Non–muscle-invasive Bladder Cancer: Overview and Contemporary Treatment Landscape of Neoadjuvant Chemoablative Therapies

Treatment Update

Treatment Update Non–muscle-invasive Bladder Cancer: Overview and Contemporary Treatment Landscape of Neoadjuvant Chemoablative Therapies Richard S. Matulewicz, MD, MS,1,2 Gary D. Steinberg, MD1 1Department of Urology, NYU Grossman School of Medicine, NYU Langone Health, New York, NY; 2Department of Population Health, NYU Grossman School of Medicine, NYU Langone Health, New York, NY Non–muscle-invasive bladder cancer (NMIBC) is a heterogeneous subclassification of urothelial carcinoma with significant variation in individual risk of recurrence and progression to muscle-invasive disease. Risk stratification by American Urological Association (AUA) and European Association of Urology (EAU) guidelines or by using nomograms/risk calculators developed from clinical trial data can help inform patient treatment decisions but may not accurately classify all patients. Risk-adapted adjuvant (post–transurethral resection of bladder tumor [TURBT]) treatment strategies using intravesical therapies are an important means of balancing disease control with potential adverse effects. Adjuvant intravesical instillation with various chemotherapy agents and bacillus Calmette-Guérin (BCG) is well studied and associated with excellent outcomes for most patients. However, upwards of 40% of patients recur within 2 years and roughly 10% progress to muscle-invasive bladder cancer. Novel approaches and agents that aim to reduce the treatment burden associated with NMIBC are increasingly needed. We review the current landscape of NMIBC as it pertains to the use of and rationale for emerging neoadjuvant chemoablative therapies. [Rev Urol. 2020;22(2):43–51] © 2020 MedReviews®, LLC KEY WORDS Non-muscle invasive bladder cancer • Urothelial carcinoma • Bacillus Calmette-Guérin (BCG) • Mitomycin Vol. 22 No. 2 • 2020 • Reviews in Urology • 43 Neoadjuvant Chemoablative Therapies for NMIBC continued T here are approximately 80,000 incident cases of bladder cancer each year in the United States, 90% of which are urothelial carcinoma.1 Median age at presentation is 70 years with male predominance. In the United States, chemical carcinogens from tobacco smoke and occupational exposures such as aromatic amines, polycyclic aromatic hydrocarbons (PAHs), and benzenes are the strongest established risk factors but the contributions of other environmental and genetic factors to the development of bladder cancer are increasingly being recognized.2 Patients with bladder cancer generally present with hematuria or voiding symptoms and are diagnosed by cystoscopy with biopsy and/or resection of the tumor(s) and cross-sectional imaging to evaluate for metastases. Bladder cancer is classified according to traditional American Joint Committee on Cancer (AJCC) TNM staging. In the absence of nodal (N stage) or distant metastases (M stage), depth of tumor invasion (T stage) is the most important determination to be made and can be dichotomized based on whether the tumor is invading into or beyond the muscularis propia (muscle-invasive bladder cancer, MIBC) or not (non– muscle-invasive bladder cancer, NMIBC). At presentation, 90% of bladder cancers are confined to the bladder wall layers and of all localized bladder cancers (≤T2), 75% are non–muscle invasive (Tis, Ta, T1).2 Tumors are further classified according to histological grade (low or high). Stratification of NMIBC into risk groups with similar rates of recurrence and progression help guide prognostication, counseling, and treatment recommendations. In this review, we describe the contemporary standards of diagnosis, risk stratification, and treatment of NMIBC with discussion of emerging neoadjuvant chemoablative treatment options. Evaluation of NMIBC Establishing an accurate diagnosis is critical to the proper treatment of bladder cancer. Diagnosis begins with a detailed history focusing on antecedent symptomatology, comorbidities, risk factors, and family history. Exploration of con­ sti­tutional symptoms and a focused physical examination may uncover findings suggestive of advanced disease. Counseling patients on smoking cessation upon diagnosis can reduce the risk of perioperative complications and may reduce the risk of NMIBC recurrence.3 Office-based cystoscopy visually confirms the presence of bladder cancer which is followed by a transurethral resection of the bladder tumor (TURBT) under anesthesia. During the TURBT, description of tumor size, location, multiplicity, appearance, and asso­ ciated mucosal changes is essential to staging. Resection of all visible tumor with safe sampling of the underlying detrusor muscle layer should be the goal of all TURBTs and is associated with improved histopathologic accuracy and improved oncologic outcomes. There are established diagnostic, prognostic, and therapeutic bene­ fits to repeat TURBT and it is generally indicated for all highgrade tumors and especially for any initial pathology specimen devoid of detrusor muscle layer.4,5 The presence of metastatic or synchronous upper tract disease is evaluated using conventional crosssectional imaging with delayed drainage films. CT or MRI urogram is the gold standard of evaluating the upper tracts concomitantly with the abdominopelvic viscera 44 • Vol. 22 No. 2 • 2020 • Reviews in Urology and lymph nodes. Chest imaging is also required to exclude metastatic disease in the lungs and is particularly important among smokers where a second primary malignancy may be present. Novel methods of visualization such as fluorescence cystoscopy with either 5-aminolaevulinic acid (5-ALA) or hexaminolevulinic acid-blue light cystoscopy (Cysview®, Photocure, Inc., Princeton, NJ; HAL-BLC) are increasingly being adopted. Compared with tradi­ tional white light cystoscopy (WLC), fluorescence cystoscopy has demonstrated improved sensitivity in detecting carcinoma in situ (CIS) and is able to detect additional primary tumors missed by WLC in roughly 20% of patients.6 Metaanalyses have also demonstrated improvements in recurrence but not progression or mortality rates when comparing HAL-BLC with WLC.7-9 Higher rates of falsepositive results with BLC can lower specificity, whereas falsepositive rates seen with traditional WLC have not been considerably different, historically.10 Narrowband imaging is another enhanced cystoscopy technique to help improve the visual contrast between normal mucosal surfaces and tissue that is “hyper vascular” such as cancer, but evidence of effectiveness is limited.11 Urine cytology is a helpful adjunct to tumor visualization and biopsy because some CIS is difficult to visualize with standard WLC. Urine cytology is quite sensitive to high-grade tumors like CIS (0.80) but performs worse with low-grade tumors (0.04-0.30) and use is discouraged among those with low-risk NMIBC and normal cystoscopy.12 Urinary biomarkers continue to be studied as diagnostic adjuncts and as potential alternatives to cystoscopy for either bladder cancer diagnosis or surveillance.13 Neoadjuvant Chemoablative Therapies for NMIBC Six urinary biomarkers are currently approved by the US Food and Drug Administration (FDA), including those which assess nuclear matrix proteins (NMP22® BladderChek® Test, Abbott, Abbott Park, IL), bladder tumor antigen (BTA STAT & TRAK tests, Polymedco, Cortlandt Manor, NY), and those that utilize fluorescence in situ hybridization (UroVysion Bladder Cancer Kit [UroVysion Kit], Abbott) and fluorescent immunohistochemistry (ImmunoCyt/uCyt1 test, Sci­ me­ dex, Denville, NJ). With sensi­ tivities ranging from 0.57-0.82 and specificities between 0.74-0.88, few have proven accurate enough for routine clinical use in lieu of cystoscopy.14 There are histopathologic challenges to the diagnosis of NMIBC because of the known interobserver variability of patho­ logic evaluation. Therefore, it is incumbent on the urologist to provide the pathologists with the best possible specimen devoid of cautery or crush injury. A systematic and complete visual resection with either fractioned or en bloc removal that adequately samples the detrusor muscle is the most important step in the diagnosis and treatment algorithm for NMIBC. The presence or absence of vari­ ant histology (eg, micropapillary, plasmacytoid, sarcomatoid, etc), as well as factors such as concurrent CIS and lymphovascular invasion are important for risk stratification and may lead to consideration of upfront extirpative treatment with radical cystectomy rather than adjuvant intravesical therapies. Adjuvant intravesical treat­ ments after TURBT have demonstrated reduction in the risk of recurrence and progression compared with TURBT alone. Although generally safe, the use of adjuvant intravesical therapy is based on a risk-adapted strategy that aims to balance reduction of recurrence and progression with side effects, especially systemic, from overtreatment. There are several available risk stratification methods using a variety of clinical and pathological factors that can be used to quantify risk of recurrence and progression. Based on each patients’ cancer risk profile after TURBT and considered in the context of their comorbidities, a patient-centered discussion about adjuvant treatment options should be undertaken to guide next steps. Risk Stratification NMIBC is a widely heterogeneous subclassification of bladder cancer and treatment should be approached accordingly. Depending on tumor characteristics, the probability of recurrence for any given patient can range from 15% to 70% at 1 year.15 Several studies and subsequent metaanalyses have proven that adjuvant intravesical treatment after TURBT is an effective means of reducing the risk of recurrence and progression of NMIBC when compared with TURBT alone.16,17 Current adjuvant treatment strategies are risk adapted because not all intravesical therapy is similarly effective nor are all treatment options recommended across risk categories. There are several stratification tools available including nomo­ grams that can be used to estimate individualized risk predictions for recurrence and progression. Post hoc analyses of patient-level data collected during large randomized, controlled trials (RCTs) conducted by the European Organization for Research and Treatment of Cancer (EORTC) and Club Urologico Espanol de Tratamiento Oncologico (CUETO) were used to generate these tools. Both the EORTC and CUETO groups’ nomograms and risk models acknowledge that there are unique factors related to an increased risk of recurrence and/ or progression in NMIBC (Table 1). As such, individual risks for recurrence and progression may be calculated from each. These nomograms have all been validated and avoid the somewhat arbitrary categorization of patients into broad risk groups. However, there are certain limiting factors with their use that are important to understand and consider. The initial EORTC risk tables were based on patient-level data from 2596 patients with NMIBC, only 4.4% of which also had CIS.15 In this study, no patients received a second TURBT and 78% were treated primarily with a variety of intravesical chemotherapy regimens. Only 6.5% of patients received bacillus CalmetteGuérin (BCG) and none received maintenance treatments. The CUETO group developed a similar nomogram based on data from 1062 patients from 4 randomized trials, all of which were treated with BCG.18 Use of maintenance treatment in the CUETO cohort was limited to 5 to 6 months. In 2016, the EORTC subsequently produced a nomogram and additional risk groups specific to a combined cohort of patients from 2 RCTs assessing the benefit of 1 to 3 years of maintenance BCG among 1812 intermediateand high-risk patients, all without CIS.19 Risk estimates of early and later recurrence are given based on prior recurrence rate and number of tumors, with tumor grade as an additional prognostic factor for early recurrence. A summary and comparison of risk factors and predicted recurrence and progression rates can be found in Table 2 for the original EORTC risk tables and the CUETO nomogram. Vol. 22 No. 2 • 2020 • Reviews in Urology • 45 Neoadjuvant Chemoablative Therapies for NMIBC continued TABLE 1 Comparison of Risk Factors for Recurrence and Progression Used in CUETO and EORTC Nomograms EORTC CUETO Number of tumors Gendera Tumor size Age Recurrent tumor Recurrent tumor T stage T stageb Concurrent CIS Association CIS WHO grade WHO grade aFactor for recurrence only. bFactor for progression only. CIS, carcinoma in situ; CUETO, Club Urologico Espanol de Tratamiento Oncologico; EORTC, European Organization for Research and Treatment of Cancer; WHO, World Health Organization. TABLE 2 Point Estimates and 95% Confidence Intervals for the 1- and 5-year Risk of Recurrence and Progression Based on the Initial EORTC Risk Groups and CUETO Nomograms for Respective NMIBC Risk Score Groups Risk Group Recurrence 1y Progression 5y 1y 5y EORTC CUETO EORTC CUETO EORTC CUETO EORTC CUETO Lowest 15 (10-19) 8 (6-11) 31 (24-37) 13 (10-15) 0.2 (0-0.7) 1 (0-2) 0.8 (0-1.7) 4 (2-6) Second 24 (21-26) 12 (8-16) 46 (42-49) 22 (17-28) 1 (0.4-1.6) 3 (1-5) 6 (5-8) 12 (8-16) Third 38 (35-41) 25 (20-31) 62 (58-65) 40 (33-46) 5 (4-7) 6 (3-8) 17 (14-20) 21 (16-27) Highest 61 (55-67) 42 (28-56) 78 (73-84) 53 (38-67) 17 (10-24) 14 (7-21) 45 (35-55) 34 (23-44) For CUETO, scores of 0-4, 5-6, 7-9, and 101 are used for quartiles scores for both recurrence and progression; for EORTC, recurrence scores for the quartiles correspond to 0, 1-4, 5-9, 10-17 points, respectively, while scores of 0, 2-6, 7-13, and 14-23 are used for progression. CUETO, Club Urologico Espanol de Tratamiento Oncologico; EORTC, European Organization for Research and Treatment of Cancer; NMIBC, non–muscle-invasive bladder cancer. As described, each nomogram was developed from pooled trial data with notable patient characteristics and specific nuances to the given treatment regimens; consideration of these factors must be given during use of each risk tool. All scoring models have been shown to overestimate recurrence and progression risk among patients treated according to contemporary standards.20-22 In addition, the historical variability of nomenclature and surveillance 46 • Vol. 22 No. 2 • 2020 • Reviews in Urology regimens inherently influences the estimated recurrence and progression rates. Therefore, it is not possible to use a single nomogram or scoring system that will be predictive for all contemporary patients with NMIBC. Indeed, Neoadjuvant Chemoablative Therapies for NMIBC each risk stratification system may be best applied only to patients whose tumor characteristics and treatment plans mirror the nomogram development cohort.23 Additionally, the American Urological Association (AUA) and the European Association of Urology (EAU) have produced evidencebased guidelines dividing NMIBC into three distinct risk categories. Comparison of evidence-based guideline recommendations from the AUA and EAU demonstrate good general agreement in how patients are categorized (Table 3). However, there are notable differences regarding how Ta high-grade (all are EAU high risk, primary Ta HG tumors #3 cm are AUA intermediate risk) and low-grade T1 (EAU high risk, AUA intermediate risk) are designa­ ted. Treatment recommendations are also well aligned aside from the AUA recommending 3 years of maintenance BCG for highrisk patients whereas the EUA suggests 1 to 3 years. During BCG shortages, it has been suggested that BCG be preferentially used for the initial induction treatment of high-risk disease. Recurrence and progression estimates at 6, 12, and 24 months for each risk category and treatment type have been developed for the AUA NMIBC risk guidelines (Table 4). Selecting an Adjuvant Therapy Types of Adjuvant Therapy Adjuvant treatment is any agent administered after complete TURBT aimed at reducing the risks of NMIBC recurrence and progression. Traditionally, only intravesical agents have been used Adjuvant treatment is any agent administered after complete TURBT aimed at reducing the risks of NMIBC recurrence and progression. Traditionally, only intravesical agents have been used in this setting, but emerging data on the use of systemic checkpoint inhibitor immunotherapies either as a monotherapy or combined with intravesical agents may radically change this treatment paradigm. TABLE 3 NMIBC Risk Stratification Groups, Criteria, and Initial Adjuvant Treatment Recommendations From AUA and EAU Guidelines Risk Category Low AUA EAU Treatment Recommendation Solitary LG Ta tumor, ,3 cm Solitary LG Ta tumor, ,3 cm PUNLMP PUNLMP Intermediate Recurrence within 1 year, LG Ta Solitary LG Ta, .3 cm LG Ta, multifocal HG Ta, #3 cm LG T1 High HG T1 Any recurrent, HG Ta HG Ta, .3 cm Any CIS Any BCG failure in HG Any variant histology Any LVI Any HG prostatic urethral involvement All tumors not defined as low or high risk Post-TURBT intravesical chemotherapy Post-TURBT intravesical chemotherapya 1 Induction 1 maintenance BCG for 1 year or Induction 1 maintenance chemotherapy for 1 yearc Any T1 Induction 1 maintenance BCG for 1-3 yearsb or Any HG tumor Radical cystectomy* Any CIS Multiple, recurrent, .3cm tumors T1HG with concurrent CIS* Variant histology* Lymphovascular invasion* *Special designation of “highest risk” and upfront radical cystectomy should be considered. aWith an EORTC recurrence score ,5; bEAU recommends 1-3 years, AUA recommends 3 years; coptimal schedule not known. AUA, American Urological Association; CIS, carcinoma in situ; EAU, European Association of Urology; HG, high grade (G2, all G3); LG, low grade (G1, some G2); LVI, lymphovascular invasion; NMIBC, non–muscle-invasive bladder cancer; PUNLMP, papillary urothelial neoplasm of low malignant potential, variant histology 5 micropapillary, plasmacytoid, sarcomatoid, etc. Vol. 22 No. 2 • 2020 • Reviews in Urology • 47 Neoadjuvant Chemoablative Therapies for NMIBC continued TABLE 4 Estimated Recurrence and Progression Rates for Each AUA NMIBC Risk Category at 6, 12, and 24 Months Based on Adjuvant Treatment Given Risk Category/Treatment Recurrence Rate (%) Progression Rate (%) 6 mo 12 mo 24 mo 6 mo 12 mo 24 mo Low risk / TURBT alone 15 20 25 0 1 1 Low risk / TURBT 1 perioperative chemo 5 10 15 0 1 1 Intermediate risk / TURBT 1 chemo 20 30 40 2 3 5 Intermediate risk / TURBT 1 BCG (induction and maintenance) 20 25 30 2 3 4 High risk / TURBT 1 BCG (induction and maintenance) 20 25 30 3 5 10 Adapted from Kamat AM.29 Rates for all intermediate- and high-risk patients are based on BCG naive. AUA, American Urological Association; BCG, bacillus Calmette-Guérin; NMIBC, non–muscle-invasive bladder cancer; TURBT, transurethral resection of bladder tumor. in this setting, but emerging data on the use of systemic checkpoint inhibitor immunotherapies either as a monotherapy or combined with intravesical agents may radically change this treatment paradigm. Current adjuvant intravesical treatments can be defined by the timing and sequence of their administration: (a) perioperatively, usually within 24h of TURBT, (b) induction, as an initial course for that particular agent, or (c) maintenance, subsequent courses in the setting of no evidence of disease after TURBT and induction treatment. Standard intravesical therapies can also be categorized as either chemotherapy or immunotherapy agents. The most used con­ temporary chemotherapy agents are mitomycin C, gemcitabine, epirubicin, and docetaxel. These are given individually or in combination depending on the indication. Historically, agents such as doxorubicin, valrubicin, cisplatin, and thiotepa, among others, were also frequently studied and used. The gold standard intravesical immunotherapy is BCG, an attenuated mycobacterium strain first described for use in bladder cancer in 1976. Interferon (IFN) has also been studied, but contemporary use is limited. There are several emerging NMIBC therapies being developed and studied in the treatmentnaive or treatment-unresponsive setting. Novel agents like oncolytic adenoviruses (CG0070), recombinant adenovirus interferon alpha2b with Syn3 (Instiladrin® [nadofaragene firadenovec], FKD Therapies Oy, Kuopio, Finland), modified herpes simplex virus (talimogene laherparepvec [TVEC]), and fusion proteins (Vicinium®, Sesen Bio, Inc., Cambridge, MA) are some examples. Additionally, as a result of KEYNOTE-057, the FDA recently approved the first systemic therapy, pembrolizumab, for the treatment of patients with BCGunresponsive CIS with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. Choosing an Adjuvant Treatment For patients with low-risk NMIBC, it is recommended that adjuvant therapy with a single instillation (SI) of perioperative chemotherapy be considered. It is critical that For patients with low-risk NMIBC, it is recommended that adjuvant therapy with a single instillation (SI) of perioperative chemotherapy be considered. It is critical that intravesical chemotherapy is not given in the setting of a bladder perforation because extravasation of chemotherapy into the peritoneum is a devastating complication. 48 • Vol. 22 No. 2 • 2020 • Reviews in Urology Neoadjuvant Chemoablative Therapies for NMIBC intravesical chemotherapy is not given in the setting of a bladder perforation because extravasation of chemotherapy into the peritoneum is a devastating complication. Therefore, a highlevel of suspicion during extensive resections and completion of a cystogram prior to chemotherapy instillation is essential. The recommendation for a single dose of chemotherapy post-TURBT is supported by meta-analyses that demonstrate an approximately 15% reduction of recurrence with instillation of mitomycin or epirubicin compared with TURBT alone in low-risk disease.24 An alternative option is perioperative gemcitabine. A randomized trial of peri-TURBT gemcitabine versus saline demonstrated a reduction in 4-year recurrence rate from 54% to 34% with few adverse effects among 215 patients with low-grade NMIBC.25 Patients with intermediate-risk NMIBC comprise a heterogeneous subgroup with few proven treatment options and represent one of the greatest unmet needs in the treatment of NMIBC. SI perioperative intravesical chemotherapy can be considered but has only demonstrated efficacy among intermediate-risk patients with an EORTC risk score <5.24 Additional adjuvant intravesical chemotherapy or immunotherapy may be given in intermediate-risk patients for up to 1 year based on data from numerous studies of commonly used agents when compared with TURBT alone.12 However, individual treatment agent choice remains somewhat controversial and may be based on risk profile, prior intravesical treatment exposure, and tolerability. The International Bladder Cancer Group (IBCG) suggests further stratification of intermediate-risk patients based on number and size of tumors, recurrence and frequency of recurrence within 1 year, and previous treatment. For those patients without any of IBCG risk factors, SI is recommended; for those with 3 to 4 factors, BCG is recommended, and for those with 1 to 2 risk factors, BCG or chemotherapy may be used based on consideration of previously received therapies. These recommendations coincide with the principle that most patients with intermediaterisk NMIBC are at significantly greater risk of recurrence rather than progression. There is no well accepted schedule for the use of intravesical chemotherapy. Comparative studies between BCG and chemotherapy agents have generally included both intermediate- and high-risk patients. A meta-analysis of individual patient–level data (n = 2820) demonstrated risk of recurrence was reduced by 32% when BCG was given compared with mitomycin C (MMC) but minimal difference in risk of progression.26 RCTs and other analyses of pooled data suggest an improvement in progression rates and time to progression when BCG is used, with the strongest signal seen among those who received maintenance therapy.27 Duration of maintenance therapy has been suggested to be up to 3 years in high-risk patients based on data from SWOG 8507 and EORTC 30962. It is notable that no adjuvant treatment has been found to change the natural history of disease and improve overall mortality.28 “Early” radical cystectomy should be a consideration among patients at the very highest risk of progression to MIBC who are fit and willing to undergo surgery. Of note, comparing data from various historical studies is difficult due to differences in nomenclature, surveillance techniques, and definitions of recurrence. Strict nomenclature and use of standard endpoints have been suggested by expert consensus groups for trial use moving forward.29 Additionally, for the purposes of this review, we have primarily considered the management of index NMIBC cases naive to intravesical treatment. Special management considerations outside the scope of this review must be made for patients where initial Main Points • Non–muscle-invasive bladder cancer is a diverse subclassification of urothelial bladder cancer with a wide variation in recurrence and progression rates. • Risk-adapted treatment is essential to balance adverse effects of treatment with adequate disease control and there are many nomograms and strategies to assist, each with specific limitations. • Standard treatment with intravesical chemotherapies and bacillus Calmette-Guérin is associated with good outcomes for most patients but novel agents and approaches will be necessary to continue to improve rates of durable cure and bladder preservation for those at highest risk of progression to muscle-invasive bladder cancer. Vol. 22 No. 2 • 2020 • Reviews in Urology • 49 Neoadjuvant Chemoablative Therapies for NMIBC continued adjuvant intravesical treatment, especially BCG, has failed. These management decisions should be based on what treatments they have been already been exposed to and the timing and aggressiveness of the recurrence. Rationale for Use of Neoadjuvant Treatments Upfront (neoadjuvant) chemo­ ablative treatments like chemohy­ perthermia (hyperthermic intra­ vesical chemotherapy (HIVEC™), mL of distilled water at 43±1 °C) in 24 patients with intermediate- or high-risk NMIBC delivered in the neoadjuvant setting with TURBT 2 weeks later.33 Of these, 15 patients (62.5%) had a complete response and 8 additional patients (33.3%) showed a partial response. The 4-year cumulative incidence of recurrence was 20.8% and the agent was well tolerated with 97% of patients completing all scheduled instillations. UGN-102 is a reverse thermal hydrogel that is formulated Upfront (neoadjuvant) chemoablative treatments like chemohyperthermia and reverse thermal gel formulated with MMC are increasingly being explored as alternatives to repeat office or ambulatory procedures in patients with established, recurrent low-grade tumors. Combat Medical Ltd., UK) and reverse thermal gel formulated with MMC (UGN-102, UroGen Pharma, Inc., Princeton, NJ) are increasingly being explored as alternatives to repeat office or ambulatory procedures in patients with established, recurrent lowgrade tumors. Chemoablation is a potentially attractive alternative to TURBT that may reduce treat­ ment time, cost, and morbidity. Alternatively, others have also advocated for office-based ful­ guration of small, recurrent lowgrade tumors when feasible and tolerable as part of a risk-adapted strategy of treatment.30,31 Active surveillance has also been suggested as a safe and cost-effective alternative for highly selected patients.32 HIVEC and UGN-102 Early Data HIVEC is neoadjuvant intravesical instillation of heated MMC delivered in a recirculated fashion by a proprietary system called the Bladder Recirculation System (BRS) from Combat Medical. Initial study of the system consisted of 8 courses (60 min dwell/recirculation time using 80 mg of MMC diluted in 50 with MMC (UroGen Pharma). It is currently being studied (NCT03558503) as a chemoablative therapy in lieu of TURBT or surgical tumor destruction in patients with low-grade bladder cancer that meet 1 to 2 of 3 criteria for AUA Intermediate Risk NMIBC: multifocal, lesion .3 cm, and recurrence within 12 months. Because patients with low-grade intermediate-risk NMIBC are at low risk of progression (~5% at 2 y) and high recurrence risk (~40% at 2 y), the proposed benefit of this agent is two-fold: drug delivery will be improved by greater surface contact time and the morbidity and cost associated with TURBT will be reduced. The active study is a multicenter, single-arm Phase IIb that is treating patients with UGN-102 weekly for 6 weeks with the primary endpoint being a complete response at 3 months. A complete response was defined as negative cystoscopy, negative cytology, and negative biopsy if possible visual evidence of disease is noted. Secondary endpoints include 12-month durability and safety. Updated interim analysis of 63 patients (38 men, 25 women; 50 • Vol. 22 No. 2 • 2020 • Reviews in Urology age range, 33-96) demonstrated a 3-month complete response (CR) rate of 65% (41/63). Of those with a CR, 97% (31/32) patient and 85% (17/20) remained free of disease at 6 and 9 months, respectively.34 Mild or moderate adverse events were common, such as dysuria (38%) and hematuria (16%). Conclusions NMIBC is a diverse subclassification of urothelial bladder cancer with a wide variation in recurrence and progression rates. Risk-adapted treatment is essential to balance adverse effects of treatment with adequate disease control and there are many nomograms and strategies to assist, each with specific limitations. Standard treatment with intravesical chemotherapies and BCG is associated with good outcomes for most patients but novel agents and approaches will be necessary to continue to improve rates of durable cure and bladder preservation for those at highest risk of progression to MIBC. References 1. 2. 3. 4. 5. 6. 7. 8. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34. Burger M, Catto JW, Dalbagni G, et al. 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Abstract LBA02-03. Vol. 22 No. 2 • 2020 • Reviews in Urology • 51