(UroToday.com) The 2023 European Society of Medical Oncology (ESMO) Annual Congress held in Madrid, Spain between October 20th and 24th, 2023 was host to a bladder preservation strategies oral session. Dr. Robert Huddart discussed radiotherapy for bladder preservation in muscle-invasive bladder cancer (MIBC).
The current paradigm for the management of localized MIBC is as follows:
The goals of radiotherapy in this MIBC setting are threefold:
- Preserve bladder and sexual functioning
- Maintain quality of life and body image
- Avoid major surgery, with many patients being elderly with numerous comorbidities
There is a plethora of data to support the role of radiotherapy, specifically chemoradiotherapy, for bladder preservation. BC2001 was a phase 3 randomised 2 × 2 factorial trial that recruited 458 patients with T2-T4a N0M0 MIBC between 2001 and 2008. 360 patients were randomised to radiotherapy (178) or chemoradiotherapy (182), and 218 were randomised to standard whole-bladder radiotherapy (108) or reduced high-dose-volume radiotherapy (111). At a median follow-up time of almost 10 years, chemoradiotherapy improved locoregional control (HR: 0.61 95% CI: 0.43 to 0.86, p = 0.004) and invasive locoregional control (HR: 0.55, 95% CI: 0.36 to 0.84, p = 0.006). This benefit translated, albeit non-significantly, for disease-related outcomes, including overall survival (HR: 0.88, 95% CI: 0.69-1.13, p = 0.3), and bladder cancer-specific survival (HR: 0.79, 95% CI 0.59-1.06, p = 0.11).1
While the results of BC2001 trial clearly demonstrate survival benefits with chemoradiotherapy, compared to radiotherapy alone, it is important to recognize that radiotherapy techniques have significantly evolved since 2001. Current radiotherapy is faster (hypofractionation), better (adaption), and stronger (dose escalation). In an individual patient meta-analysis of BC2001 and BCON trials, a hypofractionated schedule of 55 Gy in 20 fractions was shown to be non-inferior to 64 Gy in 32 fractions with regards to both invasive locoregional control and toxicity and was superior with regard to invasive locoregional control. Accordingly, it has been argued that 55 Gy in 20 fractions should be adopted as a standard of care for bladder preservation in patients with locally advanced bladder cancer.2
What about ‘better’ (i.e., adaptive) radiotherapy? The bladder is a mobile target that is influenced by the intravesical urine volume present and adjacent organs (e.g., rectum).
Numerous studies have demonstrated that adaptive radiotherapy, particularly since the emergence of cone beam CT with planning CT, are associated with significantly smaller planned target volumes (PTV) with lower associated toxic effects to the target and surrounding organs.
What about stronger radiotherapy dosages? As summarized in the flow diagram below, image guidance could lead to improved target coverage with improved control rates. Concurrently, this image guidance may allow for adaptive strategies with reduced target volume and tumor boost delineation with reduced high dose volumes, leading to potentially lower toxicity.
RAIDER (NCT02447549) is a randomized phase II trial of adaptive image-guided standard or dose escalated tumor boost radiotherapy for the treatment of urothelial carcinoma of the bladder.
Patients with cT2-T4aN0M0 unifocal MIBC are randomised (1:1:2) between:
- Standard/control whole bladder single plan radiotherapy
- Standard dose adaptive tumour-focused radiotherapy
- Dose-escalated adaptive tumour-focused radiotherapy (DART)
Adaptive tumour-focused radiotherapy uses a library of three plans (small, medium and large) for treatment. A cone beam CT taken prior to each treatment is used to visualise the anatomy and inform selection of the most appropriate plan for treatment. Two radiotherapy fractionation schedules (32f and 20f) are permitted. The trial has a two-stage non-comparative design. The primary end point of stage I is the proportion of patients meeting predefined normal tissue constraints in the DART group. The primary end point of stage II is late CTCAE grade 3 or worse toxicity aiming to exclude a rate of >20% (80% power and 5% alpha, one sided) in each DART fractionation cohort. Secondary end points include locoregional MIBC control, progression-free survival overall survival and patient-reported outcomes.
With regards to the primary endpoint of grade 3+ treatment emergent radiotherapy related late CTCAE toxicity between 6 and 18 months, this was comparable between the 3 arms, with none having grade 3+ adverse events with 32 fractions, and 1 patient in each arm having such an event with the 20-fraction schedule.
The overall local control rate at 3 months was 99% and similar for whole bladder (WBRT), standard dose adaptive (SART), and dose-escalated adaptive tumor-focused radiotherapy (DART).
The survival outcomes appear to slightly favor DART. The 2-year event-free rates were 80% for WBRT + SART, compared to 84% for DART. The bladder intact event-free survival was also slightly higher for DART (72% versus 66% for WBRT + SART).
Dr. Huddart next addressed the ‘elephant in the room’: surgery versus radiotherapy (chemoradiotherapy) for MIBC. He argued that there is ample evidence from population studies, academic center comparisons, single institution studies, and most recently meta-analyses demonstrating that radiotherapy and surgery are at least equivalent in this setting.
A recently published multicenter study of trimodality therapy versus radical cystectomy was published by Zlotta et al. in Lancet Oncology. This retrospective analysis included 722 patients with cT2-T4N0M0 muscle-invasive urothelial carcinoma of the bladder (440 underwent radical cystectomy, 282 received trimodality therapy) who would have been eligible for both approaches, treated at three university centres in the USA and Canada between January 2005 and December 2017. All patients had solitary tumours less than 7 cm, no or unilateral hydronephrosis, and no extensive or multifocal CIS. At a median follow-up of just under 5 years, the 5-year metastasis-free survival was equivalent at 75% for both treatment groups. Disease-free and cancer-specific survivals were equivalent for both groups.3
How does Dr. Huddart currently select patients for radiotherapy? Ideal candidates are those:
- Fit enough for chemoradiotherapy
- Having urothelial or small cell histology
- Single primary disease site
- No residual mass
- Good bladder function
- No or localized CIS
Poor candidates are those with:
- Large primary with residual mass post-TURBT – particularly those with bilateral hydronephrosis
- Pure squamous or adenocarcinoma
- Severe lower urinary tract symptoms
- Widespread (focal, peritumoral CIS is permissible)
- Contra-indications to radiotherapy
- Unwilling to have follow-up cystoscopy
How to decide on bladder preservation versus cystectomy? The current treatment decision-making paradigm relies on personal preference, clinical factors, treatment modality availability, and response to chemotherapy, as evaluated in the SPARE and HCRN GU 16-257 de-escalation trials. Dr. Huddart is hopeful that biomarkers, including MRE 11, expression groupings, and DNA Damage Response (DDR) genes will be available in the future to help guide therapy for MIBC patients.
Dr. Huddart next addressed some popular myths commonly believed to be contraindications to radiotherapy for the treatment of MIBC:
- Must have a complete TURBT to be eligible for radiotherapy
- ~40% of patients in the BC2001 trial had incomplete resections – although this may be prognostic irrespective of treatment chosen
- Must not have hydronephrosis
- Unilateral is permissible; bilateral is not
- Must not have CIS
- Extensive CIS is a contraindication, but peritumoral CIS is permissible given the comparable outcomes versus those without
- Bladder radiotherapy leads to a small, shrunken bladder
- Salvage cystectomy has poor outcomes
- Salvage cystectomy has been demonstrated to have comparable outcomes to primary radical cystectomy in well selected patients, as demonstrated by multiple series shown below:
Dr. Huddart concluded that:
- Radiotherapy has improved over the last decade with radiosensitization, image guidance, adaption, and shorter treatments
- Modern image-guided radiotherapy is a realistic approach for many (but not all) patients with MIBC with a high degree of effectiveness and modest toxicity.
- Further Improvement in results can obtained by continued technical developments, use of biomarkers, and additional concomitant therapies (especially immunotherapy)
- Though radiotherapy is not for everyone, it should be considered and offered to all suitable patients.
Presented by: Robert Huddart, MB, BS, MRCP, FRCR, PhD, Professor of Urological Cancer and Honorary Consultant Clinical Oncologist MA(Oxon), The Royal Marsden Hospital, London, UK
Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.
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