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Summary Of Evidence And Guidelines Forstratification Of Non

Advances in Treatment of Non-Muscle Invasive Bladder Cancer (A special support group presentation).

Summary of evidence

The EAU NMIBC 2021 scoring model and risk tablespredict the short- and long-term risks of disease progression in individualpatients with primary NMIBC using either the WHO 1973 or the WHO 2004/2016classification system .

The 2006 EORTC scoring model and risk tables predictthe short- and long-term risks of disease recurrence and progression inindividual patients with NMIBC using the WHO 1973 classification system .

Patients with TaG1/G2 tumours receiving chemotherapyhave been further stratified into three risk groups for recurrence, taking intoaccount the history of recurrences, history of intravesical treatment, tumourgrade , number of tumours and adjuvant chemotherapy .


In patients treated with 5 to 6 months of BCG, theCUETO scoring model predicts the short- and long-term risks of diseaserecurrence and progression using the WHO 1973 classification system .

In patients receiving at least 1 year of BCGmaintenance prior recurrence rate and number of tumours are the most importantprognostic factors for disease recurrence. Stage and grade are the mostimportant prognostic factors for disease progression and disease-specificsurvival patient age and grade are the most important prognosticfactors for overall survival .

Presentation On Theme: Nonmuscle

1 NonMuscle-Invasive Bladder Cancer ByDr. Mohammed S Al-Shehri

2 superficial bladder cancer, malignant urothelial tumors that have not invaded the detrusorPatients with macroscopic hematuria have reported rates of bladder cancer of 13% to 34.5%Microscopic hematuria is associated with a 0.5% to 10.5% rate of bladder cancercystoscopy and upper tract imaging are indicated in patients with hematuria and/or unexplained irritative symptoms

3 Approximately 70% of bladder tumors are nonmuscle invasive at presentation. Of these, 70% present as stage Ta, 20% as T1, and 10% as CISsessile morphology and/or the presence of necrosis suggest high-grade disease likely to be invasive

4 STAGING Pathologic GradingA papilloma is a papillary lesion with a fine fibrovascular core covered by normal bladder mucosaWell-differentiated tumors papillary urothelial tumors of low malignant potentialModerately differentiated tumors low-grade urothelial carcinomasPoorly differentiated tumors , named high-grade urothelial carcinoma

5 STAGINGPathologic Staging

6 The most important risk factor for progression is grade, not stageCIS was the second most important prognostic factor after gradePrognosis also correlates with tumor size, multiplicity, papillary versus sessile configuration, presence or absence of lymphovascular invasion, and status of the remaining urothelium

25 Impact of BCG on ProgressionTwo separate meta-analyses have reached the conclusion that BCG reduces the risk of progression by 27%

Rationale For Use Of Neoadjuvant Treatments

Upfront chemoablative treatments like chemohyperthermia , Combat Medical Ltd., UK) and reverse thermal gel formulated with MMC are increasingly being explored as alternatives to repeat office or ambulatory procedures in patients with established, recurrent low-grade tumors. Chemoablation is a potentially attractive alternative to TURBT that may reduce treatment time, cost, and morbidity. Alternatively, others have also advocated for office-based fulguration of small, recurrent lowgrade tumors when feasible and tolerable as part of a risk-adapted strategy of treatment.30,31 Active surveillance has also been suggested as a safe and cost-effective alternative for highly selected patients.32

Upfront chemoablative treatments like chemohyperthermia and reverse thermal gel formulated with MMC are increasingly being explored as alternatives to repeat office or ambulatory procedures in patients with established, recurrent low-grade tumors.

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Radical Cystectomy For Non

There are several reasons to consider immediate RC for selected patientswith NMIBC:

  • The staging accuracy for T1 tumours by TURB is low with 27-51% of patients beingupstaged to muscle-invasive tumour at RC .
  • Some patients with NMIBC experience disease progression to muscle-invasive disease.
  • Patients who experience disease progression to muscle-invasive stage have a worseprognosis than those who present with primary muscle-invasive disease.

The potential benefit of RC must be weighed against its risks, morbidity,and impact on quality of life and discussed with patients, in a shared decision-makingprocess. It is reasonable to propose immediate RC in those patients with NMIBC who are atvery high risk of disease progression .

Early RC is strongly recommended in patients with BCGunresponsive tumours and should be considered in BCG relapsing HG tumours as mentioned above. A delay in RC may lead to decreased disease-specificsurvival .

In patients in whom RC is performed before progression toMIBC, the 5-year DFS rate exceeds 80% .

Variant Histology In Bladder Cancer: How It Should Change The Management In Non


Yvonne Klaile1*, Katrin Schlack1*, Martin Boegemann1, Julie Steinestel1, Andres Jan Schrader1, Laura-Maria Krabbe1,2

1Department of Urology, University of Muenster Medical Center, Muenster, Germany 2Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Contributions: Conception and design: Y Klaile, K Schlack, LM Krabbe Administrative support: LM Krabbe Provision of study materials or patients: None Collection and assembly of data: Y Klaile, K Schlack, LM Krabbe Data analysis and interpretation: None Manuscript writing: All authors Final approval of manuscript: All authors.

*These authors contributed equally to this work.

Correspondence to:

Keywords: Bladder cancer management muscle-invasive non-muscle-invasive variant histology

Submitted May 22, 2016. Accepted for publication Jun 02, 2016.

doi: 10.21037/tau.2016.06.13

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Carcinomain Situ And Its Classification

Carcinoma in situ is a flat,high-grade, non-invasive urothelial carcinoma. It can be missed or misinterpreted as aninflammatory lesion during cystoscopy if not biopsied. Carcinoma in situ is often multifocal and can occur in the bladder,but also in the upper urinary tract , prostatic ducts, and prostatic urethra .

From the clinical point of view, CIS may be classified as :

  • Primary: isolated CIS with no previous or concurrent papillary tumours and no previousCIS
  • Secondary: CIS detected during follow-up of patients with a previous tumour that was notCIS
  • Concurrent: CIS in the presence of any other urothelial tumour in the bladder.

Rare Forms Of Bladder Cancer

Adenocarcinomas account for less than 2% of primary bladder tumors. These lesions are observed most commonly in exstrophic bladders and are often associated with malignant degeneration of a persistent urachal remnant.

Other rare forms of bladder cancer include leiomyosarcoma, rhabdosarcoma, carcinosarcoma, lymphoma, and small cell carcinoma. Leiomyosarcoma is the most common sarcoma of the bladder. Rhabdomyosarcomas most commonly occur in children. Carcinosarcomas are highly malignant tumors that contain a combination of mesenchymal and epithelial elements. Primary bladder lymphomas arise in the submucosa of the bladder. Except for lymphomas, all these rare bladder cancers carry a poor prognosis.

Small cell carcinoma of the urinary bladder is a poorly differentiated, malignant neoplasm that originates from urothelial stem cells and has variable expression of neuroendocrine markers. Morphologically, it shares features of small cell carcinoma of other organs, including the lung.

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Strategy Of The Procedure

The goal of TURB in TaT1 BC is to make the correct diagnosis and completelyremove all visible lesions. It is a crucial procedure in the management of BC. Transurethralresection of the bladder should be performed systematically in individual steps .

The operative steps necessary to achieve a successful TURB includeidentifying the factors required to assign disease risk , clinical stage , adequacy of the resection , and presence of complications . To measure the size of thelargest tumour, one can use the end of cutting loop, which is approximately 1 cm wide as areference. The characteristics of the tumour are described as sessile, nodular, papillary orflat.

Occurrence In The United States

Emerging Treatments for BCG Unresponsive Non-muscle Invasive Bladder Cancer

The American Cancer Society estimates that 83,730 new cases of bladder cancer will be diagnosed in the United States in 2021 and that 17,200 people will die of the disease. The incidence of bladder cancer increases with age, with the median age at diagnosis being 73 years bladder cancer is rarely diagnosed before age 40 years.

Bladder cancer is about 3 times more common in men than in women. Over the past 2 decades, however, the rate of bladder cancer has been stable in men but has increased in women by 0.2% annually. The male predominance in bladder cancer in the United States reflects the prevalence of transitional cell carcinoma . With small cell carcinomain contrast to TCCthe male-to-female incidence ratio is 1:2.

Bladder cancer is the fourth most common cancer in men in the United States, after prostate, lung, and colorectal cancer, but it is not among the top 10 cancers in women. Accordingly, more men than women are expected to die of bladder cancer in 2021, with 12,260 deaths in men versus 4940 in women. Nevertheless, women generally have a worse prognosis than men.

The incidence of bladder cancer is twice as high in white men as in black men in the United States. However, blacks have a worse prognosis than whites.

Limited data indicate that small cell carcinoma of the urinary bladder probably has the same epidemiologic characteristics as urothelial carcinoma. Patients are more likely to be male and older than 50 years.

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Counselling Of Smoking Cessation

It has been confirmed that smoking increases the risk of tumour recurrenceand progression . Whileit is still controversial whether smoking cessation in BC will favourably influence theoutcome of BC treatment, patients should be counselled to stop smoking due to the generalrisks connected with tobacco smoking .

Perspectives Of Bladder Microbiome And Urobiome: A New Opportunity For A Predictive Response

NGS technologies enable the study of the microbiome . Microbial dysbiosis impacts several human diseases including bladder carcinogenesis . However, the mechanistic links between microbiome signatures and bladder pathogenesis are still unknown. Urobiome studies may open the way to understand how bladder microbiota affects immunotherapy response leading to BCG-unresponsive patients .

Urinary microbiome through the 16S ribosomal RNA sequencing and expanded quantitative urine culture enable unculturable and/or rare microbes detection . The core step in microbiome analysis is the taxonomic classification of the representative sequences and clustering of operational taxonomic units . To assess the association between microbiome signatures and clinical phenotype, useful bioinformatic tools are PERMANOVA-S and MiRKAT . Bladder microbiome analysis showed that the most abundant genera are Lactobacillus , followed by Corynebacterium , Streptococcus , Actinomyces , and Staphylococcus . Innovative drug strategies based on precise antimicrobial peptides might boost the host immune system to ensure bladder microbiome homeostasis . Novel urinary biomarkers proved to be endowed with prognostic and diagnostic value in urological malignancies derived from exosomes, such as H2B1K and alpha-1 antitrypsin .

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About The Bladder Renal Pelvis And Ureter

The bladder is a hollow organ in the pelvis that stores urine before it leaves the body during urination. This function makes the bladder an important part of the urinary tract. The urinary tract is also made up of the kidneys, ureters, and urethra. The renal pelvis is a funnel-like part of the kidney that collects urine and sends it into the ureter. The ureter is a tube that runs from each kidney into the bladder. The urethra is the tube that carries urine out of the body. The prostate gland is also part of the urinary tract.

The bladder, like other parts of the urinary tract, is lined with a layer of cells called the urothelium. This layer of cells is separated from the bladder wall muscles, called the muscularis propria, by a thin, fibrous band called the lamina propria.

Genetic Factors In Pathogenesis

Management of Non Muscle Invasive Bladder Cancer

Divergent, yet interconnected and overlapping, molecular pathways are likely responsible for the development of noninvasive and invasive bladder tumors. Somatic mutations in fibroblast growth receptor3 and tumor protein p53 in tumor cells appear to be important early molecular events in the noninvasive and invasive pathways, respectively.

FGFR-3, Ras, and PIK3CA mutations occur with high frequency in noninvasive tumors, leading to upregulation of Akt and mitogen-activated protein kinase . Loss of heterozygosity on chromosome 9 is among the most frequent genetic alterations in bladder tumors and is considered an early event.

Large numbers of genomic changes have been detected using karyotyping and comparative genomic hybridization analysis in urothelial carcinoma. Numerically common are losses of 2q, 5q, 8p, 9p, 10q, 18q, and Y. Gains of 1q, 5p, 8q, and 17q are frequently present, and high-level amplifications can be found however, the target genes in the regions of amplifications have not been conclusively identified.

Alterations in the TP53 gene are noted in approximately 60% of invasive bladder cancers. Progression-free survival is significantly shorter in patients with TP53 mutations and is an independent predictor of death among patients with muscle-invasive bladder cancer.

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Nmibc Biomarkers And Clinical Impact

To date, existing non-invasive commercial biomarkers are not embedded in routine clinical practice due to poor sensitivity, specificity and lack of evidence. Several research bodies have recognised the lack of clinically useful biomarkers for bladder cancer. Fit for purpose sample resources accessible to high-throughput omic technologies will afford the greatest opportunity to generate translational hypotheses and ensure clinical validity and utility of putative candidate markers/signatures. Robust, future-proof, longitudinal serial sample archives providing critical insights of the natural history of bladder cancer correlated with clinical detail for retrospective translational biomarker discovery are lacking.

Exploration Of Patients After Haematuria Or Other Symptoms Suggestive Of Bladder Cancer

It is generally accepted that none of the currently available tests canreplace cystoscopy. However, urinary cytology or biomarkers can be used as an adjunct tocystoscopy to detect missed tumours, particularly CIS. In this setting, sensitivity forhigh-grade tumours and specificity are particularly important.

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Screening Of The Population At Risk Of Bladdercancer

The application of haematuria dipstick, followed by FGFR3, NMP22® orUroVysion tests if dipstick is positive has been reported in BC screening in high-riskpopulations . The low incidence ofBC in the general population and the short lead-time impair feasibility andcost-effectiveness . Routinescreening for BC is not recommended .

Monotherapy Combination Therapy And Multi

Highlighting Clinical Trials: Non-Muscle Invasive Bladder Cancer | Current Trials

Combination therapies based on immunomodulators such as checkpoint inhibitors have shown a synergistic effect to augment the immune response .

A discrete amount of studies are based on combination therapy with chemotherapeutic drugs, intravesical BCG, and immune checkpoint inhibitors, as some trials reported in Table 1 . Currently, an FDA-approved combination therapy is based on intravesical gemcitabine and cisplatin for NMIBCs .

As shown in Table 2, several clinical trials are designed to investigate combination therapies based on BCG immunotherapy and different chemical or biological compounds or vaccines . Combination therapies encompass also combination chemotherapies especially in recurrent and advanced BC including . Furthermore, photodynamic immunotherapy emerged recently to stimulate the immune response in NMIBC BCG-refractory or intolerant to BCG treatment as well .

One frontier of medicinal chemistry is polypharmacology . Benedetti et al. reviewed the immuno-oncological dynamic interactions to design multi-target modulators.

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Relevance Of The International Bcg Shortage To The Aua Guidelines

The global shortages in TICE BCG that occurred in 2014 and 2019 led the AUA to recommend several management strategies to maintain high quality care for patients with NMIBC. These recommendations may supersede the guideline statements below. In particular, the BCG shortage impacts guideline statements 17, 20, and 21. The AUA Statement on the BCG Shortage is available at .

Scoringmodel Using The Who 2004/2016 And Who 1973 Classification Systems NMIBC 2021 scoring model

To update the risk of disease progression and create new prognostic factorrisk groups using both the WHO 1973 and WHO 2004/2016 classification systems , individual patient data from 3,401 primary patients treated from1990 to 2018 were used . Only patients treatedwith TURB +/- intravesical chemotherapy were included, those treated with adjuvantintravesical BCG were excluded because BCG may reduce the risk of disease progression. Fromthe multivariate analysis, tumour stage, WHO 1973 grade, WHO 2004/2016 grade, concomitantCIS, number of tumours, tumour size and age were independent predictors of diseaseprogression .

This is the only available model, where the WHO 2004/2016 classificationsystem is included as one of parameters to calculate an individual patients riskgroup and probability of progression. As the WHO 2004/2016 classification system is the maingrading classification system used by pathologists, the Guidelines Panel recommends to usethe 2021 EAU NMIBC scoring model for risk groups definition .

As the 2021 EAU NMIBC scoring model determines the riskof tumour progression, but not recurrence, any of models mentioned in Section 6.1.1 may beused for calculation of an individuals risk of disease recurrence.

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Types Of Adjuvant Therapy

Adjuvant treatment is any agent administered after complete TURBT aimed at reducing the risks of NMIBC recurrence and progression. Traditionally, only intravesical agents have been used in this setting, but emerging data on the use of systemic checkpoint inhibitor immunotherapies either as a monotherapy or combined with intravesical agents may radically change this treatment paradigm. Current adjuvant intravesical treatments can be defined by the timing and sequence of their administration: perioperatively, usually within 24h of TURBT, induction, as an initial course for that particular agent, or maintenance, subsequent courses in the setting of no evidence of disease after TURBT and induction treatment.

Standard intravesical therapies can also be categorized as either chemotherapy or immunotherapy agents. The most used contemporary chemotherapy agents are mitomycin C, gemcitabine, epirubicin, and docetaxel. These are given individually or in combination depending on the indication. Historically, agents such as doxorubicin, valrubicin, cisplatin, and thiotepa, among others, were also frequently studied and used. The gold standard intravesical immunotherapy is BCG, an attenuated mycobacterium strain first described for use in bladder cancer in 1976. Interferon has also been studied, but contemporary use is limited.

Treatment Failure After Intravesical Bcg Immunotherapy


Several categories of BCG failures, broadly defined as any high-gradedisease occurring during or after BCG therapy, have been proposed .Non-muscle-invasive BC may not respond at all or may relapse after initialresponse . Some evidence suggests that patients with BCG relapse have betteroutcomes than BCG refractory patients .

To be able to specify the subgroup of patients where additional BCG isunlikely to provide benefit, the category of BCG unresponsive tumour was defined. FurtherBCG instillations in these patients are associated with an increased risk of progression . The category of BCG unresponsivetumours comprises BCG-refractory and some of BCG-relapsing tumours . The definition was developed in consultation with the FDA, inparticular to promote single-arm trials to provide primary evidence of effectiveness in thissetting .

Non-high-grade recurrence after BCG is not considered as BCG failure.

Table 7.2: Categories of high-grade recurrence during or after BCG

* Patients with low-grade recurrence during or after BCGtreatmentare not considered to be a BCG failure.

** Adequate BCG is defined as the completion of at least 5 of 6doses of an initial induction course plus at least 2 out of 6 doses of a second inductioncourse or 2 out of 3 doses of maintenance therapy.

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