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Abstract Background In case of high grade non-muscle invasive bladder cancer (HG-NMIBC), intravesical BCG represents the first-line treatment; despite the “gold” standard therapy, up to 50% of patients relapse, needing radical cystectomy. Hence, alternative therapeutic strategies have been developed. The aim of the study was to evaluate a first-lin...
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Citations
... The three most widely used devices are the radiofrequency-induced thermotherapeutic effect (RITE), which has the largest amount of literature (Tan et al. 2019;Colombo et al. 2003;Guerrero-Ramos et al. 2022), hyperthermic intravesical chemotherapy-HIVEC-using closed recirculation systems (Plata et al. 2021;Sousa et al. 2016;Colombo et al. 2001), and electromotive drug administration (EMDA) (Stasi et al. 2003;Racioppi et al. 2018;Stasi and Riedl 2009). All have been postulated as effective alternatives to BCG treatment. ...
Background
Bacillus Calmette–Guerin (BCG) maintenance therapy is the standard adjuvant treatment of high- and intermediate-risk non-muscle-invasive bladder cancer (NMIBC). However, the problems of shortages and the adverse effects, both local and systemic, that it causes lead to the search for alternatives with devices that improve the penetration of intravesical chemotherapeutics.
Materials and methods
Prospective observational study was conducted from August 2018 to August 2022. Patients diagnosed with intermediate and high-risk NMIBC without CIS who received one of the following three treatments were included: BCG in induction protocol with six weekly instillations and maintenance with three weekly instillations at months 3, 6, and 12. MMC was applied by Physionizer® 30 device with a current of 20 mA for 30 min was used in an induction protocol of 6 weekly instillations followed by 6 monthly instillations as maintenance (EMDA group). MMC was applied by COMBAT BRS System V2.0 device at 43 ± 0.5 ℃ for 60 min was used in an induction protocol of 6 weekly instillations followed by 6 monthly instillations as maintenance (HIVEC group). The primary objective was to compare the 24-month recurrence-free rate between the three groups. The secondary objectives were to evaluate the rate free of progression at 24 months and the degree of toxicity of the treatments.
Results
One hundred and eighty-three patients divided into a HIVEC group with sixty-one patients, EMDA group with fifty-nine patients, and BCG group with sixty-three patients. After a mean follow-up of 25 months (IQR 13–36), the 24-month recurrence-free rate was 82.1% for HIVEC, 80% for EMDA, and 84.6% for BCG (p > 0.05), and a progression-free rate at 24 months of 95.6% for HIVEC, 98.3% for EMDA, and 92.9% for BCG (p > 0.05). No statistically significant differences were found between the three groups with respect to the degree of reported adverse events.
Conclusion
Adjuvant treatment with BCG or MMC applied with COMBAT or EMDA does not present differences in the recurrence-free rate and progression at 24 months in our population of patients with intermediate- and high-risk NMBC without CIS.
... Two studies discussed the clinical safety and efficacy of EMDA-MMC. A phase II trial was conducted by Racioppi et al. 17 At the end of the induction course, CR rate was 73.1% at the end of the induction cycle and 61.5% after 3 years of follow-up, with a progression rate of 15.4%. ...
... 25 The stratification of patients based on histopathological data, a recommendation provided by the FDA, is of great importance in trials as it helps to identify higher efficacy of one subset over another subset in response to the study drug. 17 In patients who decline RC, but are otherwise eligible for surgical management, patients need to be informed that the window period for RC or bladder preserving therapy may be narrowed, should they opt for nonsurgical options. 18 However, DiGianfrancesco et al. compared patients that received second line device assisted therapies using MMC (CHT and EMDA) to patients that received RC, which showed that the rates of OS and CSS were comparable between the two groups (91.6% versus 90.2%; 94.4% versus 95.1%, respectively). ...
Introduction
Globally, urothelial bladder carcinoma is a disease which carries a poor prognosis. There are various treatment modalities for urothelial bladder carcinoma with intravesical Bacillus Calmette–Guérin immunotherapy being the most efficacious intravesical therapy and the treatment of choice for patients with carcinoma in situ. A number of chemotherapeutic drugs are also available for the management of Ta/T1 tumors such as mitomycin C and epirubicin. However, relapse and progression is quite common. The optimal management of patients with Bacillus Calmette–Guérin-unresponsive disease remains to be a challenge. The purpose of this study was to conduct a systematic review on the treatment modalities available for the management of Bacillus Calmette–Guérin-unresponsive carcinoma in situ and urothelial bladder carcinoma in patients who are ineligible or decline radical cystectomy.
Methods
Two authors independently searched three databases on the treatment modalities available for the management of Bacillus Calmette–Guérin-unresponsive carcinoma in situ and Bacillus Calmette–Guérin-unresponsive urothelial bladder carcinoma.
Results
The systematic search resulted in 15 studies. We recommend the use of intravesical CG0070 adenovirus or hyperthermic intravesical chemotherapy mitomycin C in patients with carcinoma in situ only disease. In patients with carcinoma in situ ± Ta/T1 disease, we recommend the use of intravesical radiofrequency-induced chemohyperthermia or electromotive drug administration of mitomycin C. In patients who have Ta/T1 disease, we recommend the use of either hyperthermic intravesical chemotherapy epirubicin or electromotive drug administration mitomycin C followed by chemohyperthermia mitomycin C. If any of these second line therapies fail, an alternative regimen would be a combination of gemcitabine, cabazitaxel, and cisplatin.
Conclusion
This recommendation is subject to the available resources and clinical expertise available in different hospitals. More studies using study designs such as randomized controlled trials comparing multiple drugs with larger sample sizes and regular follow-up intervals should be performed to accurately assess the different medications and aid in designing guidelines to guide the management of Bacillus Calmette–Guérin-unresponsive non-muscle invasive intravesical bladder cancer.
... There are currently no direct comparisons between EMDA ® -MMC and hyperthermic strategies such as RITE or HIVEC, either in terms of relative penetration into the bladder wall or in terms of oncological outcomes. Regarding the prognostic value of CIS, response rates to EMDA ® -MMC were significantly worse in the presence of CIS, with a disease-free survival rate of only 50% at 9 months in this subgroup of patients [30]. ...
CIS of the bladder is associated with a high risk of progression. In the case of BCG failure, radical cystectomy should be performed. For patients who refuse or are ineligible, bladder-sparing alternatives are evaluated. This study aims to investigate the efficacy of Hyperthermic IntraVesical Chemotherapy (HIVEC) depending on the presence or absence of CIS. This retrospective, multicenter study was conducted between 2016 and 2021. Patients with non-muscle-invasive bladder cancer (NMIBC) with BCG failure received 6–8 adjuvant instillations of HIVEC. The co-primary endpoints were recurrence-free survival (RFS) and progression-free survival (PFS). A total of 116 consecutive patients met our inclusion criteria of whom 36 had concomitant CIS. The 2-year RFS rate was 19.9% and 43.7% in patients with and without CIS, respectively (p = 0.52). Fifteen patients (12.9%) experienced progression to muscle-invasive bladder cancer with no significant difference between patients with and without CIS (2-year PFS rate = 71.8% vs. 88.8%, p = 0.32). In multivariate analysis, CIS was not a significant prognostic factor in terms of recurrence or progression. In conclusion, CIS may not be considered a contraindication to HIVEC, as there is no significant association between CIS and the risk of progression or recurrence after treatment.
... The authors report only three patients having experienced grade 3 adverse events, all for suspected bacteremia requiring hospitalization for intravenous antibiotic treatment. In a different study of EDMA in BCG-unresponsive disease, 60% of patients managed to retain their bladders avoiding cystectomy at year 3; however, three of 26 patients in that study had severe early allergic reactions to mitomycin C and underwent cystectomy [48]. Of note, EDMA is currently not available in the USA. ...
Purpose of Review
The treatment options for high-risk non-muscle invasive bladder cancer (NMIBC), particularly following BCG, remain limited. We highlight recent, promising therapies for high-risk NMIBC.
Recent Findings
Several therapies utilizing different mechanisms of action have demonstrated favorable results in the BCG-naïve and BCG-unresponsive settings. These treatments include intravenous and intravesical immunotherapy, viral- and bacterial-based intravesical therapies, combination intravesical chemotherapy regimens, and novel intravesical chemotherapy administration. Overall, the efficacy and tolerability of emerging treatments for NMIBC appear promising and provide potential alternatives to radical cystectomy.
Summary
As the landscape of managing BCG-unresponsive disease evolves, clinical trials will explore future options and determine effective alternatives.
... EMDA protocols adopted by the various centers show slight variations, with earlier studies using a lower current amplitude of 15 mA over shorter time periods of 20 min, while most subsequent studies utilize a maximum of 20 to 23 mA of pulsed DC applied over a duration of 30 min [47][48][49][50][51][52][53][54][55]. No differences in tolerability and adverse side effects were observed with the higher amplitude and longer durations. ...
... Amongst adjuvant studies, reported rates of complete response post-EMDA with MMC range from 40% to 82% while recurrence rates range from 14 to 52%. In addition, it was also found to have a potential role as salvage therapy in BCG refractory high grade NMIBC [55]. ...
Local-regional administration of cytotoxic drugs is an important adjunct to systemic chemotherapy amongst cancer patients. It allows for targeted delivery of agents at high concentration to target sites while minimizing systemic side effects. Despite the pharmacokinetic advantages of the local–regional approach, drug transport into tumor nodules remains limited due to the biophysical properties of these tissues. Electromotive enhanced drug administration (EMDA) represents a potential solution to overcome challenges in local drug transport by applying electric currents. Through electrokinetic phenomena of electromigration, electroosmosis and electroporation, electric currents have been shown to improve drug penetration and distribution in a wide variety of clinical applications. Amongst patients with non-muscular invasive bladder cancer (NMIBC) and basal and squamous cell skin cancers, EMDA has been successfully adopted and proven efficacious in several pre-clinical and clinical studies. Its application in ophthalmological and other conditions has also been explored. This review provides an overview of the underlying principles and factors that govern EMDA and discusses its application in cancer patients. We also discuss novel EMDA approaches in pre-clinical studies and explore future opportunities of developments in this field.
... We have established the parameters that permit to increase GNRs@Chit-Iso4 distribution on the top and lateral sides of the bladder, ensuring that targeted GNRs come into contact with any urothelial area in which the tumor might be located. Compared to other protocols such as the electromotive drug administration used to improve bladder wall penetration of Mytomycin C [49,50] or the use of a magnetic field to move silicon dioxide microparticles [48], US-assisted shaking from the abdomen is a safe, non-invasive protocol. ...
Detection and removal of bladder cancer lesions at an early stage is crucial for preventing tumor relapse and progression. This study aimed to develop a new technological platform for the visualization of small and flat urothelial lesions of high-grade bladder carcinoma in situ (CIS).
We found that the integrin α5β1, overexpressed in bladder cancer cell lines, murine orthotopic bladder cancer and human bladder CIS, can be exploited as a receptor for targeted delivery of GNRs functionalized with the cyclic CphgisoDGRG peptide (Iso4). The [email protected]Iso4 was stable in urine and selectively recognized α5β1 positive neoplastic urothelium, while low frequency ultrasound-assisted shaking of intravesically instilled [email protected]Iso4 allowed the distribution of nanoparticles across the entire volume of the bladder. Photoacoustic imaging of [email protected]Iso4 bound to tumor cells allowed for the detection of neoplastic lesions smaller than 0.5 mm that were undetectable by ultrasound imaging and bioluminescence.
... Another technique is the Electromotive Drug Administration (EMDA)-MMC, which exploits the phenomenon called "iontophoresis", created by intravesical electrodes, to improve the absorption of MMC. In a phase II trial enrolling patients with BCG-unresponsive NMIBC, EMDA-MMC demonstrated to have only a modest activity in CIS patients, while this system seemed to be effective in preventing the recurrence of papillary tumours (Ta or T1) [84]. ...
Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high rate of cure, but also by a non-negligible probability of recurrence and risk progression to muscle-invasive disease. NMIBC management requires a proper local resection and staging, followed by a risk-based treatment with intravesical agents. For many years, the current gold standard treatment for patients with intermediate or high-risk disease is transurethral resection of the bladder (TURB) followed by intravesical bacillus Calmette–Guérin (BCG) instillations. Unfortunately, in about half of high-risk patients, intravesical BCG treatment fails and NMIBC persists or recurs early. While radical cystectomy remains the gold standard for these patients, new therapeutic targets are being individuated and studied. Radical cystectomy in fact can provide an excellent long-term disease control, but can deeply interfere with quality of life. In particular, the enhanced immune checkpoints expression shown in BCG-unresponsive patients and the activity of immune checkpoints inhibitors (ICIs) in advanced bladder cancer provided the rationale for testing ICIs in NMIBC. Recently, pembrolizumab has shown promising activity in BCG-unresponsive NMIBC patients, obtaining FDA approval. Meanwhile multiple novel drugs with alternative mechanisms of action have proven to be safe and effective in NMIBC treatment and others are under investigation. The aim of this review is to analyse and describe the clinical activity of new emerging drugs in BCG-unresponsive NMIBC focusing on immunotherapy results.
... 12 Historical data suggest that the risk of metastasis in patients with BCG failure reaches 50% after three additional cycles of BCG. 13 The need for novel bladder preserving therapies is therefore particularly acute for these patients. ...
... A small prospective study of 26 BCG-refractory patients reported a 12-month high-grade disease-free survival of 72% for patients with papillary tumors, and 38% for those with CIS. 13 Intravesical chemohyperthermia (CHT) can utilize external heating of the chemotherapeutic agent (combat bladder recirculation) or application of microwave energy to the bladder through a specialized catheter (Synergo) that heats the bladder wall to 41-44°C. 24 The latter device was used in a prospective study of patients with high and intermediate-risk NMIBC, 81% of whom had received prior BCG, to treat with MMC or epirubicin. ...
Non-muscle invasive bladder cancer (NMIBC) has traditionally been managed with transurethral resection followed by intravesical chemotherapy and/or bacillus Calmette–Guerin (BCG) in a risk-adapted manner. These tumors commonly recur and can progress potentially to lethal muscle invasive disease. A major unmet need in the field of NMIBC is bladder preserving therapy for recurrent high-grade NMIBC after adequate intravesical BCG therapy. The current gold standard treatment for these BCG-unresponsive patients is radical cystectomy, which is associated with considerable morbidity and mortality, particularly in older and frailer patients. It is therefore critical to provide alternative treatment options with acceptable oncological outcomes. In this review we explore novel bladder-sparing treatment options including combination intravesical therapy, enhanced instillation methods, immunotherapy, gene therapy, targeted therapy, photodynamic therapy and BCG variants across the spectrum of NMIBC disease states, ranging from low grade BCG-naïve patients through to high-grade BCG-unresponsive NMIBC.
... Three patients from each group withdrew from the study because of severe AEs [55]. To date, only one study has evaluated the efficacy of EMDA in BCG failure settings [56]. This prospective phase II trial enrolled 26 patients with recurrent high-grade NMIBC after BCG therapy. ...
... This prospective phase II trial enrolled 26 patients with recurrent high-grade NMIBC after BCG therapy. The high-grade recurrence-free survival was 61.5%, with a median follow-up duration of 36 months [56]. Of patients, 10 were finally treated with RC due to persistent high-grade disease (six patients, 23. ...
... Of patients, 10 were finally treated with RC due to persistent high-grade disease (six patients, 23. 1%) or progression to muscle-invasive stage (four patients, 15.4%) [56]. Three patients (11.5%) showed severe adverse systemic events of hypersensitivity to MMC with a hand-foot reaction, which caused treatment discontinuation. ...
Intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG immuno-therapy prevents disease recurrence and progression to muscle-invasive disease following TURBT. Although most patients initially respond well to intravesical BCG, considerable concern has been raised for patients with BCG failure who are refractory or recur in 6 months after their last BCG, which implies 'BCG-unresponsiveness'. Based on current clinical guidelines, early radical cystectomy (RC) is recommended to treat BCG-unresponsive NMIBC. However, due to the high risk of morbidity and mortality of RC and patients' desire to preserve their own bladder, there is a critical unmet need for alternative conservative treatments as bladder-sparing strategies in BCG-unresponsive patients. Trials for effective bladder-sparing treatments are ongoing, and several novel agents have been recently tested in the NMIBC setting. The goal of this review is to introduce and summarize recently reported novel and emerging drugs and ongoing clinical trials for BCG-unresponsive NMIBC.
... Racioppi et al recently published the results of a phase 2, single-arm study on 26 patients using EMDA-MMC (induction and maintenance) for highrisk NMIBC who failed BCG therapy. 311 Median followup was 36 months and HG disease-free rate was 61.5%. 311 In this study, a total of 10 patients underwent RC; of those, six (23.1%) had recurrent HG NMIBC and four (15.4%) had disease progression (three patients with pT2 and one with pT4a). ...
... 311 Median followup was 36 months and HG disease-free rate was 61.5%. 311 In this study, a total of 10 patients underwent RC; of those, six (23.1%) had recurrent HG NMIBC and four (15.4%) had disease progression (three patients with pT2 and one with pT4a). 311 Moreover, a retrospective study by Juvet et al evaluated 26 patients who failed BCG (all, except four were classified as BCG-unresponsive) and were treated with sequential BCG and EMDA-MMC. ...
... 311 In this study, a total of 10 patients underwent RC; of those, six (23.1%) had recurrent HG NMIBC and four (15.4%) had disease progression (three patients with pT2 and one with pT4a). 311 Moreover, a retrospective study by Juvet et al evaluated 26 patients who failed BCG (all, except four were classified as BCG-unresponsive) and were treated with sequential BCG and EMDA-MMC. 312 Complete response rates at six, 12, and 18 months were 62%, 44%, and 30%, respectively, while PFS at two years was of 48%. ...
Risk factors 1. Former or current tobacco smoking is the most common risk factor associated with bladder cancer and smoking cessation should be encouraged in all patients (Level of Evidence [LE] 3; strong recommendation). Symptoms and diagnosis 2. White-light cystoscopy (WLC) is recommended in the initial evaluation of patients suspected to have bladder cancer. Cystoscopy should be performed with a flexible cystoscope whenever available (LE 1; strong recommendation). 3. Urine cytology (voided or collected by bladder washing) is recommended as an adjunct to cystoscopy in patients suspected to have bladder cancer (LE 2; strong recommendation). 4. Upper urinary tract imaging is recommended in the initial workup of patients suspected to have bladder cancer (LE 3; strong recommendation). Prognostic factors for recurrence and progression 5. The most important prognostic factors for recurrence and progression of non-muscle-invasive bladder cancer (NMIBC) are stage and grade (LE 2). All patients with bladder cancer should be properly staged and, specifically for NMIBC, reporting grade is paramount for further management decisions (LE 2; strong recommendation). 6. Other prognostic factors are age >70yr, large tumour size (≥3cm), multiple tumours, the presence of concomitant carcinoma in situ (CIS), extensive invasion of the lamina propria, prior recurrence rates > 1 per year and status at first assessment after transurethral resection of the bladder tumour (TURBT) (LE 2), as well as lymphovascular invasion (LVI) (LE 3). 7. Aggressive histological variants such as micropapillary, plasmacytoid and sarcomatoid are associated with increased risk of under-staging and progression (LE 3). Pathological review, preferably by a dedicated uro-pathologist, should be considered in settings where variant histology is suspected or atypical tumours are seen during TURBT (e.g., sessile mass) (LE 3; weak recommendation). Risk stratification 8. All patients with NMIBC should be stratified according to the risk of both recurrence and progression for adequate patient counselling and treatment planning (LE 2; strong recommendation). The modified CUA risk stratification system is a suitable tool for this purpose. Transurethral resection 9. Patients presenting with a bladder tumour should undergo initial TURBT for diagnostic confirmation and pathological evaluation (LE 2; strong recommendation). 10. Initial TURBT aims for complete tumour resection with sampling of the underlying detrusor muscle as the first step of curative-intent treatment of NMIBC (LE 2; strong recommendation). Patients with presumed low grade (LG) Ta or CIS might be spared from muscle sampling at initial TURBT (LE 3; weak recommendation). 11. When available, blue light cystoscopy (BLC) (LE 1; weak recommendation) or narrow band imaging (LE 2; weak recommendation) can increase tumour detection at first TURBT and reduce recurrence risk. 12. A restaging TURBT should be performed in patients with T1 NMIBC, or when a complete resection was not achieved with the first TURBT (LE 2; strong recommendation). Restaging TURBT is not required in patients who will proceed to radical cystectomy (RC) based on the findings of the first TURBT. 13. In select cases of high grade (HG) Ta tumours (e.g., large and/or multiple tumours), a restaging TURBT can be considered (LE 3; weak recommendation). 14. The suggested window for a restaging TURBT is within 6 weeks of the first resection (LE 3; weak recommendation). 15. Patients presenting with a positive urine cytology, but normal appearing bladder at WLC and normal upper urinary tract imaging are at higher risk of harbouring occult CIS and should undergo random bladder biopsies (or use of BLC with directed biopsies) (LE 2; strong recommendation). 16. Biopsies or transurethral resection of the prostatic urethra should be included with random bladder biopsies in the presence of a positive bladder urine cytology, but normal appearing bladder at WLC and normal upper tract imaging (LE 3; strong recommendation). 17. Prostatic urethral biopsy (or transurethral resection) can also be considered in the presence of extensive bladder CIS or tumour at the bladder neck or trigone (LE 3; weak recommendation). 18. Patients with prostatic urethral involvement (PUI) with CIS restricted to the urethral mucosa can be managed conservatively with transurethral resection of the prostate (TURP) plus intravesical BCG (LE 3; weak recommendation). Repeat prostatic urethral biopsies after induction BCG should be considered (LE 3; weak recommendation). RC can be discussed as an alternative option (LE 4; weak recommendation). 19. In patients with HG T1 or CIS extending into the prostatic ducts, RC should be considered (LE 3; weak recommendation). TURP followed by intravesical BCG is an alternative option. In this instance, close followup with repeat prostatic urethral biopsies after induction BCG should be considered (LE 3; weak recommendation). 20. In patients with prostatic stromal invasion, neoadjuvant cisplatin-based chemotherapy followed by RC is recommended (LE 3; strong recommendation – refer to MIBC CUA guideline). Single instillation of chemotherapy (SIC) post-TURBT 21. SIC (with mitomycin-C, epirubicin, doxorubicin, pirarubicin or gemcitabine) should be offered to all patients with presumed low-risk NMIBC at TURBT and should be administered within 24 hours after endoscopic resection (LE 1; strong recommendation). 22. SIC is recommended for intermediate-risk NMIBC and for patients with ≤ 1 recurrence/year and EORTC recurrence score < 5 (LE 1; strong recommendation). SIC should be discussed even when further adjuvant intravesical chemotherapy is planned (LE 2; weak recommendation). 23. The benefit of SIC in patients with high-risk NMIBC is unclear when intravesical Bacillus Calmette-Guérin (BCG) is planned as adjuvant treatment (LE 3). 24. SIC should not be administered after extensive resection or when bladder perforation is suspected (LE 3; strong recommendation). Adjuvant intravesical chemotherapy 25. Patients with intermediate-risk NMIBC should be considered for adjuvant induction intravesical chemotherapy (LE 1; strong recommendation) with subsequent maintenance for up to 1 year (LE 3; weak recommendation), or induction BCG with maintenance therapy (refer to statement #30). 26. Substratification of intermediate-risk patients with recurrent LG Ta NMIBC can be used to guide adjuvant treatment decisions (LE 3; weak recommendation). For this purpose, 4 factors should be considered: number of tumours, size (≥ 3cm), time to recurrence (< 1 year) and frequency of recurrence (> 1/year). - Patients with low-intermediate-risk NMIBC (0 factors) may be treated similarly to low-risk patients, with SIC alone (LE 3; weak recommendation). - Patients with high-intermediate-risk NMIBC (≥3 factors) may be treated as high-risk patients with induction and maintenance BCG (LE 3; weak recommendation). 27. Patients who develop recurrence during intravesical chemotherapy may be offered induction followed by maintenance BCG (LE 3; weak recommendation). 28. Although intravesical chemotherapy through device-assisted therapy has shown promising results in small randomized controlled trials, further studies are needed to validate its routine clinical use. Adjuvant intravesical BCG 29. In patients with high-risk NMIBC, BCG therapy with induction (weekly instillations for 6 weeks) followed by 3-year maintenance (weekly instillations for 3 weeks at 3, 6, 12, 18, 24, 30 and 36 months) is the standard of care for reducing disease recurrence and progression rates (LE 1; strong recommendation). 30. When BCG is administered for intermediate-risk NMIBC, induction (weekly instillations for 6 weeks) followed by 1-year maintenance (weekly instillations for 3 weeks at 3, 6 and 12 months) is recommended (LE 1; strong recommendation). 31. RC with pelvic lymph node dissection is the standard of care for BCG-unresponsive bladder cancer in surgically fit patients (LE 3; strong recommendation). For patients with BCG-unresponsive CIS or HG Ta, a second-line bladder-preserving therapy can be considered before RC (LE 3; weak recommendation). 32. Promising efficacy has been reported with intravenous pembrolizumab, intravesical oportuzumab monatox, nadofaragene firadenovec, and BCG plus N-803. These should be considered as potential options in patients with BCG-unresponsive CIS who are unfit for or refuse to undergo RC (LE 2; weak recommendation). 33. Alternative options such as sequential intravesical gemcitabine/docetaxel (induction plus maintenance) may be considered for patients with BCG-unresponsive disease who are unfit for or refuse to undergo RC (LE 3; weak recommendation). Additional alternatives may also include other combination intravesical therapy (e.g., sequential gemcitabine/mitomycin-C, BCG + interferon if available) or single-agent intravesical therapy (mitomycin-C, epirubicin, docetaxel, gemcitabine) (LE 3; weak recommendation). 34. Clinical trials may be considered for BCG-unresponsive patients who are unfit for or refuse to undergo RC. Treatment adjustments only if BCG shortage 35. For patients with intermediate-risk NMIBC during BCG shortage, intravesical chemotherapy is recommended as the first-line option. If BCG is planned as a second-line therapy for this population, induction might be administered with reduced dosing (1/2 or 1/3 dose) and maintenance can be omitted (LE 3; weak recommendation). 36. For patients with high-risk NMIBC, full BCG schedule (induction followed by maintenance) is recommended (LE 1; strong recommendation). Only during BCG shortage, when full dose is not possible due to limited supply, dose reduction to 1/2 or 1/3 might be considered, while maintenance can be reduced to one year (LE 3; weak recommendation). 37. When BCG is unavailable, single agent chemotherapy (e.g., mitomycin-C, gemcitabine) or sequential combination of intravesical chemotherapy (e.g., gemcitabine/docetaxel) is recommended with induction followed by monthly maintenance for up to one year (LE 3; weak recommendation). Timely cystectomy 38. Upfront RC should be considered for patients with large volume, diffuse, endoscopically unresectable NMIBC (LE 3; strong recommendation) 39. Upfront RC should be offered to patients with HG T1 disease with additional adverse tumour pathological features including: variant histology (e.g., micropapillary, plasmacytoid, sarcomatoid), extensive invasion of the lamina propria or invasion into or beyond the muscularis mucosa (T1b/c), presence of LVI, concomitant CIS in the bladder or prostatic urethra, multiple and large (≥3cm) tumours, or persistent HG T1 upon restaging TURBT (LE 3; strong recommendation). Followup 40. The first surveillance cystoscopy is recommended for all patients at 3 months after TURBT (LE 2; strong recommendation). 41. A risk-based surveillance strategy should be used in patients with no evidence of recurrence at the 3-month cystoscopy: - Low-risk patients might be followed with cystoscopy at 1 year and then yearly for 5 years (LE 3; weak recommendation). Urine cytology is not necessary in the followup of low-risk patients (LE 4; weak recommendation). - Intermediate-risk patients should be followed with cystoscopies and urine cytology every 3-6 months in the first 2 years, every 6-12 months in the 3rd year, and annually thereafter (LE 3; weak recommendation). - High-risk patients should be followed with cystoscopies and urine cytology every 3-4 months during the first 2 years, every 6 months during years 3 and 4, and annually thereafter (LE 3; weak recommendation). 42. Upper tract imaging is recommended with random bladder/prostatic urethral biopsies (or use of BLC with directed biopsies) if positive urine cytology with normal WLC is found during surveillance (LE 3; weak recommendation). 43. Upper tract imaging is recommended in the first year and every 2 years thereafter for high-risk patients (LE 3; weak recommendation). 44. Fulguration under local anesthesia might be considered for small (<5mm) papillary tumours and negative cytology in patients with a prior history of papillary urothelial neoplasm of low malignant potential or LG Ta NMIBC (LE 3; weak recommendation).
