions for bladder cancer.
Abstract Background There is a lack of consensus regarding the optimal approach to the bladder cuff during radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Objectives To ...compare the oncologic outcomes following RNU using three different methods of bladder cuff management. Design, setting, and participants Retrospective analysis of 2681 patients treated with RNU for UTUC at 24 international institutions from 1987 to 2007. Intervention Three methods of bladder cuff excision were performed: transvesical, extravesical, and endoscopic. Outcome measurements and statistical analysis Univariable and multivariable models tested the effect of distal ureter management on intravesical recurrence, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results and limitations Of the 2681 patients, 1811 (67.5%) underwent the transvesical approach; 785 (29.3%), the extravesical approach; and 85 (3.2%), the endoscopic approach. There was no difference in terms of RFS, CSS, and OS among the three distal ureteral management approaches. Patients who underwent the endoscopic approach were at significantly higher risk of intravesical recurrence compared with those who underwent the transvesical ( p = 0.02) or extravesical approaches ( p = 0.02); the latter two groups did not differ from each other ( p = 0.40). Actuarial intravesical RFS estimates at 2 and 5 yr after RNU were 69% and 58%, 69% and 51%, and 61% and 42% for the transvesical, extravesical, and endoscopic approaches, respectively. In multivariate analyses, distal ureteral management ( p = 0.01), surgical technique (open vs laparoscopic; p = 0.02), previous bladder cancer ( p < 0.001), higher tumor stage (trend; p = 0.01), concomitant carcinoma in situ (CIS) ( p < 0.001), and lymph node involvement (trend; p < 0.001) were all associated with intravesical recurrence. Excluding patients with history of previous bladder cancer, all variables remained independent predictors of intravesical recurrence. Conclusions The endoscopic approach was associated with higher intravesical recurrence rates. Interestingly, concomitant CIS in the upper tract is a strong predictor of intravesical recurrence after RNU. The association of laparoscopic RNU with intravesical recurrence needs to be further investigated.
Abstract
Intravesical recurrence (IVR) after RNU for UTUC is a frequent event, occurring in 20–50% of patients, mostly in the first postoperative year. Several retrospective studies have shown that ...predictors of IVR include clinical characteristics, surgical features and as well pathological characteristics (previous history of bladder cancer, pathological stage, lymph node involvement, cis, endoscopic distal ureter, etc.) management. Two prospective studies provide level I evidence for the safety and efficacy of intravesical single postoperative chemotherapy for patients treated with radical nephroureterectomy (RNU) for UTUC in order to prevent IVR. However, some questions remain unanswered. Yamashita et al. in the current issue of the journal have shown that early ureteral ligation during RNU decreases the risk of IVR in patients with pelvycalyceal upper tract urothelial carcinoma. This study despite its limitations represent a step towards improved outcomes for our patients with UTUC, the relatively low morbidity of the procedure added to the potential benefit associated with this early ligation make it an easy implementation in daily practice.
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