Prognostic effect of the intensity of follow-up cystoscopy in patients with high-risk non-muscle invasive bladder cancer

doi:10.21203/rs.3.rs-3221528/v1

Background

There is a significant lack of evidence regarding the effect of non-adherence to recommended protocols in the follow-up of high-risk non-muscle-invasive bladder cancer (NMIBC) or the impact of delayed detection of recurrent lesions. Here, we investigated the optimal frequency of follow-up cystoscopy for high-risk NMIBC concerning oncological safety in a real-world Japanese clinical practice.

Methods

This retrospective, single-center study included 206 patients with high-risk primary NMIBC. The intensity (%) of follow-up cystoscopy was calculated based on actual cystoscopy visits and the recommended frequency in the first 24-month follow-up period. The inverse probability of treatment weighting analysis was used to reduce the risk of bias between the groups. We performed restricted cubic spline analysis with knots at the intensity of follow-up cystoscopy ≤ in the 100% group to examine the possible association between progression risk and the intensity of follow-up as a continuous exposure.

Results

The median intensity was 87.5% (interquartile range, 75%−100%). The adjusted multivariate analysis of MIBC-free and progression-free survival demonstrated no significant differences between the adjusted ≤75% and > 75% intensity groups. Restricted cubic spline analysis suggested no significant effect of follow-up intensity on progression risk, and the hazard ratios of patients with < 100% intensity were equivalent to those of patients with 100% intensity.

Conclusion

Our findings suggest that decreased intensity of follow-up cystoscopy does not affect oncological outcomes in patients with high-risk NMIBC. Further prospective trials directly aimed at investigating optimized follow-up schedules for NMIBC are mandatory before substantial changes to the existing clinical guidelines are made.

urinary bladder neoplasms

risk

prognosis

progression

cystoscopy

surveillance

Bladder cancer (BC) is the tenth most commonly diagnosed malignancy worldwide, with 573,000 new cases and 213,000 deaths, according to Global Cancer Statistics 2020 [1]. Approximately 70%−80% of newly diagnosed BC patients have non-muscle-invasive bladder cancer (NMIBC) forms consisting of Ta, T1, and Tis, which are characterized by a high rate of intravesical recurrence and progression to muscle-invasive bladder cancer (MIBC), requiring repeated cystoscopy, urine cytology, and urinary tract imaging, especially in high-risk NMIBC [2−5]. Although cystoscopy detects papillary lesions with high sensitivity and specificity [6, 7], this examination is expensive and invasive and can cause urinary tract infections and discomfort to examinees. Early detection is required to avoid progression to MIBC, which is directly associated with cancer-specific death. Therefore, it is important to balance the risk of overexamination to detect recurrence in the early phase.

Current clinical practice guidelines regarding the follow-up of NMIBC from the Japanese Urological Association (JUA), European Urological Association (EAU), American Urological Association/Society of Urologic Oncology (AUA/SUO), and other groups offer a risk-adapted protocol [2−5]. Follow-up cystoscopy is generally recommended every 3–12 months, depending on the disease risk. Follow-up may be discontinued in patients with low-risk NMIBC after five recurrence-free years, whereas lifelong follow-up is recommended for a high-risk subset in which T1, high-grade, and carcinoma in situ (CIS) tumors are categorized according to the JUA guidelines [2]. High-risk NMIBC, which comprises the highest-risk subgroup, has a significantly higher probability of progression and cancer-specific death [8]. The risk-adapted follow-up approach in the clinical guidelines states that patients with high-risk NMIBC should undergo cystoscopy and urinary cytology every 3 months in the first two years, every 6 months in the next three years, and every year after five years. In contrast to the high prognostic value of the primary findings of the first cystoscopy performed 3 months after transurethral resection of bladder tumor (TURBT) [9], subsequent follow-up schedules are based mostly on expert opinion and low-level evidence. Culpan et al. demonstrated that cystoscopy delays > 90 days increased the probability of progression by 6.7-fold in patients followed up during the coronavirus disease of 2019 pandemic (June–September 2020) [10]. An observational, retrospective cohort study from Palestine showed that a low-compliance group with a standardized surveillance protocol in NMIBC was associated with poor outcomes compared with a compliant group [11].

There is still a significant lack of evidence regarding the effect of non-adherence to a recommended protocol in the follow-up of high-risk NMIBC or the impact of delayed detection of recurrent lesions. Here, we investigated the optimal frequency of follow-up cystoscopy for high-risk NMIBC with respect to oncological safety in a real-world Japanese clinical practice.

Study population and data collection

This retrospective, single-center study was approved by the Ethics Committee of Nara Medical University (reference protocol ID:2891) and followed the principles of the Declaration of Helsinki (2013). Informed consent was obtained from all participants through posters and/or websites using the opt-out method [12]. The medical charts of patients diagnosed with primary NMIBC and treated between 2006 and 2020 were reviewed. Of the 447 patients, 178 (40%) with low- and intermediate-risk NMIBC were excluded, and 63 (14%) who did not undergo follow-up cystoscopy due to loss to follow-up, immediate radical cystectomy, development of metastasis shortly after TURBT, etc, leaving 206 (46%) with primary high-risk NMIBC who were included in the analysis. Patient data were collected from the following medical records: age; sex; tumor multifocality; T category; presence of CIS; lymphovascular involvement (LVI) in the TUR specimens; date of the follow-up cystoscopy examination; and oncological outcome data, such as bladder recurrence, progression, and cancer-specific death.

Calculation of the intensity of follow-up cystoscopy

While all urologists in our hospital were instructed to follow a standardized protocol [2], the actual follow-up schedule was determined depending on the patients’ decisions and physicians’ preferences. The frequency (%) of follow-up cystoscopy was calculated based on actual cystoscopy visits and the recommended frequency during the first 24-month follow-up period (Fig. 1). Cutoffs were set at 75% and 100% for comparison among the groups stratified by the intensity of follow-up cystoscopy. In addition, a sensitivity analysis using the intensity of the first 12-month follow-up cystoscopy was performed to examine consistency with the original analysis ( data from the first 24-month follow-up period).

Statistical Analysis

As appropriate, clinicopathological characteristics were compared using the chi-square, Fisher’s exact, Mann–Whitney U, and Kruskal–Wallis tests. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses were performed to reduce the risk of bias using R version 4.3.1 (R Development Core Team, Vienna, Austria), and survival curves were generated using GraphPad Prism version 9.5.1 (GraphPad Software, San Diego, CA, USA). Statistical significance was set at P < 0.05 (two-tailed).

Four endpoints were evaluated: MIBC-free survival, progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Progression was defined as developing MIBC, lymph nodes, or distant organs. Event-free survival curves were obtained using the Kaplan–Meier method from the date of the initial TURBT or second TUR if performed and compared by either a log-rank test between the two groups or a log-rank test for trend among the three groups.

Baseline characteristics were matched by calculating the propensity score for each patient using a multivariable logistic regression model based on covariates such as age, sex, T category, tumor size, tumor multifocality, presence of CIS, LVI, non-UC variant, and prostate-involving CIS lesions. One-to-one matching with a caliper width of 0.2 was applied to maintain a large sample size and balance between the two groups: the intensity of follow-up cystoscopy ≤ in the 75% and > 75% groups. The standardized mean difference (SMD) was used to examine the balance of covariate distributions between groups after propensity score matching [13]. Univariate and multivariate Cox regression analyses were used to estimate IPTW-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) as outcomes for the two groups. Prognostic factors (P values < 0.2 in the univariate analysis) were incorporated into the multivariable Cox regression analysis).

We performed a dose-response analysis using a restricted cubic spline (RCS) analysis with knots at the intensity of follow-up cystoscopy ≤100% group to examine the possible association of progression risk with the intensity of follow-up as a continuous exposure after adjusting for covariates such as age, sex, T category, size, tumor multifocality, presence of CIS, LVI, non-UC histology, and prostate-involving CIS lesions. RCS analysis was used to characterize the association between continuous exposure and an outcome, to visually and statistically check the assumption of linearity of the association, and to minimize residual confounding [14].

Evaluation of the intensity of follow-up cystoscopy

Fig. 2 shows a histogram based on the intensity of follow-up cystoscopy in the first 24-month period. Seventy-three patients (35%) had 100% intensity on follow-up cystoscopy, while the median intensity was 87.5% (interquartile range, 75%-100%). The Shapiro–Wilk normality test revealed that the dataset was not normally distributed (P < 0.001). Patients were divided into three groups according to the intensity of follow-up cystoscopy: 59 (29%) with low intensity (≤75%), 120 (58%) with standard intensity (76-100%), and 27 (13%) with over intensity (>100%). The baseline characteristics of the 206 patients with high-risk NIMBC and comparisons according to the intensity of follow-up cystoscopy are listed in Table 1. Although all baseline variables tested in this study showed no significant differences among the groups, male patients tended to have a lower intensity of follow-up cystoscopy (P = 0.071).

The intensity of follow-up cystoscopy and oncological outcomes

During a median follow-up of 53 months (interquartile range, 28-96 months), of the 206 patients, 25 (12%) had progression to MIBC, 27 (13%) had disease progression to MIBC and/or distant metastasis, 15 (7.2%) died of BC, and 37 (18%) died from any cause. A comparison of survival curves demonstrated no significant differences in MIBC-free survival, PSF, CSS, and OS among the low-, standard-, and over-intensity groups (Fig. 3). However, the CSS and OS in the overintensity group tended to be shorter than those in the low-intensity group (P = 0.064 and P = 0.078, respectively).

The small number of patients in some groups could have been a significant bias influencing the survival analysis results. To decrease the influence of possible confounding factors, IPTW was used to adjust for differences in patient characteristics between the two groups: £75% intensity group and >75% intensity group (Table 2). The two groups closely balanced all the weighted baseline factors included in the IPTW model. The IPTW-adjusted analysis showed no significant differences in any survival endpoint between £ the 75% and >75% intensity groups (Fig. 4). The IPTW-adjusted univariate and multivariate Cox proportional hazards regression models for MIBC-free survival and progression-free survival demonstrated no association between the intensity of follow-up cystoscopy and survival outcomes (Table 3). Positive CIS (P=0.026), positive variant histology (P=0.03), and positive prostate-involving CIS (P=0.018), but not the intensity of follow-up (£75% vs >75%, P=0.15), were identified as independent risk factors for the development of MIBC in multivariate analysis. The intensity of follow-up was not a risk factor for progression (£75% vs >75%, P=0.33) in the univariate analysis.

Sensitivity analysis using the intensity of the first 12-month follow-up cystoscopy was performed to examine consistency with the analysis of the first 24-month follow-up cystoscopy. Additional analyses confirmed the consistency between the first 24-month follow-up cystoscopy results and those of the first 12-month follow-up cystoscopy (Online Resource 1).

A restricted cubic spline analysis for the intensity of follow-up cystoscopy

To examine the possible association between progression risk and the intensity of follow-up as a continuous exposure, RCS analysis with knots at the intensity of follow-up cystoscopy was applied to our cohort. The results suggested no significant effect of follow-up intensity on the progression risk, and the hazard ratios of patients with <100% intensity were equivalent to those of patients with 100% intensity (Fig. 5). In the cubic spline analysis, the hazard ratio curve flattened before £ the 100% intensity follow-up.

The present study suggests that a decreased frequency of follow-up cystoscopy is not associated with an increased risk of disease progression or cancer-specific death in patients with high-risk NMIBC. Dreyer et al. reported a systematic review of the association between the interval between follow-up cystoscopies and oncological safety [4]. A systematic search of 680 studies revealed only three (0.44%) with high-level evidence: two randomized control trials (RCTs) and one case series. The authors concluded that there was only low-level evidence to support current or alternative schedules of follow-up cystoscopy. Thus, the current recommendations in the clinical guidelines on the frequency, interval, and duration of follow-up cystoscopy seem to be largely based on clinical traditions and not on a large amount of high-level evidence. Here, we sought to improve the evidence-practice gap and optimize the schedule of follow-up cystoscopy using Japanese real-world data.

A US national retrospective multicenter cohort study of 2115 high-risk NMIBC patients with NMIBC reported that the adjusted frequency of follow-up cystoscopy ranged from 4.6 to 6.0 (median, 5.4) over 2 years [15], which was equivalent to an intensity of 58%−75% (median, 68%). This study did not report whether a delay in follow-up cystoscopy adversely affected the oncological results. Culpan et al. prospectively evaluated the impact of a delay in follow-up cystoscopy on recurrence and progression in 407 patients with NMIBC from four high-volume centers during the COVID-19 pandemic [10]. Among 407 patients, 105 (26%) and 20 (5.1%) had tumor recurrence on follow-up cystoscopy and disease progression according to grade or stage, respectively. In multivariate analysis, the number of recurrences (odds ratio:1.3, P = .024) and cystoscopy delay time > 90 days (odds ratio:6.704, P = 0.002) were significant risk factors for tumor progression. The authors concluded that follow-up cystoscopy should be performed according to the schedule set recommended in the current guidelines. Another study reported by Abushamma et al. retrospectively evaluated the impact of noncompliance with the surveillance protocols recommended by the European guidelines on oncological outcomes [11]. Noncompliance was defined as missing one follow-up cystoscopy over three years in low/intermediate-risk NMIBC or missing two follow-up cystoscopies over three years in high-risk NMIBC. The results demonstrated that recurrence, progression, metastasis, and mortality rates were significantly higher in the non-compliant group than in the compliant group. The subgroup analysis of high-risk NMIBC showed a progression rate of 0% in the compliant group and 56% (P = 0.001) in the non-compliant group. This evidence suggests the need for adherence to surveillance guidelines, particularly in patients with high-risk NMIBC. Contrary to previous studies, our findings suggest that the frequency of follow-up cystoscopy could be decreased because a lower frequency did not compromise oncological outcomes. Possible reasons for this discrepancy include differences among countries in analytical methods, studied cohort, inclusion and exclusion criteria, health insurance system, surgical skill, and response to drugs such as BCG and anticancer agents.

Another issue to be discussed involves medical costs. NMIBC is one of the most expensive malignancies owing to the need for treatment and long-term follow-up on a per-patient basis. A previous study applied a Markov model and demonstrated that the cumulative medical costs over 5 years required for the management of low-risk, intermediate-risk, and high-risk NMIBC were 52,125 USD, 146,250 USD, and 366,143 USD, respectively, in 2017 United States Dollars Values [18]. The sources of 5-year medical costs in high-risk NMIBC were 14,266 USD (4%) with no evidence of disease, 6,881 USD (2%) for recurrent disease, 337,529 USD (92%) for progression, and 7,467 USD. The primary driver of medical costs was progression to MIBC requiring intensified therapies, such as radical cystectomy and chemotherapy, contributing to 81%−92% of the overall cost in patients with intermediate- and high-risk NMIBC. Our study did not evaluate the medical costs or economic burden associated with the intensity of the follow-up cystoscopy. The representative medical expenses based on the Japanese health insurance system are as follows: one cystoscopy costs 9500 Japanese yen (equivalent to 67 USD as of July 2023), a single dose of BCG Tokyo 172 strain costs approximately 14,000 yen (98 USD), and one hospitalization for TURBT costs 400,000 yen (2,821 USD). A substantial proportion of patients face financial toxicity due to lifelong surveillance and repeated treatment. In fact, a population-based study targeting the health-related quality of life of NMIBC survivors demonstrated that the top five bothersome symptoms included ‘financial difficulty, ’ based on a survey using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core [19].

This study had several limitations. First, its retrospective nature and single-center analysis have an inherent potential for selection bias. Some patients with high-risk NMBIC were excluded because of immediate radical cystectomy or a significant lack of data. Second, this study did not include patients with low- or intermediate-risk NMIBC. We focused on primary high-risk NMIBC because highly intensive follow-up cystoscopy is not required for low- and intermediate-risk NMIBC compared with high-risk NMIBC. Third, for simplicity, the intensity of the follow-up cystoscopy was calculated based on the first 24 months. Thus, the follow-up intensity from the third year was not evaluated. Fourth, the analysis did not consider adjuvant therapies, such as intravesical BCG or anticancer agents.

In conclusion, this study is the first to report no differences in oncological outcomes between ≤ the 75% and > 75% intensity follow-up groups in patients with high-risk NMIBC. A follow-up intensity of 100% indicates that cystoscopy is performed once every three months for the first 24 months after TURBT, while follow-up intensities of 75% and 50% indicate once every four months and twice a year, respectively. Our findings can serve as a benchmark for future clinical studies. Further prospective trials directly aimed at investigating optimized follow-up schedules for NMIBC are mandatory before substantial changes to the existing clinical guidelines are made.

Author’s contributions

All authors made substantial contributions as follows: MM made the conception and design of the work and drafted the work; NN, YN, TF, and TM were involved in the analysis and interpretation of data; TF, YO, TM, MT, TS, TO, KO, SH, YM, DG, YN, and KT were involved in the acquisition of data; NT and KF supervised the whole study and revised it critically for important intellectual content. All authors approved the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgment

None.

Conflict of interest

Nothing to declare.

Data Availability Statements

The data underlying this article will be shared on reasonable request to the corresponding author.

Conflicts of interest: The authors disclose no potential conflicts of interest

Funding/Support and role of the sponsor: None.

Sung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71:209–249
Matsumoto H, Shiraishi K, Azuma H et al (2020) Clinical Practice Guidelines for Bladder Cancer 2019 edition by the Japanese Urological Association: Revision working position paper. Int J Urol 27:362–368
EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2023. ISBN 978-94-92671-19-6
Chang SS, Boorjian SA, Chou R et al (2016) Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol 196:1021
Schroeck FR, Smith N, Shelton JB (2018) Implementing risk-aligned bladder cancer surveillance care. Urol Oncol 36:257–264
Blick CG, Nazir SA, Mallett S et al (2012) Evaluation of diagnostic strategies for bladder cancer using computed tomography (CT) urography, flexible cystoscopy and voided urine cytology: results for 778 patients from a hospital haematuria clinic. BJU Int 110:84–94
Dreyer T, Ernst A, Jensen JB (2022) Optimal intervals for follow-up cystoscopy in non-muscle invasive bladder cancer: a systematic review regarding oncological safety. Scand J Urol 56:39–46
Miyamoto T, Miyake M, Nakahama T et al (2023) Validation of the risk stratification newly defined in the Japanese Urological Association guidelines 2019 for non-muscle invasive bladder cancer: A multi-institutional collaborative study. Int J Urol 30:473–481
Soukup V, Babjuk M, Bellmunt J et al (2012) Follow-up after surgical treatment of bladder cancer: a critical analysis of the literature. Eur Urol 62:290–302
Culpan M, Keser F, Acar HC et al (2021) Impact of delay in cystoscopic surveillance on recurrence and progression rates in patients with non-muscle-invasive bladder cancer during the COVID-19 pandemic. Int J Clin Pract 75:e14490
Abushamma F, Khayyat Z, Soroghle A et al (2021) The Impact of Non-Compliance to a Standardized Risk-Adjusted Protocol on Recurrence, Progression, and Mortality in Non-Muscle Invasive Bladder Cancer. Cancer Manag Res 13:2937–2945
Vellinga A, Cormican M, Hanahoe B et al (2011) Opt-out as an acceptable method of obtaining consent in medical research: a short report. BMC Med Res Methodol 11:40
Miyake M, Iida K, Nishimura N et al (2021) Non-maintenance intravesical Bacillus Calmette-Guérin induction therapy with eight doses in patients with high- or highest-risk non-muscle invasive bladder cancer: a retrospective non-randomized comparative study. BMC Cancer 21:266
Desquilbet L, Mariotti F (2010) Dose-response analyses using restricted cubic spline functions in public health research. Stat Med 29:1037–1057
Schroeck FR, Lynch KE, Chang JW et al (2018) Extent of Risk-Aligned Surveillance for Cancer Recurrence Among Patients With Early-Stage Bladder Cancer. JAMA Netw Open 1:e183442
Mossanen M, Wang Y, Szymaniak J et al (2019) Evaluating the cost of surveillance for non-muscle-invasive bladder cancer: an analysis based on risk categories. World J Urol 37:2059–2065
Jung A, Nielsen ME, Crandell JL et al (2020) Health-related quality of life among non-muscle-invasive bladder cancer survivors: a population-based study. BJU Int 125:38–48

Table 1. The baseline characteristics of patients with high-risk non-muscle invasive bladder cancer and comparison according to the intensity of the first 24-months follow-up cystoscopy
Variables		Total	The intensity of follow-up cystoscopy during the first 24 months			P value
Variables		Total	Low intensity (-75%)	Standard intensity (76-100%)	Over intensity (100%-)	P value
N (%)		206 (100%)	59 (29%)	120 (58%)	27 (13%)	-
Age (years-old), mean ± standard deviation		73.0 ± 8.6	74.3 ± 9.9	72.2 ± 7.6	73.9 ± 9.3	0.26
Sex	Male	183 (89%)	51 (86%)	111 (93%)	21 (78%)	0.071
	Female	23 (11%)	8 (14%)	9 (7.5%)	6 (22%)
Tumor multifocality	Monofocal	92 (45%)	25 (42%)	53 (44%)	14 (52%)	0.84
	Multifocal	114 (55%)	34 (58%)	67 (56%)	13 (48%)
Tumor size	≤30mm	151 (73%)	42 (71%)	87 (73%)	22 (82%)	0.89
	>30mm	32 (16%)	10 (17%)	19 (16%)	3 (11%)
	Unknown	23 (11%)	7 (12%)	14 (12%)	2 (7.4%)
Clinical T category	Ta	24 (12%)	8 (14%)	14 (12%)	2 (7.4%)	0.85
	Tis	31 (15%)	10 (17%)	18 (15%)	3 (11%)
	T1	151 (73%)	41 (70%)	88 (73%)	22 (82%)
Carcinoma in situ	No	101 (49%)	29 (49%)	57 (48%)	15 (56%)	0.75
	Yes	105 (51%)	30 (51%)	63 (53%)	12 (44%)
Lymphovascular invasion	No	171 (83%)	53 (90%)	96 (80%)	22 (82%)	0.25
	Yes	35 (17%)	6 (10%)	24 (20%)	5 (19%)
Variant histology	No	193 (94%)	56 (95%)	114 (95%)	23 (85%)	0.15
	Yes	13 (6.3%)	3 (5.1%)	6 (5.0%)	4 (15%)
Prostate-involving carcinoma in situ	No	200 (97%)	57 (97%)	117 (98%)	26 (96%)	0.91
	Yes	6 (2.9%)	2 (3.4%)	3 (2.5%)	1 (3.7%)

Table 2. The baseline characteristics of 206 patients with high-risk non-muscle invasive bladder cancer and comparison according to the intensity of the first 24-months follow-up cystoscopy: Unadjusted population and IPTW population
Variables		Unadjusted population				IPTW population
Variables		£75 % intensity group	>75% intensity group	P value	SMD	£75 % intensity group	>75% intensity group	SMD
N (%)		59 (29%)	147 (71%)	-	-	206.2	206	-
Age (years-old), mean ± standard deviation		74.3 ± 9.9	72.5 ± 8.0	0.19	0.2	72.4	72.9	0.064
Sex	Male	51 (86%)	132 (90%)	0.47	0.11	87.8	88.5	0.021
	Female	8 (14%)	15 (10%)			12.2	11.5
Tumor multifocality	Monofocal	25 (42%)	67 (46%)	0.83	0.13	46	44.5	0.10
	Multifocal	34 (58%)	80 (54%)			54	55
Tumor size	≤30mm	42 (71%)	109 (74%)	0.88	0.067	73.6	73.3	0.032
	>30mm	10 (17%)	22 (15%)			16.3	15.7
	Unknown	7 (12%)	16 (11%)			10.3	11
Clinical T category	Ta	8 (14%)	16 (11%)	0.72	0.12	12.2	11.8	0.021
	Tis	10 (17%)	21 (14%)			14.4	15.1
	T1	41 (70%)	110 (75%)			73.3	73.1
Carcinoma in situ	No	29 (49%)	72 (49%)	0.99	0.003	47.1	48.9	0.035
	Yes	30 (51%)	75 (51%)			52.9	51.1
Lymphovascular invasion	No	53 (90%)	118 (80%)	0.11	0.271	82.3	83	0.018
	Yes	6 (10%)	29 (20%)			17.7	17
Variant histology	No	56 (95%)	137 (93%)	0.76	0.073	94.3	93.7	0.024
	Yes	3 (5.1%)	10 (6.8%)			5.7	6.3
Prostate-involving carcinoma in situ	No	57 (97%)	143 (97%)	0.99	0.039	97.7	97.2	0.029
	Yes	2 (3.4%)	4 (2.7%)			2.3	2.8
IPTW, inverse probability of treatment weighting; SMD, standardized mean difference

Table 3. Univariate and multivariate analysis for MIBC-free surival and progression-free suruval in high-risk NMIBC: IPTW-adjusted survival analysis
Variables		MIBC-free surival						Progression-free suruval
		Univariate			Multivariate			Univariate			Multivariate
		HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value
Age	£ 75 yo	ref						ref
	> 75 yo	1.66	0.75-3.70	0.21				1.4	0.67-3.1	0.35
Sex	Male	ref						ref
	Female	1.43	0.44-4.70	0.56				1.32	0.40-4.3	0.65
Tumor multifocality	Monofocal	ref						ref
	Multifocal	0.9	0.41-1.99	0.80				0.90	0.43-1.92	0.80
Tumor size	≤30mm	ref						ref
	>30mm	0.46	0.10-2.01	0.30				0.68	0.19-2.34	0.54
Clinical T category	Ta	ref						ref
	Tis	3.4	0.41-28.1	0.26				1.6	0.32-7.6	0.58
	T1	3.8	0.10-26.5	0.19				1.8	0.45-6.9	0.41
Carcinoma in situ	No	ref			ref			ref			ref
	Yes	2.59	1.03-6.54	0.043	3.06	1.14-8.16	0.026	1.9	0.81-4.3	0.14	2.31	0.97-5.52	0.60
Lymphovascular invasion	No	ref			ref			ref			ref
	Yes	2.1	0.91-4.8	0.083	2.14	0.93-4.95	0.075	1.9	0.82-4.2	0.14	1.93	0.84-4.43	0.12
Variant histology	No	ref			ref			ref			ref
	Yes	2.2	0.67-6.8	0.18	3.55	1.13-11.10	0.03	3.0	1.2-7.5	0.023	4.47	1.55-12.91	0.005
Prostate-involving carcinoma in situ	No	ref			ref			ref			ref
	Yes	4.5	1.4-13.9	< 0.01	4.23	1.28-13.96	0.018	4.3	1.4-13.2	0.012	4.3	1.32-14.03	0.016
The intensity of follow-up cystoscopy	£ 75%	ref			ref			ref
	> 75%	2.1	0.69-2.3	0.19	2.17	0.76-6.25	0.15	1.6	0.61-4.4	0.33
MIBC, muscle invasive bladder cancer: NMIBC, non-muslce invasive bladder cancer; IPTW, inverse probability of treatment weighting

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Prognostic effect of the intensity of follow-up cystoscopy in patients with high-risk non-muscle invasive bladder cancer

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Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Patients and Methods

Study population and data collection

Calculation of the intensity of follow-up cystoscopy

Statistical Analysis

Results

Discussion

Declarations

References

Tables

Supplementary Files

Status:

Version 1