Non-muscle-invasive Bladder Cancer

6. PREDICTING DISEASE RECURRENCE AND PROGRESSION

6.1. TaT1 tumours

Treatment should take into account a patient’s prognosis. In order to predict the risk of disease recurrence and/or progression, several prognostic models for specified patient populations have been introduced.

6.1.1. Scoring models using the WHO 1973 classification system

6.1.1.1. The 2006 European Organisation for Research and Treatment of Cancer (EORTC) scoring model

To be able to predict both the short- and long-term risks of disease recurrence and progression in individual patients, the EORTC Genito-Urinary Cancer Group (GUCG) published a scoring system and risk tables based on the WHO 1973 classification in 2006 [229]. The scoring system is based on the six most significant clinical and pathological factors in patients mainly treated by intravesical chemotherapy:

• number of tumours;
• tumour diameter;
• prior recurrence rate;
• T category;
• concurrent CIS;
• WHO 1973 tumour grade.

Using the 2006 EORTC scoring model, individual probabilities of recurrence and progression at one and five years may be calculated (https://www.omnicalculator.com/health/eortc-bladder-cancer).

6.1.1.2. The model for patients with Ta G1/G2 (WHO 1973) tumours treated with chemotherapy

Patients with Ta G1/G2 tumours receiving chemotherapy were stratified into three risk groups for recurrence, taking into account the history of recurrences, history of intravesical treatment, tumour grade (WHO 1973), number of tumours and adjuvant chemotherapy [230].

6.1.1.3. Club Urologico Español de Tratamiento Oncologico (CUETO) scoring model for BCG-treated patients

A model that predicts the risk of recurrence and progression, based on 12 doses of intravesical BCG over a five to six months period following TURB, has been published by the CUETO (Spanish Urological Oncology Group). It is based on an analysis of 1,062 patients from four CUETO trials that compared different intravesical BCG treatments. No immediate post-operative instillation or second TURB was performed in these patients. The scoring system is based on the evaluation of seven prognostic factors:

• gender;
• age;
• prior recurrence status;
• number of tumours;
• T category;
• associated CIS;
• WHO 1973 tumour grade.

Using this model, the calculated risk of recurrence is lower than that obtained by the EORTC tables. For progression, probability is lower only in high-risk patients [231]. The lower risks in the CUETO tables may be attributed to the use of BCG in this study. The prognostic value of the EORTC scoring system has been confirmed by data from the CUETO patients treated with BCG [232] and by long-term follow-up in another patient population [233].

6.1.1.4. The 2016 EORTC scoring model for patients treated with maintenance BCG

In 1,812 intermediate- and high-risk patients without CIS treated with one to three years of maintenance BCG, the EORTC found that the prior disease-recurrence rate and number of tumours were the most important prognostic factors for disease recurrence, stage and WHO 1973 grade for disease progression and disease- specific survival, while age and WHO 1973 grade were the most important prognostic factors for OS. T1 G3 patients did poorly, with one- and five-year disease-progression rates of 11.4% and 19.8%, respectively. Using these data, EORTC risk groups and nomograms for BCG-treated patients were developed [234].

6.1.2. Scoring model using the WHO 2004/2016 and WHO 1973 classification systems

6.1.2.1. EAU NMIBC 2021 scoring model

To update the risk of disease progression and create new prognostic factor risk groups using both the WHO 1973 and WHO 2004/2016 classification systems, individual patient data from 3,401 primary patients treated from 1990 to 2018 were used [235] (see Section 4.5). Only patients treated with TURB ± intravesical chemotherapy were included, those treated with adjuvant intravesical BCG were excluded because BCG may reduce the risk of disease progression. From the multivariate analyses, tumour stage, WHO 1973 grade, WHO 2004/2022 grade, concomitant CIS, number of tumours, tumour size and age were independent predictors of disease progression [235].

This is the only available model where the WHO 2004/2022 classification system is included as one of the parameters to calculate an individual patient’s risk group and probability of progression. As the WHO 2004/2022 classification system is the main grading classification system used by pathologists, the Guidelines Panel recommends to use the 2021 EAU NMIBC scoring model for risk groups definition (see Section 6.4).

The 2021 EAU NMIBC scoring model determines the risk of tumour progression, but not recurrence; therefore any of the models mentioned in Section 6.1.1 may be used for calculation of an individual’s risk of disease recurrence.

6.1.3. Further prognostic factors

Further prognostic factors have been described in selected patient populations:

• In T1 HG/G3 tumours, important prognostic factors were female sex, CIS in the prostatic urethra in men treated with an induction course of BCG, and age, tumour size and concurrent CIS in BCG-treated patients (62% with an induction course only) [183,236].
• Attention must be given to patients with T1 HG/G3 tumours in bladder diverticulum because of the absence of muscle layer in the diverticular wall [237].
• In patients with T1 tumours, the finding of residual T1 disease at second TURB is an unfavourable prognostic factor [220-222].
• In patients with T1G2 tumours treated with TURB, recurrence at 3 months was the most important predictor of progression [238].
• The prognostic value of pathological factors has been discussed elsewhere (see Section 4.6). More research is needed to determine the role of molecular markers in improving the predictive accuracy of currently available risk tables [233,239].

6.2. Primary carcinoma in situ

Without any treatment, approximately 54% of patients with CIS progress to muscle-invasive disease [240]. There are no reliable prognostic factors, but some studies, however, have reported a worse prognosis in concurrent CIS and T1 tumours compared to primary CIS [241,242], in extended CIS [243] and in CIS in the prostatic urethra [183]. The response to intravesical treatment with BCG or chemotherapy is an important prognostic factor for subsequent progression and death caused by BC [231,232,238]. Approximately 10 to 20% of complete responders eventually experience disease progression to muscle-invasive disease, compared with 66% of non- responders [244,245].

6.3. Histological Subtypes

Bladder cancer is primarily composed of UC, but various histological subtypes exist, each carrying unique prognostic implications (see Section 4.8) [246]. Understanding the differences between these subtypes is critical for risk stratification, as their biological behaviour can differ significantly from conventional UC.

While most UC cases exhibit typical papillary architecture, certain subtypes, such as micropapillary, plasmacytoid, sarcomatoid, and neuroendocrine subtypes, are associated with a higher risk of progression and recurrence [247,248]. Literature on these subtypes remains limited, but retrospective studies suggest that their aggressive behaviour correlates with a more rapid progression to MIBC.

Certain pathological features further influence the prognosis of NMIBC, especially in the presence of specific histological subtypes [249,250]. Identifying unfavourable and favourable prognostic factors can assist in tailoring patient management. The following table highlights key factors influencing prognosis based on subtype.

Table 6.1: Histological subtypes [55]

* “Focal” involvement with a 25% cutoff has been associated to a less aggressive behaviour in micropapillary subtype [78]

6.4. Patient stratification into risk groups

To be able to facilitate treatment recommendations, the Guidelines Panel recommends the stratification of patients into risk groups based on their probability of progression to muscle-invasive disease. The new risk group definitions provided in these guidelines are based on an individual patient data analysis in primary patients and the calculation of their progression scores (2021 EAU NMIBC scoring model) as presented in Sections 4.5 and 6.1.2) [235].

For calculation of the risk group in individual patients, either one, or both, of the WHO 1973 and WHO 2004/2016 classification systems may be used. The probability of progression at 5 years varies from less than 1% to more than 40% between the risk groups.

For factors where individual patient data were not collected such as subtypes of UC, LVI, primary CIS and CIS in the prostatic urethra; literature data have been used to classify patients into risk groups.

The clinical compositions of the new EAU NMIBC prognostic factor risk groups based on the WHO 2004/2016 or WHO 1973 classification systems are provided in Table 6.2. Applications for the web (www.nmibc.net), iOS and Android have been developed to facilitate determining a patient’s risk group in daily clinical practice. The individual probability of disease progression at one, five and ten years for the new EAU NMIBC risk groups is presented in Table 6.3. A single-centre study validated the EAU NMIBC 2021 scoring model in 529 patients who received BCG [251]. The authors found that the progression risk for the EAU 2021 high- and very high-risk groups were significantly lower in BCG-treated patients than that in Table 6.2 [235]. These lower risks may be attributed to the use of BCG.

Table 6.2: Clinical composition of the new EAU NMIBC prognostic factor risk groups based on the WHO 2004/2016 or the WHO 1973 grading classification systems [235]

• Only one of the two classification systems (WHO 1973 or WHO 2004/2016) is required to use this table.
• If both classification systems are available in an individual patient, the Panel recommends using the risk group calculation based on the WHO 1973 as it has better prognostic value.
• The category of LG tumours (WHO 2004/2016) also includes patients with tumours classified as PUNLMP.
• Additional clinical risk factors are: age > 70; multiple papillary tumours; and tumour diameter > 3 cm.

The scoring model is based on individual patient data, but does not consider patients with primary CIS (high risk) or with recurrent tumours, as well as some pathologic parameters like subtypes of UC (see Section 4.7) and LVI. Nevertheless:

• Based on data from the literature, all patients with CIS in the prostatic urethra, with subtypes of UC (see Section 4.8) or with LVI should be included in the very high-risk group.
• Patients with recurrent tumours should be included in the intermediate-, high-, or very high-risk groups according to their other prognostic factors.

Table 6.3: Probabilities of disease progression in 1, 5 and 10 year(s) for the new EAU NMIBC risk groups [235]*

WHO = World Health Organization.
*Table 6.3 does not include patients with subtypes of urothelial carcinoma (variant histologies), LVI, CIS in the prostatic urethra, primary CIS or recurrent patients.
*Please note that these percentages refer to patients who were not (immediately) treated with adjuvant BCG instillations after their primary TURB.

To sub-stratify the heterogeneous group of intermediate-risk NMIBC, a three-tier model initially proposed by the International Bladder Cancer Group (IBCG) was refined in 2022 [252]. This model is based on five clinical risk factors: tumour size and focality, timing and frequency of recurrence and failure of previous intravesical treatment. Recently, a multi-center clinical study validated this model in 677 primary and recurrent patients with intermediate-risk disease treated with adjuvant intravesical chemotherapy [253]. At one-year follow-up, the authors found that the progression risk of patients with no risk-factors was similar to that of EAU2021 low-risk group while that of patients with ≥ 3 risk-factors aligned with that of EAU2021 high-risk group. Longer follow-up and external validation are warranted to confirm this model.

6.5. Summary of evidence and recommendations for stratification of non-muscle-invasive bladder cancer