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Non Muscle Invasive Bladder Cancer Guidelines

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Issues That Need To Be Resolved To Optimize The Treatment

Muscle Invasive Bladder Cancer Guidelines Review

Although the recommendations covered most areas for managing NMIBC patients, some issues that need to be resolved for optimizing treatment have been indicated in some guidelines.

The first important item was whether the second TURBT should be performed after the intravesical therapy followed by the TURBT and whether intravesical therapy should be offered before pathology reports are available. The ESMO guidelines described re-TURBT as a reasonable option in high-risk NMIBC tumours after intravesical therapy, whereas the grade of the recommendation was rated low at III.8 The need for further research was obvious.

Such an acknowledged item was which BCG strain is the safest and most effective option . Different BCG strains have been implicated in determining responses to BCG, and some strains could influence antitumour immune responses as has been suggested by clinical studies comparing different BCG strains . However, the trial did not reach statistical significance for progression free survival, and none of the CPGs could offer related recommendations. Further evaluation using prospective trials might be needed .

Discussing Treatment Options For High

Quality statement


Quality measures


Data source:


Data source:


Data source:

What the quality statement means for service providers, healthcare professionals and commissioners

Service providersHealthcare professionalsCommissioners

What the quality statement means for patients and carers

Adults with bladder cancer that has not grown into the muscle wall of the bladder, but has a high-risk of doing so,

Definitions of terms used in this quality statement

  • the type, stage and grade of the cancer, the presence of carcinoma in situ, the presence of variant pathology, prostatic urethral or bladder neck status and the number of tumours
  • risk of progression to muscle invasion, metastases and death
  • risk of understaging
  • factors that affect outcomes
  • impact on quality of life, body image, and sexual and urinary functions.

Equality and diversity considerations

Chemotherapy During Transurethral Resection Of Bladder Tumour

Quality statement


Quality measures


Data source:


Data source:

What the quality statement means for service providers, healthcare professionals and commissioners

Service providersHealthcare professionalsCommissioners

What the quality statement means for patients and carers

Adults who are having a first operation to take tissue samples to check for bladder cancer

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Machine Learning Methods Training And Model Test

We selected support vector machine and random forest as ML algorithms. Data were analyzed using the statistical software package R version 3.6.1 . We employed the package e1071 on R to perform the SVM, and the package randomForest on R to perform the RF analysis. We used ROI features based on nuclear morphological information for machine learning and created a prediction model. The primary outcome was recurrence within 2 years. We randomly selected the test set to be 25% of the total patients. We used the average recurrence probabilities from each ROI, which were outputted by SVM and RF, as the case prediction result. The cases of equivalent probabilities were determined as undecidable. Finally, we checked the accuracy of correct classification in the test validation of the SVM model and the RF model. In the RF algorithm, we concurrently confirmed the out-of-bag error to evaluate the prediction performance of RF model.

Upperurinary Tract Urothelial Carcinoma

EAU Guidelines: Non tomography urography

Computed tomography urography has the highest diagnostic accuracy of theavailable imaging techniques . The sensitivity of CT urographyfor UTUC is 0.671.0 and specificity is 0.930.99 .

Rapid acquisition of thin sections allows high-resolutionisotropic images that can be viewed in multiple planes to assist with diagnosis without lossof resolution. Epithelial flat lesions without mass effect or urothelialthickening are generally not visible with CT.

The secondary sign of hydronephrosis is associated withadvanced disease and poor oncological outcome . The presence of enlarged LNs is highly predictive ofmetastases in UTUC . resonance urography

Magnetic resonance urography is indicated in patients who cannot undergo CTurography, usually when radiation or iodinated contrast media are contraindicated . The sensitivity of MR urography is 0.75 after contrastinjection for tumours < 2 cm . The use of MR urography withgadolinium-based contrast media should be limited in patients with severe renal impairment, due to the risk of NSF. Computed tomography urographyis generally preferred to MR urography for diagnosing and staging UTUC.

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Theimpact Of Second Resection On Treatment Outcomes

A second TURB can increase recurrence-free survival , improve outcomes afterBCG treatment and provide prognostic information .

In a retrospective evaluation of a largemulti-institutional cohort of 2,451 patients with BCG-treated T1G3/HG tumours , the second resection improved RFS,progression-free survival and overall survival only in patients without detrusormuscle in the specimen of the initial resection .

Radicalcystectomy And Urinary Diversion

Two systematic reviews and meta-analyses focused on HRQoL after RC andurinary diversion .

Yang et al. comparedHRQoL of incontinent and continent urinary diversions including 29 studies of which 9 had a prospective design . Only three studies reported HRQoL data both pre- andpost-operatively. In these three studies, an initial deterioration in overall HRQoL wasreported but general health, functional and emotional domains at 12 months post-surgery wereequal or better than baseline. After 12 months, the HRQoL benefits diminished in alldomains. Overall, no difference in HRQoL between continent and incontinent urinary diversionwas reported although an ileal conduit may confer a small physical health benefit .

Cerruto et al.reported HRQoL comparing ileal conduit with orthotopic neobladder reconstruction . A pooled analysis was performed including 18 studies of which the vast majority were retrospective studies. The analysis showed nostatistical significant difference in overall HRQoL, but methodological limitations need tobe considered.

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European Association Of Urology Guidelines On Nonmuscle

  • Otakar CapounAffiliationsDepartment of Urology, General Teaching Hospital and 1st Faculty of Medicine, Charles University Praha, Prague, Czech Republic
  • Paolo GonteroAffiliationsDepartment of Urology, Città della Salute e della Scienza, University of Torino School of Medicine, Torino, Italy
  • Department of Translational Medicine, Lund University, Malmö, SwedenDepartment of Urology, Skåne University Hospital, Malmö, Sweden
  • Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, GermanyDepartment of Surgical Oncology , Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  • Shahrokh F. ShariatAffiliationsDepartment of Urology, Teaching Hospital Motol and 2nd Faculty of Medicine, Charles University Praha, Prague, Czech RepublicDepartment of Urology, Comprehensive Cancer Center, Medical University Vienna, Vienna General Hospital, Vienna, Austria
  • Viktor SoukupAffiliationsDepartment of Urology, General Teaching Hospital and 1st Faculty of Medicine, Charles University Praha, Prague, Czech Republic

Interventions And Outcomes For Non

Diagnosis & Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guidelines

Once bladder cancer has been diagnosed, a number of factors affect prognosis and treatment options. These include the stage of the cancer, tumor grade, whether the tumor is an initial tumor or a recurrence, the patients age and general health, and other factors. The main treatment for Non-MIBC is local resection with transurethral resection of the bladder tumor , often with adjuvant intravesical therapy, such as the immediate post-TURBT instillation of chemotherapy or the use of adjuvant intravesical Bacillus Calmette-Guerin or interferon immunotherapy.10 All of these treatments are FDA approved and available in the U.S. Electromotive Drug Administration is a method for enhancing the effectiveness of intravesical chemotherapy that is increasingly used, especially in Europe. Clinical trials of EMDA are ongoing in the U.S., but the method is not widely available or FDA approved.

Some patients may not receive adjuvant therapy immediately post-TURBT due to potential side effects, potentially increasing the risk of recurrence or progression. The European Association of Urology advocates an assessed risk-adapted approach to treatment decision-making, based on available prognostic factors including grade, stage, number and size of tumors.11 This approach, which stratifies patients into three risk groups, may be especially useful for patients in the intermediate and high risk groups.

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A Criteria For Inclusion/exclusion Of Studies In The Review

The criteria for inclusion and exclusion of studies will be based on the Key Questions and discussion with TEP members, and are described in the previous PICOTS section.

Below are additional details on the scope of this project:

Study Designs

For KQ1, KQ 3, KQ 4, KQ 6, KQ 7 and KQ 8 we will include randomized controlled trials and cohort studies with comparators if RCTs are not available. For KQ 2 and KQ 5, studies that report diagnostic accuracy will be included. For all KQs we will exclude uncontrolled observational studies, case-control studies, case series, and case reports, as these studies are less informative than studies with a control group.

Systematic reviews will be used as primary sources of evidence if they address a key question and are assessed as being at low risk of bias, according to the AMSTAR quality assessment tool.12,13 If systematic reviews are included, we will update findings with any new primary studies identified in our searches, update meta-analyses if appropriate, and re-assess SOE based on the totality of evidence. If multiple systematic reviews are relevant and low risk of bias, we will focus on the findings from the most recent reviews and evaluate areas of consistency across the reviews.14,15


Non-English Language Studies

Summary Ofevidence And Guidelines For The Primary Assessment Of Presumably Invasive Bladdertumours

Summary of evidence


Strength rating

Describe all macroscopic features of the tumour and mucosal abnormalities during cystoscopy.Use a bladder diagram.


Take a biopsy of the prostatic urethra in cases ofbladder neck tumour, when bladder carcinoma insitu is present or suspected, when there is positive cytology withoutevidence of tumour in the bladder, or when abnormalities of the prostaticurethra are visible.


In men with a negative prostatic urethral biopsyundergoing subsequent orthotopic neobladder construction an intra-operativefrozen section can be omitted.


In men with a prior positive transurethral prostaticbiopsy, subsequent orthotopic neobladder construction should not be denied a priori, unless an intra-operative frozensection of the distal urethral stump reveals malignancy at the level of urethraldissection.


In women undergoing subsequent orthotopic neobladderconstruction, obtain procedural information of the bladder neck and urethral margin, either prior to, or at the time ofcystectomy.


In the pathology report, specify the grade, depth oftumour invasion, and whether the lamina propria and muscle tissue are present inthe specimen.


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Turbt/ Repeat Resection: Timing Technique Goal Indication

Guideline Statement 12

12. In a patient with non-muscle invasive disease who underwent an incomplete initial resection , a clinician should perform repeat transurethral resection or endoscopic treatment of all remaining tumor if technically feasible.


Incomplete resection is likely a significant contributing factor to what have been described and diagnosed as early recurrences, as tumors have been noted at the first follow-up cystoscopic evaluation in up to 45% of patients. 57 The Panel recognizes specific, albeit rare, circumstances in which transurethral resection is not likely to impact clinical management and may be omitted for patients with incompletely resected non-muscle invasive disease. Examples of such patients include those with large-volume, high-grade tumors not amenable to complete endoscopic resection for whom immediate radical cystectomy is planned. An additional example includes those patients with a tumor diagnosed within a bladder diverticulum and for whom subsequent surgical resection is planned. However, for the majority of patients, complete resection is essential for adequate staging and optimal clinical management. Although surgeons may utilize BLC for this situation, of note, there is insufficient evidence in this repeat transurethral resection setting to support the routine use of enhanced or BLC versus standard WLC, particularly in light of the noted increase in false positive diagnosis with BLC following recent TURBT. 116-118


Prognosticvalue Of Histological Grading

EAU Guidelines: Non

A systematic review and meta-analysis did not show that the 2004/2016classification outperforms the 1973 classification in prediction of recurrence andprogression .

To compare the prognostic value of both WHOclassifications, an IPD analysis of 5,145 primary Ta/T1 NMIBC patients from 17 centresthroughout Europe and Canada was conducted. Patients had a transurethral resection ofbladder tumour followed by intravesical instillations at the physiciansdiscretion. In this large prognostic factor study, the WHO 1973 and the WHO 2004/2016 wereboth prognostic for progression but not for recurrence. When compared, the WHO 1973 was astronger prognosticator of progression in Ta/T1 NMIBC than the WHO 2004/2016. However, afour-tier combination of both classificationsystems proved to be superior to either classification system alone, as it divides the largegroup of G2 patients into two subgroups with different prognoses .

In a subgroup of 3,311 patients with primary Ta bladder tumours, a similarprognosis was found for PUNLMP and TaLG carcinomas . Hence, theseresults do not support the continued use of PUNLMP as a separate grade category in the WHO2004/2016.

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Histopathological And Clinical Markers

The most important histopathological prognostic variables after RC and LNdissection are tumour stage and LN status . In addition, otherhistopathological parameters of the RC specimen have been associated with prognosis.

The value of lymphovascular invasion was reported in asystematic review and meta-analysis including 78,000 patients from 65 studies treated withRC for BC . Lymphovascular invasion was present in 35% of thepatients and correlated with a 1.5-fold higher risk of recurrence and CSM, independent ofpathological stage and peri-operative chemotherapy. This correlation was even stronger inthose patients with node-negative disease .

In a systematic review andmeta-analysis including 23 studies and over 20,000 patients, the presence of concomitantCIS in the RC specimen was associated with a higher odds ratio of ureteralinvolvement . Concomitant CIS was not independentlyassociated with OS, recurrence-free survival and DSS in all patients, but inpatients with organ-confined disease concomitant CIS was associated with worse RFS and CSM .

Tumour location has been associated with prognosis. Tumours located at thebladder neck or trigone of the bladder appear to have an increased likelihood of nodalmetastasis and have been associated with decreasedsurvival .

Evaluation Of Nmibc Guidelines

Four reviewers from different backgrounds, consisting of urologists and methodologists, with extensive experience in evaluating CPGs independently evaluated the eligible guidelines using the AGREE II instrument. AGREE II consists of 23 key items organized within 6 domains .

Each domain identified a unique dimension of guideline quality rated on a 7-point scale scored from 1 to 7 . We summarized the domain scores individually and scaled the total of that domain, calculated by the following formula: /×100% .

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Lymphadenectomy: Role And Extent

Controversies in evaluating the clinical significance of lymphadenectomy are related to two main aspects of nodal dissection: therapeutic procedure and/orstaging instrument.

Two important autopsy studies have been performed for RC so far. The firststudy showed that in 215 patients with MIBC and nodal dissemination, the frequency ofmetastasis was 92% in regional , 72% in retroperitoneal, and 35% inabdominal LNs. There was also a significant correlation between nodal metastases andconcomitant distant metastases . Approximately 47% of the patients had bothnodal metastases and distant dissemination and only 12% of the patients had nodaldissemination as the sole metastatic manifestation .

The second autopsy study focused on the nodal yield whensuper-extended pelvic LND was performed. Substantial inter-individual differences were foundwith counts ranging from 10 to 53 nodes . These findingsdemonstrate the limited utility of node count as a surrogate for extent of dissection.

Regional LNs have been shown to consist of all pelvic LNsbelow the bifurcation of the aorta . Mapping studiesalso found that skipping lesions at locations above the bifurcation of the aorta withoutmore distally located LN metastases is rare .

Clinical Trial Design For Non

Dr. Rosenberg on Non-Metastatic Muscle Invasive Bladder Cancer Guidelines
Thu, Nov 18 9:00 AM –
Fri, Nov 19 9:00 AM – ET

Organized By:Oncology Center of Excellence and the Center for Drug Evaluation and Research/Office of Oncologic Diseases



The U.S. Food and Drug Administration Oncology Center of Excellence and Center for Drug Evaluation and Research welcome you to this FDA Virtual Public Workshop: Clinical Trial Design for Non-Muscle Invasive Bladder Cancer .

The purpose of this workshop is to discuss challenges and opportunities in clinical trial design for patients with NMIBC. The ultimate goal of the workshop is to identify actionable next steps towards facilitating feasible trial designs that can capture interpretable and clinically meaningful results.

Sessions 1-3 are on the first day of the workshop .

  • The first two sessions will cover the BCG shortage, impact on clinical practice, and implications for trial design for the BCG-naïve population.
  • The third session will focus on trial design in the BCG-unresponsive population and potential trial designs with cystectomy-free survival as a secondary endpoint.

Sessions 4-6 will be on the second day of the workshop .

  • Sessions 4 and 5 will cover issues related to trial design for the two distinct classifications of NMIBC i.e., carcinoma in situ and papillary disease.
  • Session 6 will focus on capturing the patients perspective in trial design including experiences, needs, and priorities.

Meeting Goals


Online Attendance

Workshop Materials

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Time Schedule For Surveillance

Although, based on low level evidence only, some follow-up schedules havebeen suggested, guided by the principle that recurrences tend to occur within the firstyears following initial treatment. A schedule suggested by the EAU Guidelines Panel includesa CT scan until the third year, followed by annual imaging thereafter.Patients with multifocal disease, NMIBC with CIS or positive ureteral margins are at higherrisk of developing UTUC, which can develop late . In those cases, monitoringof the UUT is mandatory during follow-up. Computed tomography is to be used for imaging ofthe UUT .

Since data for follow-up strategies are sparse, a numberof key questions were included in a recently held consensus project . Outcomes for all statements for whichconsensus was achieved are listed in Section 8.6.

Mibc And Health Status

Complications from RC may be directly related to pre-existing comorbidityas well as the surgical procedure, bowel anastomosis, or urinary diversion. A significantbody of literature has evaluated the usefulness of age as a prognostic factor for RC,although chronological age is less important than frailty . Frailty is a syndrome of reduced ability to respondto stressors. Patients with frailty have a higher risk of mortality and negative sideeffects of cancer treatment . Controversy remains regardingage, RC and the type of urinary diversion. Radical cystectomy is associated with thegreatest risk reduction in disease-related and non-disease-related death in patients aged< 80 years .

The largest retrospective study on RC in septuagenariansand octogenarians based on data from the National Surgical Quality Improvement Programdatabase showed no significant difference for wound, cardiac, or pulmonarycomplications. However, the risk of mortality in octogenarians compared to septuagenariansis higher . Although some octogenarianssuccessfully underwent a neobladder procedure, most patients were treated with an ilealconduit diversion. It is important to evaluate functioning and quality of life ofolder patients using a standardised geriatric assessment, as well as carrying out a standardmedical evaluation .

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