Bladder cancer starts in the urothelial cells lining the inside of the bladder, the organ responsible for storing urine. The approach to treatment depends heavily on the cancer’s stage, which describes how far the tumor has spread through the bladder wall. Clinicians categorize the disease into non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), with the latter representing a more aggressive form. Treatment is moving beyond traditional methods to embrace systemic therapies that offer more personalized and effective options for patients.
Managing Non-Muscle Invasive Bladder Cancer
Most bladder cancers are diagnosed at an early stage, confined to the lining and not having invaded the muscle layer. The initial treatment for this stage involves a surgical procedure called Transurethral Resection of Bladder Tumor (TURBT), where the tumor is shaved off the bladder wall using an instrument passed through the urethra. This procedure serves both to remove the visible tumor and to provide tissue for accurate staging.
Following the TURBT, patients often receive intravesical therapy, where a liquid medication is instilled directly into the bladder to reduce the risk of recurrence and progression. The standard therapy for high-risk NMIBC has long been Bacillus Calmette-Guérin (BCG), an immunotherapy that triggers a strong immune response within the bladder to target cancer cells. However, persistent global shortages of BCG have driven the development and adoption of alternative treatments and modified protocols.
Due to BCG supply issues, clinicians prioritize its use for patients with the highest-risk disease, sometimes administering reduced or “split” doses. Alternative intravesical agents, such as the chemotherapy drug Mitomycin C, or a sequential combination of Gemcitabine and Docetaxel, have become more common, with the combination therapy showing comparable efficacy to BCG in some high-risk settings. For patients whose high-risk NMIBC is unresponsive to BCG, new options are emerging, including the immune checkpoint inhibitor Pembrolizumab, which is administered intravenously, or the recently approved gene therapy Nadofaragene firadenovec, which is delivered directly into the bladder.
Treatment Strategies for Muscle-Invasive Disease
When cancer has grown into the muscle layer (MIBC), a more intensive treatment approach is required. The traditional and most common curative strategy remains radical cystectomy, which is the surgical removal of the entire bladder, nearby lymph nodes, and potentially surrounding organs. Following the cystectomy, a urinary diversion procedure is performed to create a new way for the body to store and eliminate urine.
For patients who are fit enough, a platinum-based chemotherapy regimen is administered before the surgery, a practice known as neoadjuvant chemotherapy. This systemic treatment, often using agents like Cisplatin and Gemcitabine, is given to shrink the tumor and treat any microscopic cancer cells that may have already spread outside the bladder, which can improve survival rates by 5% to 10%. For those unable to tolerate Cisplatin due to other health conditions, systemic immunotherapy is increasingly being used in the neoadjuvant setting as an alternative to chemotherapy.
An alternative for select patients is a bladder-sparing approach called trimodal therapy (TMT), which combines a maximal TURBT with concurrent chemotherapy and radiation therapy. TMT is a complex, multidisciplinary approach that offers comparable long-term survival to radical cystectomy for properly selected patients, while preserving the native bladder and its function. Achieving a complete response is associated with excellent long-term outcomes, fueling interest in bladder preservation strategies for MIBC patients.
The Power of Immunotherapy
Immunotherapy has become a primary strategy for advanced bladder cancer treatment. These treatments work by harnessing the body’s own immune system to recognize and attack cancer cells, rather than directly killing the cells with chemotherapy. The primary agents in this category are immune checkpoint inhibitors (ICIs), which block proteins like PD-1 or PD-L1 that cancer cells use to hide from the immune system.
These checkpoint inhibitors are now a standard treatment for metastatic urothelial carcinoma, both as a first-line therapy for patients who cannot receive Cisplatin and as a second-line option for those whose cancer progresses after initial chemotherapy. The use of ICIs is expanding into earlier disease stages, including the perioperative setting for MIBC, where they are given either before or after radical surgery. For example, the PD-1 inhibitor Nivolumab is approved as an adjuvant therapy following cystectomy for high-risk patients.
ICI effectiveness is often linked to the expression of the PD-L1 protein, which serves as a biomarker to determine which patients are most likely to benefit. The integration of ICIs into the perioperative setting for MIBC is rapidly evolving, sometimes replacing or being combined with traditional chemotherapy to improve outcomes and potentially reduce treatment-related side effects.
Precision Medicine and Targeted Treatments
Precision medicine in bladder cancer involves identifying specific genetic alterations within a tumor and using drugs designed to target those changes, moving away from a one-size-fits-all approach. This strategy requires molecular testing, such as genomic sequencing, to analyze the tumor’s unique genetic blueprint before treatment can begin. This testing helps uncover alterations that make the cancer susceptible to a targeted therapy.
One of the most clinically relevant targets is the Fibroblast Growth Factor Receptor (FGFR) pathway, which is altered in about 15% to 20% of advanced bladder cancers, often through mutations or fusions in the FGFR3 gene. The oral targeted drug Erdafitinib is an FGFR inhibitor that works by blocking this overactive signaling pathway, thereby inhibiting the cancer cells’ ability to grow and divide. This drug is a key option for patients with metastatic disease who test positive for these specific FGFR alterations.
Another major advancement is the use of Antibody-Drug Conjugates (ADCs), which are sophisticated agents that combine a potent chemotherapy drug with a monoclonal antibody. The antibody acts like a “homing device,” precisely delivering the chemotherapy payload directly to cancer cells that express a specific protein on their surface, such as Nectin-4 or Trop-2. Agents like Enfortumab vedotin and Sacituzumab govitecan have shown significant efficacy in advanced bladder cancer, offering a new systemic treatment option that minimizes damage to healthy cells compared to traditional chemotherapy.
Emerging Concepts in Treatment
Research is continually introducing novel treatment concepts that show significant promise in clinical trials. One area of intense investigation is the development of personalized cancer vaccines, which are designed to train a patient’s own immune system to recognize and attack the unique mutations, or neoantigens, found in their tumor. These vaccines, sometimes based on messenger RNA (mRNA) technology, are being tested in combination with immune checkpoint inhibitors to amplify the anti-cancer immune response.
Another promising avenue is the exploration of novel combinations, such as pairing different types of immunotherapy or combining targeted drugs with chemotherapy, to overcome resistance and improve response rates. Furthermore, early-stage trials are investigating the use of gene therapy to deliver immune-activating agents directly into the bladder or the tumor, with the goal of generating a more localized and potent anti-tumor effect.