In 2020, approximately 81,000 cases of urothelial carcinoma of the bladder will be diagnosed in the United States, with nearly 18,000 associated deaths.1 Bladder cancer disproportionally affects men and is associated with well-defined environmental risk factors—tobacco use underlies approximately 50% of cases.2 Nonmuscle-invasive bladder cancer (NMIBC) is primarily managed by transurethral resection, risk-stratified use of intravesical chemotherapeutic or immunotherapeutic agents, and close surveillance.
Approximately 70% of bladder tumors are nonmuscle-invasive at diagnosis. These patients have a generally favorable prognosis, but tumors often recur and progress. Recurrence and progression are heavily stage- and grade-dependent and are important surrogate endpoints for patient counseling and clinical trials. For low-grade pTa tumors, estimated rates of recurrence and progression are 55% and 6%, respectively, compared with rates of 45% and 17% for high-grade pT1 tumors.3-5
Current guidelines on NMIBC offer risk-stratification tools that inform prognosis, use of intravesical therapy, and surveillance strategies.3,6,7 Bacillus Calmette-Guérin (BCG) is the cornerstone of intravesical therapy. Several available nomograms predict treatment response based on largely redundant clinicopathologic factors, including tumor focality, stage, grade, prior recurrences, and concomitant carcinoma in situ (CIS), with varying degrees of success.8-10 In this review article, we discuss current challenges in NMIBC, emerging diagnostic approaches, and advances in intravesical and systemic therapy.
DIAGNOSIS
Transurethral resection is both diagnostic and therapeutic for NMIBC. Thorough endoscopic resection is paramount to optimize treatment response and can achieve pT0 in upwards of 15% of patients with clinical stage T2 disease.11 A key indicator of oncologically sound transurethral resection of bladder tumor (TURBT) is complete endoscopic resection of all papillary tumor and appropriate sampling of the muscularis propria in high-risk tumors.12
Several recent advances in risk stratification, cystoscopic technique, pathologic tumor evaluation, and biomarker identification can potentially improve diagnostic yield and prevent or delay NMIBC recurrence and progression.
Tumor Visualization and Resection
For patients with high-grade (HG) T1 tumors, rates of residual disease and pathologic upstaging are approximately 50% and 10%, respectively, even when detrusor muscle is available for evaluation.13 Current consensus guidelines call for repeat transurethral resection (reTUR) of all HG T1 lesions.3,6 In a retrospective multicenter study, restaging of T1 lesions was associated with a survival benefit only when the index specimen lacked detrusor muscle.14 An ongoing randomized trial (NCT03266900) compares reTUR versus no reTUR among patients with complete endoscopic resection of HG T1 tumors. Experts have debated the utility of restaging reTUR in HG Ta lesions, with some recommending a risk-adapted approach.
Conventional TURBT produces unoriented, piecemeal pathologic specimens, making margin evaluation impossible. In the past five years, en bloc resection of endophytic bladder tumors has gained traction and is referenced in current European Association of Urology (EAU) guidelines.6 In prospective studies, bipolar/monopolar resection and YAG laser techniques achieved high percentages of detrusor muscle sampling and were associated with oncologic outcomes resembling those of conventional piecemeal TURBT.15,16 Currently, several clinical trials are evaluating en bloc resection techniques and conventional TURBT.
Conventionally, cystoscopy and TURBT are performed with white light, which has been found to miss approximately 25% of TaT1 papillary tumors and 27% of CIS lesions.17 Several recent and emerging advances in cystoscopy and tumor visualization during TURBT can potentially improve lesion detection. We discuss four of these technologies here.
Photodynamic diagnosis uses blue light (375-440 nm excitation) to fluorescently visualize a photoactive porphyrin, either 5-aminolevulinic acid (ALA) or hexaminolevulinate hydrochloride (HAL), which is instilled intravesically before TURBT. In a meta-analysis of 14 randomized clinical trials, blue light cystoscopy reduced rates of recurrence but did not affect progression or mortality compared with white light cystoscopy.18 Blue light cystoscopy has been found to be safe and effective when used with flexible cystoscopy in outpatient settings.19 While photoactive porphyrins preferentially concentrate in hyper vascularized tumors, false positives can result from inflammation, intravesical therapy, and recent instrumentation, reducing specificity for lesion detection compared with white light cystoscopy.20
Narrowband imaging (NBI) exploits differences in vascularity between tumors and normal bladder mucosa by excluding the red light spectrum. This technique is part of many current cystoscopy systems and is suitable for routine use in the upper tract because it requires no instillation of an agent. In a recent systematic review, NBI detected lesions in 10% more patients with NMIBC and significantly reduced recurrence compared with white light cystoscopy.21 To date, no trials have directly compared NBI with blue light cystoscopy.
Another recent development in endoscopic tumor evaluation is the Storz professional image enhancement system (SPIES, also known as IMAGE1 S), which produces digitally contrasted images by filtering white light into four finite spectra. This system has been studied in cystoscopic discrimination of bladder lesions but not in prospective randomized studies.22 A fourth novel technology uses confocal laser endomicroscopy to characterize endophytic bladder lesions. This probe-based technique evaluates cellular architecture in real-time and has exhibited 76% and 70% concordance with low- and high-grade lesions, respectively.23 Both these advances require further prospective validation.
Pathologic Evaluation
When possible, a genitourinary pathologist should review histologic specimens, especially if there is suspicion for variant differentiation, which is seen in nearly one-third of bladder cancers.3 Experts have proposed further stratifying specimens based on the percent of variant differentiation, or by distinguishing variant histologies (i.e. micropapillary, nested, plasmacytoid, sarcomatoid) from divergent urothelial squamous or glandular differentiation. Some histologic variants are associated with worse survival in patients with muscle-invasive bladder cancer, but their effect on response to neoadjuvant therapy remains uncertain.24-26
The role of variant histology in recurrence, progression, and response to intravesical therapy in NMIBC is even less clear. Micropapillary NMIBC has been most studied. A single-center observational study of 72 patients with clinical stage T1 micropapillary disease managed with intravesical BCG identified a 45% rate of stage progression and a 35% rate of lymph node metastasis.27 Five-year disease-free survival (DFS) was relatively favorable when patients received early cystectomy but only 24% when cystectomy was postponed until progression to muscle-invasive disease. Results from other single-center studies also support early cystectomy for micropapillary NMIBC.28,29
A current challenge in pathologic risk stratification is that much of the available prognostic data relate to the 1973 World Health Organization (WHO) classification system, which is based on the European Organisation for Research and Treatment of Cancer (EORTC) studies conducted approximately 20 years ago. There is a relative lack of prognostic data for the more recent, dichotomized 2004/2016 WHO classification system, which recognizes only low-grade versus high-grade tumors. While the EAU Guidelines continue to recognize the 1973 classification, current American Urological Association (AUA) guidelines are based exclusively on the 2004/2016 system.3 Efforts are underway to determine whether a hybrid system (e.g. high-grade/low-grade plus G1,2,3 would provide all the variables needed to optimize patient care.
Urine-Based Biomarkers
Molecular urine-based biomarkers have been used for screening, detection, and surveillance but are not proven replacements for cystoscopic evaluation and urine cytology. The most recent FDA approval for NMIBC was of UroVysion in 2005 (Table 1). In a post hoc study comparing urine cytology with BTA stat®, BladderChek®, and ImmunoCyt in patients with known bladder cancer, cytology was most specific (86%), while BladderChek® was most sensitive for HG tumors (92%).30
Several other biomarkers are under investigation or available for use in the clinic. The Cxbladder test assays voided specimens for mRNA expression of genes involved in ubiquitous cellular processes. This test is available and covered by Medicare for the adjudication of atypical urine cytology31 and surveillance.32 ADXBLADDER is an enzyme immunoassay that detects MCM5 protein, a proliferation marker. In a multicenter prospective validation study of over 1,400 patients, ADXBLADDER exhibited a 735% sensitivity and 99% negative predictive value (NPV) in high grade tumors.33 Urine-based genomic assays have also showed promise, including Bladder EpiCheck® (DNA methylation biomarker; 92% sensitivity and 99% NPV for high grade tumors)34 and a new assay evaluating the mutation/methylation signature of 6 genes from a voided specimen that has shown promising discrimination for screening patients with hematuria (96% sensitivity and 99% negative predictive value).35
Table 1. FDA-approved urine-based tests for NMIBC.
Abbreviations: FISH, fluorescent in situ hybridization; IHC, immunohistochemistry; EIA, enzyme immunoassay; BCG, Bacillus Calmette-Guérin,
TREATMENT
TURBT is central to NMIBC diagnosis and treatment. Current guidelines from the AUA/Society of Urologic Oncology (SUO) and the EAU use risk stratification to guide additional treatment.3,6 Two differences between the guidelines merit mention: HG Ta lesions can be intermediate-risk according to the AUA/SUO guidelines but are exclusively classified as high-risk by the EAU guidelines, and variant histology is a high-risk feature in the AUA/SUO guidelines but signifies the highest-risk category in the EAU guidelines. Most experts, the authors included, use the EAU risk stratification.
When administered immediately after TURBT, single-instillation adjuvant intravesical chemotherapy treats residual tumor and helps prevent dispersed tumor cells from implanting. This practice is recommended by the AUA guidelines for low- and intermediate-risk patients and by the EAU guidelines for low-risk patients and those with historically low recurrence rates. Mitomycin C, epirubicin, and gemcitabine reduce recurrence but not progression compared with TURBT alone.43-45 There are no head-to-head trials of these agents and only low-quality evidence to support the superiority of one over another. In the randomized, double-blind, placebo-controlled SWOG S0337 trial of patients with presumed low-grade NMIBC, intravesical gemcitabine reduced recurrence but not progression or death and was well tolerated, with no grade 4 or 5 events.46 Mitomycin C has fallen out of favor because of cost and availability issues.
Apaziquone is a synthetic pro-drug that generates cytotoxic alkylating agents when activated by DT diaphorase, which is expressed by bladder tumor cells. In 2 large double-blind, placebo-controlled trials, single-instillation apaziquone after TURBT was well tolerated and reduced recurrence compared with TURBT alone.47 Unfortunately, this agent was rejected by the FDA at the last evaluation.
Intravesical BCG
Patients with high-risk NMIBC have a 60% to 70% risk for recurrence and 10% to 45% risk for progression at 5 years.3 Immunotherapy with intravesical BCG is the standard adjuvant treatment for intermediate- and high-risk NMIBC. Six weeks of BCG induction significantly decreases risk for recurrence and progression compared with no adjuvant intravesical therapy. BCG also is more effective for preventing recurrence than chemotherapy (doxorubicin, epirubicin, and mitomycin C), particularly when used as maintenance therapy in high-risk patients.48 In the SWOG 8507 trial, high-risk patients who received maintenance BCG for 3 years had a 60% recurrence-free survival (RFS) at 5 years, compared with 41% with induction BCG only. The EORTC 30692 trial reported similar results for high-risk patients, but for intermediate-risk patients, 3 years of maintenance BCG was not superior to 1 year.49 For this reason, many experts recommend 1 year of maintenance BCG for intermediate-risk (low grade) patients.3
BCG has largely replaced chemotherapy as an intravesical adjuvant outside the peri-operative setting. However, international BCG shortages have significant implications for therapeutic indication and dosing. A recent consensus statement recommends prioritizing BCG for high-risk, BCG-naïve patients with high-grade T1 disease or CIS.50 If full-strength dosing is not possible, a reduced one-half to one-third dose is an option for induction in these and other high-risk patients. For recurrent or multifocal low-grade Ta disease, induction with mitomycin, gemcitabine, epirubicin, or docetaxel is recommended in lieu of BCG. Maintenance BCG should be limited to 1 year and should not be used if doing so jeopardizes the availability of BCG for induction. Finally, if BCG is unavailable, gemcitabine, epirubicin, docetaxel, valrubicin, mitomycin, or sequential gemcitabine/docetaxel or gemcitabine/mitomycin are options for induction and potentially for maintenance.
In the face of BCG shortages and in attempts to reduce side effects, reduced dosing schedules have been investigated. In the randomized NIMBUS trial, patients with HG NMIBC received either conventional BCG induction and maintenance or a reduced-frequency schedule consisting of induction instillations at weeks 1, 2, and 6, and maintenance instillation at weeks 1 and 3 for 1 year.51 The trial was stopped prematurely after reduced-frequency BCG met predefined criteria for inferiority. Thus, the current gold standard remains the SWOG “6+3” schedule.52
Combining other intravesical therapies with BCG has varying results. In a Cochrane meta-analysis of four randomized trials, adding interferon-alpha to BCG did not improve recurrence or progression compared with BCG alone.53 In other randomized studies, adding mitomycin C to BCG reduced recurrence but showed variable effects on safety and progression compared with BCG alone.54,55 A currently recruiting study (NCT02948543) compares mitomycin C plus BCG with BCG alone in high-risk NMIBC. Table 2 lists this and other ongoing Phase III and IV trials.
Systemic immuno-oncologic therapy with immune checkpoint inhibitors has demonstrated efficacy in metastatic and muscle-invasive bladder cancer and is being investigated in earlier disease settings in combination with intravesical BCG. Ongoing trials are evaluating BCG plus agents such as atezolizumab, nivolumab, durvalumab, pembrolizumab, and sasanlimab.56-58
Chemohyperthermia (heated intravesical chemotherapy) has also been extensively investigated as a BCG alternative. In a randomized trial, induction and maintenance therapy with heated intravesical mitomycin C significantly improved 24-month RFS compared with BCG, without increasing rates of adverse events.59 In another randomized trial, radiofrequency-induced chemohyperthermia was well tolerated and showed similar DFS compared with BCG when used in patients whose NMIBC recurred after BCG maintenance.60 These findings require prospective validation, but they present a potentially viable option to in lieu of a second BCG induction during BCG shortages.
BCG-Unresponsive NMIBC
The FDA and the International Bladder Cancer Group have defined BCG-unresponsive bladder cancer based on criteria that largely overlap with those for BCG-relapsed and refractory disease.61,62 Characterizing subgroups of high-risk patients for whom additional BCG is not an option helps consistently identify them for escalated therapy or clinical trials. The FDA has approved this definition for accrual to single-arm registrational trials that use historical rates of BCG recurrence and progression as a reference.
Salvage intravesical options for BCG-unresponsive NMIBC have historically exhibited limited effects on progression and survival. Valrubicin was the first FDA-approved therapy for BCG-refractory CIS but is not used due to a dismal 18% complete response (CR) rate and a 2-year RFS of 4%.63 Several emerging therapeutics and combination intravesical regimens have more promising efficacy.
Nadofaragene firadenovec is a non-replicating adenovirus harboring IFN-2α. In a single-arm phase III prospective trial, it was generally well tolerated and achieved 12-month RFS rates of 24% in CIS and 44% in HG papillary tumors.64,65 Results from this registration trial are being considered for FDA approval in BCG-unresponsive disease. An additional replication-deficient recombinant adenovirus combined with the surfactant Syn3 (rAD-IFN/Syn) showed a 12-month DFS of 35% and was well tolerated in a Phase II randomized dose-escalation study of patients with HG BCG-refractory or relapsed NMIBC.66
Vicineum is a recombinant fusion protein consisting of an anti-EpCAM antibody linked to a variant of Pseudomonas exotoxin A. An ongoing single-arm Phase III trial (NCT02449239) is evaluating intense regimens for induction and maintenance. Initial results have included a 42% rate of CR at 3 months.67
A multicenter retrospective study of combination gemcitabine plus docetaxel for the treatment of BCG-unresponsive patients reported a 2-year RFS of 46%, with 7% of patients progressing to muscle-invasive disease.68 These results are promising but are limited by inconsistent definitions of BCG failure and variable use of maintenance regimens.
The replication-competent oncolytic adenovirus CG0070 targets bladder cancer cells through their defective retinoblastoma (RB) pathway. In a Phase II study of CG0070 in BCG-unresponsive patients, 47% achieved a CR at 6 months, and toxicity was acceptable.69 Phase II and III studies of CG0070 alone and in combination with pembrolizumab are ongoing.
Intravesical agents in earlier-phase development include ALT-803, PANVAC, linrodostat mesylate, and ABI-009. ALT-803, a synthetic interleukin-15 superagonist, has shown preclinical anti-tumor activity in solid malignancies and positive results in case reports of patients with BCG-unresponsive disease.70 A Phase II trial (NCT03022825) of this agent is recruiting, and preliminary results suggest promising rates of CR in CIS and papillary disease.71 PANVAC is a pox viral vector-based vaccine that induces immunogenic responses against bladder cancer antigens. A phase 2 study (NCT02015104) of PANVAC in patients with BCG failure has completed accrual. The IDO-1 inhibitor linrodostat mesylate is being evaluated in combination with nivolumab in another Phase II study that is currently recruiting (NCT03519256).72 ABI-009, which consists of rapamycin encapsulated in an albumin-bound nanoparticle, was well tolerated in a Phase I-II trial of BCG-refractory patients.73
Systemic Therapy for BCG-Unresponsive NMIBC
Pembrolizumab is the only FDA-approved systemic therapy for BCG-unresponsive NMIBC. In the single-arm Phase II KEYNOTE-057 study of pembrolizumab in BCG-unresponsive disease, 41% of CIS patients had CRs at 3 months.74 Median response duration was 16.2 months, and 46% of responders maintained a CR at 12 months.
Two novel fibroblast growth factor receptor (FGFRs) inhibitors merit mention. Erdafitinib (pan FGFR 1-4 inhibitor) has shown efficacy in advanced disease with FGFR genetic alterations and is FDA-approved for locally advanced and metastatic bladder cancer. A phase 2 study (NCT04172675) is evaluating erdafitinib in patients with FGFR mutations or fusions whose NMIBC recurred after BCG.75 Enfortumab vedotin also is FDA-approved for the third-line treatment of disseminated bladder cancer with FGFR alterations, and NMIBC trials are being planned.
The Role of Early Cystectomy in BCG-Unresponsive NMIBC
Early cystectomy remains the primary guideline-recommended therapy for BCG-unresponsive NMIBC.3,6 In the pre-neoadjuvant era, patients treated with intravesical BCG who developed muscle-invasive disease had worse outcomes than those with de novo disease when managed with radical cystectomy.76,77 Patients should be offered initial radical cystectomy if they have high-risk features (i.e. HG T1 disease with additional risk factors, such as concomitant CIS, lymphovascular invasion, prostatic urethral involvement, and variant histology) and do not wish to receive alternative intravesical therapies. If these patients are not candidates for cystectomy, they should be encouraged to enroll in a suitable clinical trial.
Table 2. Active Phase 3-4 Therapeutic Trials for NMIBC as of September 16, 2020.
Emerging Biomarkers
Predictive and prognostic tissue-based biomarkers have been well characterized in muscle-invasive bladder cancer but less so in NMIBC. Three molecular subtype categories (Class I-III) have been proposed based on RNA sequencing, which reflect distinct molecular phenotypes, histopathologic features, and risk for progression, but they do not accurately predict BCG response.78
Recently, next-generation sequencing was used to characterize the entire transcriptome of more than 100 treatment-naive NMIBC tumors, most of which were found to harbor actionable mutations.79 In the BCG-unresponsive setting, researchers identified a high prevalence of DNA damage repair mutations in high-risk, highly mutated tumors and frequent mutations in ARID1A, a gene involved in chromatin remodeling. This study also confirmed prior reports of near-ubiquitous variants in the telomerase reverse transcriptase (TERT) gene, which may represent a biomarker for bladder cancer detection.
Researchers also have developed a tissue-based microarray expression signature that quantifies expression of 12 genes that independently predict bladder cancer progression.80 Epigenetic modification through DNA methylation also has been proposed for subtyping. A recent genome-wide DNA methylation study of baseline tumor specimens from BCG responders and non-responders identified unique methylation signatures of genes involved in cellular integrity.81 These molecular and genetic techniques are promising, but they are limited by cost and access to expertise in the preclinical setting. Although prospective studies are needed to incorporate biomarker assays into risk-stratification systems, a more refined expression panel already has been used to increase the accuracy of EAU risk-stratification categories and identify patients at high risk for progression.82
SUMMARY
Novel intravesical therapies for patients who fail BCG have historically been limited by modest recurrence- and progression-free survival benefits. Recent FDA support for single-arm registration studies in BCG unresponsive patients has led to several emerging salvage intravesical treatment options with promising results in Phase III studies. Furthermore, molecular characterization of NMIBC as well as urine- and tissue-based biomarkers with predictive and prognostic capacities afford unique opportunities for bladder preservation in high-risk patients.
Written by: Patrick Hensley, MD and Ashish M. Kamat, MD, MBBS
Patrick Hensley, MD
Urological Oncology Fellow at The University of Texas MD Anderson Cancer Center
Dr. Hensley was awarded the AUA South Central Section Research Scholar Award for 2020-2021
for a one-year research study on predicting bladder cancer response to chemotherapy at the University of Texas MD Anderson Cancer Center under the mentorship of Ashish Kamat, MD and Charles Guo, MDy and
Ashish M. Kamat, Professor of Urology and Cancer Research and Wayne B. Duddleston, Professor of Cancer Research at MD Anderson Cancer Center in Houston, Texas. Dr. Kamat serves as President of International Bladder Cancer Group, (IBCG), and Co-President of the International Bladder Cancer Network.
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