Recurrence patterns in patients with low-grade intermediate-risk non-muscle invasive bladder cancer eligible for active surveillance

doi:10.21203/rs.3.rs-4902791/v1

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Recurrence patterns in patients with low-grade intermediate-risk non-muscle invasive bladder cancer eligible for active surveillance

https://doi.org/10.21203/rs.3.rs-4902791/v1

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Objective

The intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) prognostic group is heterogeneous. Growing evidence supports the role of active surveillance (AS) for patients with low-risk NMIBC, however, no clear data exists considering IR-NMIBC.

Methods

We retrospectively evaluated 174 LG IR-NMIBC patients who underwent transurethral resection of bladder tumor (TURBT) from 2012 to 2023 at a tertiary referral center and fulfilled the inclusion criteria for enrollment in AS protocols at the index TURBT (≤ 5 suspicious lesions, no macrohematuria, negative urine cytology, lesions ≤ 1cm). Patients were then stratified according to the International Bladder Cancer Group (IBCG) risk factors: frequent recurrence, early recurrence, previous instillation, and multifocality. Kaplan Meier plots and multivariable Cox regression analysis (MVA) were used to assess the risk of any and high-grade (HG) recurrence according to the number of risk factors.

Results

Overall, 168 (97%) patients had a TaLG disease. After a median follow-up of 36 months (IQR 20–54), 75 (43%) and 32 (18%) patients experienced any- and HG recurrence, respectively. The 3-year RFS was 86% [95% Confidence Interval (CI), 76–98%] for patients with 0, 76% (95% CI, 68–84%) for those with 1–2, and 54% (95% CI, 34–84%) for those with ≥ 3 risk factors. The 3-year HG-RFS was > 90% for patients with 0 and 1–2 risk factors, compared to 76% (95% CI, 58–99%) of those with ≥ 3 risk factors. At MVA, the presence of ≥ 3 risk factors was associated with a higher risk of recurrence [hazard ratio: 4.74, 95% CI: 1.75–12.8, p = 0.002].

Conclusion

Among patients with LG IR-NMIBC eligible for AS, those with more than 2 IBCG risk factors may not be suitable candidates due to a higher risk of HG recurrence. Randomized controlled trials with standardized AS protocols are necessary to validate these findings and optimize patient selection for AS in LG IR-NMIBC.

Intermediate-risk

Non-muscle invasive bladder cancer

Low-grade

Active surveillance

International bladder cancer group

Non-muscle invasive bladder cancer (NMIBC) is a diverse disease, presenting a wide range of recurrence and progression rates (1, 2). Traditionally, the European Association of Urology (EAU) guidelines intermediate-risk NMIBC (IR-NMIBC) category includes patients who do not fit into the low- or high-risk groups, encompassing a variety of disease presentations (3, 4). The updated International Bladder Cancer Group (IBCG) Consensus Definition specifies that the IR-NMIBC group should include only patients with pTa low-grade (LG) tumors that are recurrent or multifocal, or larger than 3 cm, as well as any T1 LG-NMIBC and TaG2 cancers (5, 6). Due to the high heterogeneity of the IR-NMIBC, the IBCG has introduced a new risk stratification algorithm for IR-NMIBC (6). The prognosis for IR-NMIBC is further stratified based on key risk factors, including early recurrence (within less than 1 year), frequent recurrence (more than one recurrence per year), tumor multifocality, tumor size (≥ 3 cm), and recurrence despite prior intravesical treatment (5, 6).

This stratification system has been validated in a recent multicenter study (7), demonstrating that the risk of recurrence and progression varies within the IR-NMIBC group. Patients with no risk factors exhibit similar behavior to those with low-risk NMIBC (5–8). Consequently, active surveillance (AS) has been tested in patients with IR-NMIBC, showing promising results for those with fewer risk factors (9).

In this study, we aimed to assess the recurrence patterns of patients with LG IR-NMIBC who are potentially eligible for AS. By stratifying these patients using the IBCG prognostic risk factors, our objective was to identify which individuals within our single-center cohort could have been managed with AS based on their recurrence patterns.

2.1. Study population

After institutional review board approval, we relied on a prospectively maintained database including patients diagnosed with NMIBC from 2012 to 2023 who underwent transurethral resection of bladder tumor (TURBT) at our center. We included patients with histologically confirmed low-grade IR-NMIBC according to the IBCG criteria: prior early recurrence (a recurrence within 1 year), frequent recurrence (more than 1 recurrence/year), tumor multifocality and presence of recurrence despite prior intravesical treatment, aged > 18 years of age and who fulfilled the criteria for enrollment for active surveillance (≤ 5 suspicious lesions, no macrohematuria as presenting symptom, negative urine cytology collected before surgery, lesions ≤ 1cm in diameter). Patients who had a history of upper tract urothelial carcinoma and/or patients with missing data on oncological outcomes of interest were excluded. This process led to the selection of 174 patients.

2.2. Study design and variables definition

Patients were stratified according to the IBCG scoring algorithm based on the number of risk features they harbored (0, 1–2, and ≥ 3 risk factors) in reference to the index TURBT (6):

Frequent recurrence (defined as more than 1 recurrence/year)
Early recurrence (defined as a recurrence which occurs earlier than 1 year)
Prior intravesical instillations
Multifocality (> 1 lesion)

Size ≥ 3 cm was not considered since only patients with size ≤ 1 cm were included to fulfill the eligibility for AS.

All analyzed patients received an adjuvant instillation scheme with chemotherapy (Epirubicin or Mitomycin C) or Bacillus Calmette-Guérin (BCG) as per guidelines based on physicians’ choice. Follow-up protocols were based in accordance with international guidelines (3).

Recurrence was defined as the detection of any NMIBC during follow-up, whereas high-grade (HG) recurrence was defined as any detection of HG disease (defined as HG or CIS) according to the World Health Organization (WHO) classification of tumors 2016, UICC: TNM 8th edition 2017, criteria. Finally, we also collected histological grading according to the WHO classification of tumors 1973 for all patients.

2.3. Statistical analysis

For categorical variables, descriptive statistics consisted of absolute and relative frequencies while continuous variables were reported as the median and interquartile ranges (IQR). Chi-square and/or Fisher exact tests were used to compare categorical variables.

Kaplan Meier curves were used to estimate the 1 and 3-year recurrence-free survival (RFS) and HG-RFS according to the number of IBCG risk factors harbored by patients and the long-rank test was used for comparisons. A Multivariable Cox regression analysis was performed to evaluate the association of the increasing number of risk factors on any disease recurrence and HG recurrence, after adjusting for the number of instillations performed, early instillation, and T stage (pTa, pT1). For all statistical analyses, R software environment for statistical computing and graphics (version 5.4) was used (version 5.4; http://www.r-project.org/). All tests were two-sided with a level of significance set at p < 0.05.

3.1. Baseline characteristics

Of 174 patients included in the study, the median age at TURBT was 68 years [interquartile range (IQR): 58–74]. pTa stage was detected in 168/174 (97%) patients and all patients had a LG disease according to the 2004 grade group definition. All patients underwent subsequent adjuvant intravesical therapy, with 88% receiving chemotherapy instillations. There were 43 patients with 0 risk factors, 113 patients with 1–2 risk factors, and only 18 with ≥ 3 risk factors.

All baseline characteristics are provided in Table 1.

Table 1

Characteristics of 174 patients diagnosed with low-grade intermediate-risk non-muscle invasive bladder cancer according to International Bladder Cancer Group criteria at a single tertiary referral center.
Participants (%)
Characteristics	All (%)
No. of patients	174
Age at TURBT, years
Median, (IQR)	68 (58–74)
Gender
Male	138 (79)
Female	36 (21)
T stage
Ta	168 (97)
T1	6 (3.4)
Tumor grade 1973 classification system
G1	40 (23)
G2	134 (77)
Tumor grade 2004 classification system
LG	174 (100)
Adjuvant intravescical instillations agent
BCG	20 (12)
Chemotherapy (Epirubicin or Mitomycin C)	154 (88)
Adjuvant intravescical instillations
6	135 (78)
≥ 7	39 (22)
Early instillation at index TURBT	53 (31)
Multifocality (2–5 lesions)	60 (34)
Tumor size (mm)	10 (5–10)
Early recurrence prior to index TURBT	75 (43)
Highly recurrent prior to index TURBT	32 (18)
Adjuvant intravescical treatment prior to index TURBT	49 (28)
Abbreviations: TURBT, transurethral resection of bladder tumor; MMC, Mitomycin C; BCG, Bacillus Calmette Guerin.

3.2. Recurrence patterns and oncological outcomes

After a median follow-up of 36 months (IQR 20–54), the 1-yr RFS was 95% (95% CI, 89–95%) for patients with 0 risk factors, 91% (95% CI, 85–96%) for patients with 1–2 risk factors and 72% (95% CI, 54–96%) for patients with ≥ 3 risk factors. At 3 years, RFS was 86% (95% CI, 76–98%), 76% (95% CI, 68–84%), and 54% (95% CI, 34–84%) for patients with 0, 1–2 and ≥ 3 risk factors. (Fig. 1)

At multivariable Cox regression analysis, patients with ≥ 3 risk factors [hazard ratio (HR) 4.74, 95% confidence Interval (CI), 1.75–12.8, p = 0.002] had a higher risk of any recurrence in reference to patients with 0 risk factors. On the contrary patients with 1–2 risk factors did not reach independent predictor status (p = 0.071). (Table 2)

Table 2

Multivariable Cox regression analyses to predict the risk of any recurrence according to the number of International Bladder Cancer Group (IBCG) risk factors.
Characteristic	Hazard-ratio	95% Confidence Interval	p
IBCG risk factors
0	Ref	-	-
1–2	2.12	0.94, 4.81	0.071
≥ 3	4.74	1.75, 12.8	0.002
Total instillations received	0.93	0.82, 0.98	< 0.001
Early instillation
No	Ref	-	-
Yes	0.38	0.17, 0.86	0.020
T stage
pT1	Ref	-	-
pTa	0.46	0.14, 1.48	0.2

Patients with ≥ 3 risk factors were more likely to have a TaHG (33% vs 9% vs 9%, p = 0.011) recurrence and TaLG (22% vs 17% vs 12%, p = 0.011) recurrence compared to patients with 0 and 1–2 risk factors. (Table 3)

Table 3

Histology at recurrence according to the number of International Bladder Cancer Group (IBCG) risk factors.
Histology at recurrence	IBCG risk factors (%)
Histology at recurrence	0 (n = 43)	1–2 (n = 113)	≥ 3 (n = 18)	p¹
No recurrence	34 (79)	81 (72)	7 (39)	0.011
TaLG	5 (12)	19 (17)	4 (22)
Tis	0 (0)	2 (1.8)	0 (0)
TaHG	4 (9)	10 (9)	6 (33)
T1HG	0 (0)	1 (0.9)	1 (6)
Fisher’s exact test¹

The 3-yr HG-RFS was 92% (95% CI, 82–100%) for patients with less 0 risk factors, 94% (95% CI, 90–99%) for patients with 1–2 risk factors and 76% (95% CI, 58–99%) for patients with ≥ 3 risk factors (Fig. 2).

We conducted a retrospective analysis investigating the recurrence patterns in patients with LG IR-NMIBC, defined according to IBCG criteria and potentially eligible for AS at the time of index TURBT. Specifically, we investigated the risk of any recurrence and HG recurrence after stratifying patients based on the IBCG risk factors.

Various guidelines classify IR-NMIBC differently. The latest EAU 2021 classification includes patients not in the low or high-risk NMIBC groups, which may include some TaHG cancers without additional risk factors, (e.g., tumor size > 3 cm or multifocality) (2, 3). Conversely, the IBCG classification recommends selecting patients with Ta/T1LGG2 or any TaG2 if a three-tier system is used (6). Soria et al. have recently validated the IBCG scoring system in a multicenter retrospective cohort, showing significant differences in RFS and PFS when IR-NMIBC patients were stratified into three risk groups based on IBCG risk factors (0 risk factors = IR-low; 1–2 risk factors = IR-intermediate; ≥ 3 risk factors = IR-high) and, therefore, supporting the use of the IBCG scoring system in clinical practice (7). While AS is a more established management for low-risk NMIBC, its use in LG IR-NMIBC requires further validation (8). Recent studies, such as the study from Tan et al. in the context of the BIAS trial have explored this issue. They found that IR-NMIBC patients with 0 IBCG risk factors were over twice as likely to remain on AS compared to patients with ≥ 3 risk factors (59% vs. 24%) (9). In this context, our study has revealed several noteworthy findings.

First, we assessed the efficacy of the IBCG scoring system in predicting the risk of recurrence in LG IR-NMIBC patients. Our results indicated that the presence of ≥ 3 risk factors was associated with a four-fold increase in the risk of any recurrence. Additionally, the same observation was made for the risk of HG recurrence in the Kaplan-Meier analysis. Notably, the 3-year RFS rates were 86%, and the HG-RFS rates were 92% for patients with 0 risk factors, whereas the 3-year RFS was 54% and the HG-RFS was 76% for patients with ≥ 3 risk factors. These results showed slightly lower recurrence rates compared to other studies validating the IBCG scoring system. For example, in the study by Soria et al., the 3-year recurrence risk for patients with 0 risk factors was 30%, while those with ≥ 3 risk factors had a 68% risk of recurrence. However, within our study we only included patients potentially eligible for active surveillance (AS) (i.e., those with less aggressive cancers), and all of them were treated with intravesical therapy after the index TURBT. In consequence, these differences are therefore largely justified (7). In addition to the Soria et al. study, we have also documented the risk of HG recurrence for LG IR-NMIBC. In the study by Tan et al., the rates of dropout from AS were higher than the recurrence rates in our study. However, the triggers to consider an event in this study were defined as the violation of any of the AS criteria, therefore comparisons of outcomes with our cohort cannot be made (9).

Second, our results support emerging evidence that selected IR-NMIBC patients could be treated with AS, similar to low-risk patients (9, 10). Repeated TURBTs expose patients, especially the elderly with multiple comorbidities, to general anesthesia risks and post-operative complications like infection, hematuria, and bladder perforation (11). The NCCN guidelines do not clearly address the use of AS, while other guidelines such as the EAU 2024 recommend AS as a possible alternative to TURBT for low-risk NMIBC (3, 12). Our study indicates that LG IR-NMIBC patients with 0 risk IBCG factors have a lower risk of both any- and HG recurrence compared to patients with 1–2 or 3 risk factors and therefore these patients might be those with a lower risk of dropout from AS protocols. Additional prospective data on AS are needed to optimize protocols and standardize the selection of the right candidates as currently being done in the BIAS study (9).

Third, HG recurrence in LG IR-NMIBC patients classified by IBCG guidelines involves a minority of these patients regardless of risk factors, however, in our study, it was higher when considering patients with ≥ 3 risk factors. These results align with Sylvester et al., who reported that while most pTa low-grade tumors may recur, only a small minority progress to MIBC: the 5-year progression rate of pTa low-grade tumors is 0.8%, and their likelihood of progressing to MIBC after recurrence does not exceed 6% (5). Fernandez-Gomez et al. reported that most low-grade tumors recur, with less than 2% progressing to a higher grade or stage (13). Additionally, Ourfali et al. showed that IR-NMIBC patients have higher recurrence and lower high-grade recurrence rates compared to high-risk NMIBC patients, who have higher progression rates (14). Finally, the study by Matulay et al. demonstrated that HG-RFS is rare in IR-NMIBC patients treated with adequate BCG therapy. Indeed, the 1-year and 2-year HG-RFS rates were 95% and 92%, respectively, aligning closely with our estimates (15).

Our study is not devoid of limitations. Although focusing on patients potentially eligible for AS, all patients underwent TURBT and standard adjuvant intravesical treatment, preventing strong conclusions about the oncological safety of AS; however, we aimed to identify which patients among the IR-NMIBC might benefit from AS. As a consequence, we advocate for more randomized control trials to explore this issue and select the “best” IR-NMIBC candidates for AS. The long accrual time and retrospective design may introduce bias, such as potential confounding by indication or recall bias. For instance, we were not able to evaluate the reasons regarding the choice to treat these patients with BCG or chemotherapy, which was based on the physician preference. Most likely, the choice depended on the aggressiveness of cancers. For example, more "aggressive" IR-NMIBC cases might have been treated with BCG rather than chemotherapy. However, there is evidence suggesting similar outcomes for treatment IR-NMIBC patients undergoing BCG versus chemotherapy (16–18) and current guidelines suggest either the use of BCG vs chemotherapy for these patients, based on the choice of the physician and on a case-by-case scenario (3).

Patients with LG IR-NMIBC have heterogeneous prognoses based on different prognostic factors. Among those potentially eligible for AS, patients with more than 2 IBCG risk factors might not be suitable candidates due to a higher risk of subsequent HG recurrence. Randomized controlled trials with standardized AS protocols are needed to validate these findings and optimize patient selection for AS in patients with LG IR-NMIBC.

Acknowledgment

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

All authors declare no conflict of interest relative to the content of the paper.

Authors contribution

Study concept and design: P.Z., P.S., M.M

Acquisition of data: P.Z., P.S., M.L., M.d.A., C.R., L.Q., G.T., G.B.

Analysis and interpretation of data: P.Z., P.S.

Drafting of the manuscript: P.Z., P.S., M.M.

Critical revision of the manuscript for important intellectual content: P.Z., P.S., M.L., M.d.A., C.R., L.Q., G.T., G.B., F.P., G.R., A.N., R.C., G.G., A.S., F.M., A.B., M.M

Obtaining funding: None.

Supervision: M.M.

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No competing interests reported.

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You are reading this latest preprint version

Recurrence patterns in patients with low-grade intermediate-risk non-muscle invasive bladder cancer eligible for active surveillance

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusion

Figures

1. Introduction

2. Materials and methods

2.1. Study population

2.2. Study design and variables definition

2.3. Statistical analysis

3. Results

3.1. Baseline characteristics

3.2. Recurrence patterns and oncological outcomes

4. Discussion

5. Conclusions

Declarations

References

Additional Declarations

Status:

Version 1