CME-CERTIFIED ARTICLE
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Sandip M. Prasad, MD, MPhil1,2,3; Joshua J. Meeks, MD, PhD4
1Genitourinary Oncology, Morristown Medical Center/Atlantic Health System, Morristown, New Jersey2Division of Urology, Rutgers New Jersey Medical School, Newark, New Jersey3Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania4Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
KEYWORDS:
Non-muscle invasive bladder neoplasms; carcinoma in situ; cystoscopy; BCG vaccine; cystectomy; immunotherapy
Abstract
Background: Non–muscle-invasive bladder cancer represents a substantial proportion of bladder cancers and is associated with clinically significant morbidity and mortality. Carcinoma in situ (CIS) is a stage of high-grade non–muscle-invasive bladder cancer with an increased risk of recurrence, progression, and death. Standard therapy for CIS is intravesical therapy with BCG, though additional radical cystectomy–sparing treatment approaches are needed for patients with BCG-unresponsive CIS.
Methods: Current guidelines from the American Urological Association, Society of Urologic Oncology, and European Association of Urology provide recommendations for the detection and management of CIS. Additional data and novel intravesical agents, however, have emerged in recent years, that offer additional effective, personalized, and minimally invasive options.
Results: The evaluation of CIS involves cystoscopy, urine-based testing, and biopsy of the bladder or transurethral resection of the bladder tumor. Mapping bladder biopsies and enhanced techniques such as photodynamic diagnosis with blue-light cystoscopy and narrow-band imaging can aid in accurate detection and diagnosis. Although traditional therapies for CIS such as BCG and radical cystectomy remain foundational to management, novel intravesical treatments offer additional options for personalized, noninvasive therapy as upfront treatment for BCG-unresponsive CIS. Agents for BCG-unresponsive CIS recently approved by the US Food and Drug Administration include pembrolizumab, nadofaragene firadenovec, and nogapendekin alfa inbakicept-pmln.
Conclusions: Given the aggressive nature of CIS, urologists should optimize disease detection using enhanced techniques and mapping strategies. Although their role is still being clarified in BCG-unresponsive CIS, promising novel agents use innovative approaches that demonstrate robust treatment response in initial clinical trials.
In 2025, there are predicted to be 170 470 new cancers of the urinary bladder, ureter, and kidneys or renal pelvis in the United States, ranking it as the fourth-most common cancer behind breast, prostate, and lung.1 Approximately 75% of patients with bladder cancer have non–muscle-invasive bladder cancer (NMIBC) at diagnosis, and many patients will develop recurrent disease, experience substantial emotional burdens, and experience poor healthrelated quality of life.2-5
Carcinoma in situ (CIS) is a type of high-grade NMIBC along the lining of the urothelium and carries an increased risk of recurrence (up to 78% in 5 years), progression (up to 50% in 5 years), and death.6-9 Ten percent of all NMIBC is pure CIS and can occur with papillary tumors that confer an increased risk of recurrence and progression to more advanced disease.10 Among patients with NMIBC, the risk of progression to muscle-invasive disease is approximately 10% to 20% over 5 years, with an estimated cancer-specific mortality of 6.5% at 2 years, 10% at 5 years, and 12% at 10 years, respectively.11,12 Carcinoma in situ at diagnosis is more favorable than CIS with progression because rates are more than doubled in the patients with secondary disease.13,14
New technologies have enabled increased detection accuracy of CIS, but routine diagnosis and follow-up of CIS remain challenging with white-light technology.10 The standard first-line therapy for CIS is BCG, which includes induction and maintenance for at least 12 months.10 Many patients, however, have an inadequate response to BCG, making alternative treatments necessary. New and emerging data regarding CIS recurrence and progression following BCG treatment need to be incorporated for best outcomes with the evaluation, diagnosis, and treatment of BCG-unresponsive CIS.
Patients with CIS present with symptoms of gross hematuria and irritative voiding symptoms, including dysuria, frequency, and urgency.15 The evaluation of CIS involves cystoscopy, urine-based testing, and biopsy of the bladder or transurethral resection of bladder tumor. Urine cytology has a high specificity in CIS and is graded according to the Paris System.16-19 The diagnosis of CIS can be challenging, however, because of limited bladder changes visualized by white light. Carcinoma in situ is a “flat” tumor without visual extension into the lumen of the bladder. It can often appear red and velvety but may also be nearly invisible and extremely difficult to identify visually. Carcinoma in situ is particularly challenging to identify in a bladder affected by inflammation, infection, or prior BCG therapy. Once detected, CIS is considered a “field” change that can present multifocally in different locations or even diffusely throughout the bladder. Mapping bladder biopsies, in which each bladder region is sampled, can help determine the number of quadrants affected by CIS. There are limited data to determine whether the amount of CIS correlates to differences in clinical outcomes.
Several enhanced techniques may be helpful in certain situations for the diagnosis and detection of CIS. Traditional white-light cystoscopy remains the overwhelming standard of care for CIS but has known limitations in detection, with almost 20% of CIS tumors undetected by white-light cystoscopy compared with enhanced cystoscopy.20 Photodynamic diagnosis with blue-light cystoscopy identifies enhanced metabolic activity by increased uptake of the photosensitizing agent between benign and malignant cells.21,22 Narrow-band imaging uses filters to pull out the blue (415-nm) and green (540- nm) wavelengths to visualize the capillaries of the mucosa. The increased vascularity of the CIS can often help differentiate between benign tissue and CIS.20 Because of the potential for positive cytology with negative white-light cystoscopy, European Association of Urology guidelines recommend random biopsies of normal-looking mucosa in patients with CIS.23 The guidelines recommend routine prostatic urethral biopsy and selective upper tract cytology because upper tract CIS is notoriously difficult to identify endoscopically or on crosssectional imaging.
Carcinoma in situ is classified as high-risk bladder cancer by the American Urological Association, the Society of Urologic Oncology, and the European Association of Urology.23,24 The standard treatment for CIS is intravesical immunotherapy with BCG for up to 3 years when sufficient BCG is available (6 induction doses and maintenance at 3, 6, 12, 18, 24, 30, and 36 months).25-27 Completing 36 months of treatment, however, can be challenging because of tolerability (18% of participants in the original SWOG Cancer Research Network study completed treatment) and because of limitations of BCG supply.28-30
Carcinoma in situ may have a delayed response to intravesical therapy. Response rates at 3-month and 6-month evaluations are 55% and 80% in response to induction and maintenance BCG.27 Because of the number of doses of BCG, BCG-unresponsive CIS is defined by the following parameters31 :
Persistent or recurrent CIS alone; recurrent, noninvasive papillary disease (Ta); or recurrent disease in which the tumor invades the subepithelial connective tissue (T1) within 12 months of completion of adequate BCG therapy
Recurrent high-grade Ta or T1 disease within 6 months of completion of adequate BCG therapy
T1 high-grade disease at the first evaluation following an induction BCG course
Receiving adequate BCG is therefore defined as receiving at least 5 of 6 induction doses plus 2 additional doses (2 of 3 maintenance doses or 2 of 6 repeat induction doses).31 The role of full or partial BCG has not been evaluated with these definitions, and the term “BCG experienced” has recently been used to describe patients who have received fewer than 7 doses.
Late relapse for CIS occurs after 12 months have passed since the last BCG dose and is managed by retreatment with BCG rechallenge.32,33 Recurrence rates for BCG-treated CIS can be 40% at initial 3-month surveillance cystoscopy; at 10 years, up to 30% of patients remain disease free.32,33
Because of the high rates of recurrence, lack of response, and the limited value of repeated BCG treatment as a result of decreasing response rates in this patient population, additional treatment approaches are needed to improve clinical outcomes.27 Most patients, after counseling regarding risks for recurrence and progression, opt for salvage intravesical therapy to preserve the bladder. After multiple recurrences, bladder preservation should be dissuaded in patients willing and able to consider cystectomy.
The American Urological Association and the European Association of Urology recommend radical cystectomy with urinary diversion as the standard of care for BCG-unresponsive NMIBC because of an increased risk of recurrence and progression.23,34,35 The cancer-specific survival rate is greater than 80% at 5 years when radical cystectomy is performed for NMIBC.34 Although radical cystectomy is the most oncologically effective treatment for patients who are fit for surgery, many patients defer cystectomy because of the surgical morbidity and its impact on quality of life.15,34 It is unclear how many “cycles” or lines of salvage therapy are safe after BCG because of the heterogeneous nature of BCG-unresponsive CIS.
The primary alternative to radical cystectomy is intravesical therapy. SWOG S0353 was a phase 2 trial of intravesical gemcitabine that demonstrated that 47% of patients with recurrent NMIBC were free of disease 3 months after treatment but with less than 20% durability at 12 months.36 In 1998, intravesical valrubicin was approved by the US Food and Drug Administration (FDA) for BCG-unresponsive CIS, with data showing that out of a cohort of 90 patients, approximately 21% of patients had a complete response (CR), with a median follow-up period of 30 months.37 Intravesical valrubicin is not used because of a limited 12-month response compared with contemporary regimens. Sequential intravesical chemotherapy following transurethral resection of bladder tumor has been used as an alternative to BCG to treat intermediate-risk and high-risk NMIBC as well as in the rescue setting for patients whose disease is BCG unresponsive. The chemotherapy drug combinations commonly used in this setting, such as gemcitabine-docetaxel, are off-label for bladder cancer; however, they have shown promising results as well-tolerated and effective therapies, with recurrence-free survival rates of approximately 80% and 56% at a weighted mean of 12 months and 24 months in BCG-unresponsive cohorts, respectively.38
In 2018, the FDA recognized the lack of treatment options for patients with BCG-unresponsive NMIBC by providing a guidance document for the development of drugs and biologics to treat the disease. Since then, 3 new immunotherapies have been approved: pembrolizumab, nadofaragene firadenovec, and nogapendekin alfa inbakicept-pmln (Table 1).39-44 In KEYNOTE-057, adults with histologically confirmed BCG-unresponsive CIS with or without papillary tumors who were ineligible for or declined radical cystectomy received pembrolizumab every 3 weeks for up to 24 months, with a median follow-up period of 36.4 months, until disease persistence, recurrence, or progression or until they experienced intolerable adverse effects.40 At 3 months, 39 (41%) of 96 patients had a CR.40 At 12 months, 40% of 3-month responders were without recurrence.
Nadofaragene firadenovec is an intravesically administered, replication-deficient recombinant adenovirus that delivers human interferon α-2b complementary DNA into the bladder epithelium. In an open-label phase 3 trial, patients with BCG-unresponsive NMIBC received nadofaragene firadenovec, and 55 of 103 patients (53.4%) achieved CR within 3 months of the first dose.42
Nogapendekin α inbakicept-pmln is an immune cell–activating interleukin-15 superagonist that may act synergistically with BCG to elicit durable CR in patients with BCG-unresponsive NMIBC.45 In the phase 2/3 single-arm QUILT-3.032 trial, patients with BCG-unresponsive CIS who received intravesical nogapendekin α inbakicept-pmln plus BCG (82 patients) achieved a 71% CR rate, with a median duration of 26.6 months.45
The rapidly evolving landscape of NMIBC treatment offers new and emerging therapies that may reshape disease management by offering bladderpreserving options that prioritize quality of life.46 Although sequencing and selection of novel therapies remain unclear with current data, additional FDA-approved treatment options offer patients with BCG-unresponsive disease potential treatments to improve survival and reduce recurrence. Additional clinical trials and real-world evidence will be crucial in defining the role of these personalized, effective, and minimally invasive novel therapies in NMIBC.46
Many agents are in various stages of development and clinical trials for BCG-unresponsive NMIBC or CIS. Notable agents include the following:
Detalimogene voraplasmid (EG-70), which is a nonintegrating, nonviral gene therapy engineered for intravesical administration to elicit local antitumor immune responses in the bladder.47 In the phase 1 LEGEND trial, 16 of 22 patients (73%) had CR.47
TAR-200, which is an intravesical targeted releasing system designed to provide sustained delivery of gemcitabine in the bladder over 3 weeks, and/or cetrelimab, which is an immune checkpoint inhibitor.48 The phase 2b SunRISe-1 trial assessed the efficacy of these agents, noting topline results in May 2024: 67.9% CR with TAR-200 and cetrelimab, 83.5% CR with TAR-200 monotherapy, and 46.4% CR with cetrelimab monotherapy.48
TARA-002, which is a cell-based therapy that showed 63% CR rates at 3 months in patients with CIS. It is being studied in the phase 2 ADVANCED-2 clinical trial.49
Non–muscle-invasive bladder cancer—particularly CIS—is associated with clinically significant morbidity and mortality, necessitating improvement in diagnosis and management in clinical practice. Given the aggressive nature of CIS, urologists should optimize disease detection using enhanced techniques and mapping strategies. Although traditional therapies for CIS such as BCG and radical cystectomy remain foundational to management, novel intravesical treatments offer additional options for personalized, noninvasive therapy as upfront treatment for BCG-unresponsive CIS. Recently FDA-approved agents for BCG-unresponsive CIS include pembrolizumab, nadofaragene firadenovec, and nogapendekin α inbakicept-pmln. Their role is still being clarified in treating BCG-unresponsive CIS, but promising novel agents use innovative approaches that have demonstrated robust treatment response in initial clinical trials.
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Published: March 31, 2025.
Conflict of Interest Disclosures: Joshua J. Meeks, MD, PhD received consulting fees from Merck, Astra-Zeneca, Janssen, BMS, UroGen Pharma, Prokarium, Imvax, Pfizer, Seagen/Astellas, Ferring Pharmaceuticals, CG Oncology, Calibr, ImmunityBio, Protara therapeutics, and Photocure. Sandip M. Prasad, MD, DPhil, engaged in contracted research with Merck, UroGen, Astellas, and CG Oncology and participated on the Speakers’ Bureau of UroGen Pharma.
Funding/Support: This continuing medical education activity is supported by an educational grant from ImmunityBio.
Author Contributions: All authors had the final responsibility for the decision to submit for publication.
Data Availability Statement: All data sources used in this article are publicly available.
Acknowledgments: The authors would like to thank Austin Ulrich, PharmD, BCACP, of Dragonfly Editorial for medical writing assistance in preparing the manuscript.
Citation: Prasad SM, Meeks JJ. Contemporary diagnosis and treatment of BCG-unresponsive carcinoma in situ of the bladder. Rev Urol. 2025;24(1):e83-e90.
Corresponding author: Sandip M. Prasad, MD, MPhil, Morristown Medical Center/Atlantic Health System, 261 James St, Ste 2G, Morristown, NJ 07960 (sandip.prasad@atlantichealth.org)
