Rationale

In general, recurrence is a problem for patients (because any tumour recurrence raises the concern that the cancer will progress and/or spread) and for the NHS (because of the need to provide capacity for treatment of recurrence), but it does not threaten patients' lives. In contrast, progression does threaten patients' lives, because if the muscle coat of the bladder becomes involved with cancer, between 20 and 25 out of 100 such patients will have spread into their lymph glands, and their chance of cure falls sharply.

We have some pathological markers of the risks of recurrence and progression, such as stage, grade, and the presence of carcinoma in situ, and other clinical markers, such as tumour size, number and the presence of recurrence at three months from the initial resection. On the basis of EORTC chemotherapy study data, it was suggested many years ago that the management of LRNMIBC could be streamlined significantly by the use of two easily established clinical variables alone, namely whether the initial tumour is solitary or multifocal, and whether there was recurrence or not at three months. Despite the evidence base for this, and its ease of assessment, it has not become widely used in the NHS.

So the use of these factors remains unsatisfactory for an individual patient, and does not predict the individual risks of recurrence and progression. Molecular markers (such as EGFR) have been studied for over 20 years, to see if some laboratory studies are able to be useful in clinical practice, but none has emerged as useful to the NHS.

If we knew better for individual patients about their risk of recurrence and particularly progression, it would be possible to inform the discussion of the cancer risk, which is one of the pillars of the discussion about which treatment option is best for a given patient. Many patients would consider better forecasting of their own personal cancer risk to be a very useful step forward.

Question in PICO format

METHODS

RESULTS

Result of the literature searches

Figure 30Study flow diagram

Study quality and results

The NICE prognostic studies methodological checklist was used to assess the quality of the prognostic studies. All studies were assessed as being of high quality as they included the population of interest, measured the outcome adequately, and used appropriate statistical analysis. However, validation studies of the EORTC risk tables were limited by heterogeneous patient populations and treatments received and by low numbers of progression events. Studies exploring the prognostic factors of lymphovascular invasion, TCC variants and TCC differentiation were limited by small sample sizes and few patients with the factor under investigation. The results of the study quality assessment is provided in Table 30. The results of the included studies are summarised in Tables 26-33 and Figures 31-35.

Table 30

Study quality assessment.

Table 31

Univariate and multivariate analyses of recurrence.

Table 32

Univariate and multivariate analyses of progression.

Table 33

Univariate and multivariate analyses of overall survival.

Figure 31

Univariate analyses of lymphovascular invasion on recurrence.

Figure 32

Multivariate analyses of lymphovascular invasion on recurrence.

Figure 33

Univariate analyses of lymphovascular invasion on progression.

Figure 34

Multivariate analyses of lymphovascular invasion on progression.

Narrative summary of evidence

EORTC risk factors: Recurrence & Progression

The European Organization for Research and Treatment of Cancer (EORTC) Genito-Urinary Group published risk tables that provide the probabilities that a patient with superficial bladder cancer (Ta,T1) will recur or progress to muscle-invasive disease after transurethral resection of the bladder tumour (TURBT) (Sylvester, 2006). Seven randomised trials including 2596 patients and with a maximum follow-up of 15 years were included in the analysis by Sylvester (2006). 6% of patients were randomised to intravesical bacillus Calmette-Guérin (BCG) and none of the patients received maintenance therapy. The EORTC scoring system was derived based on six clinical and pathological factors: number of tumours, tumour size, prior recurrence rate, T category, carcinoma in situ (CIS), and grade. Fernandez-Gomez (2011) reported a validation of the EORTC risk tables in a cohort of 1062 patients treated with BCG from 4 randomised trials (CUETO studies). 73% of this cohort received 10-12 BCG instillations. The EORTC risk tables successfully divided CUETO patients into four risk groups for recurrence and progression.

The c-indices for recurrence were similar in the EORTC and CUETO series. For recurrence the PSEP in the CUETO series was lower than the EORTC at 1-year (0.3/0.26 vs. 0.46), similar results were found at 5-years (0.49/0.51 vs. 0.47). For progression, the c-index in the CUETO cohort was 0.69 at 1-year and 0.68 at 5-year, which are lower than the EORTC c-indices for progression at 1-year (0.74) and 5-years (0.75). The PSEP in the CUETO series was lower than the EORTC for progression at 5-years (0.25 vs. 0.442). Xylinas (2013) presented a validation study of 4689 patients, and reported c-indices which demonstrated poor discrimination of the EORTC risk models for recurrence and progression.

In 7 validation studies (Fernandez-Gomez 2011; Seo 2010; Altieri 2012; Hernandez 2011; van Rhijn 2010; Xu 2013; Lammers 2014), the EORTC risk tables generally overestimated the risk of recurrence in all risk groups and the risk of progression at 5-years especially in high risk groups. However, many of these studies were limited by a low number of progression events. In an earlier report from the CUETO cohort, Fernandez-Gomez (2008) reported that, in multivariate analysis, female gender (HR=1.71) compared to male gender, recurrent tumours (HR=1.9) compared to primary tumours, multiplicity, and presence of associated tumour in situ (TIS) (HR=1.55), were significant independent factors for recurrence. For progression, recurrent tumours (HR=1.62) compared to primary tumours, high-grade tumours (HR=5.64) compared to G1 tumours, T1 tumours (HR=2.15) compared to Ta tumours, and recurrence at 3-month cystoscopy (HR=4.6) were independent predictive factors.

One study of 592 Japanese patients, half of whom received no intravesical therapy after TURBT, attempted to validate the EORTC risk scores for recurrence (Sakano, 2010). There was only a significant difference in recurrence-free survival when the low-risk and intermediate-low risk groups were combined into one group, and the intermediate-high risk and high risk groups were considered as another group. Multivariate analysis showed that prior recurrence rate, number of tumours, and T category were independent predictors for time to first recurrence.

In another validation study including 230 patients with primary non-muscle invasive bladder cancer (van Rhijn, 2010), EORTC risk scores for progression and recurrence were significant factors in multivariate analysis. However, none of the patients in this cohort were at high risk of recurrence and all patients had primary NMIBC, which limits the usefulness of this study. One study of patients with T1 bladder cancer, all of whom were treated with BCG, reported that EORTC risk scores were not significant predictors of progression or recurrence (van Rhijn, 2012). Multiplicity was the most important variable for predicting recurrence, whilst sub-stage (T1m/T1e), female gender and CIS were the most important variables for progression in multivariate analysis.

One prognostic study of 146 patients with T1G3 NMIBC treated with an induction course of BCG reported that female gender and presence of CIS in the prostatic urethra were associated with an increased risk of recurrence, progression and disease-specific mortality (Palou, 2012).

Lymphovascular invasion: Recurrence and progression

Seven studies included lymphovascular invasion as a prognostic factor for recurrence or progression (Brimo 2013; Miyake 2011; Kwon 2012; Cho 2009; Tilki 2012; Park 2009; Olsson 2013). Some studies reported that the presence of lymphovascular invasion was a prognostic factor for recurrence or progression and some studies reported no significant effect in univariate and multivariate analyses (see Figures 31-35 below for forest plots of reported hazard ratios from univariate and multivariate analyses). Analysis of this factor was limited by the low number of patients with invasion. Park (2009) reported that lymphovascular invasion was not a predictor of recurrence or progression in patients with T1G3 bladder cancer who received BCG therapy (HRs were not reported so could not be included in the forest plots).

Lymphovascular invasion: Disease-specific survival

Two studies (Lopez, 1995; Tilki, 2012) reported that lymphovascular invasion was an independent prognostic factor for disease-specific survival and one study reported no significant effect (Olsson, 2013) (see Figure 35).

Figure 35

Multivariate analyses of lymphovascular invasion on disease-specific survival.

Lymphovascular invasion: Overall survival

One study of 108 patients (Branchereau 2013) reported that lymphovascular invasion was an independent prognostic factor for overall survival for patients with high grade T1 tumours (p=0.003, HR not reported).

Histological subtype (‘usual TCC vs. micropapillary/sarcomatoid TCC): Recurrence and progression

One study (Brimo, 2013) reported that adverse histological variants were significantly associated with progression and recurrence on univariate analysis but were insignificant on multivariate analysis. Only 4 tumours were not ‘usual TCC. 3 had features of micropapillary TCC and 1 had features of sarcomatoid TCC.

Histological subtype (TCC vs. squamous cell carcinoma): Overall survival and disease specific survival

Scosyrev (2009) reported that squamous cell histologic features were associated with overall mortality and disease-specific mortality compared to TCC in patients who did not undergo cystectomy, but was not associated with increased mortality in those who were treated with cystectomy.

Micropapillary pattern (MPP): Progression

One study (Alkibay, 2009), reported that progression rates increased in patients with NMIBC and MPP compared with MPP-negative patients but this difference was not statistically significant (p=0.064). This analysis was based on only 6 patients with T1 bladder cancer and MPP, and 125 TaT1 MPP-negative patients.

Evidence statements

The EORTC risk tables (Sylvester et al., 2006) have been validated in several studies, which report that the tables successfully stratify patients into risk groups for recurrence and progression, but generally overestimate the risk of recurrence in all risk groups and the risk of progression in high risk groups (Fernandez-Gomez et al., 2011; Seo et al., 2010; Altieri et al., 2012; Hernandez et al., 2011; van Rhijn et al., 2010; Xu et al., 2013; Lammers et al., 2014).

There is some low quality evidence to suggest that the presence of lymphovascular invasion increases the risk of recurrence, progression and disease-specific survival. However, this is based on low numbers of patients with evidence of lymphovascular invasion.

One study (Brimo et al., 2013) reported that adverse histological variants were significantly associated with progression and recurrence on univariate analysis but were insignificant on multivariate analysis. Only four tumours were not ‘usual TCC. Three had features of micropapillary TCC and one had features of sarcomatoid TCC.

One study (Scosyrev et al., 2009) reported that squamous cell histologic features were associated with overall mortality and disease-specific mortality compared to TCC in patients who did not undergo cystectomy, but was not associated with increased mortality in those who were treated with cystectomy.

One study (Alkibay et al., 2009), reported that progression rates increased in patients with NMIBC and micropapillary pattern (MPP) compared with MPP-negative patients but this difference was not statistically significant (p=0.064). This analysis was based on only six patients with T1 bladder cancer and MPP, and 125 TaT1 MPP-negative patients.

Table 34

Univariate and multivariate analyses of disease-specific survival.

Table 35

Validation studies of the EORTC risk tables. Concordance index (c-index) used to asses model accuracy. It represents the probability of concordance between the predicted and observed outcomes. A c-index of 0.50 represents agreement by chance. Perfect (more...)

Table 36

Validation studies of the EORTC risk tables. Prognostic separation index (PSEP) (P_worst − P_best) is based on the difference between the P_worst (the predicted probability of recurrence or progression in the group with the poorest prognosis) and (more...)

Table 37

Probabilities of recurrence according to EORTC risk tables and validation studies at 1-year and 5-year.

Table 38

Probabilities of progression according to EORTC risk tables and validation studies at 1-year and 5-year.

References to included studies

1. Alkibay T, et al. Micropapillary pattern in urothelial carcinoma: a clinicopathological analysis. Urologia Internationalis. 2009;83(3):300–305. [PubMed: 19829030]
2. Altieri VM, et al. Recurrence and progression in non-muscle-invasive bladder cancer using EORTC risk tables. Urologia Internationalis. 2012;89(1):61–66. [PubMed: 22722366]
3. Branchereau J, et al. Prognostic value of the lymphovascular invasion in high-grade stage pT1 bladder cancer. Clinical Genitourinary Cancer. 2013;11(2):182–188. [PubMed: 23276589]
4. Brimo F, et al. Prognostic factors in T1 bladder urothelial carcinoma: the value of recording millimetric depth of invasion, diameter of invasive carcinoma, and muscularis mucosa invasion. Human Pathology. 2013;44(1):95–102. [PubMed: 22939956]
5. Cho KS, et al. Lymphovascular invasion in transurethral resection specimens as predictor of progression and metastasis in patients with newly diagnosed T1 bladder urothelial cancer. Journal of Urology. 2009;182(6):2625–2630. [PubMed: 19836779]
6. Fernandez-Gomez J, et al. Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin: Multivariate analysis of data from four randomized CUETO trials. European Urology. 2008;53(5):992–1002. [PubMed: 17950987]
7. Fernandez-Gomez J, et al. The EORTC tables overestimate the risk of recurrence and progression in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin: external validation of the EORTC risk tables. European Urology. 2011;60(3):423–430. [PubMed: 21621906]
8. Hernandez V, et al. External validation and applicability of the EORTC risk tables for non-muscle-invasive bladder cancer. World Journal of Urology. 2011;29(4):409–414. [PubMed: 21190023]
9. Kwon DH, Song PH, Kim HT. Multivariate analysis of the prognostic significance of resection weight after transurethral resection of bladder tumor for non-muscle-invasive bladder cancer. Korean Journal of Urology. 2012;53(7):457–462. [PMC free article: PMC3406190] [PubMed: 22866215]
10. Lammers RJ, et al. Comparison of expected treatment outcome provided by risk models and international guidelines with observed treatment outcome in a cohort of Dutch non-muscle-invasive bladder cancer patients treated with intravesical chemotherapy. BJU Int. 2014 [PubMed: 24304638]
11. Lopez JI, Angulo JC. The prognostic significance of vascular invasion in stage T1 bladder cancer. Histopathology. 1995;27(1):27–33. [PubMed: 7557903]
12. Miyake M, et al. Clinical significance of subepithelial growth patterns in non-muscle invasive bladder cancer. BMC Urology. 2011;11(1):17. [PMC free article: PMC3167754] [PubMed: 21816111]
13. Olsson H, et al. Population-based study on prognostic factors for recurrence and progression in primary stage T1 bladder tumours. Scandinavian Journal of Urology. 2013;47(3):188–195. [PubMed: 22954205]
14. Palou J, et al. Female Gender and Carcinoma In Situ in the Prostatic Urethra Are Prognostic Factors for Recurrence, Progression, and Disease-Specific Mortality in T1G3 Bladder Cancer Patients Treated With Bacillus Calmette-Guerin. European Urology. 2012;62(1):118–125. [PubMed: 22101115]
15. Park J, et al. Prognostic significance of non-papillary tumor morphology as a predictor of cancer progression and survival in patients with primary T1G3 bladder cancer. World Journal of Urology. 2009;27(2):277–283. [PubMed: 19020879]
16. Sakano S, et al. Risk group stratification to predict recurrence after transurethral resection in Japanese patients with stage Ta and T1 bladder tumours: validation study on the European Association of Urology guidelines. BJU International. 2011;107(10):1598–1604. [PubMed: 21087393]
17. Scosyrev E, Yao J, Messing E. Urothelial carcinoma versus squamous cell carcinoma of bladder: is survival different with stage adjustment? Urology. 2009;73(4):822–827. [PubMed: 19193403]
18. Seo KW, et al. The efficacy of the EORTC scoring system and risk tables for the prediction of recurrence and progression of non-muscle-invasive bladder cancer after intravesical bacillus calmette-guerin instillation. Korean Journal of Urology. 2010;51(3):165–170. [PMC free article: PMC2855454] [PubMed: 20414391]
19. Sylvester RJ, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. European Urology. 2006;49(3):466–475. [PubMed: 16442208]
20. Tilki D, et al. Lymphovascular invasion is independently associated with bladder cancer recurrence and survival in patients with final stage T1 disease and negative lymph nodes after radical cystectomy. BJU International. 2013;111(8):1215–1221. [PubMed: 23181623]
21. van Rhijn BW, et al. Molecular grade (FGFR3/MIB-1) and EORTC risk scores are predictive in primary non-muscle-invasive bladder cancer. European Urology. 2010;58(3):433–441. [PubMed: 20646825]
22. van Rhijn BW, et al. Prognostic value of molecular markers, sub-stage and European Organisation for the Research and Treatment of Cancer risk scores in primary T1 bladder cancer. BJU International. 2012;110(8):1169–1176. [PubMed: 22448597]
23. Xu T, et al. Predicting recurrence and progression in Chinese patients with nonmuscle-invasive bladder cancer using EORTC and CUETO scoring models. Urology. 2013;82(2):387–393. [PubMed: 23759377]
24. Xylinas E, et al. Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder. British Journal of Cancer. 2013;109(6):1460–1466. [PMC free article: PMC3776972] [PubMed: 23982601]

Evidence tables

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Rationale

The risk of recurrence can be reduced by the administration of chemotherapy medication, in liquid form, into the bladder (intravesical chemotherapy). This can be done immediately, or shortly after telescopic removal of the tumour (transurethral resection), and subsequently, as a planned outpatient procedure. Several different chemotherapy drugs have been used, and studied.

There is debate (and variation) about which patients with which sort of LRNMIBC should be treated with intravesical chemotherapy, including whether patients with small or very small tumours should be treated, and what sort of recurrent tumours should be treated.

The advantage of not being treated is that no side effects of treatment are suffered, whereas the benefit of being treated may be that recurrence becomes less likely. The disadvantage of not being treated is that there is no reduction in the risk of recurrence, and the disadvantage of being treated is that side effects (such as urine infection, bladder pain, and genital rashes) are suffered.

Instillation of BCG vaccine is also offered to some patients who have recurrence of LRNMIBC following previous intravesical chemotherapy. The side effects of BCG include irritation of the bladder, urine infection, occasional rare consequences probably related to the effects of BCG on the body's immune system, and very rare infections with the BCG bacteria. These side effects need to be considered in a consideration of the advantages and disadvantages of BCG equivalent to the consideration of the advantages and disadvantages of intravesical chemotherapy.

The topic is being considered because LRNMIBC is common, recurrence is common, and because intravesical chemotherapy has significant efficacy, but the pattern of disease is not homogeneous, meaning the grade, size, number and recurrence history of tumours can combine to present a significantly mixed group of patients and tumours, so that determining which patients with which tumours should be treated is an important area for guidance.

Question in PICO format

METHODS

RESULTS

Result of the literature searches

Figure 36Study flow diagram

Study quality and results

The quality and results of the included studies are summarised in GRADE evidence profiles (Tables 39-65).

Table 39

GRADE evidence profile: TUR + BCG versus TUR alone.

Table 40

GRADE evidence profile: TUR + BCG versus TUR + other treatment (chemotherapy or other immunotherapy) or TUR alone.

Table 41

GRADE evidence profile: TUR + BCG versus TUR + other treatment (chemotherapy or other immunotherapy) of TUR alone for T1G3 bladder cancer.

Table 42

GRADE evidence profile: TUR + chemotherapy versus TUR alone.

Table 43

GRADE evidence profile: TUR+ one single post-operative chemotherapy instillation versus TUR alone.

Table 44

GRADE evidence profile: TUR + single dose epirubicin (100mg) versus TUR + double dose epirubicin (2×100mg).

Table 45

GRADE evidence profile: TUR + 2×20mg/40ml epirubicin versus TUR + 2×50mg/100ml epirubicin versus TUR only.

Table 46

GRADE evidence profile: Adriamycin versus Epirubicin.

Table 47

GRADE evidence profile: TUR + chemotherapy versus TUR + BCG.

Table 48

GRADE evidence profile: TUR + chemotherapy versus TUR + BCG for CIS only.

Table 49

GRADE evidence profile: BCG versus MMC.

Table 50

GRADE evidence profile: BCG versus Epirubicin.

Table 51

GRADE evidence profile: BCG versus Gemcitabine.

Table 52

GRADE evidence profile: Maintenance BCG versus induction BCG.

Table 53

GRADE evidence profile: Standard dose BCG (81mg) versus reduced dose BCG (27mg).

Table 54

GRADE evidence profile: Low dose BCG (27mg) versus very low dose BCG (13.5mg).

Table 55

GRADE evidence profile: Standard dose BCG (81mg) versus reduced dose BCG (27mg).

Table 56

GRADE evidence profile: Standard dose BCG (81mg) versus reduced dose BCG (54mg).

Table 57

GRADE evidence profile: 120mg BCG versus 80mg BCG versus 40mg BCG.

Table 58

GRADE evidence profile: One immediate instillation chemotherapy versus one instillation plus maintenance.

Table 59

GRADE evidence profile: One immediate instillation followed by short-term versus long-term instillations during 12 months.

Table 60

GRADE evidence profile: One immediate instillation chemotherapy versus delayed instillations to month 12.

Table 61

GRADE evidence profile: One immediate instillation chemotherapy + additional instillations during 6 mo versus delayed instillations during 6 mo.

Table 62

GRADE evidence profile: One immediate instillation chemotherapy + additional instillations during 12 mo versus delayed instillations during 12 mo.

Table 63

GRADE evidence profile: Short-term delayed instillations versus long-term delayed instillations.

Table 64

GRADE evidence profile: Less intense or frequent schedule of chemotherapy versus more intense or frequent schedule of chemotherapy.

Table 65

GRADE evidence profile: Intravesical chemotherapy + BCG versus maintenance BCG alone.

Narrative summary of evidence

TUR + BCG versus TUR alone

Moderate quality evidence from a meta-analysis (Shelley et al., 2000) of 585 medium-high risk patients from six randomised trials (all published prior to 1999) produced an overall HR of 0.44 (95% CI 0.34 to 0.56), indicating a 56% reduction in the possibility of tumour recurrence for TUR+BCG compared to TUR alone.

Figure 37

TUR+BCG versus TUR alone. Outcome: recurrence-free survival (Shelley 2000)

29% (79/275) of the BCG group presented with a recurrence at 12 months, compared to 56% (144/257) in the TUR only group with a risk ratio (RR) of 0.54 (95% CI 0.44 to 0.66), indicating a 46% reduced risk of recurrence at 12 months with BCG compared to TUR alone.

Figure 38

TUR+BCG versus TUR alone. Outcome: Recurrence at 12 months (Shelley 2000)

Another meta-analysis (Han, 2006) provided high quality evidence from 9 RCTs and controlled observational cohort studies (1100 patients) published between 1997 and 2005. BCG+TUR was associated with a lower risk of recurrence compared to TUR alone (RR 0.59, 95% CI 0.45 to 0.78).

The systematic review by Shelley (2000) reported that the main toxicities associated with BCG were urinary frequency (71%), cystitis (67%), haematuria (23%), and fever (25%). No BCG sepsis or deaths were reported.

TUR + BCG versus TUR alone or TUR + another treatment

Moderate quality evidence from a meta-analysis (Pan, 2014) of 48 RCTs and observational cohort studies (9482 patients) reported a pooled random effects OR for recurrence of 0.59 (95% CI 0.49 to 0.71) for TUR + BCG compared to those treated with resection alone or TUR plus another treatment other than BCG, with significant heterogeneity across studies (p<0.01). Evidence from an earlier meta-analysis (Han, 2006) suggested that the effect of BCG is less conclusive when induction BCG only is given compared to control groups (RR 0.99, 95% CI 0.77 to 1.28). In the maintenance BCG subgroup the combined random effect RR is 0.65 (95% CI 0.48 to 0.88), suggesting that maintenance BCG reduces the risk of recurrence by 35%. There were no differences when studies were stratified by BCG strain. Another meta-analyses (Pan, 2008) of 13 trials or controlled studies, which compared maintenance BCG versus no maintenance BCG for T1G3 bladder cancer, reported that overall 41% of the maintenance BCG group recurred compared to 45% in the control group (RR 0.73, 95% CI 0.61, 0.88).

High quality evidence from one meta-analysis (Sylvester 2002) of 24 randomised trials with 4863 patients reported that the risk of progression was 27% lower for patients treated with BCG compared to those treated with either resection alone or TUR plus another treatment other than BCG (HR 0.73, 95% CI 0.60 to 0.88). There was no difference in the size of treatment effects across the different control groups (see figure 39 below) or according to the strain of BCG used.

Figure 39

TUR+BCG versus TUR+other treatments. Outcome: Progression (Sylvester, 2002)

No reduction in the risk of progression was seen in the four trials where maintenance BCG was not used (HR 1.28, 95% CI 0.82 to 1.98). In trials where maintenance BCG was used, the risk of progression was lower for those treated with BCG compared to the control groups (HR 0.57, 95% CI 0.44 to 0.75).

Figure 40

TUR+BCG versus TUR+another treatment. Outcome: Progression (Sylvester, 2002)

There were no significant differences in overall survival (HR 0.89, 95% CI 0.75 to 1.06) or disease-specific survival (HR 0.81, 95% CI 0.57 to 1.13) between those treated with BCG and those in the control groups. The two meta-analyses by Han (2006) and Pan (2008) both reported that drug-related and systemic toxicities were significantly more frequent in the BCG groups than chemotherapy or immunotherapy groups.

TUR + chemotherapy versus TUR alone

One systematic review and meta-analysis of 11 studies and 3703 patients with primary bladder cancer reported a Peto Odds Ratio (pOR) of 0.56 (95% CI 0.48 to 0.65) for 1-year recurrence in favour of adjuvant intravesical chemotherapy compared to TUR alone (Huncharek, 2000). However, significant statistical heterogeneity was reported and sensitivity analyses were conducted. The data were stratified by duration of treatment, which indicated that short-term therapy (≤2 months duration) reduced recurrence at 1-year (pOR 0.70, 95% CI 0.55 to 0.90) and 2-years (pOR 0.68, 95% CI 0.54 to 0.85) by approximately 30%, as compared to TUR alone (moderate quality evidence). The pooled pOR for 5 trials where patients received 2 years of chemotherapy was 0.27 (95% CI 0.19 to 0.39), indicating a 73% reduction in the risk of recurrence at 2 years for those treated with chemotherapy.

One systematic review and meta-analysis of 8 studies and 1609 patients with recurrent bladder cancer reported a pooled pOR for 1-year recurrence of 0.62 (95% CI 0.51 to 0.76), in favour of chemotherapy over TUR alone, with no evidence of statistical heterogeneity (moderate quality evidence). For the 2- and 3-year recurrence rates, significant statistical heterogeneity was reported, which was not accounted for by treatment duration. Therefore, moderate quality evidence was reported from the data when stratified by drug type (adriamycin versus other drugs). The pOR for 2-year recurrence of studies using adriamycin was 0.57 (95% CI 0.43 to 0.75), with no significant heterogeneity, indicating that drug type was a major contributor to outcome heterogeneity. Drugs other than adriamycin showed a reduction in 2-year recurrence of 73% (versus 43% for adriamycin) with an pOR of 0.27 (95% CI 0.19 to 0.37). The non-overlapping CIs indicate a significant difference in tumour reduction effect, with adriamycin appearing less effective than other drugs (e.g. thiotepa, MMC).

A systematic review and meta-analysis (Pawinski, 1996) provided moderate quality evidence from 6 randomised trials, which suggests there is uncertainty about the effect of intravesical chemotherapy on progression (HR 1.19, 95% CI 0.97 to 1.47), overall survival (HR 1.1, 95% CI 0.95 to 1.27), and disease-specific survival (HR 1.1, 95% CI not reported but effect size was non-significant), compared to TUR alone.

TUR + one post-operative instillation of chemotherapy versus TUR alone

Low to moderate quality evidence was provided from a systematic review and meta-analysis of 18 trials comparing one post-operative dose of chemotherapy with TUR alone (Abern, 2013). 36.6% (577/1576) of those in the TUR + chemotherapy group experienced a recurrence compared with 50.4% (769/1527) of those treated with TUR alone (RR 0.67, 95% CI 0.56 to 0.79), with significant statistical heterogeneity. This corresponds to a number needed to treat of 7.2 patients to avoid one recurrence. Gemcitabine and interferon α-2b did not show a benefit on recurrence, whereas the other chemotherapy agents did. The pooled RR for mitomycin C and epirubicin was 0.71 (95% CI 0.64 to 0.78), in favour of chemotherapy, with no clear dose-response relationship. Individual tumour risk factors such as recurrence, multiplicity, stage, and grade, did not appear to alter the efficacy of a single dose of chemotherapy. Funnel plots suggested the existence of publication bias with small trials contributing disproportionately to the protective effect of chemotherapy. A meta-analysis (Sylvester, 2004) of 7 trials (1476 patients) reported mild, transient, irritative bladder symptoms including dysuria, frequency and macroscopic haematuria, in approximately 10% of patients treated with intravesical chemotherapy.

TUR + chemotherapy versus TUR + BCG

One systematic review of 9 trials and 2261 patients (Huncharek, 2003) reported low quality evidence of an overall OR for 1-year recurrence of 0.89 (95% CI 0.74 to 1.07), with significant heterogeneity. Heterogeneity persisted despite stratification by chemotherapy drug type. A sensitivity analysis was therefore performed stratifying by previous intravesical chemotherapy. Pooling all studies that enrolled patients with prior chemotherapy (1480 patients) provided moderate quality evidence, with an OR of 0.54 (95% CI 0.43 to 0.69), in favour of BCG. This reflects a 46% reduction in tumour recurrence at 1-year among patients treated with BCG versus chemotherapy, and a lack of statistical heterogeneity. Pooling data from 2 studies which excluded patients previously treated with chemotherapy gave an OR of 1.82 (95% CI 1.37 to 2.41), in favour of chemotherapy. This suggests that amongst patients not previously treated, intravesical chemotherapy (MMC) reduces tumour recurrence by 82% versus BCG. Similar results were found for 2-year and 3-year recurrence when stratified by previous therapy.

One systematic review of 8 randomised trial and 2427 patients (Huncharek, 2004) randomised to either adjuvant intravesical BCG or chemotherapy provided moderate quality evidence of an OR for progression of 1.24 (95% CI 0.95 to 1.61), in favour of BCG. The confidence intervals include the value of no effect which suggests uncertainty of a difference between the two treatments in terms of progression. The total number of events in each arm was not reported. Subgroup analyses of MMC vs. BCG (4 trials, 1478 patients) provided an OR of 1.04 (0.76 to 1.42) suggesting no difference in risk of progression. The pooled OR of the two trials (781 patients) which excluded patients who had previously been treated with intravesical chemotherapy was 0.75 (0.45 to 1.25) in favour of MMC. In trials which included patients previously treated with chemotherapy the OR was 1.49 (1.09 to 2.03) in favour of BCG.

One meta-analysis (Sylvester 2005) of 9 randomised trials and 700 patients with CIS provided moderate quality evidence that 34% of complete responders treated with BCG and 50% of complete responders treated with chemotherapy recurred during follow-up (HR 0.47, 95% CI 0.31 to 0.73) in favour of BCG. 47% of patients treated with BCG and 26% treated with chemotherapy had no evidence of disease during follow-up, an absolute difference of 20% and a relative reduction of 59% in the odds of treatment failure on BCG (HR 0.41, 95% CI 0.30 to 0.56). BCG only appeared to be superior to MMC in the trials where maintenance BCG was given (see Figure 41). Data on progression was less conclusive with an HR of 0.74 (95% CI 0.45 to 1.22). Overall survival was reported in three studies (407 patients). 35.9% of patients treated with chemotherapy and 34.2% treated with BCG therapy died from any cause. Two trials reported disease-specific survival. 13.3% of patients treated with chemotherapy and 10.5% of patients treated with BCG died due to bladder cancer.

Figure 41

BCG versus MMC according to BCG maintenance. Outcome: no evidence of disease (Sylvester, 2005)

BCG vs. MMC

Moderate quality evidence was reported from one systematic review and meta-analysis (Bohle 2003) of 2749 patients from 9 prospective trials and 2 observational studies. A further trial of 92 patients was indentified and added to the pooled analysis for overall recurrence and recurrence by maintenance therapy (Mangiarotti 2008). The overall RR for recurrence was 0.77 (95% CI 0.63 to 0.95) in favour of BCG over MMC. BCG maintenance showed superiority over MMC with an RR or 0.68 (95% CI 0.55 to 0.83) (Figure 42). A dose response relationship was observed, where at least 12 instillations of BCG are required for its relevant superiority over MMC. The studies using BCG strain RIVM or RIVM plus TICE reported much weaker efficacy results for BCG than any other study in the meta-analysis. Cystitis was more frequent in the BCG group compared to the MMC group (53.8% vs. 39.2%, p<0.001). Local and systemic toxicities were more frequent in the BCG group, except for allergy and skin reactions which were more common in MMC group. The risk of cystitis was no different between maintenance BCG and no maintenance BCG. No deaths from sepsis were reported in either arm.

Figure 42

BCG versus MMC by maintenance. Outcome: Recurrence (Bohle, 2003)

Moderate quality evidence from one meta-analysis including 1277 patients (Bohle, 2004) reported no difference between BCG and MMC in terms of disease progression. Overall, 7.7% (98/1127) of the BCG group progressed versus 9.4% (107/1133) of the MMC group (RR 0.79, 95% CI 0.61 to 1.03). However, BCG did show superiority over MMC in the subgroup of BCG maintenance trials (RR 0.70, 95% CI 0.52 to 0.94). There were no significant confounding effects when stratified by BCG strain, BCG dose, risk group, MMC dose, number of MMC instillations, follow-up duration, or year of publication.

Figure 43

BCG versus MMC by BCG maintenance. Outcome: Progression (Bohle, 2004)

High quality evidence from a meta-analysis of individual patient data (Malmstrom, 2009) including 9 trials (2820 patients) reported that in trials with BCG maintenance, there was a 32% reduction in the risk of recurrence with BCG compared to MMC (HR 0.68, 95% CI 0.58 to 0.8), whilst there was a 28% risk increase for BCG trials without maintenance (HR 1.28, 95% CI 1.07 to 1.52) (see Figure 44). Maintenance BCG was more effective than MMC in both patients previously treated and those not previously treated with intravesical chemotherapy.

Figure 44

BCG versus MMC, by BCG maintenance. Outcome: Time to first recurrence (Malmstrom, 2009)

Moderate quality evidence from 7 trials (1880 patients) in the IPD meta-analyses reported that after a median follow-up of 4.8 years, 12% of patients progressed to MIBC and 24% died (of those 30% died from bladder cancer). There were no significant differences between MMC and BCG for these end-points, even when stratified by BCG maintenance and patient risk groups.

BCG versus Epirubicin (EPI)

One systematic review of 5 randomised trials (Shang, 2011), reported that the risk of recurrence was reduced in patients treated with BCG (35.5%) compared to EPI (51.4%) with a RR of 0.69 (95% CI 0.60 to 0.79), in favour of BCG. Subgroup analyses demonstrated that two trials which treated patients with Pasteur strain BCG found no significant difference in recurrence between BCG and EPI (RR 0.78, 95% CI 0.56 to 1.10).

Figure 45

BCG versus EPI. Outcome: Recurrence (Shang, 2011)

There was no significant difference between BCG and EPI for disease progression (RR 0.78, 95% CI 0.54 to 1.13). No differences were found for overall mortality (2 studies) or disease-specific mortality (2 studies). However, overall mortality was less frequent in the TICE BCG group compared to the EPI group in the study by Sylvester (2010) (RR 0.79, 95% CI 0.62 to 0.99) (see Figure 46). Drug-induced cystitis (54% versus 32%), haematuria (31% versus 16%), and systemic side-effects (35% versus 1%) were significantly more frequent with BCG than EPI. However, there was significant heterogeneity between trials for systemic side-effects due to the frequency of BCG administration. There were no significant differences for delayed or terminated treatment due to adverse events between BCG and EPI (9% versus 7%) (RR 0.91, 95% CI 0.41 to 2.04).

Figure 46

BCG versus EPI. Outcome: Overall survival (Shang, 2011)

BCG versus Gemcitabine

One systematic review by Jones (2012) reported 3 studies comparing Gemcitabine with BCG (one of these trials and the trial comparing BCG with MMC included patients who had failed BCG therapy which is covered in another topic). Heterogeneity between trials prevented pooling of data. One trial of 80 patients at intermediate risk of recurrence (primary Ta-T1, no CIS) provided low quality evidence that BCG (no maintenance) and Gemcitabine showed similar rates of recurrence (25% vs. 30%) and progression, with significantly more adverse effects with BCG (Bendary 2011). Moderate quality evidence was provided by one trial of 64 high risk patients, which reported that recurrence rate was higher for Gemcitabine than BCG (53% vs. 28%) and time to recurrence was shorter with Gemcitabine (25.6 months vs. 39.4 months). No patients in either group had disease progression at a mean follow-up of 44 months. Local and systemic toxicity were similar between groups. In this trial maintenance therapy for non-recurring patients in each group was up to 36 months duration (Porena, 2010).

Duration of BCG

In 6 meta-analyses (Sylvester, 2002; Han, 2006; Sylvester, 2005; Malmstrom, 2009; Bohle, 2003; Bohle 2004) BCG was superior to chemotherapy only if a maintenance schedule was used.

Six trials of maintenance versus induction BCG were indentified which varied in the population included and the schedule and duration of maintenance therapy. High quality evidence from five of these trials demonstrated that 53.9% of patients in the BCG induction arm had a recurrence, compared to 37.6% in the maintenance BCG arm (RR 0.70, 95% CI 0.60 to 0.81). Moderate quality evidence from 5 trials showed that there were no overall differences in progression (27.6% versus 31.8%). However, this data should be interpreted with caution due to the variation in BCG maintenance schedules and the duration of follow-up across studies.

Figure 47

Maintenance versus induction BCG. Outcome: Recurrence

Two controlled trials published in 1987 (Hudson 1987; Badalament 1987) showed no significant benefit of maintenance BCG therapy on recurrence. A study of 384 patients with recurrent bladder cancer or CIS were randomised to BCG induction alone or BCG induction plus 3-week maintenance schedule for up to 3-years (Lamm, 2000). With a median follow-up of 7 years, maintenance BCG significantly improved median recurrence-free survival (from 36 months to 77 months, p<0.0001). 5-year survival also increased from 78% to 83% with BCG maintenance, but this difference was non-significant (p=0.08). A Japanese Cooperative study (Hinotsu, 2010) of 115 patients with multiple or recurrent NMIBC without CIS, reported that 2-year recurrence-free survival was significantly longer in the combined BCG groups compared with 9 weeks Epirubicin therapy, and for BCG maintenance versus induction BCG only (Recurrence rate: 12% versus 33%). No difference in progression was reported between BCG maintenance and non-maintenance, although there were no cases of progression in the maintenance arm. A further study randomised 53 patients (88% with CIS) who had achieved a complete response after induction BCG therapy into maintenance (4 instillations) therapy or observation (Koga, 2010). The 2-year recurrence free survival was higher in the maintenance group (95.8%) than the observation group (74.1%), although this was not significant. Two patients in each group died during follow-up. There were no significant changes in quality of life scores (EORTC-QLQ) in either group from induction treatment to 14 months after randomisation. Very low quality evidence from one observational study reported that overall quality of life was moderate, and more patients rated it as good during maintenance than during induction therapy (Mack 1996). Drug-related toxicities, such as dysuria, haematuria and fever, were generally more prevalent with maintenance BCG than with induction BCG.

Dose of BCG

Two trials provided moderate quality evidence of no difference in recurrence, progression, overall survival and disease-specific survival between one-third (27mg) dose and full dose (81mg) BCG. One trial (Martinez-Pineiro, 2002) included 500 patients (Ta/T1/CIS, G1-G3) and the other trial (Martinez-Pineiro, 2005) included 155 patients with T1G3 disease or CIS. Martinez-Pineiro (2002) reported that in patients with multifocal disease the standard dose was more effective against recurrences and progression than the reduced dose. Local toxicity was significantly reduced in the low dose BCG arm (53% versus 67%), and fewer patients had delayed instillations or withdrew from treatment. There were no differences between groups for severe systemic toxicities (3.8% versus 2.7%).

Moderate quality evidence from another CUETO group trial (Ojea, 2007) reported that there were no differences in recurrence-free survival between low dose BCG (27mg) and very-low dose BCG (13.5mg) in intermediate risk patients. There were no differences in time to progression and cancer-specific survival between the two BCG treatment groups. Rates of local (65.5% vs. 64.1%) and systemic (11.3% vs. 10.8%) adverse events were also similar between the two groups.

Moderate quality evidence was reported in one trial of 1355 patients randomised into 4 trial arms (Oddens, 2012). With a median follow-up of 7.1 years, there were no differences in recurrence, progression, overall survival and toxicity between one-third (27mg) dose and full dose (81mg) BCG. When results were stratified by maintenance and dose, one-third dose BCG with 1-year maintenance was suboptimal compared to full-dose BCG with 3-year maintenance (HR for disease-free interval 0.75, 95% CI 0.59 to 0.94). In intermediate-risk patients, 3 years of maintenance was more effective than 1 year in patients receiving one-third dose (HR 1.35, 95% CI 1.03 to 1.79) but not in patients receiving full-dose (HR 0.88, 95% CI 0.64 to 1.21). In high-risk patients, 3 years of maintenance was more effective than 1 year in patients receiving full dose (HR 1.61, 95% CI 1.13 to 2.30) but not in patients receiving one-third dose BCG (HR 1.01, 95% CI 0.69 to 1.47). There were no significant differences between treatment groups for the time to progression or overall survival.

Figure 48

1-year of maintenance versus 3-year of maintenance BCG according to dose and risk group. Outcome: Disease-free interval (Oddens, 2012)

References to included studies

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6. *. Bohle A, et al. Single postoperative instillation of gemcitabine in patients with non-muscle-invasive transitional cell carcinoma of the bladder: a randomised, double-blind, placebo-controlled phase III multicentre study. European Urology. 2009;56(3):495–503. [PubMed: 19560257]

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10. Malmstrom PU, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus Bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. European urology. 2009;56:247–256. (Structured abstract) [PubMed: 19409692]
11. *. Friedrich MG, et al. Long-term intravesical adjuvant chemotherapy further reduces recurrence rate compared with short-term intravesical chemotherapy and short-term therapy with Bacillus Calmette-Guerin (BCG) in patients with non-muscle-invasive bladder carcinoma. European urology. 2007;52:1123–1130. [PubMed: 17383080]
12. *. Gardmark T, et al. Analysis of progression and survival after 10 years of a randomized prospective study comparing mitomycin-C and bacillus Calmette-Guerin in patients with high-risk bladder cancer. BJU International. 2007;99(4):817–820. [PubMed: 17244282]
13. *. Jarvinen R, et al. Long-term efficacy of maintenance Bacillus Calmette-Guerin versus maintenance mitomycin C instillation therapy in frequently recurrent TAT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised Finnbladder I study with a 20-year follow-up. European urology. 2009;56:260–265. [PubMed: 19395154]
14. Mangiarotti B, et al. A randomized prospective study of intravesical prophylaxis in non-musle invasive bladder cancer at intermediate risk of recurrence: mitomycin chemotherapy vs. BCG immunotherapy. Archivio italiano di urologia, andrologia : organo ufficiale [di] Società italiana di ecografia urologica e nefrologica / Associazione ricerche in urologia. 2008;80:167–171. [PubMed: 19235434]
15. Martínez-Piñeiro JA, et al. Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial. The Journal of urology. 2005;174:1242–1247. [PubMed: 16145378]
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17. Oddens J, et al. Final Results of an EORTC-GU Cancers Group Randomized Study of Maintenance Bacillus Calmette-Guerin in Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the Urinary Bladder: One-third Dose Versus Full Dose and 1 Year Versus 3 Years of Maintenance. European Urology. 2013;63(3):462–472. [PubMed: 23141049]
18. Ojea A, et al. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. European urology. 2007;52:1398–1406. [PubMed: 17485161]
19. Oosterlinck W, et al. Sequential intravesical chemoimmunotherapy with mitomycin C and bacillus Calmette-Guérin and with bacillus Calmette-Guérin alone in patients with carcinoma in situ of the urinary bladder: results of an EORTC genito-urinary group randomized phase 2 trial (30993). European urology. 2011;59:438–446. [PubMed: 21156335]
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21. Palou J, et al. Control group and maintenance treatment with bacillus Calmette-Guerin for carcinoma in situ and/or high grade bladder tumors. Journal of Urology. 2001;165(5):1488–1491. [PubMed: 11342902]
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23. Pawinski A, Sylvester R, Kurth KH, et al. A combined analysis of European Organization for Research and Treatment of Cancer, and Medical Research Council randomized clinical trials for the prophylactic treatment of stage TaT1 bladder cancer. J Urol. 1996;156:1934. [PubMed: 8911360]
24. Saika T, et al. Two instillations of epirubicin as prophylaxis for recurrence after transurethral resection of Ta and T1 transitional cell bladder cancer: a prospective, randomized controlled study. World Journal of Urology. 2010;28:413–418. [PubMed: 20054553]
25. Serretta V, et al. A 1-year maintenance after early adjuvant intravesical chemotherapy has a limited efficacy in preventing recurrence of intermediate risk non-muscle-invasive bladder cancer. BJU International. 2010;106(2):212–217. [PubMed: 20070299]
26. Shang PF, et al. Intravesical Bacillus Calmette-Guérin versus epirubicin for Ta and T1 bladder cancer. Cochrane Database of Systematic Reviews. 2011 [PubMed: 21563157]
27. *. Sylvester RJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. European Urology. 2010;57(5):766–773. [PMC free article: PMC2889174] [PubMed: 20034729]
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Evidence tables

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Background

Non-muscle invasive bladder cancer (NMIBC) tumours can be surgically removed using transurethral resection of bladder tumour (TURBT). However, these tumours are likely to return on the urothelium. This high risk of recurrence is a problem for patients because it raises the concern that the cancer will progress and so the patient will need to undergo further treatment (either another TURBT or diathermy).

The risk of recurrence can be reduced by the administration of chemotherapy medication into the bladder (intravesical chemotherapy), which can be done immediately, or shortly after TURBT. However, there are disadvantages to using intravesical chemotherapy as it is associated with some side effects and comes at an additional cost.

Aim of analysis

To estimate the cost-effectiveness of a single instillation of intravesical chemotherapy in addition to TURBT in comparison to TURBT alone in patients with NMIBC.

Existing Economic Evidence

A systematic literature review identified one paper related to the decision problem, a cost-utility analysis by Green et al. 2013. In the study, a decision analytic model was utilised to estimate the cost-effectiveness of fulguration compared to TURBTs with and without perioperative intravesical chemotherapy in patients with low risk NMIBC.

The authors concluded that fulguration without perioperative intravesical chemotherapy was the most cost-effective strategy for treating low-risk NMIBC. However, unusually, the authors based this conclusion upon individual cost-effectiveness calculations rather than the standard incremental calculations. When following the more standard cost-effectiveness methodology using incremental cost-effectiveness ratios (ICERs), it appears that perioperative intravesical chemotherapy plus fulguration would be the most cost-effective strategy. This strategy has an ICER of $4,169 per QALY, which is likely to fall below the cost-effectiveness threshold³. The authors also conducted sensitivity analysis, which showed that the effectiveness of perioperative intravesical chemotherapy and the cost of TURBT were likely to be key drivers of the cost-effectiveness result.

However, Green et al. 2013 can only be deemed partially applicable to the decision problem this guideline seeks to address. The analysis considered the US healthcare system, which differs substantially from the UK system. In addition, the study only partially addressed our decision problem as it only evaluated cost-effectiveness in low risk NMIBC patients, whereas we are interested in all NMIBC risk groups.

Overall, it was considered that the current economic literature was partially useful but further analysis would be required to robustly estimate the cost-effectiveness. It should also be noted that the existing economic literature was useful for informing the development of our own economic model.

De Novo Economic Model

Since the current economic literature did not adequately address the decision problem, a de novo economic evaluation was undertaken to assess cost-effectiveness. A Markov decision model was developed using Microsoft Excel.

The patient enters the model in a ‘disease free state following an initial transurethral resection of the bladder tumour (TURBT) with or without a single instillation of chemotherapy (depending upon modelled treatment arm). At each 3-monthly model cycle the patient may experience a bladder cancer recurrence. If the recurrence is detected, the patient will undergo a further TURBT (or fulguration of the tumour) and return to a disease free state. However, if the recurrence is not detected, then the patient will be at risk of progression and will have to undergo further treatment once this progression is eventually detected (cystectomy and possibly neo-adjuvant chemotherapy). The patient may also die from bladder cancer related mortality after experiencing progression and may die from other cause mortality from any health state.

Estimated total costs and quality adjusted life yefars (QALYs) are collected over the modelled 10 year time horizon for each follow-up strategy. Future costs and benefits were discounted at a rate of 3.5% per year as recommended by NICE.

The risk of recurrence and progression in patients with NMIBC was estimated using risk equations based on an analysis of 2,596 patients from seven EORTC⁴ trials (Sylvester et al. 2006). Patients are ‘scored based on a number of risk factors, such as number of tumours, tumour size, prior recurrence rate, T category, presence of CIS and grade. An individual's one year and five year risks of recurrence and progression can then be estimated based upon these scores.

For the purposes of the economic model, it was necessary to convert these five year and one year risks into 3-monthly risks. The higher risk of recurrence and progression in the first year was captured by calculating separate 3 monthly risks for the first year and subsequent years (based on the one year risk and five year EORTC risks). Furthermore, since the EORTC risk equations consider recurrence and progression independently, it was necessary to link the progression rates to the recurrence rate i.e. estimate the probability of progression given recurrence in each of the risk groups.

Table 66

Three Monthly Recurrence And Progression Risk Applied In The Model.

As the modelled time horizon of 10 years exceeds the predicted risk estimates from the EORTC trials (5 years), it was also necessary to make some assumptions about the risk profile of patients in years 5-10. In the base case, it was assumed that the subsequent year rate (i.e. years 2-5) would be maintained in years 6-10 except in the case of low-risk patients in whom it was assumed that risk would be zero after 5 years (reflecting clinical practice of discharging low-risk patients from follow-up after 5 years).

The key effectiveness data utilised in the model is the reduction in recurrence risk associated with a single instillation of intravesical chemotherapy following a TURBT. According to the systematic review of the clinical evidence, the use of a single instillation of intravesical chemotherapy in addition to TURBT has a relative risk of 0.67 in comparison to TURBT alone. This treatment effect was assumed to last for two years reflecting the general consensus around its possible duration. Thereafter, the risk of recurrence was assumed to be equal to that with TURBT only. In addition, the treatment effect is not assumed to affect future recurrences if the patient has a recurrence during the two years after the single chemotherapy instillation.

Note that the single instillation of chemotherapy does not directly reduce the rates of progression. This is in line with the evidence base, which suggests that there is no treatment effect on the rates of progression. However, it should be noted that because of the model structure, a lower rate of recurrences would lead to a lower rate of progression because progression is dependent upon recurrence. Therefore, an indirect treatment effect on progression is essentially included in the model. This assumption is relaxed in a sensitivity analysis where the rates of recurrence and progression are assumed to be independent.

No comparative data on morbidity were identified in the systematic review of the clinical evidence. However a meta-analysis (Sylvester 2004) of seven trials suggested that mild irritative bladder symptoms (including dysuria, frequency and macroscopic haematuria) would occur in approximately 10% of patients treated with a single post-operative dose of intravesical chemotherapy. In addition, allergic skin reactions were reported in 1-3% of patients in two studies.

Since no data were available on morbidity in patients treated with TURBT, it was conservatively assumed that 5% would have irritative bladder symptoms and there would be no skin reactions. The treatment related morbidity rates applied in the model are shown in the table below.

The diagnostic accuracy data for flexible cystoscopy were sourced from the systematic review of the clinical evidence conducted for this guideline, with most data being sourced from a systematic review by Mowatt et al. 2010.

Bladder cancer related mortality rates were estimated using data from a systematic review by Van den Bosch et al. 2011. Using the data in the study, separate three mortality rates were estimated for patients that progressed to muscle invasive disease and those that remained non-muscle invasive following a cystectomy (3.6% and 0.5%, respectively). The lower rate in NMIBC patients reflects an assumption that patients would have to first progress to MIBC before dying of bladder cancer.

Death from other causes was captured using 2009-2011 life tables for England and Wales from the office of national statistics (ONS). These life tables give an estimate of the annual probability of death given a person's age and gender with the model assuming that 50% of patients were female and that the average age was 60 years old. These annual probabilities were converted to three-monthly probabilities for use in the model.

Costs and utilities

Modelled patients accrue costs associated with any treatment, monitoring or management strategy that they are undergoing. The costs considered in the model reflect the perspective of the analysis, thus only costs that are relevant to the UK NHS & PSS were included. These costs include drug costs, treatment costs and any other resource use that may be required (e.g. GP visit). Where possible, all costs were estimated in 2012-13 prices.

The majority of costs were sourced from NHS reference costs 2012/13 by applying tariffs associated with the appropriate HRG code. Drug costs were calculated using dosages from the British National Formulary (BNF) and unit cost information from the electronic market information tool (eMit). Where unit costs for drugs were not available from eMit, prices from the BNF were used. Resource use and cost information were obtained from the Personal Social Services Research Unit (PSSRU) and the advice of the GDG.

The model estimates effectiveness in terms of quality adjusted life years (QALYs). QALYs were estimated by combining the life year estimates with utility values (or QOL weights) associated with being in a particular health state. These utility values were identified through a search of the available literature.

Base case results

The base case results of the analysis are presented in the table below for patients in each risk category. It can be seen that, in every risk category, a strategy of TURBT plus a single instillation of chemotherapy is more effective than a strategy of TURBT alone.

In the case of low and intermediate risk patients, it can also be seen that the addition of a single instillation of chemotherapy is cost saving over the modelled time horizon. This shows that the initial additional costs associated with the single chemotherapy instillation are outweighed by the cost savings associated with a reduction in recurrences (recurrence reductions of 17% and 10% were estimated over the modelled time horizon in the low and intermediate risk groups, respectively). Therefore in low and intermediate risk patients, a single instillation of chemotherapy can be considered dominant i.e. more effective and cost saving.

However, in the case of high risk patients, it can be seen that this is not the case. In high risk patients, the single instillation of chemotherapy is more costly than TURBT alone, suggesting that the potential cost savings are not as large in this group. However, it can also be seen that the addition of a single chemotherapy instillation provides an additional QALY at a cost of £6,432 and thus would be considered cost-effective using the NICE threshold (i.e. <£20,000 per QALY).

Table 67

Base Case Results Of The Model.

Sensitivity analysis

A series of one-way sensitivity analyses were conducted, whereby the value of an input parameter is changed and its effect on the overall outcome is recorded and assessed.

The analyses showed that the conclusion of the model is insensitive to changes in the input parameters over plausible ranges i.e. TURBT plus a single instillation of chemotherapy remains cost-effective in the all the analyses across all the risk groups.

The variations in the treatment effect duration are perhaps particularly notable as this is one of the uncertainties around the effectiveness of the single instillation of chemotherapy. The analysis shows, unsurprisingly, that the intervention is less cost-effective when the treatment effect duration is decreased. However, crucially, the single instillation of chemotherapy remains cost-effective in all analyses, even when making very pessimistic assumptions about the likely treatment effect duration (i.e. even when assuming that the chemotherapy instillation only reduces recurrences in the first 3 months after administration).

In addition to the core cost-utility analysis, the GDG were also interested in a cost analysis comparing the cost of delivering the single instillation of chemotherapy on the ward against the cost of delivering it in theatre. It was found that delivering the single instillation of chemotherapy in theatre was the cheaper of the two approaches (delivery by nurse estimated to cost an additional £23.83). This was primarily a result of the longer amount of time taken to deliver the instillation in the ward setting compared to in theatre.

A probabilistic sensitivity analysis was also conducted to assess the combined parameter uncertainty in the model. In this analysis, the mean values that were utilised in the base case were replaced with values drawn from distributions around the mean values. It was found that, at a threshold of £20,000 per QALY, TURBT plus a single instillation of chemotherapy has a very high probability of being cost-effective in the low and intermediate risk groups (100%). However, the probability is substantially lower in high risk patients at 66%, although still very much in favour of TURBT plus a single instillation of chemotherapy.

Conclusion

The results of the analysis suggest that the use of a single instillation of chemotherapy after a TURBT, in comparison to a TURBT alone, was found to be strongly cost-effective in all risk groups. It was found to be particularly cost-effective in low and intermediate risk groups, in which the strategy was cost saving as well as more effective (dominant). Furthermore, this result was found to be robust in alternative scenario analyses, one-way and probabilistic sensitivity analysis.

Rationale

Treatment of low risk bladder cancer recurrences may be with endoscopic resection to remove the cancer, fulguration by electrocautery or laser energy to destroy the cancer in situ (with or without biopsy), intravescial chemotherapy (also known as chemoresection) or merely observation (so called active surveillance). The former allows pathological evaluation of the cancer and may be necessary to remove tissue from large tumors, but requires regional or general anaesthesia and a rigid cystoscopy and bladder resection. Consequently, the risks of intervention are higher than for fulguration (which may performed under local anaesthesia), chemotherapy or active surveillance. However, these other approaches do not sample the tissue of the cancer recurrence and could miss the minority of cases in which the cancer is becoming more aggressive. Also these approaches are less effective at removing the cancer and so could lead to higher recurrence (or residual cancers) rates and more post-treatment symptoms.

In this review we will evaluate each approach to treating recurrence within the bladder following a previous low risk bladder cancer. We will attempt to determine in which patients the benefits of transurethral resection outweigh the risks from the treatment and from the cancer. We will attempt to identify low risk cancers in which the rate of disease progression is higher and so the evaluation of tissue is necessary for patient safety. We will look to identify tumors in which less intensive intervention is sufficient and to compare the outcomes of the different approaches.

Question in PICO format

METHODS

RESULTS

Result of the literature searches

Figure 49Study flow diagram

Study quality and results

Very low quality evidence was obtained from seven observational studies. Evidence is presented in Table 68.

Table 68

GRADE evidence profile: Treatment with histological sampling versus treatment without histological sampling (e.g. cystodiathermy).

References to included studies

1. Biers SM, Mostafid AH. Electromotive drug administration of local anesthesia for biopsy and cystodiathermy of recurrent low grade bladder tumors. Current Urology. 2009;3(1):15–18.
2. Davenport K, Keeley FX Jr., Timoney AG. Audit of safety, efficacy, and cost-effectiveness of local anaesthetic cystodiathermy. Annals of the Royal College of Surgeons of England. 2010;92(8):706–709. [PMC free article: PMC3229385] [PubMed: 20615299]
3. Donat SM, et al. Efficacy of office fulguration for recurrent low grade papillary bladder tumors less than 0.5 cm. Journal of Urology. 2004;17(2:Pt 1) t-9. [PubMed: 14713776]
4. Park DS, et al. An Analysis of the Efficacy, Safety, and Cost-Effectiveness of Fulguration Under Local Anesthesia for Small-Sized Recurrent Masses: A Comparative Analysis to Transurethral Resection of Bladder Tumors in a Matched Cohort. Journal of Endourology. 2013;27(10):1240–1244. [PubMed: 23964922]
5. Syed HA, et al. Flexible cystoscopy and Holmium:Yttrium aluminum garnet laser ablation for recurrent nonmuscle invasive bladder carcinoma under local anesthesia. Journal of Endourology. 2013;27(7):886–891. [PubMed: 23537221]
6. Syed HA, et al. Holmium:YAG laser treatment of recurrent superficial bladder carcinoma: initial clinical experience. Journal of Endourology. 2001;15(6):625–627. [PubMed: 11552789]
7. Wong KA, et al. Outpatient laser ablation of non-muscle-invasive bladder cancer: is it safe, tolerable and cost-effective? BJU International. 2013;112(5):561–567. [PubMed: 23819486]

Evidence tables

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Review questions

In patients with recurrent bladder cancer and previous low risk bladder cancer does treatment without histological sampling affect outcome?

Information sources and eligibility criteria

The following databases were searched for economic evidence relevant to the PICO: MEDLINE, EMBASE, COCHRANE, NHS EED and HEED. Studies conducted in OECD countries other than the UK were considered.

Studies were selected for inclusion in the evidence review if the following criteria were met:

• Both cost and health consequences of interventions reported (i.e. true cost-effectiveness analyses)
• Conducted in an OECD country
• Incremental results are reported or enough information is presented to allow incremental results to be derived
• Studies that matched the population, interventions, comparators and outcomes specified in PICO
• Studies that meet the applicability and quality criteria set out by NICE, including relevance to the NICE reference case and UK NHS

Note that studies that measured effectiveness using quality of life based outcomes (e.g. QALYs) were desirable but, where this evidence was unavailable, studies using alternative effectiveness measures (e.g. life years) were considered.

Selection of studies

The literature search results were screened by checking the article's title and abstract for relevance to the review question. The full articles of non-excluded studies were then attained for appraisal and compared against the inclusion criteria specified above.

Results

Three searches for economic evidence were run over the development of the guideline; one at the start of the process, an update midway through and a further update at the end of the process. The diagram below shows the combined results of the three searches and illustrates the sifting process.

Figure 50Summary Of Evidence Search And Sifting Process For This Topic

It can be seen that, in total, 1,189 possibly relevant papers were identified. Of these, 1,124 papers were excluded at the initial sifting stage based on the title and abstract while 65 full papers were obtained for appraisal. A further 56 papers were excluded based on the full text as they were not applicable to the PICO or did not include an incremental analysis of both costs and health effects. Therefore, nine papers were included in the systematic review of the economic evidence for this guideline.

Two of these nine papers related to the topic at hand and were thus included in the review of published economic evidence for this topic; Green et al. 2013 and Wong et al. 2013. The studies included a cost-effectiveness analysis where effectiveness was measured using quality adjusted life years (QALYs) i.e. a cost-utility analysis.

Quality and applicability of the included study

Green et al. 2013 was deemed only partially applicable to the guideline. This was primarily because it considered the US health care system, which differs substantially from the UK system. Wong et al. 2013 was also deemed to be only partially applicable despite being based in the UK. This was because of uncertainty over the applicability of some model inputs (QoL values and discount rates), details of which were omitted in the report.

Potentially serious limitations were identified in the study by Green et al. 2013. There was uncertainty over the treatment effect that had been applied in the model and there were concerns about the conclusions that had been drawn by the authors when interpreting the cost-effectiveness results. Very serious limitations were identified in the study by Wong et al. 2013. Omissions in the study report make it difficult to assess the quality of many of the input parameters used in the model e.g. the value and source of unit costs and resource use in the model are not fully reported.

Modified GRADE table

The primary results of the analyses by Green et al. 2013 and Wong et al. 2013 are summarised in the modified GRADE table below.

Table 71

modified grade table showing the included evidence (Green et al. 2013 and Wong et al. 2013) for the treatment of recurrent bladder cancer and previous low risk bladder cancer with and without histological sampling.

Evidence statements

Green et al. 2013 concluded that fulguration without perioperative intravesical chemotherapy was the most cost-effective strategy for treating low-risk NMIBC. However, unusually, the authors based this conclusion upon individual cost-effectiveness calculations rather than the standard incremental calculations. When following the more standard cost-effectiveness methodology using incremental cost-effectiveness ratios (ICERs), the strategy of perioperative intravesical chemotherapy (PIC) plus fulguration would most likely be considered the most cost-effective strategy with an ICER of $4,169 per QALY.

Of particular relevance to the topic at hand, was the finding that fulguration was more cost-effective than TURBT when both were used alone or when both were used in combination with intravesical chemotherapy. In both instances fulguration was found to be more effective and cheaper than TURBT alone i.e. dominant. However, as the study is US based, these results may lack applicability to the UK healthcare system.

Wong et al. 2013 found that outpatient laser ablation was cost-effective in comparison to inpatient cystodiathermy for the treatment of NMIBC, especially in elderly patients. In the base case, outpatient laser ablation was found to be cheaper (cost reduction of $2,526) and more effective (0.12 QALYs) than inpatient cystodiathermy and is thus dominant. A further analysis showed that using PDD in addition to outpatient laser ablation was also cost-effective and indeed dominant in comparison to inpatient cystodiathermy.

Probabilistic sensitivity analysis showed that, at a threshold of £30,000 per QALY, outpatient laser ablation had approximately an 80%⁵ probability of being cost-effective in comparison to intravesical chemotherapy. With the addition of PDD to OLA, the strategy was more cost-effective than IC in 79.2% of simulations.

However, while the study is of some interest, it does not directly address the decision problem at hand because TURBT is not used as a comparator. The study instead compares two alternatives to TURBT and thus the key aspect of our decision problem remains unanswered by this study.

While both of these studies are somewhat useful, their lack of direct applicability to the decision problem under consideration makes it difficult to draw firm conclusions. As such, the cost-effectiveness of perioperative intravesical chemotherapy remains, to a large extent, uncertain.

References

1.

Green DA, Rink M, Cha EK, Xylinas E, Chughtai B, Scherr DS, Shariat SF, Lee RK. Cost-effective treatment of low-risk carcinoma not invading bladder muscle. BJU Int. 2013;111(3B):E78–E83. [PubMed: 22958598]

2.

Wong KA, Zisengwe G, Athanasiou T, O'Brien T, Thomas K. Outpatient laser ablation of non-muscle invasive bladder cancer: is it safe, tolerable and cost-effective? BJU Int. 2013;112(5):561–7. Epub. [PubMed: 23819486]

Full evidence table

The full details of the studies included in the evidence review are presented in the evidence table below.

Table 72

full evidence table showing the included evidence (Green et al. 2013 and Wong et al. 2013) for the treatment of recurrent bladder cancer and previous low risk bladder cancer with and without histological sampling.

Information sources

A literature search was performed by the information specialist (EH).

Selection of studies

The information specialist (EH) did the first screen of the literature search results. One reviewer (NB) then selected possibly eligible studies by comparing their title and abstract to the inclusion criteria in the PICO. The full articles were then obtained for potentially relevant studies and checked against the inclusion criteria. A second sift of the literature was conducted by another reviewer (JH) and any disagreement between reviewers was discussed. Data from randomised trials and one systematic review of observational studies was identified.

Data synthesis

Evidence was synthesised using RevMan and pooled effect sizes are reported in a GRADE evidence profile (Table 73) and forest plots (see Figures 52-53).

Table 73

GRADE Profile for re-resection versus no re-resection in people with high risk NMIBC.

Figure 52

Recurrence free survival forest plot.

Figure 53

Cystectomy rate forest plot.

Result of the literature searches

Figure 51Study flow diagram

Study quality and results

Low quality evidence was identified. The quality and results are summarised with GRADE in Table 73.

Evidence statements

Low quality evidence (Divrik et al., 2010; Kim et al., 2012) suggests a benefit for repeat transurethral resection in patients with high risk non muscle invasive bladder cancer in terms of bladder cancer recurrence, disease progression and bladder cancer specific mortality.

Using event free survival rates from the no re-resection group in Divrik et al. (2010) trial combined with the hazard ratios reported in Table 73 we could expect five year recurrence free survival rates of 63% following re-resection versus 33% without no re-resection. Estimated five-year progression-free survival would be 92% following re-resection group versus 76% without re-resection.

Low quality evidence (Divrik et al., 2010) suggests re-resection is associated with minor complications in approximately 9% of cases, including prolonged bleeding, epididymitis and transient urinary retention. Such complications could be avoided in patients who do not undergo re-resection

A systematic review of observational studies (Vianello et al., 2011) provided evidence of upstaging and tumour persistence rates at re-resection. For patients with stage T1 tumours at initial TURB, approximately 32% were found to have persistent tumour of the same or lower stage at repeated TURB. Around 9% of patients with T1 tumours at initial TURB were upstaged at repeat TURB.

No evidence was found about the impact of re-resection on health related quality of life in this population.

References to excluded studies (with reasons for exclusion)

1. Divrik RT, Sahin AF, Ergor G. Reply from authors re: Marko Babjuk. Second resection for non-muscle-invasive bladder carcinoma: current role and future perspectives. Eur Urol 2010;58:191-2 and Giacomo Novara, Vincenzo Ficarra. Does routine second transurethral resection affect the long-term outcome of patients with T1 bladder cancer? Why a flawed randomized controlled trial cannot address the issue. Eur Urol 2010;58:193-4. European Urology. 2010;58:195–196. Reason: Authors reply to comment . [PubMed: 20471156]
2. Divrik RT, Yildirim U, Zorlu F, Ozen H. Re: The effect of repeat transurethral resection on recurrence and progression rates in patients with T1 tumors of the bladder who received intravesical mitomycin: A prospective, randomized clinical trial. European Urology. 2007;51:1753. Reason: Comment on the Divrik et al trial . [PubMed: 16600720]
3. Angbein S, Guzman S, Haecker A, Weib C, Michel MS, Alken P. [The influence of “differentiated trandurethral resection” in the recurrence and progression of superficial bladder cancer]. Archivos Espanoles de Urologia. 2006;59:25–30. [Spanish] Reason: Spanish language – is differentiated resection the same as repeated resection? [PubMed: 16568690]
4. Aning JJ. Early re-resection for T1 transitional cell carcinoma of the bladder-A study of current practice in the South West of England. British Journal of Medical and Surgical Urology. 2011;4:18–23. Reason: Non comparative, possibly relevant to update Vianello review .
5. Jahnson S, Wiklund F, Duchek M, Mestad O, Rintala E, Hellsten S, et al. Results of second-look resection after primary resection of T1 tumour of the urinary bladder. Scandinavian Journal of Urology & Nephrology. 2005;39:206–210. Reason: All patients had early second-look resection – non comparative study . [PubMed: 16127800]
6. Katumalla FS, Devasia A, Kumar R, Kumar S, Chacko N, Kekre N. Second transurethral resection in T1G3 bladder tumors - Selectively avoidable? Indian Journal of Urology. 2011;27:176–179. Reason: Only patients with second TUR are reported – non comparative study . [PMC free article: PMC3142825] [PubMed: 21814305]
7. Klan R, Loy V, Huland H. Residual tumor discovered in routine second transurethral resection in patients with stage T1 transitional cell carcinoma of the bladder. Journal of Urology. 1991;146:316–318. Reason: Non – comparative, results are not reported for the 23 patients who did not have repeat TUR . [PubMed: 1856924]
8. Kohrmann KU, Woeste M, Kappes J, Rassweiler J, Alken P. The Value of Secondary Transurethral Resection for Superficial Bladder-Tumors. Aktuelle Urologie. 1994;25:208–213. Reason: German language non comparative .
9. Langbein S, Badawi K, Haecker A, Weiss C, Hatzinger M, Alken P, et al. Persistence, recurrence, and progression rates of superficial bladder tumours after resection using the differentiated technique. Medical Principles & Practice. 2006;15:215–218. Reason: All patients had second resection – the comparison was between differentiated and non-differentiated technique . [PubMed: 16651838]
10. Lopatkin NA, Martov AG, Gushchin BL, Gnatiuk AP, Ergakov DV, Serebrianyi SA. [Diagnosis and treatment of recurrent surface cancer of the urinary bladder (early repeated cystoscopy and biopsy)]. Urologiia (Moscow, Russia). 2003:45–49. [Russian] Reason: Russian language . [PubMed: 14658273]
11. Ojea CA, Nunez LA, Alonso RA, Rodriguez IB, Benavente DJ, Barros Rodriguez JM, et al. [Value of a second transurethral resection in the assessment and treatment of patients with bladder tumor]. Actas Urologicas Espanolas. 2001;25:182–186. [Spanish] Reason: Spanish language non comparative . [PubMed: 11402530]
12. Orsola A, Cecchini L, Raventos CX, Trilla E, Planas J, Landolfi S, et al. Risk factors for positive findings in patients with high-grade T1 bladder cancer treated with transurethral resection of bladder tumour (TUR) and bacille Calmette-Guerin therapy and the decision for a repeat TUR. BJU International. 2010;105:202–207. Reason: Repeat TUR done in all T1b or greater cases – no matched comparison group, possibly relevant to update Vianello review . [PubMed: 19558557]
13. Parkin J. G3T1 bladder cancer: Is early re-resection necessary? British Journal of Medical and Surgical Urology. 2011;4:13–17. Reason: Non-comparative study, possibly relevant to update Vianello review .
14. Richterstetter M, Wullich B, Amann K, Haeberle L, Engehausen DG, Goebell PJ, et al. The value of extended transurethral resection of bladder tumour (TURBT) in the treatment of bladder cancer. BJU International. 2012;110:E76–E79. Reason: Non-comparative study, possibly relevant to update Vianello review . [PubMed: 22313727]
15. Rigaud J, Karam G, Braud G, Glemain P, Buzelin JM, Bouchot O. [T1 bladder tumors: value of a second endoscopic resection]. Progres En Urologie. 2002;12:27–30. [French] Reason: All patients had early second TUR – non comparative study . [PubMed: 11980011]
16. Rodriguez-Rubio Cortadellas FI, Garrido IS, Rivas AD, Hens PA, Bachiller BJ, Beltran AV, et al. [Second resection in patients with Ta-T1 bladder tumors]. Actas Urologicas Espanolas. 2001;25:553–558. [Spanish] Reason: Spanish language non comparative . [PubMed: 11692797]
17. Schulze M, Stotz N, Rassweiler J. Retrospective analysis of transurethral resection, second-look resection, and long-term chemo-metaphylaxis for superficial bladder cancer: indications and efficacy of a differentiated approach. Journal of Endourology. 2007;21:1533–1541. Reason: Repeat TUR done in all high risk cases – no matched comparison group . [PubMed: 18186695]
18. Shen H-B. Clinical analysis of re-transurethral resection in management of non-muscle invasive bladder urothelial cancer. Journal of Shanghai Jiaotong University (Medical Science). 2012;32:491–494. Reason: Chinese language – no mention of randomization .
19. Shen YJ, Ye DW, Yao XD, Zhang SL, Dai B, Zhu YP, et al. [Repeat transurethral resection for non-muscle invasive bladder cancer]. Chung-Hua Wai Ko Tsa Chih. [Chinese Journal of Surgery]. 2009;47:725–727. [Chinese] Reason: Exclude – Chinese language, non comparative . [PubMed: 19615201]
20. Vasdev N. The role of early re-resection in pTaG3 transitional cell carcinoma of the urinary bladder. British Journal of Medical and Surgical Urology. 2011;4:158–165. Reason: Non randomized study – historical comparison group .
21. Vogeli TA, Grimm MO, Simon X, Ackermann R. [Prospective study of effectiveness. Reoperation (re-TUR) in superficial bladder carcinoma]. Urologe (Ausg, A). 2002;41:470–474. [German] Reason: German language non comparative . [PubMed: 12426865]
22. Wilby D. Comparison of re-resection rates for new G3pT1 bladder cancer, in patients randomised to initial blue light or white light resection: 1 year follow up data. Journal of Endourology, Conference. 2009:A67. Reason: Abstract only – compares blue with white light resection .
23. Wong SSW. Pathological staging of superficial high-grade bladder transitional cell carcinoma at re-resection. Journal of Urology, Conference. 2009 var- Reason: Abstract only – non comparative all had re-resection .
24. Yucel M, Hatipoglu NK, Atakanli C, Yalcinkaya S, Dedekarginoglu G, Saracoglu U, et al. Is repeat transurethral resection effective and necessary in patients with T1 bladder carcinoma? Urologia Internationalis. 2010;85:276–280. Reason: All patients had early second TUR – non comparative study, possibly relevant to update Vianello review . [PubMed: 20733272]
25. Holmang S. High-grade non-muscle-invasive bladder cancer: is re-resection necessary in all patients before intravesical bacillus Calmette-Guerin treatment? Scandinavian Journal of Urology. 2013;47(5):363–369. Reason: Non randomized study . [PubMed: 23394122]
26. Sfakianos JP, et al. The effect of restaging transurethral resection on recurrence and progression rates in patients with nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-Guerin. Journal of Urology. 2014;191(2):341–345. Reason: Non randomized study . [PMC free article: PMC4157345] [PubMed: 23973518]
27. Suer E, et al. Time between first and second transurethral resection of bladder tumors in patients with high-grade T1 tumors: is it a risk factor for residual tumor detection? Urologia Internationalis. 2013;91(2):182–186. Reason: Non-comparative study, possibly relevant to update Vianello review . [PubMed: 23751593]
28. Lazica DA, et al. Second transurethral resection after ta high-grade bladder tumor: a 4.5-year period at a single university center. Urologia Internationalis. 2014;92(2):131–135. Reason: Non-comparative study, possibly relevant to update Vianello review . [PubMed: 23988813]

Rationale

High-grade non-muscle invasive (HGNMI) bladder cancer is an aggressive disease. The natural history of these cancers is difficult to predict. Around 1 in 4 will eventually progress to invade the bladder wall and may spread beyond the bladder to cause death. Invasion marks a dramatic worsening in prognosis for the patient and needs aggressive treatment if cure is to be obtained. Whilst various pathological factors can be used to guide the risk of developing invasion from a HGNMI tumour, none offer absolute certainty to the patient.

Currently, many urologists offer an initial treatment of BCG immunotherapy for HGNMI bladder cancer. BCG may reduce the chance of a tumour progressing to invasion but has side effects and can delay the identification of worsening cancers. This delay may affect the cure rate for aggressive cancers. Advocates of BCG suggest this treatment may reduce progression rates for individual tumours, allows the identification of patients with non-progressing cancers (and so these patients do not receive radical treatment) and is safe if the bladder is monitored closely. In contrast, other physicians claim that BCG is not effective at reducing progressing and delays the identification of worsening disease such that it reduces the chances of cure in the patients. An alternate approach to BCG is primary radical treatment (usually cystectomy) for HGNMI cancers. This may be the safest option for patients, but will lead to over treatment for those whose cancers would not progress to invasion and carries the risks of major surgery or radiotherapy. Although radical radiotherapy / chemo-radiotherapy is used to treat muscle invasive bladder cancer, evidence to support its use in the HGNMI disease is less compelling. Various pathological and clinical factors may be used to guide the risk of progression and the treatment options.

This review will look at the evidence of BCG and primary radical treatment (cystectomy) for HGNMI bladder cancer. It will estimate the risks and benefits of each approach and try to identify factors that would be useful in aiding patient choice.

Question in PICO format

METHODS

Data synthesis

Data from comparative studies were pooled using RevMan to provide overall effect estimates. The case series studies are summarised in Table 74-78.

Table 75

GRADE evidence profile: Primary cystectomy versus conservative treatment (surveillance or intravesical therapy) for high-risk non muscle invasive bladder cancer.

Table 76

GRADE evidence profile: Early cystectomy versus deferred cystectomy for high-risk non-muscle invasive bladder cancer.

Table 77

Disease-specific survival (DSS) in patients with high-risk NMIBC and progression after initial conservative treatment (reported in systematic review by van den Bosch, 2011).

RESULTS

Result of the literature searches

Figure 51Study flow diagram

Study quality and results

The quality of the evidence was assessed using GRADE. The evidence is summarised in Tables 74-78 and Figures 52-53.

Table 74

GRADE evidence profile: Radiotherapy versus control (observation or intravesical therapy) for T1G3 bladder cancer.

Table 78

Recurrence, disease-specific mortality and overall mortality of 1136 T1G3 NMIBC patients treated with radical cystectomy and bilateral lymphadenectomy (Fritsche, 2011) (51% of patients were upstaged to pT2 or higher).

Figure 52

Primary cystectomy versus primary conservative therapy; Outcome, Disease-specific mortality rate.

Figure 53

Early cystectomy versus deferred cystectomy; Outcome, 5-yr disease-specific mortality rate.

References to included studies

1. Ali-El-Dein B, et al. Survival after primary and deferred cystectomy for stage T1 transitional cell carcinoma of the bladder. Urology annals. 2011;3(3):127–132. [PMC free article: PMC3183703] [PubMed: 21976924]
2. Badalato GM, et al. Immediate radical cystectomy vs conservative management for high grade cT1 bladder cancer: is there a survival difference? BJU International. 2012;110(10):1471–1477. [PubMed: 22487512]
3. Canter D, et al. Use of radical cystectomy as initial therapy for the treatment of high-grade T1 urothelial carcinoma of the bladder: A SEER database analysis. Urologic Oncology-Seminars and Original Investigations. 2013;31(6):866–870. [PubMed: 21906968]
4. Cheng L, et al. Survival of patients with carcinoma in situ of the urinary bladder. Cancer. 1999;85:2469–2474. [PubMed: 10357420]
5. Dalbagni G, et al. Clinical outcome in a contemporary series of restaged patients with clinical T1 bladder cancer. European Urology. 2009;56(6):903–910. [PMC free article: PMC8177014] [PubMed: 19632765]
6. De BE, et al. T1G3 high-risk NMIBC (non-muscle invasive bladder cancer): conservative treatment versus immediate cystectomy. International Urology & Nephrology. 2011;43(4):1047–1057. [PubMed: 21442469]
7. Denzinger S, et al. Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? European Urology. 2008;53(1):146–152. [PubMed: 17624657]
8. Fritsche HM, et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort. European Urology. 2010;57(2):300–309. [PubMed: 19766384]
9. Harland SJ, et al. A randomized trial of radical radiotherapy for the management of pT1G3 NXM0 transitional cell carcinoma of the bladder. The Journal of urology. 2007;178:807–813. [PubMed: 17631326]
10. Hautmann RE, Volkmer BG, Gust K. Quantification of the survival benefit of early versus deferred cystectomy in high-risk non-muscle invasive bladder cancer (T1 G3). World Journal of Urology. 2009;27(3):347–351. [PubMed: 19319539]
11. Iida S, et al. Clinical outcome of high-grade non-muscle-invasive bladder cancer: a long-term single center experience. International Journal of Urology. 2009;16(3):287–292. [PubMed: 19207115]
12. Kamat AM, et al. The case for early cystectomy in the treatment of nonmuscle invasive micropapillary bladder carcinoma. Journal of Urology. 2006;175(3 Pt 1):881–885. [Erratum appears in J Urol. 2006 May;175(5):1967] [PubMed: 16469571]
13. Park J, et al. Prognostic significance of non-papillary tumor morphology as a predictor of cancer progression and survival in patients with primary T1G3 bladder cancer. World Journal of Urology. 2009;27(2):277–283. [PubMed: 19020879]
14. Patard J, et al. Tumor progression and survival in patients with T1G3 bladder tumors: multicentric retrospective study comparing 94 patients treated during 17 years. Urology. 2001;58(4):551–556. [PubMed: 11597537]
15. Thalmann GN, et al. Primary T1G3 bladder cancer: organ preserving approach or immediate cystectomy? Journal of Urology. 2004;172(1):70–75. [PubMed: 15201740]
16. van den Bosch S, Alfred WJ. Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review. European Urology. 2011;60(3):493–500. [Review] [PubMed: 21664041]
17. Wong SW. Immediate versus delayed cystectomy for high-grade PT1 Transitional Cell Carcinoma of the bladder. BJU International. :4. Conference(var.pagings)

Evidence tables

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Review question

For which patients with non-muscle invasive bladder cancer would primary cystectomy produce better outcomes than BCG?

Information sources and eligibility criteria

The following databases were searched for economic evidence relevant to the PICO: MEDLINE, EMBASE, COCHRANE, NHS EED and HEED. Studies conducted in OECD countries other than the UK were considered.

Studies were selected for inclusion in the evidence review if the following criteria were met:

• Both cost and health consequences of interventions reported (i.e. true cost-effectiveness analyses)
• Conducted in an OECD country
• Incremental results are reported or enough information is presented to allow incremental results to be derived
• Studies that matched the population, interventions, comparators and outcomes specified in PICO
• Studies that meet the applicability and quality criteria set out by NICE, including relevance to the NICE reference case and UK NHS

Note that studies that measured effectiveness using quality of life based outcomes (e.g. QALYs) were desirable but, where this evidence was unavailable, studies using alternative effectiveness measures (e.g. life years) were considered.

Selection of studies

The literature search results were screened by checking the article's title and abstract for relevance to the review question. The full articles of non-excluded studies were then attained for appraisal and compared against the inclusion criteria specified above.

Results

Three searches for economic evidence were run over the development of the guideline; one at the start of the process, an update midway through and a further update at the end of the process. The diagram below shows the combined results of the three searches and illustrates the sifting process.

Figure 51Summary Of Evidence Search And Sifting Process For This Topic

It can be seen that, in total, 1,189 possibly relevant papers were identified. Of these, 1,124 papers were excluded at the initial sifting stage based on the title and abstract while 65 full papers were obtained for appraisal. A further 56 papers were excluded based on the full text as they were not applicable to the PICO or did not include an incremental analysis of both costs and health effects. Therefore, nine papers were included in the systematic review of the economic evidence for this guideline.

One of these nine papers related to the topic at hand and was thus included in the review of published economic evidence for this topic; Kulkarni et al. 2009. The study included a cost-effectiveness analysis where effectiveness was measured using quality adjusted life years (QALYs) i.e. a cost-utility analysis.

Quality and applicability of the included study

The study was only partially applicable to the decision problem that we are evaluating, primarily because it was a Canadian study and as such the estimated costs and benefits might not apply to the UK health care setting. In addition, quality of life values were not all reported directly from patients and were often not drawn from bladder cancer patients (data from prostate, lung and breast cancer patients)

Potentially serious limitations were also identified with the analysis. Although a systematic literature review was conducted, the evidence identified and utilised was not always of high quality. The costs applied in the model were not always sourced from patients with bladder cancer e.g. chemotherapy costs were based on patients with non-small cell lung cancer. In addition, while PSA and scenario analyses were performed, further sensitivity analyses could have been conducted to better explore uncertainty.

Modified GRADE table

The primary results of the analysis by Kulkarni et al. 2009 are summarised in the modified GRADE table below.

Table 81

Modified Grade Table Showing The Included Evidence For Treatments For High Risk Non-Muscle Invasive Bladder Cancer.

Evidence statements

The base case results of the cost-effectiveness analysis showed that immediate cystectomy was cheaper and more effective than conservative therapy (BCG with possible delayed cystectomy) i.e. immediate cystectomy was found to be the dominant strategy.

Scenario analyses, in which age and co-morbid status were varied, showed that the optimal strategy is likely to be different for different patient subgroups. The analysis showed that immediate cystectomy was dominant in patients aged ≤55 years old regardless of co-morbid status. For patients ≥70 years old, conservative therapy was either dominant or had an ICER that was likely to be considered cost-effective (≤$32,700 per QALY). For patients between ages 60 and 70 years old, the optimal choice was dependent upon co-morbidities, with increased co-morbid burden making conservative therapy more cost-effective.

The probabilistic sensitivity analyses (PSA) showed that immediate cystectomy was found to be cost-effective in 70% and 67% of simulations at thresholds of $20,000 and $50,000 per QALY, respectively.

The results suggest that, compared with a conservative strategy using BCG, immediate radical cystectomy yielded better outcomes and lower costs for the average patient. Furthermore, the results suggest that tailoring therapy based on patient age and co-morbidity may increase survival and yield significant costs savings for the health care system.

However, there are reservations about the applicability of the analysis because it considered the Canadian health care system which may not reflect the UK setting. There were also concerns about the quality of life data that were used as they were not all patient reported and were often not drawn from patients with bladder cancer (data from prostate, lung and breast cancer were used). Potentially serious limitations were also identified as, although a systematic literature review was conducted, some of the evidence informing the model was not considered to be of high quality. Furthermore, costs were not always sourced from patients with bladder cancer, such as chemotherapy costs, which were based on patients with non-small cell lung cancer.

References

1.

Kulkarni GS, et al. Cost-effectiveness analysis of immediate radical cystectomy versus intravesical Bacillus Calmette-Guerin therapy for high-risk, high-grade (T1G3) bladder cancer. Cancer. 2009;115(23):5450–59. (Structured abstract) [PubMed: 19685529]

Full evidence table

The full details of the study included in the evidence review are presented in the evidence table below.

Table 82

full evidence table showing the included evidence (Kulkarni et al. 2009) for treatments for high risk non-muscle invasive bladder cancer.

Rationale

Intravesical BCG is an immunotherapy used to treat intermediate and high-risk non-muscle invasive bladder cancer. This therapy may be administered as either a single 6 week course (known as “induction BCG”) or as repeated instillations episodically for several years (known as “maintenance BCG”). Each treatment includes the instillation of live BCG bacteria, of which various strains are known to exist, into the bladder. Failure to respond to BCG occurs when a further bladder cancer arises following or during BCG treatment. These cancers may be better, similar or worse to the original tumour, and may be detected during, shortly after, or many years following BCG treatment. Therefore the term BCG failure includes a wide spectrum of events. It can also include patients who did not complete their treatment due to BCG related side effects (called BCG intolerant). In general most physicians agree that the development of tumour with muscle invasion following or during BCG treatment requires radical treatment - either bladder removal (cystectomy) or radiotherapy, if cure is to be obtained. In contrast, there is less consensus regarding the treatment of BCG failure when the disease is not muscle invasive. Some physicians feel that the timing of failure (early versus late) is important, whilst other feel that failure at any time requires more aggressive treatment.

Whilst radical cystectomy is perceived as the gold standard treatment for BCG failure, it may be over treatment in some patients and other patients are keen to avoid bladder removal regardless of risks. Therefore “bladder-sparing” treatments are reported for use in this context. These include immunotherapies (e.g. repeated BCG instillations with or without additional immune modulator), intravesical chemotherapy (such as gemcitabine), device assisted intravesical chemotherapy (e.g. mitomycin-c administration using EDMA or hyperthermia) and radiotherapy. These approaches avoid removal of the bladder, but carry the risk that the tumour may not respond and will progress to invasion or spread beyond the bladder. They also have side effects and toxicity. Given the spectrum of events encompassed by the term BCG-failure, it is possible that different treatments will be better for different types of failure.

This review will compare different treatments for patients who fail BCG. It will identity the risks and benefits of each treatment and try to identify if some are more suited to certain types of BCG failure.

Question in PICO format

METHODS

RESULTS

Result of the literature searches

Figure 55Study flow diagram

Study quality and results

The evidence is summarised in GRADE evidence profiles (Tables 83-86)

Table 83

GRADE evidence profile: mitomycin C compared to gemcitabine for patients diagnosed with NMIBC who have failed BCG.

Table 84

GRADE evidence profile: gemcitabine compared to BCG for patients diagnosed with NMIBC who have failed BCG.

Table 85

GRADE evidence profile: BCG compared to chemotherapy for patients diagnosed with NMIBC who have failed BCG.

Table 86

GRADE evidence profile: BCG alone compared to BCG plus interferon α2B for patients diagnosed with NMIBC who have failed BCG.

References to included studies

1. Addeo R, Caraglia M, Bellini S, Abbruzzese A, Vincenzi B, Montella L, Miragliuolo A, Guarrasi R, Lanna M, Cennamo G, Faiola V, Prete S. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(4):543–548. [PubMed: 19841330]
2. Di Lorenzo G, Perdona S, Damiano R, Faiella A, Cantiello F, Pignata S, Ascierto P, Simeone E, De Sio M, Autorino R. Gemcitabine versus bacille Calmette-Guerin after initial bacille Calmette-Guerin failure in non-muscle-invasive bladder cancer: a multicenter prospective randomized trial. Cancer. 2010;116(8):1893–1900. [PubMed: 20162706]
3. Gacci M, Bartoletti R, Cai T, Nerozzi S, Pinzi N, Repetti F, Viggiani F, Ghezzi P, Nesi G, Carini M. TUR (Toscana Urologia) Group. Intravesical gemcitabine in BCG-refractory T1G3 transitional cell carcinoma of the bladder: a pilot study. Urologia Internationalis. 2006;76(2):106–111. [PubMed: 16493208]
4. Matsumoto K, Kikuchi E, Shirakawa H, Hayakawa N, Tanaka N, Ninomiya A, Miyajima A, Nakamura S, Oya M. Risk of subsequent tumour recurrence and stage progression in bacille Calmette-Guerin relapsing non-muscle-invasive bladder cancer. BJU International. 2012;110(11 Pt B):E508–E513. [PubMed: 22574662]
5. Prasad SM. Durability of response: The achilles heel of salvage combination immunotherapy with intravesical bacillus calmette-guerin and interferon-alpha 2B in bladder cancer. Journal of Urology. 2009. Conference abstract.

Evidence tables

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Information sources

A literature search was performed by the information specialists (EH and SA).

Selection of studies

The information specialist (EH) did the first screen of the literature search results. One reviewer (JH) then selected possibly eligible studies by comparing their title and abstract to the inclusion criteria in the PICO. Randomised trial and comparative studies were included when available. Non-comparative data was considered for interventions where there were no comparative studies.

Data synthesis

Evidence was presented using GRADE. Meta-analysis was not possible for this review.

Result of the literature searches

Figure 56Study flow diagram

Study quality and results

No evidence was identified for health-related quality of life across any of the interventions. No evidence was identified for the following interventions specified in the PICO: cystectomy, botox, alum, embolisation, catheterisation, increased time between treatments of BCG, elmiron. Evidence is summarised in Tables 87-93.

Table 87

GRADE evidence profile: Ofloxacin for the prevention of BCG-induced toxicity in superficial bladder cancer.

Table 88

GRADE evidence profile: Isoniazid for the prevention of BCG-induced bladder toxicity in superficial bladder cancer.

Table 89

GRADE evidence profile: Oxybutynin for the prevention of BCG-induced toxicity in superficial bladder cancer.

Table 90

GRADE evidence profile: Reduced BCG dose for BCG-induced toxicity: 1/3 dose versus standard dose.

Table 91

GRADE evidence profile: Formalin for the treatment of bladder haemorrhage secondary to radiation-induced cystitis.

Table 92

GRADE evidence profile: Hyperbaric oxygen therapy (HBOT) for the treatment of radiation-induced hemorrhagic cystitis.

Table 93

GRADE evidence profile: Sodium hyaluronate for the treatment of chemical-induced cystitis.

Evidence statements

References to excluded studies (with reasons for exclusion)

Reason: expert review/commentary

1. Witjes JAP. Clinical Practice Recommendations for the Prevention and Management of Intravesical Therapy-Associated Adverse Events. European Urology, Supplements. 2008;7(10):667–674.
2. O'Donnell M, O'Donnell M. Does ofloxacin protect against BCG-related toxic effects in patients with bladder cancer? Nature Clinical Practice Urology. 2007;4(6):304–305. [PubMed: 17426721]

Reason: not relevant to PICO

1. Wammack R. Long-term results of ileocecal continent urinary diversion in patients treated with and without previous pelvic irradiation. Journal of Urology. 2002;167(5):2058–2062. [PubMed: 11956438]
2. Kowalski M, et al. A Phase I study of an intravesically administered immunotoxin targeting EpCAM for the treatment of nonmuscle-invasive bladder cancer in BCG-refractory and BCG-intolerant patients. Drug Design Development and Therapy. 2010;4:313–320. [PMC free article: PMC2998804] [PubMed: 21151619]
3. Harris V. Planning outcomes and acute toxicity of intensity modulated radiotherapy (IMRT) used for simultaneous treatment of bladder and pelvic nodes. Radiotherapy and Oncology. 2010 September; Conference(var.pagings)
4. Grant T, Donaldson I. Natural history and outcome of patients with high risk non-muscle invasive bladder cancer treated with Bacille Calmette Guerin: A contemporary UK series. Journal of Urology. 2012.:e676. Conference(var.pagings)
5. Ferrandez MLJ. Effectiveness of hyaluronic acid in prevention of acute urinary toxicity in HDR brachytherapy. Radiotherapy and Oncology. 2010 September; Conference(var.pagings)
6. Damiano R. Short-term administration of prulifloxacin in patients with nonmuscle-invasive bladder cancer: An effective option for the prevention of bacillus Calmette-Guerin-induced toxicity? BJU International. 2009;104(5):633–639. [PubMed: 19298412]
7. Harris V. Planning outcomes and acute toxicity of intensity-modulated radiotherapy (IMRT) for treatment of bladder and pelvic lymph nodes. Journal of Clinical Oncology. 2011. Conference(var.pagings)
8. Paterson DL, Patel A. Bacillus Calmette-Guerin (BCG) immunotherapy for bladder cancer: review of complications and their treatment. Australian and New Zealand Journal of Surgery. 1998;68(5):340–344. [PubMed: 9631906]
9. Denton AS, Clarke N, Maher J. Non-surgical interventions for late radiation cystitis in patients who have received radical radiotherapy to the pelvis. Cochrane Database of Systematic Reviews. 2002;(3) [PMC free article: PMC7025765] [PubMed: 12137633]
10. Nabi G, et al. Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database of Systematic Reviews. 2006;(4) [PMC free article: PMC8729219] [PubMed: 17054185]
11. Madhuvrata P, et al. Which anticholinergic drug for overactive bladder symptoms in adults. Cochrane Database of Systematic Reviews. 2012;(1) [PubMed: 22258963]
12. Huddart R. Updated results of the BC2001 phase III randomized trial of standard vs reduced high dose volume radiotherapy for muscle invasive bladder cancer (ISCRTN:68324339): Tumour control, toxicity and quality of life. European Journal of Cancer, Supplement. 2009.:423. Conference(var.pagings)
13. Huddart RAJ. BC2001: A multicenter phase III randomized trial of standard versus reduced volume radiotherapy for muscle invasive bladder cancer (ISCRTN:68324339). Journal of Clinical Oncology. 2009.:5022. Conference(var.pagings)
14. Mangar SA, et al. Evaluating the effect of reducing the high-dose volume on the toxicity of radiotherapy in the treatment of bladder cancer. Clinical Oncology. 2006;18(6):466–473. [PubMed: 16909970]
15. Plenk HP. Hyperbaric Radiation-Therapy - Preliminary Results of A Randomized Study of Cancer of Urinary-Bladder and Review of Oxygen Experience. American Journal of Roentgenology. 1972;114(1):152. &. [PubMed: 4333187]
16. Dische S. Hyperbaric-Oxygen Chamber in Radiotherapy of Carcinoma of Bladder. British Journal of Radiology. 1973;46(541):13–17. [PubMed: 4566856]
17. Cade IS, et al. Hyperbaric-Oxygen and Radiotherapy - Medical-Research-Council Trial in Carcinoma of Bladder. British Journal of Radiology. 1978;51(611):876–878. [PubMed: 361143]
18. Suvorova YV, Tarazov PG. Transcatheter embolization vs surgical ligation in the treatment of bleeding bladder neoplasms. European Journal of Cancer. 1997;33:149–149.
19. Losa A, Hurle R, Lembo A. Low dose bacillus Calmette-Guerin for carcinoma in situ of the bladder: long-term results. Journal of Urology. 2000;163(1):68–71. [PubMed: 10604316]
20. Mack D, et al. The ablative effect of quarter dose bacillus Calmette-Guerin on a papillary marker lesion of the bladder. Journal of Urology. 2001;165(2):401–403. [PubMed: 11176382]
21. Mugiya S, et al. Long-term outcome of a low-dose intravesical bacillus calmette-guerin therapy for carcinoma in situ of the bladder: Results after six successive instillations of 40 mg BCG. Japanese Journal of Clinical Oncology. 2005;35(7):395–399. [PubMed: 15976065]
22. Shindel AW, et al. Ureteric embolization with stainless-steel coils for managing refractory lower urinary tract fistula: a 12-year experience. BJU International. 2007;99(2):364–368. [PubMed: 17026590]
23. Bui Q-C. The efficacy of hyperbaric oxygen therapy in the treatment of radiation-induced late side effects. International Journal of Radiation Oncology Biology Physics. 2004;60(3):871–878. [PubMed: 15465205]
24. Safra T. Improved Quality of Life with Hyperbaric Oxygen Therapy in Patients with Persistent Pelvic Radiation-induced Toxicity. Clinical Oncology. 2008;20(4):284–287. [PubMed: 18222656]
25. Shao Y, Lu GL, Shen ZJ. Comparison of intravesical hyaluronic acid instillation and hyperbaric oxygen in the treatment of radiation-induced hemorrhagic cystitis. BJU International. 2012;109(5):691–694. [PubMed: 21895939]
26. Lamm DL, et al. Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer. Journal of Urology. 1992;147(3):596–600. [PubMed: 1538436]
27. Rawls WH, et al. Fatal sepsis following intravesical bacillus Calmette-Guerin administration for bladder cancer. Journal of Urology. 1990;144(6):1328–1330. [PubMed: 2231917]
28. Mack D. Low-dose bacille Calmette-Guerin (BCG) therapy in superficial high-risk bladder cancer: A phase II study with the BCG strain connaught Canada. British Journal of Urology. 1995;75(2):185–187. [PubMed: 7850323]
29. Whillis D, et al. Radical radiotherapy with salvage surgery for invasive bladder cancer: results following a reduction in radiation dose. Journal of the Royal College of Surgeons of Edinburgh. 1992;37(1):42–45. [PubMed: 1573607]
30. Takashi M, et al. Evaluation of a low-dose intravesical bacillus Calmette-Guérin (Tokyo strain) therapy for superficial bladder cancer. International Urology and Nephrology. 1995;27(6):723–733. [PubMed: 8725038]
31. Oddens J, et al. Final Results of an EORTC-GU Cancers Group Randomized Study of Maintenance Bacillus Calmette-Guerin in Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the Urinary Bladder: One-third Dose Versus Full Dose and 1 Year Versus 3 Years of Maintenance. European Urology. 2012 Nov 2; epub ahead of print. [PubMed: 23141049]
32. Pagano F, et al. A low dose bacillus Calmette-Guerin regimen in superficial bladder cancer therapy: is it effective? The Journal of urology. 1991;146(1):32–35. [PubMed: 2056600]
33. Goswami AK, et al. How Safe Is 1-Percent Alum Irrigation in Controlling Intractable Vesical Hemorrhage. Journal of Urology. 1993;149(2):264–267. [PubMed: 8426397]
34. Koya MP, Simon MA, Soloway MS. Complications of intravesical therapy for urothelial cancer of the bladder. Journal of Urology. 2006;175(6):2004–2010. [PubMed: 16697786]
35. Agrawal MS, et al. The safety and efficacy of different doses of bacillus Calmette Guérin in superficial bladder transitional cell carcinoma. Urology. 2007;70(6):1075–1078. [PubMed: 18158020]
36. Ojea A, et al. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. European Urology. 2007;52(5):1398–1406. [PubMed: 17485161]
37. Martinez-Pineiro JAF. Long-term follow-up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette-Guerin with a reduced dose of 27 mg in superficial bladder cancer. BJU International. 2002;89(7):671–680. [PubMed: 11966623]
38. Irie A, et al. Sufficient prophylactic efficacy with minor adverse effects by intravesical instillation of low-dose bacillus Calmette-Guerin for superficial bladder cancer recurrence. International Journal of Urology. 2003;10(4):183–189. [PubMed: 12657096]
39. Martinez-Pineiro JA, et al. Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial. Journal of Urology. 2005;174(4 Pt 1):1242–1247. [PubMed: 16145378]
40. Yoneyama T, et al. Low-dose instillation therapy with bacille Calmette-Guerin Tokyo 172 strain after transurethral resection: historical cohort study. Urology. 2008;71(6):1161–1165. [PubMed: 18279920]
41. Yalçinkaya F, et al. Prospective randomized comparison of intravesical BCG therapy with standard dose versus low doses in superficial bladder cancer. International Urology and Nephrology. 1998;30(1):41–44. [PubMed: 9569110]
42. Fergany AF, Moussa AS, Gill IS. Laparoscopic Cystoprostatectomy for Radiation-Induced Hemorrhagic Cystitis. Journal of Endourology. 2009;23(2):275–278. [PubMed: 19187011]
43. Pagano F, et al. Improving the efficacy of BCG immunotherapy by dose reduction. European Urology. 1995;27 Suppl 1:19–22. [PubMed: 7750527]
44. Malhotra P, et al. Isoniazid resistance among Bacillus Calmette Guerin strains: implications on bladder cancer immunotherapy related infections. Canadian Journal of Urology. 2011;18(3):5671–5675. [Review] [PubMed: 21703038]

Reason: duplicate of included study

1. Brausi MAO. Bacillus Calmette-Guerin: One third dose versus full dose and one year versus three years of maintenance. Final results of an EORTC GU Cancers Group randomized trial in non muscle invasive bladder cancer. European Urology, Supplements. 2012.:e1050–e1050a. Conference(var.pagings)
2. Vegt PD, et al. Does isoniazid reduce side effects of intravesical bacillus Calmette-Guerin therapy in superficial bladder cancer? Interim results of European Organization for Research and Treatment of Cancer Protocol 30911. Journal of Urology. 1997;157(4):1246–1249. [PubMed: 9120912]
3. Van der Meijden APM. Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: Results from a European organisation for research and treatment of cancer genito-urinary group phase III trial. European Urology. 2003;44(4):429–434. [PubMed: 14499676]
4. Norkool DM, et al. Hyperbaric-Oxygen Therapy for Radiation-Induced Hemorrhagic Cystitis. Journal of Urology. 1993;150(2):332–334. [PubMed: 8326555]

Reason: meeting abstract only – insufficient information for inclusion

1. Mayr M, Sommerhuber A, Loidl W. Dose Reduction of Bacillus Calmette-Guerin (Bcg) in the Treatment of Carcinoma in Situ (Cis) of the Bladder: Does A Less Intense and Shorter Maintenance Regime Have An Impact on Efficacy and Patient Compliance? A 14 Year Experience. European Urology Supplements. 2009;8(4):284–284.
2. Yari H, et al. Comparison of Full-Dose Intravesical Bcg Versus Half Dose Bcg and Mitomycin-C in Treatment of Patients with Superficial Bladder Cancer. European Urology Supplements. 2010;9(6):595–596.
3. Fotouhi GA. Hyperbaric oxygen treatment, alpha-tocopherol, and ascorbic acid are effective for reducing late radiation-induced side effects of pelvic radiation therapy. International Journal of Radiation Oncology Biology Physics. 2012.:3–S653. Conference(var.pagings)
4. A randomized controlled trial of standard dose BCG versus low dose BCG and interferon alpha in patients with superficial bladder cancer - A five-year series. European Urology Supplements. 2005;4(3):221–221.
5. Esuvaranathan K. Five-year data of a randomized controlled trial of standard dose BCG versus low dose BCG and interferon alpha in patients with superficial bladder cancer. Journal of Urology. 2004;171(4):73–73.

Reason: foreign language

1. Serretta V, et al. [Prevention of topic toxicity of BCG with single-dose prulifloxacin. Preliminary results of a randomized pilot study]. Urologia. 2010;77(4):240–247. [PubMed: 21234866]

Information sources

A literature search was performed by the information specialist (EH).

Selection of studies

The information specialist (EH) did the first screen of the literature search results. One reviewer (JH) then selected possibly eligible studies by comparing their title and abstract to the inclusion criteria in the PICO.

Data synthesis

One randomised trial was identified. No other comparative data was found. Therefore, data is presented from observational studies about recurrence rates during follow-up for non-muscle invasive bladder cancer. No meta-analysis was possible for this review.

Result of the literature searches

Figure 57Study flow diagram

Study quality and results

Evidence is summarised in Tables 94-96.

Table 94

GRADE evidence profile: Frequent versus less frequent follow-up for TaG1-2 bladder cancer.

Table 95

GRADE evidence profile: Follow-up for non-muscle invasive bladder cancer.

Table 96

Patient experience and preference for follow-up of NMIBC.

Evidence statements

Moderate quality evidence from one randomised trial of 97 patients (Olsen et al., 1995) suggests uncertainty over whether follow up frequency of three months is more or less effective than follow up with a frequency of six months in terms of recurrence, progression or overall survival.

Low quality evidence from five observational studies of patients with low-grade superficial bladder cancer report recurrence rates over long-term follow-up. Two studies including 470 patients suggest that tumour detection at the first follow-up cystoscopy is associated with a greater risk of recurrence during subsequent follow-up compared to those who are tumour-free at the first cystoscopy (Holmang et al., 2002; Mariappan & Smith, 2005). All studies report a reduction in the risk of recurrence over time. Some studies suggest the risk of recurrences is greatly reduced after a tumour-free period of five years or more (Mariappan & Smith, 2005; Zieger et al., 2000). In Mariappan & Smith (2005) only one (0.9%) patient had a first recurrence after being tumour-free for five years, whereas LeBlanc et al. (1999) reports recurrence rates of approximately 30% in patients after remaining tumour-free for two to ten years. Another study reports that of 20 primary Ta-T1 patients who were tumour-free for five years, seven (35%) had muscle-invasive disease (Thompson et al., 1993).

One retrospective observational study of 542 intermediate-high risk patients who had received BCG treatment reports that 338/542 (62%) patients were not tumour-free for five years or more. 22/204 (10.8%) patients had a recurrence after being tumour-free for five years or more (Holmang et al., 2012). During the first five-years after BCG, 57 patients (10.5%) died from bladder cancer and between years six and 25, 32 patients (5.9%) died from bladder cancer.

Five observational studies report rates of upper urinary tract (UUT) recurrence ranging between 2.6% and 5.5%. Median times to UUT recurrence vary from 22 to 33 months in three studies (Miyake et al., 2005; Canales et al., 2006; Holmang et al., 1998) and one study (Hession et al., 1999) reports a mean time to recurrence of 78 months. In one study, two out of 18 UUT cancers were diagnosed by routine intravenous urography, and the other 18 presented with symptoms suggesting UUT recurrence before IVU (Miyake et al., 2006). Holmang et al. (1998) reported that IVU performed 0 to ten months before the UUT cancer was diagnosed failed to raise suspicion of a tumour in eight out of 16 patients (including three patients with initial muscle-invasive bladder cancer).

Two studies provide low quality evidence of the accuracy of ultrasound compared with cystoscopy for the detection of recurrent tumours in patients with superficial bladder cancer. In one study, three tumours detected by cystoscopy were missed by ultrasound (Stamatiou et al., 2011, and in the second study 15 patients with recurrence were not detected by ultrasound (Vallencien et al., 1986).

Low quality evidence for health-related quality of life is provided by three studies (503 patients) which report that most patients experience minimal pain (Yossepowitch et al., 2007) from undergoing cystoscopic follow-up, although the introduction of the cystoscope is rated as the most painful part of the procedure (van der Aa et al., 2008). Waiting for test results is rated as the most distressing part of follow-up by urine testing (van der Aa et al., 2008).

References to excluded studies (with reasons for exclusion)

1. Hernandez V, et al. Safety of active surveillance program for recurrent nonmuscle-invasive bladder carcinoma. Urology. 2009;73(6):1306–1310. Reason: not relevant to PICO – active surveillance . [PubMed: 19375783]
2. Anastasiadis A, et al. Follow-up procedures for non-muscle-invasive bladder cancer: an update. Expert Review of Anticancer Therapy. 2012;12(9):1229–1241. Reason: expert review . [PubMed: 23098122]
3. Ceylan K, et al. Comparison of cystoscopy with diffusion-weighted magnetic resonance images used in the diagnosis and follow-up of patients with bladder tumors. Asian Pacific Journal of Cancer Prevention: Apjcp. 2010;11(4):1001–1004. Reason: population not relevant – non follow-up patients . [PubMed: 21133614]
4. David KA, et al. Surveillance of urothelial carcinoma: stage and grade migration, 1993-2005 and survival trends, 1993-2000. Cancer. 2009;115(7):1435–1447. Reason: not relevant to PICO . [PubMed: 19215030]
5. Forsyth I, Shaikh S, Gunn I. The nurse cystoscopist. Extending the role. British Journal of Perioperative Nursing. 2005;15(8):342–345. Reason: outcomes not relevant to PICO . [PubMed: 16128420]
6. Kent DL, et al. Evaluation of nonlinear optimization for scheduling of follow-up cystoscopies to detect recurrent bladder cancer. The Bladder Cancer follow-up Group. Medical Decision Making. 1991;11(4):240–248. Reason: outcomes not relevant to PICO . [PubMed: 1662739]
7. Nam RK, et al. Comparison of molecular and conventional strategies for followup of superficial bladder cancer using decision analysis. Journal of Urology. 2000;163(3):752–757. Reason: not relevant to PICO – health economics . [PubMed: 10687970]
8. Schmidbauer J, Lindenau G. Follow-up of nonmuscle invasive transitional cell carcinoma of the bladder: how and how often? Current Opinion in Urology. 2008;18(5):504–507. [Review] [32 refs] Reason: expert review . [PubMed: 18670275]
9. Schrag D, et al. Adherence to surveillance among patients with superficial bladder cancer. Journal of the National Cancer Institute. 2003;95(8):588–597. Reason: outcomes not relevant to PICO . [PubMed: 12697851]
10. Mazzonetto M. Postcystectomy follow-up in bladder neoplasm and continent urinary diversion. The role of CT. Italian Current Radiology. 1991;10(3-4):129–133. Reason: foreign language .
11. Abel PD. Follow-up of patients with “superficial” transitional cell carcinoma of the bladder: the case for a change in policy. British Journal of Urology. 1993;72(2):135–142. [Review] [41 refs] Reason: expert review . [PubMed: 8402013]
12. Hall RR, et al. Proposal for changes in cystoscopic follow up of patients with bladder cancer and adjuvant intravesical chemotherapy. BMJ. 1994;308(6923):257–260. Reason: expert review . [PMC free article: PMC2539314] [PubMed: 8179678]
13. Dubernard JM, et al. Correlation between cytology and cystoscopy in the follow-up of patients with bladder tumours. European Urology. 1982;8(1):5–8. Reason: outcomes not relevant to PICO . [PubMed: 7060611]
14. Gakis G, Kruck S, Stenzl A. Can the burden of follow-up in low-grade noninvasive bladder cancer be reduced by photodynamic diagnosis, perioperative instillations, imaging, and urine markers? Current Opinion in Urology. 2010;20(5):388–392. Reason: expert review . [PubMed: 20657287]
15. Mathers MJ, et al. Is there evidence for a multidisciplinary follow-up after urological cancer? An evaluation of subsequent cancers. World Journal of Urology. 2008;26(3):251–256. Reason: not relevant to PICO . [PubMed: 18421461]
16. Parmar MK, et al. Prognostic factors for recurrence and followup policies in the treatment of superficial bladder cancer: report from the British Medical Research Council Subgroup on Superficial Bladder Cancer (Urological Cancer Working Party). The Journal of urology. 1989;142:284–288. Reason: not relevant to PICO – prognostic factors . [PubMed: 2501516]
17. Aa MN, et al. Sexual function of patients under surveillance for bladder cancer. BJU International. 2009;104:35–40. Reason: not relevant to PICO – questionnaire completed before starting surveillance program . [PubMed: 19154473]
18. Gulliford MC, Petruckevitch A, Burney PG. Can efficiency of follow-up for superficial bladder cancer be increased? Annals of the Royal College of Surgeons of England. 1993;75(1):57–61. Reason: outcomes not relevant to PICO . [PMC free article: PMC2497742] [PubMed: 8422147]
19. Rabbani F, et al. Upper-tract tumors after an initial diagnosis of bladder cancer: argument for long-term surveillance. Journal of Clinical Oncology. 2001;19(1):94–100. Reason: recurrence not reported separately for NMIBC and MIBC/metastatic disease . [PubMed: 11134200]
20. Taylor J. An evaluation of a nurse-led cystoscopy surveillance service. Professional Nurse. 2003;18(10):580–583. Reason: not relevant to PICO . [PubMed: 12808860]
21. Lee CT, et al. Early-stage bladder cancer surveillance does not improve survival if high-risk patients are permitted to progress to muscle invasion. Urology. 2007;69(6):1068–1072. Reason: not relevant to PICO – follow-up schedule not reported . [PubMed: 17572188]
22. Chang SS, et al. Routine postoperative intensive care monitoring is not necessary after radical cystectomy. Journal of Urology. 2002;167(3):1321–1324. Reason: not relevant to PICO . [PubMed: 11832723]
23. Tran W, et al. Longitudinal risk of upper tract recurrence following radical cystectomy for urothelial cancer and the potential implications for long-term surveillance. Journal of Urology. 2008;179(1):96–100. Reason: method of UUT tumour detection not reported . [PubMed: 17997449]
24. Drake R. Bladder cancer: Routine follow-up after radical cystectomy improves survival. Nature Reviews Urology. 2010;7(8):419. Reason: comment on Giannarini 2010 .
25. Vrooman OP, Witjes JA. Follow-up of patients after curative bladder cancer treatment: guidelines vs. practice. Current Opinion in Urology. 2010;20(5):437–442. Reason: expert review . [PubMed: 20657286]
26. Wagner KR, et al. Prospective intermediate follow-up of carcinoma in situ involving the distal ureter at cystectomy: is there a role for ureteroscopy? Journal of Endourology. 2008;22(6):1241–1246. Reason: intervention not relevant to PICO . [PubMed: 18578657]
27. Hellenthal NJ, et al. The role of surveillance in the treatment of patients with muscle-invasive bladder cancer after chemotherapy. BJU International. 2010;105(4):485–488. Reason: not relevant to PICO . [PubMed: 19849694]
28. Gogus C, et al. 3-Dimensional computerized tomography in follow-up of patients with urinary diversion. International Urology & Nephrology. 2005;37(4):739–742. Reason: intervention not relevant to PICO, comparing 3D-CT with CT (no pathological findings) [PubMed: 16362591]
29. Faithfull S, et al. Evaluation of nurse-led follow up for patients undergoing pelvic radiotherapy. British Journal of Cancer. 2001;85:1853–1864. Reason: Not relevant to PICO (nurse-led care versus control) [PMC free article: PMC2364007] [PubMed: 11747326]
30. Soukup V, et al. Follow-up after surgical treatment of bladder cancer: a critical analysis of the literature. European Urology. 2012;62(2):290–302. Reason: Expert review . [PubMed: 22609313]
31. Boorjian SA, et al. Detection of asymptomatic recurrence during routine oncological followup after radical cystectomy is associated with improved patient survival. Journal of Urology. 2011;186(5):1796–1802. Reason: Relevant to another topic . [PubMed: 21944088]
32. Kuroda M, et al. Stage specific follow-up strategy after cystectomy for carcinoma of the bladder. International Journal of Urology. 2002;9(3):129–133. Reason: Relevant to another topic . [PubMed: 12010321]
33. Slaton JW, et al. A stage specific approach to tumor surveillance after radical cystectomy for transitional cell carcinoma of the bladder. Journal of Urology. 1999;162(3 Pt 1):710–714. Reason: Relevant to another topic . [PubMed: 10458349]
34. Yafi FA, et al. Surveillance guidelines based on recurrence patterns after radical cystectomy for bladder cancer: the Canadian Bladder Cancer Network experience. BJU International. 2012;110(9):1317–1323. Reason: Relevant to another topic . [PubMed: 22500588]
35. Segal AJ, et al. Follow-up imaging of bladder carcinoma. American College of Radiology. ACR Appropriateness Criteria. Radiology. 2000;215 Suppl:765–772. Reason: Expert review . [PubMed: 11037498]
36. Volkmer BG, et al. Oncological followup after radical cystectomy for bladder cancer-is there any benefit? Journal of Urology. 2009;181(4):1587–1593. Reason: Relevant to another topic . [PubMed: 19233433]
37. Giannarini G, et al. Do patients benefit from routine follow-up to detect recurrences after radical cystectomy and ileal orthotopic bladder substitution? European Urology. 2010;58(4):486–494. Reason: Relevant to another topic . [PubMed: 20541311]
38. Kamat AM, et al. Prospective trial to identify optimal bladder cancer surveillance protocol: reducing costs while maximizing sensitivity. BJU International. 2011;108(7):1119–1123. Reason: Outcomes not relevant to PICO (sensitivity and Health economics) [PubMed: 21426474]
39. Tahoun NS, Abdel Maksoud AM, Mohamed DB. Evaluation of the Value of Combined Urine Cytology and Cystoscopy for Follow-up of Superficial Transitional Cell Carcinoma of the Urinary Bladder. Journal of Egyptian National Cancer Institute. 2010;22(2):105–111. Reason: Outcomes not relevant to PICO (sensitivity) [PubMed: 21860467]
40. Perlis N, et al. Upper urinary tract and urethral recurrences following radical cystectomy: review of risk factors and outcomes between centres with different follow-up protocols. World Journal of Urology. 2013;31(1):161–167. Reason: Relevant to another topic . [PubMed: 22810052]
41. Shinagare AB, Sadow CA, Silverman SG. Surveillance of patients with bladder cancer following cystectomy: yield of CT urography. Abdominal Imaging. 2013;38(6):1415–1421. Reason: Relevant to another topic . [PubMed: 23881008]

References

1. Bekker-Grob EW, et al. Non-muscle-invasive bladder cancer surveillance for which cystoscopy is partly replaced by microsatellite analysis of urine: a cost-effective alternative? BJU International. 2009;104(1):41–47. (Provisional abstract) [PubMed: 19500328]
2. Van Kessel KEM. FGFR3 mutation analysis in voided urine samples to decrease cystoscopies and cost in nonmuscle invasive bladder cancer surveillance: A comparison of 3 strategies. Journal of Urology. 2013;189(5):1676–81. [PubMed: 23142690]
3. Zhang Y, Denton BT, Nielsen ME. Comparison of surveillance strategies for low-risk bladder cancer patients. Medical Decision Making. 2013;33(2):198–214. [PubMed: 23178638]
4. Sylvester RJ, van der Meijden APM, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DWW, Kurth Karlheinz. Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer Using EORTC Risk Tables: A Combined Analysis of 2596 Patients from Seven EORTC Trials. European Urology. 2006;49:466–477. [PubMed: 16442208]
5. Hall RR, Parmar MKB, Richards AB, Smith PH. Proposal for changes in cystoscopic follow–up of patients with bladder cancer and adjuvant intravesical chemotherapy. BMJ. 1994;308:257–260. [PMC free article: PMC2539314] [PubMed: 8179678]
6. Mowatt G, et al. Systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer. Health Technology Assessment. 2010:1. (Structured abstract) [PubMed: 20082749]
7. Van den Bosch S, Alfred WJ. Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review. European Urology. 2011;60(3):493–500. [Review] [PubMed: 21664041]
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13. Kulkarni GS, Finelli A, Fleshner NE, Jewett MAS, Lopushinsky SR, Alibhai SMH. Optimal management of high-risk T1G3 bladder cancer: a decision analysis. PLoS Med. 2007;4:1538–49. [PMC free article: PMC1989749] [PubMed: 17896857]
14. Yoshimura K, et al. Impact of superficial bladder cancer and transurethral resection on general health-related quality of life: an SF-36 survey. Urology. 2005;65(2):290–94. [PubMed: 15708040]
15. Ara R, Brazier J. Deriving an Algorithm to Convert the Eight Mean SF-36 Dimension Scores into a Mean EQ-5D Preference-Based Score from Published Studies (Where Patient Level Data Are Not Available). Value in Health. 2008;11(7):1131–1143. [PubMed: 18489495]