(UroToday.com) The 2024 American Society for Radiation Oncology (ASTRO) Annual Meeting held in Washington, DC between September 29th and October 2nd, 2024, was host to a clinical trials session. Dr. Vedang Murthy presented the acute and late toxicity results from the multicenter, randomized phase III Bladder Adjuvant RadioTherapy (BART) trial.
Dr. Murthy noted that there have been long-term concerns regarding the safety of post-cystectomy radiotherapy, both from urologists and radiation oncologists.
What is the rationale for post-cystectomy radiotherapy? First, long-term evidence has demonstrated that patients who are locally controlled have significantly reduced risks of distant metastases.
Secondly, while neoadjuvant chemotherapy improves overall survival by 5–8%, it does not improve local recurrence rates.
Thirdly, there are subsets of high-risk patients (≥pT3, pN+, <10 lymph nodes removed, LVI+, margin positivity) that have a high risk of local recurrence (30-40%), and may thus, in theory, benefit from the adjuvant radiotherapy.
BART (Bladder Adjuvant RadioTherapy) is an Indian multicenter phase III randomized trial that randomized 153 high-risk muscle-invasive bladder cancer patients to either adjuvant radiotherapy (50.4 Gy in 28 fractions) or observation. The primary study endpoint was 2-year locoregional failure-free survival.
From a technical standpoint, contouring was performed according to the 2016 IJROBP consensus guidelines. The contouring volume was modified to include the cystectomy bed (2 cm above the pubic symphysis to the penile bulb). They also included the common iliac nodes up to the aortic bifurcation in the radiotherapy clinical target volume. The standard ‘organs at risk’ were contoured, including the stoma, anorectum, femurs, and neobladder or ileal conduit, where applicable.
All patients were treated with intensity-modulated, image-guided radiotherapy. Below are images of the constraints that were used. A typical dose distribution below demonstrates that only 50% of the prescribed isodose reaches the bowel, which minimizes bowel radiation doses in the lower abdomen/upper pelvis.
Over eight years, 153 patients were randomized. For this report, the toxicity results for 134 patients were presented.
The median patient age was 57 years. The surgical margins were positive for 4.6% of included patients. 77% had cT3-4 disease, and 33% had cN+ disease. 91% of patients had received systemic chemotherapy, either in the neoadjuvant or adjuvant settings. Pathologic nodal involvement was present in 41% of patients. Variant urothelial histology was present in 27.5% of cases.
In the acute setting., none of the patients had to discontinue radiotherapy secondary to toxicity. Grade 2 acute toxicity was observed more commonly in the radiotherapy arm (17.5% versus 1.4%) and were most commonly bowel symptoms that self-resolved and did not require surgical intervention or inpatient hospitalization. Grade 3 events were observed less frequently in the radiotherapy arm (1.6% versus 4.1%). Notably, 67% of patients who received radiotherapy experienced no symptoms (red arrow below).
At a median follow-up of 27 months, late grade 2 adverse events were observed in 15% of radiotherapy-treated patients and 7% of patients in the observation arm. Conversely, grade 3/4 adverse events were observed less frequently in the radiotherapy arm (8.4% versus 10.5%).
Overall, 23.3% of radiotherapy-treated patients experienced late grade ≥2 toxicity events, compared to 17.5% of patients in the observation arm.
On multivariable analysis, radiotherapy administration was the only variable significantly predictive of an increased risk of acute events (HR: 4.6, p=0.03).
Dr. Murthy noted that this is the largest randomized controlled trial of adjuvant radiotherapy in bladder cancer. Strengths of this trial include its multicentricity, the fact that 90% of patients received systemic chemotherapy, including 70% in the neoadjuvant setting, and consensus contouring guidelines were followed. Numerous radiotherapy safety checkpoints were followed, including use of IMRT + daily IGRT, strict stomal sparing, controlling bowel spill, and use of 1.8 Gy/fraction.
Follow-up for the primary endpoint of locoregional failure-free survival is ongoing, and patient-reported outcome measures (PROM) collection is ongoing. He noted that none of the patients received adjuvant immunotherapy, given that ~80% were accrued prior to the approval of immunotherapy agents in the adjuvant setting.
Presented by: Vedang Murthy, MD, DNB, DipEPP, Professor, Department of Radiation Oncology, Tata Memorial Centre, Mumbai, India
Written by: Rashid Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2024 ASTRO Annual Congress held in Washington, DC between September 29th and October 2nd, 2024