BLADDER cancer is classified as either non-muscle invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC) based on the American Joint Committee on Cancer (AJCC) TNM staging.
At diagnosis, 75% of cases are NMIBC, which is further stratified into risk classifications according to tumour characteristics and response to BCG therapy. The primary treatment for intermediate and high-risk NMIBC includes transurethral resection of the bladder tumour (TURBT) followed by intravesical therapy with chemotherapy agents such as mitomycin C, gemcitabine, epirubicin, or docetaxel. The gold standard adjuvant therapy remains intravesical BCG, an attenuated mycobacterium strain. Despite initial responses, more than half of NMIBC patients experience recurrence or progression within two years, with a significant proportion becoming BCG-unresponsive. Factors contributing to BCG-unresponsive disease include tumour biology, immune response failure, or incomplete BCG therapy adherence.
The US Food and Drug Administration (FDA) defines BCG-unresponsive disease based on recurrence timelines following adequate BCG treatment, which includes at least five of six induction doses and two maintenance doses. The most commonly used BCG regimen involves a six-week induction phase, followed by maintenance therapy at scheduled intervals. However, adherence remains suboptimal, with a study of 5,803 high-risk NMIBC patients showing that only 41.5% received both adequate induction and maintenance BCG. Patients who do not respond to BCG have limited options, with radical cystectomy (RC) being the standard of care due to its high cancer-specific survival rate exceeding 80%. However, many patients decline RC due to its morbidity, impact on quality of life, or medical ineligibility. For these individuals, alternative treatments such as intravesical chemotherapy, immunotherapy (e.g., pembrolizumab), and gene therapy (e.g., nadofaragene firadenovec) offer bladder-sparing options.
Recent FDA approvals for BCG-unresponsive NMIBC include pembrolizumab, Nogapendekin Alfa-Inbakicep, and nadofaragene firadenovec. However, challenges remain regarding treatment sequencing, long-term efficacy, and cost-effectiveness. Future research should focus on optimising therapy combinations, evaluating patient-tailored approaches, and ensuring access to emerging treatments. As clinical trials progress, multidisciplinary strategies will be essential to balancing survival outcomes with quality-of-life considerations for patients with BCG-unresponsive NMIBC.
Katie Wright, EMJ
Reference
Lange A et al. Therapeutic advances in bladder preservation for BCG-unresponsive non-muscle invasive bladder cancer. Cancers (Basel). 2025;17(4):636.
