Current Approaches to the Management of Non-Muscle Invasive Bladder Cancer: Comparison of Current Guidelines and Recommendations

doi:10.1016/j.eursup.2008.07.007

European Urology Supplements

Volume 7, Issue 10, October 2008, Pages 637-650

https://doi.org/10.1016/j.eursup.2008.07.007 Get rights and content

Abstract

Context

The guidelines of the European Association of Urology (EAU), the First International Consultation on Bladder Tumors (FICBT), the National Comprehensive Cancer Network (NCCN), and the American Urological Association (AUA) all provide an excellent evidence-based background for the management of non-muscle invasive bladder cancer (NMIBC). Although there are areas of consensus among the four guidelines, their recommendations vary with respect to important issues surrounding NMIBC.

Objective

To provide community urologists with practical and unified guidance on the management of NMIBC through a comprehensive review of current influencing guidelines.

Evidence acquisition

A committee of internationally renowned leaders in bladder cancer management, known as the International Bladder Cancer Group (IBCG), was convened in October 2006 to review current literature surrounding the management of NMIBC as well as the current clinical practice guidelines of the EAU, the FICBT, the NCCN and the AUA. Following the inaugural meeting in October 2006, the IBCG met on three subsequent occasions (March 2007, September 2007, and March 2008) to critically analyze and compare the EAU, FICBT, NCCN, and AUA guidelines.

Evidence synthesis

The IBCG critically analyzed and summarized the EAU, FICBT, NCCN, and AUA guidelines and identified the key similarities and differences in their recommendations.

Conclusions

Established areas of consensus among the four guidelines include the importance of transurethral resection of the bladder tumour (TURBT) and an immediate, postoperative dose of chemotherapy (agent optional) in all patients with NMIBC, as well as the benefit of adjuvant bacillus Calmette-Guérin (BCG) therapy in high-risk disease. However, the four guideline recommendations vary with regard to the following important issues: (1) the definitions of low-, intermediate-, and high-risk disease, and (2) the appropriate management and follow-up of patients in each of these risk categories. Furthermore, there is currently no consensus on the definition and appropriate management strategies for primary intravesical treatment failures among the four guidelines.

Introduction

The guidelines of the European Association of Urology (EAU) [1], the First International Consultation on Bladder Tumors (FICBT) [2], the National Comprehensive Cancer Network (NCCN) [3], and the American Urological Association (AUA) [4], [5] all contribute to an excellent evidence-based framework for the management of non-muscle invasive bladder cancer (NMIBC). However, there are differences in the recommendations made in these guidelines as well as contentious areas and topics that are not addressed.

To provide more practical and uniform recommendations that would be applicable to community urologists, the International Bladder Cancer Group (IBCG) for NMIBC critically analyzed and compared the EAU, FICBT, NCCN, and AUA guidelines. This article summarizes these guidelines and identifies the key similarities and differences in their recommendations.

Before comparing the guidelines, it is important to note the categories of consensus or evidence-based grading systems used by each of the individual guideline panels. The level of evidence and grade of recommendations used in the EAU guidelines are shown in Table 1[6], [7]. The recommendations of the FICBT are based on the International Consultation on Urologic Disease (ICUD) grading system presented in Table 2[2], [8], and the NCCN recommendations are based on the categories of consensus shown in Table 3. All NCCN recommendations are category 2A unless otherwise specified [3]. The AUA Guidelines Panel conducted its own meta-analyses of randomised controlled trials and developed tables that provided outcome estimates for different treatment modalities for NMIBC. Based on evidence in the outcome tables and expert opinion, the AUA guideline statements were graded with respect to the degree of flexibility in their application [4], [5]. These three levels of flexibility are defined in Table 4.

The treatment and management of NMIBC ultimately depends on the patient's risk of recurrence and/or progression. The following article compares the EAU, FICBT, NCCN, and AUA risk-stratification definitions and treatment recommendations for each level of risk.

Section snippets

Definitions of levels of risk

Although the EAU, FICBT, NCCN, and AUA guidelines agree on the importance of risk stratification for NMIBC management, there are differences in their definitions of level of risk as well as their proposed treatments for each risk category. Table 5 summarizes the definitions for low-, intermediate-, and high-risk disease proposed by the EAU, FICBT, NCCN, and AUA [1], [3], [4], [5], [9], [10], [11].

Transurethral resection of the bladder tumour

All guideline recommendations agree that transurethral resection of the bladder tumour (TURBT) is the gold standard for the initial diagnosis and treatment of NMIBC, regardless of level of risk.

According to the FICBT recommendations, complete tumour resection should be attempted, except in cases of diffuse carcinoma in situ (CIS), and bladder perforation should be avoided [12]. The AUA acknowledges that the size and/or multiplicity of tumours or obvious deep muscle invasion may prevent complete

Defining treatment failure

The ability to determine the optimal management strategies for treatment failures has been hampered by the lack of a standard definition for failure. In fact, the EAU, FICBT, NCCN, and AUA all have varying definitions of treatment failure. The EAU, for example, does not define primary intravesical treatment failure but does provide the following definition for BCG failure [1]:

a.
Whenever muscle-invasive tumour is detected during follow-up
b.
If high-grade non-muscle invasive tumour is present at both

Follow-up regimens

Many urologists perform life-long, frequent follow-up cystoscopies in patients with NMIBC. However, such frequent follow-up is unnecessary, since approximately 50% of these patients have a very low risk of recurrence and a negligible risk of progression [27].

The recommended follow-up schedules proposed by the EAU, FICBT, NCCN, and AUA vary. In low-risk patients, for example, the EAU recommends surveillance cystoscopy at 3 mo. If negative, the following cystoscopy is advised at 9 mo and,

Conclusions

Through critical analysis and comparison of the EAU, FICBT, NCCN, and AUA guidelines, the IBCG has established areas of consensus on NMIBC management as well as on contentious topics that need to be addressed. Established areas of consensus among the four guidelines include the importance of TURBT and an immediate, postoperative dose of chemotherapy (agent optional) in all patients with NMIBC and the benefit of adjuvant BCG therapy in high-risk disease.

However, the four guideline

References (29)

M.C. Hall et al.
Guidelines for the management of non-muscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update
J Urol
(2007)
W. Oosterlinck et al.
Low-grade Ta (non-invasive) urothelial carcinoma of the bladder
Urology
(2005)
A.M. Nieder et al.
Management of stage T1 tumours of the bladder: international consensus panel
Urology
(2005)
R.J. Sylvester et al.
High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder
Urology
(2005)
Z. Kirkali et al.
Bladder cancer: epidemiology, staging and grading, and diagnosis
Urology
(2005)
R.J. Sylvester et al.
A single immediate post-operative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials
J Urol
(2004)
E. Kaasinen et al.
Factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently recurring superficial bladder carcinoma
Eur Urol
(2002)
R.J. Sylvester et al.
The schedule and duration of intravesical chemotherapy in patients with non–muscle-invasive bladder cancer: a systematic review of the published results of randomized clinical trials
Eur Urol
(2008)
R.J. Sylvester et al.
Long-term efficacy results of EORTC GU Group study 30911 comparing epirubicin, bacillus Calmette-Guérin (BCG), and BCG plus isoniazid in patients with intermediate and high risk stage Ta T1 papillary carcinoma of the bladder
Eur Urol Suppl
(2008)
R.J. Sylvester et al.
Intravesical bacillus Calmette-Guérin reduces the risk of progression in patients with superficial bladder cancer: a combined analysis of the published results of randomized clinical trials
J Urol
(2002)

A. Böhle et al.

Intravesical bacille Calmette-Guérin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumour progression

Urology

(2004)

A. Böhle et al.

Intravesical bacillus Calmette-Guérin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity

J Urol

(2003)

A.P. van der Meijden et al.

EAU Working Party on Non Muscle Invasive Bladder Cancer. EAU guidelines on the diagnosis and treatment of urothelial carcinoma in situ

Eur Urol

(2005)

D.L. Lamm et al.

Maintenance bacillus Calmette-Guérin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study

J Urol

(2000)

Cited by (27)

Care Quality and Variability in the Use of Intravesical Therapy for Initial Treatment of Nonmuscle Invasive Bladder Cancer Within a Large, Diverse Integrated Delivery System
2019, Urology
To examine treatment variability, disparities, and quality among newly diagnosed nonmuscle invasive bladder cancer (NMIBC) patients, and to identify factors associated with treatment use in a large, diverse integrated delivery system.
Retrospective cohort study of 5386 NMIBC patients diagnosed between January 2001 and June 2015 within Kaiser Permanente Southern California. Electronic health data were used to identify treatment outcomes and patient, provider, and tumor characteristics. Outcomes were use of (1) postoperative intravesical chemotherapy, (2) induction Bacille Calmette-Guérin (BCG) immunotherapy, and (3) any intravesical therapy. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using generalized linear mixed models with a binary outcome and urologist as a random effect.
From 2001 to 2015, 41% of newly diagnosed NMIBC patients were treated with intravesical therapy. Postoperative chemotherapy use increased significantly over this period (OR per-year = 1.16, 95% CI: 1.07-1.25). BCG use was strongly associated with tumor characteristics: patients with high-grade or carcinoma in situ tumors were more likely to receive BCG (OR = 10.10, 95% CI: 8.39-12.16). Few treatment differences were found by sex or race/ethnicity, but were observed by age. Wide treatment variability across urologists was observed, with some urologists never using intravesical therapy as part of initial treatment while others almost always used it. Differences across urologists accounted for more variability in postoperative chemotherapy (intraclass correlation coefficient = 0.52) than BCG immunotherapy (intraclass correlation coefficient = 0.11) use.
Substantial variability in initial treatment of NMIBC was observed across urologists, accounting for tumor, patient, and provider characteristics. Results suggest a considerable opportunity for quality improvement programs to reduce unwanted treatment variability and improve care for patients.
Second transurethral resection and prognosis of high-grade non-muscle invasive bladder cancer in patients not receiving bacillus Calmette- Guérin
2014, Actas Urologicas Espanolas
Definir la historia natural del tumor vesical T1G3 que no recibe bacilo de Calmette-Guerin (BCG) endovesical y evaluar el valor diagnóstico y terapéutico de una segunda resección transuretral (Re-RTU) en estos pacientes.
Estudio retrospectivo sobre la historia natural de 210 pacientes tratados en 2 instituciones por carcinoma vesical T1G3 sin CIS asociado. En ningún caso se administró BCG; 79 (37,6%) recibieron exclusivamente RTU y 131 (62,4%) Re-RTU 4-6 semanas después; 23 (12,4%) recibieron cistectomía por progresión tumoral.
La mediana de seguimiento fue 55 (78 IQR) meses, la proporción hombre/mujer 8/1 y la edad media 70,6 + 11,8 SD (37-93). Se encontraron libres de recurrencia a 10 años el 19,5%, y libres de progresión el 61,9%. Los factores pronóstico independientes de progresión fueron patrón sólido (HR: 2,71; p = 0,0004), multiplicidad (HR: 2,26; p = 0,003) y recidiva a 3 meses (HR: 3,4; p = 0,003). La supervivencia cáncer-específica fue del 81,5% a 5 años y del 69% a 10 años. Fueron factores independientes predictivos de supervivencia la progresión el primer año (HR: 17,9; p < 0,0001), el patrón sólido (HR: 2,13; p = 0,02), la multiplicidad (HR: 2,05; p = 0,03) y la edad > 65 años (HR: 2,9; p = 0,03). La Re-RTU evitó infraestadificación (7,4%), detectó enfermedad residual T1G3 (10,7%), redujo la tasa de recidiva a 3 meses (11,4 a 4,6%; p = 0,06) y la tasa de progresión al año (13,9 a 3,8%; p = 0,0075). Ahora bien, en estos pacientes el riesgo se mantiene y a largo plazo no se detectaron diferencias en términos de recurrencia (log-rank, p = 0,14), progresión (p = 0,91) o muerte por cáncer (p = 0,21) en pacientes tratados con Re-RTU.
La recurrencia en los primeros 3 meses de un tumor T1G3 que no recibe BCG es el principal factor de riesgo de progresión, y la progresión de este tipo de tumores en el primer año es el principal factor de muerte por cáncer. La Re-RTU mejora ambas variables, pero no modifica el pronóstico a largo plazo.
To define the natural history of T1G3 bladder tumor not receiving intravesical Bacillus Calmette-Guerin (BCG) and assess the diagnostic and therapeutic value of a second transurethral resection (Re-TUR) in these patients.
Retrospective study on the natural history of 210 patients treated at two institutions for T1G3 bladder carcinoma without associated CIS. In no case was BCG administered; 79 (37.6%) received TUR alone, and 131 (62.4%) Re-TUR 4 to 6 weeks later; 23 (12.4%) underwent cystectomy for tumor progression.
Median follow-up was 55 (78 IQR) months, male/female ratio 8/1, and mean age 70.6 + 11.8 (range 37-93). 19.5% were free of recurrence at 10 years, and 61.9% free of progression. Independent prognostic factors for progression were solid pattern (HR: 2.71; P = .0004), multiplicity (HR: 2.26; P = .003), and recurrence at 3 months (HR: 3.4; P = .003). Cancer-specific survival was 81.5% at 5 and 69% at 10 years. Independent predictors of survival were: progression during the first year (HR: 17.9; P < .0001), solid pattern (HR: 2.13; P = .02), multiplicity (HR: 2.05; P = .03), and age > 65 years (HR: 2.9; P = .03). Re-TUR avoided under-staging (7.4%), detected T1G3 residual disease (10.7%), reduced recurrence rate at 3 months (11.4 to 4.6%; P = .06), and rate of progression on the 1st year (13.9 to 3.8%; P = .0075). However, in these patients the risk remains and no differences were detected in the long term in terms of recurrence (log-rank, P = .14), progression (P = .91), or cancer death (P = .21) in patients treated with Re-TUR.
The recurrence in the first 3 months of a T1G3 tumor not receiving BCG is the main risk factor for progression, and progression of this type of tumors within the first year is the main factor of cancer death. The Re-TUR improves both variables but it does not change the long-term prognosis.
Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guérin
2013, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
CIS is considered a high-risk form of NMIBC because of frequent recurrences or progression [2,3], and treatment is directed at reducing or eliminating these events [2,3]. Guidelines recommend transurethral resection of the bladder tumor (TURBT) followed by bacillus Calmette-Guérin (BCG) induction and maintenance treatments for patients with high-risk NMIBC [2–6]. In these patients, BCG is superior to intravesical chemotherapy [7], especially when maintenance therapy is provided [2,8–10].
Evaluate the efficacy and safety of valrubicin for bacillus Calmette-Guérin (BCG)–refractory carcinoma in situ (CIS) of the bladder based on updated phase III pivotal trial efficacy data together with efficacy and safety data from a supportive phase II/III study.
In a phase II/III open-label study (A9303), BCG refractory/intolerant adults with CIS (≥1 previous course of BCG or could not complete a BCG course owing to toxicity or contraindication) were randomized to receive 6 or 9 weekly intravesical valrubicin (800 mg) instillations. In the pivotal phase III open-label study, BCG-refractory/recurrent adults with CIS (≥2 previous courses of intravesical therapy, including ≥1 BCG course) received 6 weekly intravesical valrubicin (800 mg) instillations. Patients with muscle-invasive disease were excluded. Patients underwent a primary disease evaluation (PDE) at 3 months (∼6 weeks after last dose) that included cytoscopy, biopsy, and cytology. Disease recurrence was monitored at 3-month intervals. Complete response (CR) was defined as no evidence of disease at the PDE (month 3) and follow-up (month 6). Efficacy data from the pivotal trial reflect updated information based on US Food and Drug Administration review. Safety assessments in A9303 included local bladder adverse events (LBAEs) and other adverse events (AEs).
Eighty patients enrolled and 78 completed treatment and underwent the PDE in study A9303; in the pivotal trial, the respective numbers were 90 and 87 patients. In study A9303, 39% of patients had received ≥2 previous courses of BCG and 11% had received ≥3 courses vs. 70% and 28%, respectively, in the pivotal trial. In both studies, the CR rate was 18%. In A9303, LBAEs were the most common AEs, reported by 86% of patients during treatment and 45% during follow-up; most treatment-related LBAEs were mild to moderate. 2 serious AEs in 1 patient (azotemia/reflux nephropathy) were judged as definitely or possibly treatment related; none of the patient deaths were judged to be related to valrubicin.
Two trials of valrubicin in patients with CIS demonstrate a consistent degree of efficacy in highly pretreated patients (pivotal trial; BCG-refractory patients) and those with fewer previous therapies (A9303; BCG-refractory/intolerant patients).
A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the international bladder cancer group
2011, Journal of Urology
Citation Excerpt :
Recommendations are based on consensus interpretation of the current guidelines and literature. Although the 4 guidelines agree on the importance of risk stratification for NMIBC management based on patient risk of recurrence and/or progression, there are differences in the definitions of risk as well as in the proposed treatments for each risk category (Appendix 1).1,3–5,7–10 Upon review of the 4 guidelines the IBCG proposed the practical definitions of low, intermediate and high risk disease based on risk of recurrence and disease progression (see figure).
Although the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines all provide an excellent evidence-based framework for the management of nonmuscle invasive bladder cancer, these guidelines vary with respect to important issues such as risk level definitions and management strategies for these risk categories. Therefore, we built on the existing framework provided by current guidelines, and provide consensus on the definitions of low, intermediate and high risk nonmuscle invasive bladder cancer, as well as practical recommendations for the treatment of patients in each of these risk categories.
An international committee of experts on bladder cancer management identified and analyzed the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines as well as the published English language literature related to the treatment and management of nonmuscle invasive bladder cancer available as of April 2010.
Based on review of the current guidelines and literature, the International Bladder Cancer Group developed practical recommendations for the management of nonmuscle invasive bladder cancer.
Complete transurethral bladder tumor resection is recommended for all patients with nonmuscle invasive bladder cancer. For low risk disease a single, immediate chemotherapeutic instillation after transurethral bladder tumor resection is recommended. For intermediate or high risk disease there is no significant benefit from an immediate, postoperative chemotherapeutic instillation. For intermediate risk disease intravesical bacillus Calmette-Guérin with maintenance or intravesical chemotherapy is recommended. For high risk disease bacillus Calmette-Guérin induction plus maintenance is recommended. The appropriate management of recurrence depends on the patient level of risk as well as previous treatment, while the management of treatment failure depends on the type of failure as well as the level of risk for recurrence and disease progression.
Modern transurethral resection in the management of superficial bladder tumours
2011, British Journal of Medical and Surgical Urology
Citation Excerpt :
They observed that multiplicity of the bladder tumour was a significant risk factor for upper tract lesions, and this is supported by other studies [53–55]. In high grade disease, tumours in the trigone or CIS the incidence of upper tract lesions is higher, and upper tract imaging in the form of IVU or CT-IVU is recommended by BAUS, EAU and AUA guidelines [56]. Due to the irregularity of subsequent upper tract involvement there is no consensus as to how often imaging takes place and as such imaging decisions will be made on a case-by-case basis.
Bladder cancer is the 5th commonest cancer in the UK and up to 85% will present with superficial disease. Considering the principals of oncological surgery, best practice is to excise a tumour whole with clear circumferential margins. The inherent flaw of transurethral resection (TUR) is tumour fragmentation. However, high quality resection and immediate single-dose chemotherapy decreases recurrence rates and disease progression for superficial disease. TUR is the current gold standard for diagnosis and treatment of superficial bladder cancer. The associated morbidity is usually low.
Good quality TUR can be difficult with tumours in diverticula, over ureteric orifices, on the dome/anterior/posterior wall or if obturator nerve stimulation occurs. As such technical tips are provided.
Modern TUR relies on white light. The use of fluorescence cystoscopy will almost certainly increase, challenging white light TUR as the current gold standard. Furthermore, the development of bladder cancer urinary markers may provide a cost effective and non-invasive means of determining the frequency of surveillance cystoscopy.
Modern transurethral resection in the management of superficial bladder tumours
2011, Journal of Clinical Urology
Citation Excerpt :
They observed that multiplicity of the bladder tumour was a significant risk factor for upper tract lesions, and this is supported by other studies [53–55]. In high grade disease, tumours in the trigone or CIS the incidence of upper tract lesions is higher, and upper tract imaging in the form of IVU or CT-IVU is recommended by BAUS, EAU and AUA guidelines [56]. Due to the irregularity of subsequent upper tract involvement there is no consensus as to how often imaging takes place and as such imaging decisions will be made on a case-by-case basis.
Bladder cancer is the 5th commonest cancer in the UK and up to 85% will present with superficial disease. Considering the principals of oncological surgery, best practice is to excise a tumour whole with clear circumferential margins. The inherent flaw of transurethral resection (TUR) is tumour fragmentation. However, high quality resection and immediate single-dose chemotherapy decreases recurrence rates and disease progression for superficial disease. TUR is the current gold standard for diagnosis and treatment of superficial bladder cancer. The associated morbidity is usually low.
Good quality TUR can be difficult with tumours in diverticula, over ureteric orifices, on the dome/anterior/posterior wall or if obturator nerve stimulation occurs. As such technical tips are provided.
Modern TUR relies on white light. The use of fluorescence cystoscopy will almost certainly increase, challenging white light TUR as the current gold standard. Furthermore, the development of bladder cancer urinary markers may provide a cost effective and non-invasive means of determining the frequency of surveillance cystoscopy.

View all citing articles on Scopus

View full text

Current Approaches to the Management of Non-Muscle Invasive Bladder Cancer: Comparison of Current Guidelines and Recommendations

Abstract

Context

Objective

Evidence acquisition

Evidence synthesis

Conclusions

Introduction

Section snippets

Definitions of levels of risk

Transurethral resection of the bladder tumour

Defining treatment failure

Follow-up regimens

Conclusions

J Urol

Urology

Urology

Urology

Urology

J Urol

Eur Urol

Eur Urol

Eur Urol Suppl

J Urol

Urology

J Urol

Eur Urol

J Urol