Urothelial carcinoma is a type of cancer that originates in the urothelium, the specialized lining of the urinary tract. When this cancer is classified as metastatic, or mUC, it means that malignant cells have spread beyond the original tumor site to distant organs or lymph nodes throughout the body. This advanced stage of the disease requires systemic treatments, which are therapies designed to travel through the bloodstream to destroy cancer cells wherever they have spread. The goal of systemic therapy is to control the disease, reduce symptoms, and extend life.
Defining Metastatic Urothelial Carcinoma
Urothelial carcinoma arises from the transitional cells that form the urothelium, which lines the renal pelvis, the ureters, the bladder, and the urethra. Although it is most frequently diagnosed in the bladder, this cancer can originate anywhere along this lining. The disease is often colloquially referred to as bladder cancer because the bladder is the largest anatomical site lined by the urothelium.
When the cancer progresses to a metastatic stage, tumor cells have broken away from the primary site and established new growth elsewhere. The most common sites for this distant spread, or metastasis, include the lymph nodes outside the immediate pelvic region, the lungs, the liver, and the bones. While approximately 5% of cases are metastatic at the time of initial diagnosis, nearly half of patients with muscle-invasive disease will eventually develop distant spread.
Confirming the Diagnosis and Location of Spread
Confirming that urothelial carcinoma has spread beyond the primary tumor requires a combination of imaging studies and tissue analysis. Computed Tomography (CT) scans of the chest, abdomen, and pelvis are routinely utilized to identify distant lymph node involvement and soft tissue metastases in the lungs or liver. Positron Emission Tomography (PET) combined with CT scanning is often employed to enhance the detection of metabolically active cancer cells throughout the body.
Magnetic Resonance Imaging (MRI) is another valuable tool, particularly for assessing local tumor invasion and detecting bone metastases. Beyond imaging, a biopsy of the primary tumor or a metastatic lesion provides tissue for pathological confirmation and molecular analysis. Molecular analysis of the tumor tissue is routinely performed to identify specific genetic alterations, such as mutations in the Fibroblast Growth Factor Receptor (FGFR) or the expression of PD-L1 protein. These molecular details inform the selection of targeted therapies and immunotherapies.
Current Systemic Treatment Strategies
Systemic treatment for metastatic urothelial carcinoma has rapidly evolved beyond traditional chemotherapy to include immunotherapy and targeted agents. The selection of a first-line treatment regimen is highly individualized, depending on a patient’s overall health, kidney function, and the tumor’s specific molecular characteristics. For many patients with mUC, a combination of an antibody-drug conjugate and an immune checkpoint inhibitor has recently become the preferred first-line approach, demonstrating superior efficacy over older regimens.
Chemotherapy
For decades, platinum-based chemotherapy was the standard first-line treatment for patients who were healthy enough to tolerate it, particularly those with good kidney function. The combination of gemcitabine and cisplatin (GC) is a common regimen, generally resulting in less toxicity than the older MVAC combination. Cisplatin-based regimens are highly effective. However, patients who are deemed “cisplatin-ineligible” due to poor kidney function or other medical conditions are typically treated with a less potent platinum agent, such as carboplatin, combined with gemcitabine.
Immunotherapy
Immune checkpoint inhibitors (ICIs) have fundamentally changed the management of mUC by harnessing the body’s own immune system to attack cancer cells. These drugs, such as pembrolizumab or avelumab, block proteins like PD-1 or PD-L1, which cancer cells use to hide from the immune system. Immunotherapy is utilized in several settings: as a first-line agent for some cisplatin-ineligible patients, as a second-line treatment following progression on chemotherapy, and as maintenance therapy. For example, avelumab maintenance therapy, given after initial platinum-based chemotherapy, significantly improves overall survival compared to observation alone.
Targeted Therapy
Targeted therapies focus on specific genetic vulnerabilities within the cancer cells. One significant advance is the use of Fibroblast Growth Factor Receptor (FGFR) inhibitors, which target tumors harboring specific FGFR genetic alterations. These drugs are typically reserved for patients whose cancer has progressed after initial systemic therapy, and their use requires prior molecular testing to confirm the presence of the mutation. Antibody-drug conjugates (ADCs) are another innovative class of targeted agents, linking a potent chemotherapy drug to an antibody that specifically seeks out a protein on the cancer cell surface. The ADC enfortumab vedotin, which targets the protein Nectin-4, has shown high efficacy and is now frequently combined with immunotherapy as a preferred first-line treatment.
Prognosis and Supportive Care
The outlook for patients with metastatic urothelial carcinoma has improved dramatically due to the introduction of modern systemic treatments. While median overall survival has improved significantly with the introduction of modern systemic treatments, current strategies, particularly those incorporating maintenance immunotherapy, have extended survival in clinical trials. Prognosis remains highly variable, influenced by factors such as the patient’s performance status, the location of metastases, and the tumor’s responsiveness to the initial treatment regimen.
Supportive care, or palliative care, is a simultaneous part of treatment from the time of diagnosis, not just for end-of-life situations. This specialized care focuses on managing physical symptoms and treatment side effects to maintain the best possible quality of life. Common symptoms managed include pain, fatigue, nausea, appetite loss, and anxiety.
Specific interventions address complications such as using palliative radiotherapy to control bleeding (hematuria) or alleviate pain from bone metastases. For patients experiencing urinary tract obstruction (hydronephrosis), placement of a ureteral stent or a nephrostomy tube provides relief. Clinical trials also offer access to novel agents and emerging combination strategies for patients who have exhausted standard treatment options.