ASTRO 2024: Bladder Cancer - The Dawn or Era of More Personalized Radiotherapy

(UroToday.com) The 2024 American Society for Radiation Oncology (ASTRO) annual meeting held in Washington D.C., between September 29 and October 2 was host to the session Presidential Symposium: Innovations in Genitourinary Cancers: Session II - Bladder Preservation - A Modern Choice for Patients. Dr. Ananya Choudhury gave a presentation titled The Dawn or Era of More Personalized Radiotherapy in Bladder Cancer.

Dr. Choudhury began her presentation by highlighting a significant issue in bladder cancer: the underutilization of radical therapy, as evidenced by data from both the US and the UK. Specifically, the use of aggressive treatments decreases with age and among patients with lower socioeconomic status, which means a considerable number of eligible patients do not receive radical treatment. As a community, we must address these disparities and work toward personalizing treatment for bladder cancer patients.

The solution to this issue may lie in the evolution of modern radiotherapy, which has significantly advanced over the past 60 years. One example of this evolution is the concept of adaptation. The bladder changes its position daily and even minute by minute, but we now have the technology to adapt and adjust treatment in response to these changes.

Adaptive therapy also enhances planning target volume (PTV) coverage in bladder cancer. Evidence suggests that without image-guided radiotherapy, we are less likely to cover the target adequately compared to adaptive radiotherapy, where targeting improves significantly. The RAIDER study involved 240 patients with pT2-T4a N0M0 urothelial bladder cancer who were randomized into three groups. Group one received standard planning and delivery of whole bladder radiotherapy (WBRT). Group two received standard dosing with daily adaptive tumor-focused radiotherapy (SART), while group three received dose-escalated daily adaptive radiotherapy, utilizing a radiotherapy boost to the tumor bed (DART).¹

This study demonstrated that regardless of the fractionation scheme (20 fractions vs. 32 fractions) or whether patients received standard dosing or dose-escalated radiotherapy, the quality of life remained excellent across all three groups, as measured by the EQ-5D-5L overall health score as shown in the graphic below:

When comparing conventional doses between the WBRT or SART approach versus the concomitant boost to the tumor bed, the DART arm appeared to perform better in terms of 2-year event-free survival; however, this difference was not statistically significant (HR 0.78, 95% CI 0.47, 1.29, p=0.335). Overall, there was minimal difference among the three groups, with similar 2-year event-free rates, indicating that bladder preservation is an effective treatment for patients with MIBC and localized disease. One concern was the pelvic recurrence rate, especially since the margins were reduced for patients undergoing the daily adaptive RT and the concomitant boost. Nevertheless, the rate of pelvic recurrences remained low (7%), consistent with data from other studies evaluating bladder preservation therapies.

This raises the question of whether we should routinely irradiate the pelvic lymph nodes in N0 patients. Data from the US indicate an increasing trend in the use of bladder plus pelvic RT over time, as illustrated in the graphic on the left. However, there is no evidence to suggest that this rising use of pelvic nodal irradiation is improving survival outcomes.² This is a question that remains to be answered.

Dr. Choudhury discussed the available data supporting an optimal dose and fractionation for bladder cancer treatment, raising the question of how this applies in the era of hypofractionation. Findings from the BC2001 trial and the BCON study, which utilized individual patient-level data and a non-inferiority design, demonstrated that hypofractionation (55 Gy) was non-inferior to conventional fractionation (64 Gy), with a hazard ratio (HR) in the combined population of 0.71 (95% CI 0.52–0.96). The benefits of hypofractionation were also evident in patients receiving RT alone, as illustrated in the figure below.

Optimal management of localized MIBC has evolved significantly over the past decade. Dr. Choudhury's preferred treatment approach includes maximal TURBT, followed by neoadjuvant chemotherapy, and then radiotherapy combined with a radiosensitizing agent (such as weekly gemcitabine, 5-FU, MMC, or cisplatin) using a hypofractionation scheme. Unfortunately, it is unlikely that we will conduct clinical trials exploring all available radiosensitizing agents; therefore, individualizing treatment for each patient to choose the optimal agent is essential. The follow-up recommendations can be seen in the figure below.

An important question that needs to be addressed is how to treat patients with nodal involvement (N+). Unfortunately, there are very few clinical trials in this area, and most patients are not eligible for randomization, making it challenging to conduct adequately powered randomized clinical trials in this setting. Retrospective data from multiple centers in the UK assessing patients treated radically with platinum-based chemotherapy followed by either radical cystectomy or radiotherapy indicate that those who received radical treatment fared better than those who received chemotherapy alone. This strengthens the rationale for treating these patients as radically as possible in hopes of improving their survival. However, despite the treatment modality, survival remains poor for these patients. In this study, the median OS for patients treated with radical therapy was 2.4 years (95% CI, 1.9-2.8), while the median OS for those receiving RT was 2.53 years (95% CI, 2.02-3.44), and for surgery was 2.09 years (95% CI, 1.79-3.13). For patients with a poor prognosis, it is difficult to justify radical cystectomy, considering the increased morbidity and impact on quality of life. Thus, for these patients, she argues that the choice should be chemotherapy and RT.³

Dr. Choudhury discussed how we can further personalize treatment, noting that there have been decades of research aimed at identifying biomarkers to predict outcomes and benefits from RT. Multiple studies have explored factors such as hypoxia, necrosis, and molecular subtypes (luminal, basal). While several biomarkers associated with hypoxia can help identify patients who might benefit the most from hypoxia modification therapies, analyses of patients treated in the BC2001 trial who received chemoradiotherapy or RT alone indicate that these hypoxia and molecular signature biomarkers are not predictive. Nevertheless, this suggests that we may be able to select patients who could benefit from one treatment over another (RT vs. CRT vs. RC). However, these hypotheses need to be validated in randomized clinical trials.

We have imaging biomarkers, and there is emerging data on how we can image tumors using carbogen, with carbogen and nicotinamide serving as primary radiosensitizers. This approach allows us to detect bladder tumors that are more hypoxic in nature while patients are on treatment. By tracking these tumors' responses to treatment, we can observe changes in the hypoxic areas. This could enable us to adaptively modify treatment by adjusting the dose and fractionation specifically for the hypoxic regions. Additionally, it may help identify patients who require treatment intensification, such as the addition of immune checkpoint inhibitors (ICIs). This is an exciting area of research, and we hope to have more detailed answers in the future.

Dr. Choudhury concluded her presentation by saying that we have made significant progress over the last two decades toward personalized RT in bladder cancer. Advances in image-guided RT and daily adaptations, including real-time planning, enable us to deliver treatment more accurately to our patients. Furthermore, we can enhance our selection of the appropriate treatment for each individual. There is a promising future in which predictive imaging and tissue biomarkers may facilitate more accurate patient selection, as well as RT dose adjustments, fractionation, and treatment intensification. All these efforts aim to provide RT to patients who are currently underserved by the community and not receiving optimal treatment and will get the right treatment in the future.

Presented by: Ananya Choudhury, PhD, MA MRCP FRCR, Chair and Honorary Consultant in Clinical Oncology at The Christie NHS Foundation Trust Manchester, Greater Manchest, United Kingdom

Written by: Julian Chavarriaga, MD – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @chavarriagaj on Twitter during the 2024 American Society for Radiation Oncology (ASTRO) annual meeting held in Washington D.C., between the 29^th of September and the 2^nd of October.

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