Exploring radiotherapy combined with a radiosensitizer for Bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ

The treatment options for Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) are evolving, with an increasing focus on bladder-sparing therapies (1,2). Radical cystectomy, although considered the standard of care, is often declined by patients or is not feasible because of its significant impact on quality of life and high surgical risks (3). Achard et al. proposed a novel combination of moderate hypofractionated radiotherapy with a radiosensitizer as a viable alternative for patients with BCG-unresponsive NMIBC with carcinoma in situ (CIS) who are either ineligible for or decline radical cystectomy (4).

The European Organisation for Research and Treatment of Cancer (EORTC) conducted a phase 2 trial (EORTC 2235) to investigate the efficacy of combining moderate hypofractionated radiotherapy with a radiosensitizer (4). This open-label, single-arm, multicenter study enrolled patients with histologically confirmed BCG-unresponsive CIS of the bladder, with or without high-grade Ta or T1 papillary masses. The treatment involved the administration of external beam radiotherapy (EBRT) in 20 fractions over 4 weeks, combined with 1 of 4 radiosensitizers: carbogen and nicotinamide, 5-fluorouracil and mitomycin C, cisplatin, or gemcitabine (4). The primary endpoint was the complete response (CR) rate (CRR) at 6 months. Secondary endpoints included durability or CR, progression-free survival, radical cystectomy free survival, overall survival, safety, and quality-of-life metrics (4).

Recent systematic reviews and studies have demonstrated varying degrees of success with bladder-sparing therapies for BCG-unresponsive NMIBC. For instance, Li et al. [2020] reported median CRRs of 26% at 6 months and 17% at 12 months for CIS (5). Shah et al. [2020] emphasized the variability in trial outcomes due to differences in patient populations and definitions of BCG failure, underlining the importance of robust evaluation of new therapeutic candidates (6).

The combination of EBRT and radiosensitizers is promising. James et al. [2012] found that synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer compared to that with radiotherapy alone, without a significant increase in adverse events (7). The study by Achard et al. adds to this body of evidence, suggesting that combining radiotherapy with a radiosensitizer can be a viable alternative to radical cystectomy for patients with BCG-unresponsive NMIBC (4).

When compared to existing treatments, such as intravesical instillation of newer agents like pembrolizumab, nadofaragene firadenovec, IL-15 superagonists, or TAR 200 or systemic therapy with pembrolizumab, combined radiotherapy with a radiosensitizer was shown to be equally efficacious (8-11) (Table 1). The nadofaragene firadenovec study had the largest sample size, with 157 patients enrolled (9). The radiotherapy study had the smallest planned sample size of 50 patients, which reflects its exploratory phase 2 design. The EORTC 2235 trial used a Simon’s two-stage design to determine the number of patients (4). The null hypothesis assumed a 30% CRR, with an alternative hypothesis of 50% CR (4). This two-stage design allows for early termination if the treatment is not effective, thereby minimizing the exposure of patients to potentially ineffective treatments (4). However, it carries inherent risks of early termination, which might preclude the identification of beneficial therapies (4). Other studies, such as the QUILT-3.032 study, opt for larger sample sizes to ensure a more comprehensive evaluation, though at a higher cost and greater patient burden (10). Dahl et al. reported on a phase 2 trial of trimodality therapy (TMT) for BCG-unresponsive high-grade T1 bladder cancer, with a 3-year freedom from cystectomy rate of 88%, underscoring the potential of TMT as a viable bladder-preserving alternative (12). Additionally, Hahn et al. investigated durvalumab combined with BCG or radiotherapy in BCG-unresponsive NMIBC, achieving CRRs of 85% at 3 months in the durvalumab + BCG group (13). These findings highlight the promise of radiotherapy combined with radiosensitizers or immunotherapies in achieving comparable outcomes to current bladder-sparing therapies, reinforcing the need for further studies to confirm these promising results.

The EORTC 2235 study provides two valuable pieces of evidence supporting the use of radiotherapy combined with radiosensitizers as a feasible treatment option for patients with BCG-unresponsive NMIBC with CIS. First, it underscores the role of hypofractionated radiotherapy as an effective treatment modality for NMIBC and demonstrates its potential to achieve significant clinical outcomes. Secondly, it identifies the optimal radiosensitizer for use in conjunction with radiation therapy for bladder cancer, providing critical insights into improving therapeutic efficacy. This approach could significantly impact clinical practice by offering a viable alternative to radical cystectomy, thus preserving bladder function and enhancing patients’ quality of life. However, further clinical trials and longitudinal studies are necessary to confirm these findings and establish standardized treatment protocols to ensure the broad applicability and consistency of this promising treatment strategy.

Acknowledgments

Funding: This work was supported by the Korean National Cancer Center grant (NCC23F-1910).

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