The Role of Definitive Radiotherapy in Non Muscle Invasive Bladder Cancer

Bladder cancer is one of the most common malignancies worldwide and represents a major global health burden. According to the GLOBOCAN 2022 estimates, approximately 614,298 new cases and 220,596 deaths from bladder cancer were reported worldwide, making it the ninth most commonly diagnosed malignancy globally.

Non-muscle-invasive bladder cancer (NMIBC), comprising Ta, T1, and carcinoma in situ (CIS), accounts for approximately three-quarters of newly diagnosed bladder cancers. Although NMIBC is confined to the mucosa or submucosa, it represents a heterogeneous group of tumors with markedly different risks of recurrence and progression, with the highest risk observed in high-grade and high-risk disease.

NMIBC is classified according to the risk of recurrence and progression into low-, intermediate-, high-, and very-high-risk groups. Risk stratification incorporates tumor stage, histological grade, tumor size, number of tumors, recurrence pattern, presence of CIS, age, and other adverse pathological and clinical features. High-grade histology, particularly T1 high-grade disease, is associated with a substantially increased risk of progression to muscle-invasive bladder cancer.

Risk Stratification of Non-Muscle-Invasive Bladder Cancer Risk group Main clinical and pathological characteristics Low-risk Primary, solitary, small low-grade Ta tumor without CIS and without significant adverse risk factors Intermediate-risk Tumors that do not fulfill the criteria for low-, high-, or very-high-risk disease High-risk Includes high-grade T1 tumors and CIS, as well as selected high-grade Ta/T1 tumors with additional adverse risk factors Very-high-risk High-grade tumors with multiple adverse features, including selected T1 high-grade tumors associated with CIS and/or multiple additional risk factors Risk classification should follow current guideline-defined criteria and should not be based on histological grade alone.

The management of high-risk NMIBC is based on complete transurethral resection of the bladder tumor (TURBT), followed by risk-adapted intravesical therapy. Full-dose intravesical Bacillus Calmette-Guérin (BCG) with maintenance therapy for one to three years remains an established standard treatment for high-risk disease, while radical cystectomy should be discussed in selected patients, particularly those with very-high-risk features.

T1 high-grade disease represents a particularly challenging subgroup because of its substantial potential for recurrence and progression despite bladder-preserving treatment. Clinical series of patients treated with TURBT followed by BCG have demonstrated considerable rates of both recurrent and progressive disease, emphasizing the need for effective treatment strategies in patients at high risk of treatment failure.

Radiotherapy has historically had a limited role in NMIBC. Nevertheless, its biological activity against urothelial carcinoma and its established role in bladder-preserving treatment of selected muscle-invasive bladder cancer have provided a rationale for investigating radiotherapy at earlier stages of bladder cancer. Modern radiotherapy techniques may allow treatment of the bladder while limiting radiation exposure to surrounding normal tissues.

Clinical evidence for radiotherapy in high-risk NMIBC has been reported since the early 1980s. Retrospective series evaluating radiotherapy in high-risk T1 bladder cancer demonstrated clinically meaningful complete response rates, local control, long-term survival, and bladder preservation. These findings suggest that radiotherapy may represent a potential bladder-preserving treatment option in carefully selected patients.

A systematic review and meta-analysis evaluating radiotherapy for high-risk NMIBC identified 13 studies involving 746 patients. The reported five-year recurrence-free survival, cancer-specific survival, and overall survival were 54%, 86%, and 72%, respectively. Approximately 13% of patients subsequently underwent salvage radical cystectomy and 9% developed metastatic disease. However, the available evidence was considered low quality because most studies were retrospective and heterogeneous, emphasizing the need for prospective clinical evaluation.

The potential role of radiotherapy in BCG-naïve high-risk NMIBC is of clinical interest because it could provide a bladder-preserving local treatment approach without prolonged intravesical therapy in selected patients. However, current guidelines do not consider radiotherapy a standard replacement for BCG-naïve high-risk NMIBC, and prospective evidence remains limited.

Therefore, there is a need for prospective evaluation of radiotherapy as a bladder-preserving treatment strategy in selected patients with high-risk NMIBC, who present without previous BCG exposure, and Evaluation of local disease control, bladder preservation, progression, survival, and treatment-related toxicity may help clarify the potential role of RTH