Abstract
Introduction:
Bladder cancer is a common cause of morbidity and mortality worldwide. The primary treatment for intermediate and high-grade non-muscle-invasive bladder cancer (HS-NMIBC) involves the bladder preservation approach (BPA) transurethral resection of bladder tumor (TURBT) followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy. For BCG-unresponsive patients, radical cystectomy (RC) is the gold standard.
Materials and Methods:
A comprehensive literature search was conducted on PubMed, Scopus, and Cochrane Central to identify relevant studies. Eligibility criteria used were patients suffering from HS-NMIBC and studies that exhibited the comparison between the BPA and RC followed by TURBT. All analyses were conducted using Review Manager version 5.4, and the statistical significance level was set at P < 0.05.
Results:
This systematic review and meta-analysis included five studies. The most prominent outcomes being assessed were overall survival (OS) between BPA and RC at intervals of 2 years, 5 years, and 10 years and cancer-specific mortality (CSM) between BPA and RC at intervals of 2 years and 5 years. OS showed insignificant results at 2 years (RR 0.79, 95%CI 0.95–1.30; P = 0.19), RC favoring OS in 5 years (RR 1.17, 95%CI 1.10–1.24; P<0.00001) and insignificant differences between the two managements in terms of OS for 10 years (RR 1.19, 95% CI 0.87–1.63; P = 0.27). BPA favors CSM in 2 years (RR 0.28, 95%CI 0.23–0.34; P<0.001) and 5 years (RR 0.46, 95%CI 0.40–0.52; P<0.001).
Conclusion:
Both approaches prevent CSM and progression from HG-NMIBC; bladder preservation with BCG may be a superior strategy when compared to RC. The former approach improves OS notably in the elderly and those with T1G3 tumors. However, RC may still be a preferable alternative for the younger population. Despite this, determining the optimal BPA method remains a challenge and future high-quality studies are needed to verify these findings and provide impactful reviews.
Keywords: bladder preservation, high-grade non-muscle-invasive bladder cancer, meta-analysis, radical cystectomy
Background
Bladder cancer (BCa) ranks as the 10th most frequent malignancy globally and the sixth most prevalent cancer in the United States[1,2], resulting in over 16 000 fatalities annually[3]. In 2020, 573 278 individuals were estimated to receive a diagnosis of BCa worldwide[4]; approximately 75% of these patients have non-muscle-invasive bladder cancer (NMIBC)[5]. The highest-risk NMIBC is defined as T1 Grade 3 (G3)/high grade (HG) associated with concurrent bladder carcinoma in situ (CIS), multiple and/or large T1G3/HG (>3 cm), and/or recurrent T1G3/HG, T1G3/HG with CIS in the prostatic urethra[6]. The survival rate in high-grade disease at 10 years is approximately 70%–85% as per the guidelines of the American Urological Association (AUA)[7]. However, the recurrence rate and progression to muscle-invasive bladder cancer (MIBC) are significant endpoints for overall prognosis, as they are crucial variables defining the long-term oncological outcome[7,8].
The primary treatment modality for intermediate and HG-NMIBC regarding bladder preservation approach (BPA) is transurethral resection of bladder tumor (TURBT) followed by adjuvant intravesical Bacillus Calmette–Guérin (BCG) immunotherapy instillation[9,10]. The latter treatment modality has an overall failure rate of 40%–50%[11]. For NMIBC, the overall recurrence rate ranges from 60% to 70%, with an overall progression rate of 20% to 30%[12].
In the case of BCG-unresponsive individuals, the current gold-standard therapy is radical cystectomy (RC)[13]. However, this method is associated with poor quality of life, thus making optimal standard care for these patients clinically challenging. It was also crucial for HG-NMIBC patients to undergo prompt RC because inappropriate delay may result in cancer cell dissemination through lymph nodes to surrounding organs[14,15].
In this meta-analysis, we aim to explore the comparative analysis between BPA and RC for HG-NMIBC by systematically pooling all relevant evidence-yielding outcomes that include overall survival (OS) and cancer-specific mortality (CSM).
Methodology
This systematic review and meta-analysis fully comply with the preferred reporting items for the systematic review and meta-analysis (PRISMA) 2020 statement. The protocol is registered in PROSPERO with protocol ID CRD42024586605.
Data sources and search strategy
The preferred reporting items for systemic reviews and meta-analyses (PRISMA) guidelines were employed to conduct this meta-analysis[16]. An electronic search of MEDLINE, Scopus, and Cochrane CENTRAL was performed to gather relevant studies from the inception of databases until Aug 2024 without any language barriers, using the search strategy: (high-grade bladder cancer) OR (carcinoma)) OR (cancer)) OR (neoplasm)) OR (malignant)) OR (tumor)) OR (neoplasia)) AND (bladder)) AND (T1G3)) OR (high grade)) OR (high risk)) OR (urinary bladder neoplasm)) AND (bladder preservation approach)) OR (conservative)) OR (conservative treatment)) OR (administration intravesical)) OR (intravesical)) OR (instillation)) OR (BCG)) OR (BCG vaccine)) OR (Calmette)) OR (preservation)) AND (radical cystectomy))) OR (cystectomy)) OR (cystectom). The PRISMA flow diagram is shown in Fig. 1.
Figure 1.
The PRISMA flow diagram.
Study selection and eligibility criteria
Articles retrieved from the systematic search were transferred to the EndNote Reference Library software version X4 (Clarivate Analytics, Philadelphia, PA), and duplicate articles were screened and removed. The abstracts and titles of the remaining articles were evaluated, and the full text of the articles was screened for relevance of the data. Two independent reviewers performed the inspection of the articles. The following eligibility criteria were used for the inclusion of the studies: (1) Patients suffering from HG-NMIBC; (2) studies that exhibited the comparison between RC and BPA (observation, intravesical BCG, or other types of intravesical instillation) followed by TURBT. A delayed RC was conducted after the failure of BPA or for the intolerable adverse effects; (3) the data of survival outcomes were available. Reviews, letters, or case reports were excluded from the study.
Outcomes of interest, data extraction, and quality assessment
The main survival outcomes of interest were: (1) OS at a time interval of 2 years, 5 years, and 10 years; (2) CSM at a time interval of 2 years and 5 years. Study characteristics, baseline demographics, outcome data, and safety data were extracted onto a predesigned Excel spreadsheet. The quality assessment of included articles was performed using the Newcastle–Ottawa Scale (NOS) to assess the quality of the studies[17]. Two independent reviewers performed data extraction and quality assessment, and they resolved discrepancies through discussion.
HIGHLIGHTS
Comparative Outcomes: This meta-analysis evaluates overall survival (OS) and cancer-specific mortality (CSM) of bladder preservation approaches (BPA) versus radical cystectomy (RC) in managing high-grade non-muscle-invasive bladder cancer.
Significant Findings: RC shows superior 5-year OS (RR 1.17, 95% CI 1.10–1.24; P<0.00001), while BPA significantly lowers CSM at 2 years (RR 0.28, 95% CI 0.23–0.34; P<0.001) and 5 years (RR 0.46, 95% CI 0.40–0.52; P<0.001).
Tailored Approach: BPA emerges as a better option for elderly patients and those with T1G3 tumors, emphasizing the need for personalized treatment strategies.
Clinical Relevance: The findings underscore BPA as a viable alternative to RC, particularly for patients seeking bladder preservation and improved quality of life.
Call for Future Research: The study highlights the necessity of high-quality randomized trials to refine BPA methods and validate these results for broader clinical application.
Statistical analysis
All statistical analyses were performed using Review Manager [version 5.3, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014]. The results from studies were presented as risk ratios (RRs) with corresponding 95% confidence intervals (CIs) and were pooled using a random-effects model. Forest plots were created to evaluate the survival outcomes. Subgroup analyses based on 2-year, 5-year, and 10-year for OS and 2-year and 5-year for CSM were performed. The Higgins I2 statistic[18] was used to assess heterogeneity across studies, and a value less than 50% for I2 was considered acceptable. A P ≤ 0.05 was considered statistically significant in all cases.
Quality assessment
All eligible studies were cohort studies, and the NOS was used for quality assessment. The scale contained three categories: Selection, Comparability, and Outcome. Each numbered item within the Selection and Outcome were awarded one star. As for the Comparability group, a maximum of two stars were assigned. After the assessment, a total score ranging from 0 to 9 stars was calculated for every study. Study bias was scaled as high risk of bias (0–3 stars), middle risk of bias (4–6 stars), and low risk of bias (7–9 stars) and represented inferior quality, medium quality, and superior quality, respectively.
Results
Literature search results
The literature search of three databases preliminarily yielded 100 articles: 33 from MEDLINE, 23 from Scopus, and 44 from Cochrane Library. After removing duplicates, 70 articles remained for analysis. After screening the titles and abstracts, 46 articles were excluded, with 24 articles meeting the inclusion criteria. After a full-text review, 23 articles including reviews, letters, protocols, viewpoints, editorials, comments, and case reports were excluded. Another seven studies lacking key outcomes were excluded. After exclusion, five articles were selected for the meta-analysis.
Study characteristics
A total of 4867 patients were included in the analysis. All studies focused on the tumor stage of T1G3 high-risk NMIBC with two studies[3,4] also including patients with T1 + G2 or Ta + G3 or Tis + G3. The common modality of bladder preservation was intravesical BCG instillation, with one study[3] also using observation as the bladder preservation modality. Patients in one cohort received RC within 3 months[1], and another cohort had surgery within a median time of 2 months[2], while two studies did not specify the timing of the RC[3,4]. Summarizing the eligible data, males had an advantage in gender composition in all studies. The average patient age in all cohorts was older than 67 years, while the average age of the BPA was older compared with the RC groups. The median follow-up time ranged from 46 months to 99.6 months. Extracted outcomes were OS and CSM. Table 1 shows the study characteristics of the included studies.
Table 1.
Study characteristics of included studies.
| Author, year | Tumor stage | RC timing | Bladder preservation modality | Study size (BCG vs RC) | Age (BCG vs RC) | Median follow up time (BCG vs RC) | Types of outcomes |
|---|---|---|---|---|---|---|---|
| Thalmann et al (2004)[19] | T1G3 | Within 6 mo | TURB, BCG | 92 vs 29 | 69 vs 66 | 82.8 mo | OS,CSS,PFS |
| De Berardinis et al (2011)[20] | T1G3 high risk NMIBC | Within 2 mo | TURB, BCG | 80 vs 72 | 70.4 vs 69.6 | 99.6 mo | OS, CSS,PFS |
| Spaliviero et al (2014)[21] | HGT1 micropapillary NMIBC | Within 3 mo | BCG, observation | 16 vs 15 | 69 vs 68 | 38.4 mo | CSS, metastasis |
| Jungyo Suh et al (2019)[22] | T1 or CIS or HG or TaG1/G2 with multiple, recurrent, large tumors | Not given | BCG, observation | 30 vs 15 | 67.6 vs 68.2 | 60 mo | OS, CSS |
| Wang et al (2020)[23] | T1 + G2,G3 or Ta + G3 or Tis + G3 | Not given | BCG | 3862 vs 687 | 70.7 vs Initial RC 67 vs Delayed RC 67 | 46 mo | 2 and 5 years OS, CSS |
BCG, bacillus Calmette–Guérin; CIS, carcinoma in situ; CSS, cancer-specific survival; HG, high grade; mo, months; NMIBC, non‑muscle-invasive bladder cancer; OS, overall survival; PFS, progression‑free survival; RC, radical cystectomy; TURB, transurethral resection of bladder tumor.
Comparison of OS between BPA and RC
At a time interval of 2 years
Three studies reported this outcome with 3628 out of 3984 patients in the BPA group and 566 out of 731 patients in the RC group. Analysis of the available data showed insignificant differences between the two management strategies (RR 0.79, <>95% CI 0.95–1.30; P = 0.19) as shown in Fig. 2.
Figure 2.
Forest plots for overall survival (OS) at a time interval of 2 years.
At a time interval of 5 years
Out of the four selected studies, 3 reported this outcome with 2870 out of 3984 patients in the BPA group and 488 out of 731 patients in the RC group. Analysis of the available data showed that out of the two management modalities, RC favors OS in 5 years (RR 1.17, 95% CI 1.10–1.24; P<0.00001) as shown in Fig. 3.
Figure 3.
Forest plots for overall survival (OS) at a time interval of 5 years.
At a time interval of 10 years
Out of the four selected studies, 2 reported this outcome with 97 out of 172 patients in the BPA group and 46 out of 101 patients in the RC group. Analysis of the available data showed insignificant differences between the two management strategies in terms of OS for 10 years (RR 1.19, 95% CI 0.87–1.63; P = 0.27) as shown in Fig. 4.
Figure 4.
Forest plots for overall survival (OS) at a time interval of 10 years.
Comparison of CSM between BPA and RC
At a time interval of 2 years
Out of the four selected studies, 3 reported this outcome with 198 out of 3984 patients in the BPA group and 129 out of 731 patients in the RC group. Analysis of the available data showed that out of the two management modalities, BPA favors CSM in 2 years (RR 0.28, 95% CI 0.23–0.34; P<0.001) as shown in Fig. 5.
Figure 5.
Forest plots for Cancer Specific Mortality (CSM) at a time interval of 2 years.
At a time interval of 5 years
Out of the four selected studies, 3 reported this outcome with 523 out of 3984 patients in the BPA group and 210 out of 731 patients in the RC group. Analysis of the available data showed that out of the two management modalities, BPA favors CSM in 5 years (RR 0.46, 95% CI 0.40–0.52; P<0.001) as shown in Fig. 6.
Figure 6.
Forest plots for cancer-specific mortality at a time interval of 5 years.
A summary of pooled outcomes for OS and CSM between BPA and RC across multiple time intervals is presented in Table 2.
Table 2.
Comparison of BPA vs RC for OS and CSM.
| Time interval | Outcome | No. of studies | BPA group (events/total) | RC group (events/total) | Risk ratio (RR) | 95% CI | P-value | Interpretation |
|---|---|---|---|---|---|---|---|---|
| 2 years | OS | 3 | 3628/3984 | 566/731 | 0.79 | 0.95–1.30 | 0.19 | No significant difference |
| 5 years | OS | 3 | 2870/3984 | 488/731 | 1.17 | 1.10–1.24 | <0.00001 | RC favors OS |
| 10 years | OS | 2 | 97/172 | 46/101 | 1.19 | 0.87–1.63 | 0.27 | No significant difference |
| 2 years | CSM | 3 | 198/3984 | 129/731 | 0.28 | 0.23–0.34 | <0.001 | BPA favors CSM |
| 5 years | CSM | 3 | 523/3984 | 210/731 | 0.46 | 0.40–0.52 | <0.001 | BPA favors CSM |
BPA, bladder preservation approach; CI, confidence interval; CSM, cancer‑specific mortality; OS, overall survival; RC, radical cystectomy; RR, risk ratio.
NOS assessment
All five studies that have been selected are of high methodological quality as they have been assessed using the NOS standard, and the total scores of these studies are from seven to eight out of nine. Besides receiving the highest number of stars in the Selection domain, these studies indicate that both exposed and non-exposed cohorts were appropriately selected and that the exposure was clearly ascertained in the participants who were free of the outcome at the beginning of the study. In the same way, all the studies obtained full points in the Comparability domain, which indicates that they took into account the potential confounding variables, such as age or other relevant factors, in an adequate manner. Thalmann (2004), De Berardinis (2011), Jungyo Suh (2019), and Wang (2020) are four out of the five studies that, in the Outcome domain, have met almost the entire lengthy list of criteria, including outcomes, assessment, follow-up duration, and completeness. Spaliviero (2014) research is still of good quality, although it scored only seven points due to a minor shortcoming in the outcome evaluation, which is the reason for the lower score. In general, the uniformity and rigor of scoring in the included studies lend themselves to the greater reliability of this review’s findings. The methodological quality of the included studies, as the NOS shows, is given in Table 3.
Table 3.
Quality assessment of included studies.
| Selection | Comparability | Outcome | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Study | Year | Exposed | Non-exposed | Ascertainment of exposure | Start without outcome present | Major factor | Addition factor | Outcome assessment | Follow-up length | Adequacy of outcome | Scale |
| Thalmann | 2004 | * | * | * | * | * | * | * | * | 8 | |
| De Berardinis | 2011 | * | * | * | * | * | * | * | * | 8 | |
| Spaliviero | 2014 | * | * | * | * | * | * | * | 7 | ||
| Jungyo Suh | 2019 | * | * | * | * | * | * | * | * | 8 | |
| Wang | 2020 | * | * | * | * | * | * | * | * | 8 | |
Discussion
Intravesical BCG has been used for the treatment of superficial bladder cancer since 1976[1]. This therapy has progressively established itself as the gold standard throughout the years and has stood the test of time. Several innovative bladder preservation techniques have evolved recently to replace BCG offering equivalent treatment effectiveness and improved quality of life. However, because of the significant risk of recurrence, progression, and disease-specific mortality in HG-NMIBC, RC cannot be ruled out throughout the therapy decision process.
We conducted this meta-analysis to evaluate BPA and RC in HG-NMIBC patients and assess the overall effectiveness of either treatment modality. The RR was utilized in this study to compare the levels of risk associated with the two treatment modalities over a specified period. The short- to long-term survival results were assessed at 2, 5, and 10 years for overall survival, and 2 and 5 years for cancer-specific mortality.
This meta-analysis result indicates that there is an insignificant difference between the two management approaches in relation to the overall survival rate at 2 and 10 years for HG-NMIBC. These results suggest that the standalone use of either of the modalities for HG-NMIBC management confers no significant superiority over the other with regard to overall survival. Interestingly, the findings demonstrate that RC has a favorable outcome on OS at 5 years. However, this difference is negligible at the 10-year mark. Adjusted analysis that accounts for comorbidities and age needs to be performed in future studies to represent trends in the data accurately.
CSM is defined as death due to a specified cancer as the outcome of interest[6]. The findings of our meta-analysis indicate that between the two approaches to management, the conservation of the bladder exhibits a higher CSM at 2 and 5 years.
When comparing the outcomes of our meta-analysis against those of a preexisting study conducted in 2018[8], significant differences emerge. These disparities can be attributed to the inclusion of new retrospective studies with larger patient populations, which can substantially impact the statistical outcomes. It is pertinent to mention that no further relevant studies have been published till mid-February, 2024.
In order to grasp the economic and clinical effects of therapy options in muscle-invasive bladder cancer (MIBC), Table 4 illustrates the BPA and RC in terms of key parameters. BPA is generally associated with lower initial costs and shorter hospital stays but may result in higher recurrence and follow-up expenses. RC, although more costly upfront, gives lower recurrence and can be more certain in the long-term outcomes, with differences in cost-effectiveness depending on patient suitability[24–29].
Table 4.
Comparison of treatment costs, clinical outcomes, and cost-effectiveness between BPA and RC over 5 years.
| Category | BPA | RC |
|---|---|---|
| Initial treatment cost | $20 000–$35 000[24] | $60 000–$90 000[25,26] |
| Hospital stay (avg. duration) | Outpatient or 1–3 days[24] | 5–10 days[26] |
| Hospitalization cost | $10 000–$20 000 total for full cycles[24] | Included in total cost[26] |
| Maintenance & follow-up cost | $25 000–$40 000[27] | $10 000–$20 000[25] |
| Complication management | $5 000–$15 000 (due to recurrence or salvage RC)[27] | $15 000–$30 000 (e.g., stoma, infection, readmission)[4,25,28] |
| 5-year recurrence rate | ~30–50%[27] | ~10–20%[27] |
| 5-year overall survival Rate | ~55–70% (in selected patients)[27] | ~55–65%[25,27] |
| Quality-adjusted life years | 3.5–4.5[27] | 3.0–4.0[27] |
| Estimated total cost (5 yrs) | $55 000–$90 000[24,27] | $100 000–$130 000[24,25] |
| Cost per QALY (estimated) | $12 000–$25 000[27] | $25 000–$60 000[25,27] |
BPA, bladder preservation approach; OS, overall survival; QALY, quality‑adjusted life year; RC, radical cystectomy; RR, risk ratio; US$, United States dollar.
Notable heterogeneity was noticed among the included studies – specifically, Jungyo Suh et al (2019), Spaliviero et al (2014), Thalmann et al (2004), Wang et al (2020), and De Berardinis et al (2011) – which can be linked to discrepancies in sample sizes, follow-up periods, timing and indications for RC, and variations in bladder preservation protocols. Furthermore, factors associated with tumors (like multifocality, size, and grade) and individual patient characteristics (such as age, gender, race, and clinical risk classification) probably played a role in the variability of reported outcomes. A key factor contributing to variability is the lack of standardized criteria for identifying BCG failure; none of the studies included utilized consistent definitions in accordance with international guidelines. This lack of consistency, coupled with differences in institutional treatment approaches, may have considerably affected the comparative survival outcomes
Limitations
Our study included several limitations. First, no randomized control trials were discovered throughout our search most likely due to ethical concerns; therefore, only retrospective cohort studies were included in our analysis. Second, the variations among the eligible studies included were inevitable. Within the BPA group, numerous treatment drugs and management regimens were employed. Additionally, the inclusion of observational studies introduces the potential for divergent impacts on bladder preservation outcomes across studies. Third, according to the NOS scale, certain studies that were included displayed limitations such as insufficient control of additional factors to ensure comparability, short-term follow-up periods, or an absence of disclosure concerning the follow-up plan. These factors collectively contributed to potential biases in the studies. Fourth, several analyses were performed on limited studies due to missing or insufficient data, and numerous subgroup analyses were unable to be completed. Fifth, the lack of information on recurrence in the included studies represents a notable limitation, as it is a crucial outcome that could not be analyzed.
Recommendations
The management of HG-NMIBC should consider the impact on quality of life and prioritize discussions on potential functional outcomes. BPA may offer advantages over RC in maintaining urinary continence and preserving bladder function. However, further high-quality prospective randomized trials comparing the two groups are needed to establish the optimal approach for different patient populations. Comparative studies should also be conducted to evaluate the long-term outcomes and cost-effectiveness to finalize which treatment modality is preferable.
Conclusion
In conclusion, we determined that while both approaches prevent CSM and progression from HG-NMIBC, bladder preservation with BCG may be a superior strategy when compared to RC. The former approach improves overall survival notably in the elderly and those with T1G3 tumors. However, RC may still be a preferable alternative for the younger population. Despite this, determining the optimal BPA method remains a challenge. It is also important to note that this conclusion is drawn from a relatively limited dataset and should be confirmed in forthcoming research.
Acknowledgements
Not applicable.
Footnotes
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Published online 17 March 2026
Contributor Information
Aiman Anjum, Email: aiman.anjum97@gmail.com.
Malaika Jawaid Siddiqui, Email: malaikasiddiqui@gmail.com.
Ameenudeen Mohammed Nushrath Ali, Email: nushrathali3@gmail.com.
Jawad Ahmed, Email: jawadahmedd13@gmail.com.
Hussain Haider Shah, Email: hussainhydershah03@gmail.com.
Md Ariful Haque, Email: arifulhaque58@gmail.com.
Ethical approval
Ethics approval was not required for this review.
Consent
Informed consent was not required for this review.
Sources of funding
None.
Author contributions
A.A. and M.J.S.: Protocol development, Data collection, Data analysis, Manuscript writing. A.M.N.A. and J.A.: Protocol development, Data collection, Data analysis, Manuscript writing. H.H.S. and M.A.H.: Data collection, Manuscript writing.
Conflicts of interest disclosure
The authors declare that there is no conflict of interest.
Research registration unique identifying number (UIN)
Name of the registry: PROSPERO. Unique Identifying number or registration ID: CRD42024586605. Hyperlink to your specific registration (must be publicly accessible and will be checked): Not applicable.
Guarantor
Aiman Anjum.
Provenance and peer review
Not commissioned, externally peer-reviewed
Data availability statement
The data presented in this study are available within the article and its Supplementary Materials.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data presented in this study are available within the article and its Supplementary Materials.