What Are Non-Muscle Invasive Bladder Cancer and its Treatment Options?

Dr. Patrick J. Hensley, assistant professor of Urology at the University of Kentucky and physician at Markey Cancer Center, explained in an interview with CURE that non-muscle invasive bladder cancer affects the bladder lining and hasn’t reached the muscle.

Treatment depends on tumor stage, grade and prior therapies. High-risk or treatment-resistant cases may require bladder removal, while lower-risk or first-time tumors often use bladder-preserving approaches, including monitoring or medications delivered directly into the bladder, such as BCG, chemotherapy or newer FDA-approved treatments like Adstiladrin (nadofaragene firadenovec).

Eligibility for clinical trials and novel therapies depends on bladder function, prior treatments and disease type. Research is focused on sequencing treatments, predicting responses, combining systemic and bladder-targeted therapies and reducing long-term bladder toxicity. Expanding access to effective treatments remains a priority to preserve bladders and improve outcomes for more patients.

What patients should know about this disease type?

To kick things off, we'll set the stage on what defines non-muscle invasive bladder cancer and how we triage patient counseling and treatment options accordingly. Generally speaking, our recommended treatments are based on the patient's tumor stage, grade and history of previous treatments.

Certain bladder cancer states are commonly treated with bladder removal, called radical cystectomy, due to a high risk of progression to metastatic disease or spread outside the bladder. Patients treated with radical cystectomy are typically those with higher-risk disease, including very high-risk non-muscle invasive bladder cancer and treatment-refractory states such as BCG-unresponsive non-muscle invasive bladder cancer. This also includes a spectrum of invasive disease called muscle-invasive bladder cancer, which is stage 2 or higher and is commonly treated with radical cystectomy.

From a bladder-preserving standpoint, we commonly treat patients — especially those who are treatment-naive or experiencing their first tumor occurrence — using bladder-preserving approaches. These include close cystoscopic surveillance or treatments like intravesical installations of medications and chemotherapy agents to prevent recurrence and progression to higher-risk disease. These treatments are instilled into the bladder through a catheter and remain for a predefined dwell time.

Regarding medications for non-muscle invasive bladder cancer, we use several classes. Immunotherapy, like classic BCG, is an attenuated mycobacterium that stimulates the body’s immune system to attack cancer cells. Chemotherapy agents, either as single agents or combinations, have cytotoxic effects that directly kill cancer cells. Novel treatments have also been FDA approved, with others in development. For example, Adstiladrin is a non-replicating adenoviral vector that elicits an anti-tumor immune response and is approved for BCG-unresponsive non-muscle invasive disease. This is where many of these novel drugs are coming into play.

How do you guide patients on weighing the benefits and risks of different post-BCG treatment strategies?

I think you start by helping patients identify their treatment goals and then tailor options to those goals. Each novel bladder-preserving treatment comes with different expected side effects, efficacy profiles from clinical trials and dosing strategies.

For instance, Adstiladrin is an intravesical adenoviral vector dosed every three months, which patients often find favorable and is generally well tolerated. By contrast, a novel drug delivery system like an intravesical immunostimulant combined with BCG — such as oportuzumab monatox — is given in six weekly induction courses with ongoing maintenance therapy. Each medication has unique side effects, and dosing schedules must be considered for patients often heavily pretreated with BCG or dual-agent chemotherapy.

What factors influence whether a patient might be eligible for clinical trials or novel treatments?

Eligibility often depends on the state of the bladder before treatment. Repeated resections, biopsies and intravesical drug installations can contribute to long-term bladder deterioration. A patient’s baseline bladder function, ability to empty fully, and any urinary symptoms or bladder-related pain can influence eligibility.

In the clinical trial setting, BCG-unresponsive non-muscle invasive bladder cancer is narrowly defined. Only a fraction of treatment-refractory patients meet the criteria. The FDA specifically recognizes BCG-unresponsive carcinoma in situ (CIS) for trial registration because CIS is a flat, spreading tumor often not eradicated by biopsy or resection alone, serving as a marker lesion to evaluate drug efficacy. In the real world, many patients need bladder-preserving medications but do not meet this narrow definition.

What are some of the most promising areas of research for these patients?

One major area is treatment sequencing: determining the next drug or line of therapy for treatment-refractory patients. This is likely tumor-biology driven. We’re exploring biomarkers in urine or through molecular studies of tumors to predict exceptional responders to immunotherapy, adenoviral vector therapy, or chemotherapy.

We’re also beginning to incorporate systemic therapies for non-muscle invasive bladder cancer. Identifying which patients might benefit from systemic therapy alone or in combination with intravesical therapy is a key area of interest.

Another critical focus is understanding acute and long-term bladder toxicity. Repeated biopsies, resections and intravesical treatments for bladder preservation can impact bladder function. Finding ways to objectively define this deterioration and toxicity will help us counsel patients on the feasibility and appropriateness of long-term bladder preservation in this recurrent, morbid disease.

How do you envision the standard of care evolving over the next few years?

Patient access is a major concern. The FDA label for many of these drugs is narrow, so only a small fraction of patients are eligible for treatment. Improving access to patients who don’t meet strict criteria is a critical discussion point.

Many treatment-refractory patients do not meet the definition for BCG-unresponsive CIS disease, whether due to timing with prior BCG or lack of access because of BCG shortages. We need to consider how to broaden access to patients with other disease states, including BCG-unresponsive papillary-only disease or the larger “BCG-exposed” population.

NCCN guideline adoption for papillary-only disease has helped with insurance approval, but this use is still largely off-label. Novel intravesical treatments are expensive, so the medical community must thoughtfully consider how to expand access across treatment-refractory disease to preserve more bladders and provide more patients with these therapies.

Transcript has been edited for clarity and conciseness.

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