Introduction
Patients with non-metastatic muscle-invasive bladder cancer (MIBC) can be treated by radical cystectomy or chemoradiation following maximal trans-urethral resection of the bladder tumour (TURBT) with curative intent. The surgical procedure and subsequent reconstruction of the urinary bladder involved in a radical cystectomy can lead to significant patient morbidity and perioperative mortality[
1]. Alternatively, chemoradiation avoids major surgery and enables preservation of the native bladder which may be a preferable option for some patients. The main toxicities of chemoradiation are gastrointestinal, genitourinary and hematological; with grade 3 or 4 toxicities occurring in a minority of patients[
2].
Difficulties with patient selection have led to an absence of completed randomized control trials, however large multi-centre retrospective analyses have shown similar oncological outcomes between radical cystectomy and chemoradiation in well-selected patients[
3,
4]. Despite now being an accepted treatment option for MIBC in several international guidelines[
5,
6], chemoradiation is often only reserved for and discussed with patients who are non-surgical candidates.
Using retrospective data from a single tertiary centre, we explored whether patients with MIBC deemed suitable for either radical cystectomy or chemoradiation, received a discussion about both treatment options and were referred appropriately to have those discussions.
Materials and methods
Study design and participants
This retrospective cohort study included patients with non-metastatic, muscle invasive T2−T4 bladder cancer treated with cystectomy or chemoradiation at Austin Health, Melbourne Australia from January 2016 to December 2023. Ethics approval was gained from the Austin Health Research Ethics Committee. Patients were identified using Austin Health radiation oncology and urology databases. Clinical stage was based on the histology from the initial diagnostic TURBT and radiographic imaging excluded the presence of nodal or distant metastatic disease at time of diagnosis. Patients were categorized as being suitable for both treatment options, suitable for surgery only or chemoradiation only. Patients were deemed suitable for surgery if they were documented to be a surgical candidate in multi-disciplinary team (MDT) notes, anesthetic reviews and/or urology clinic letters. Patients were deemed suitable for chemoradiation if they were documented to be a chemoradiation candidate in MDT notes, medical oncology and radiation oncology clinic letters; or they did not meet the following exclusion criteria: significant renal impairment (eGFR < 30), presence of small cell features, concurrent prostate/upper tract cancer, bilateral hydronephrosis, presence of diffuse CIS, prior pelvic radiation or severe bladder symptoms. The exclusion criteria were determined by local expert clinical opinion and commonly accepted criteria utilized in previous studies and Radiation Therapy Oncology Group (RTOG) protocols[
3,
4,
7,
8].
Outcomes
The primary outcome was the proportion of patients suitable for both cystectomy and chemoradiation that had a documented discussion about both treatment modalities in either MDT notes, urology, medical oncology or radiation oncology letters. The second primary outcome was the proportion of patients referred and reviewed by a urologist and radiation oncologist to have an in-depth discussion about the option of cystectomy and chemoradiation respectively. The secondary outcomes were the cumulative incidence of distant metastatic disease and overall survival of each treatment modality. All time to event endpoints were measured from the documented date of commencement of treatment (either cystectomy or chemoradiation) to the date of distant metastasis or death. The date of distant metastasis was identified by documentation of radiographic findings in MDT notes and/or clinic letters. Alive patients without documented recurrence were censored at the most recent documented follow-up time-point.
Statistical analysis
Descriptive statistics were prepared to summarise baseline patient characteristics. Results were presented as mean and standard deviation (SD) for continuous variables that were normally distributed or median and interquartile range (IQR) for non-normally distributed continuous variables. A Shapiro-Wilk test was used to determine which variables were normally or non-normally distributed. A Student’s t-test was used to test for differences between two groups for normally distributed continuous variables, while a Mann-Whitney (ranksum) test applied for non-normally distributed variables. Categorical data was presented as counts and percentage frequencies, with Chi-squared or Fishers’ Exact tests applied to test for differences between the cystectomy and chemoradiation groups. Fishers’ Exact tests were used on occasions when categorical frequencies were fewer than 5. Proportional hazards cox regression models were used to assess differences in time to event outcomes between cystectomy and chemoradiation groups with results presented as Hazard Ratios (HR) with 95% confidence intervals (CIs) and as Kaplan–Meier curves. Deaths and progression were considered as competing events when assessing the distant metastasis outcome. Multivariable analysis was conducted adjusting for age and ECOG status. Sub-group analysis was conducted that considered those patients who were candidates for either cystectomy or chemoradiation treatment. Statistical analysis was conducted using Stata version 18.0 (StataCorp, College Station, Texas, USA), with a two-sided p-value of less than 0.05 considered to indicate statistical significance.
Results
Patient population
In total, 64 patients were included in the study: 36 (56%) deemed suitable for either surgery or chemoradiation, 7 (11%) suitable for surgical management alone and 21 (33%) suitable for chemoradiation alone. Of the 36 patients deemed suitable for either modality, 22 (61%) patients underwent a radical cystectomy and 14 (39%) underwent chemoradiation. Amongst the patients that were suitable for both modalities, the average age of those who underwent a radical cystectomy was 65.8 years and 69 years for those who underwent chemoradiation. Of patients with a documented ECOG status, 95% (18/19) of cystectomy patients and 29% (2/7) of chemoradiation patients had an ECOG 0. All patients from both cohorts had T2 disease with 1 patient (5%) in the cystectomy cohort having nodal disease (N2) 91% of cystectomy patients and 100% of chemoradiation patients had a urothelial cell type and 9% (2/22) of cystectomy patients had squamous cell type (Table 1).
Patients who underwent chemoradiation received cisplatin, mitomycin C plus 5-fluorouracil or gemcitabine with radiotherapy regimes ranging from 50−64 Gray in 20−32 fractions. A proportion of these patients also received immunotherapy on clinical trials. Patients who underwent surgery received variations of a radical cystectomy with ileal conduit or neobladder formation with or without pelvic lymph node dissection. Just over half of cystectomy patients (12/22, 55%) received neoadjuvant chemotherapy.
MDT discussion and referral patterns
The majority of patients were discussed in an MDT meeting (92%) and were referred and reviewed by a medical oncologist (98%). All 14 patients suitable for both modalities that underwent chemoradiation had a documented discussion about the alternative option of cystectomy with a urologist. Conversely, 36% (8/22) of patients suitable for either modality that underwent a radical cystectomy had a documented discussion about the alternative option of chemoradiation and 9% (2/22) of them were referred to and saw a radiation oncologist to have these discussions (Figure 1).
Oncological outcomes
The median follow up was 1.9 years (IQR: 0.81−4.09). The cumulative incidence of distant metastatic disease at 2-year follow-up in patients undergoing radical cystectomy was 18.5% (95% CI: 5.8%−36.9%) compared to 13.7% (95% CI: 2.2%−34.7%) for chemoradiation. There was no statistically significant difference in overall survival in patients receiving chemoradiation compared to cystectomy (HR = 0.26, 95% CI: 0.04−1.94) adjusting for age and ECOG status (p = 0.191) (Figure 2, Table 2).
Discussion
Our study demonstrated that a significant proportion of patients deemed suitable for both cystectomy and chemoradiation did not have a discussion about bladder preservation therapy. All patients that underwent chemoradiation were seen by a urologist and discussed the option of surgery. Conversely, a minority of patients that underwent a radical cystectomy had a documented discussion about the bladder-sparing option of chemoradiation and even fewer were referred to a radiation oncologist. By nature of diagnosis of MIBC with TURBT, all patients are subsequently followed up by a urologist and are likely to discuss surgical management. However, given that a number of studies show similar outcomes between surgery and chemoradiation in well selected patients, bladder preservation therapy appears to be an appropriate alternative treatment to discuss with suitable patients[
3,
4].
Chemoradiation allows patients to avoid a major surgery and its potential perioperative complications as well as possible quality-of-life-altering changes from removal of the native bladder and reconstruction of the urinary system. This is particularly relevant in the MIBC patient population who are largely 65 years or older and often with multiple comorbidities[
1,
5]. Although chemoradiation can be associated with pelvic toxicity, previous RTOG protocols demonstrate modest rates −21.7% grade 1, 10.22% grade 2, and 7% grade 3 gastrointestinal or genitourinary toxicities[
2]. Decision analytic modelling studies have shown that chemoradiation has been associated with increased quality-adjusted life years compared to cystectomy[
9] and a cross-sectional study reported better general quality of life (QOL) and higher physical, social and emotional functioning[
10]. However, no prospective studies have compared long-term QOL and toxicities between both groups[
11].
Our study demonstrated no statistically significant difference in overall survival with chemoradiation. However, as shown in the Kaplan–Meier curve (Figure 2) and the magnitude of the hazard ratios, there is a numerically lower early survival for cystectomy patients that may be partly driven by measurable postoperative mortality following a radical cystectomy. The observed lower cumulative incidence of distant metastatic disease in chemoradiation candidates may be due to the more rigorous follow up required and subsequent early management of recurrence in these patients compared to those with a radical cystectomy. Furthermore, given that approximately half of the surgical patients did not receive neoadjuvant chemotherapy, some did not undergo lymph node dissection, and several patients in the chemoradiotherapy group appeared to have received immunotherapy, the heterogeneity in treatment regimens may have significantly impacted outcomes.
A limitation of our study was the retrospective nature of the data collection which was primarily based on clinical documentation. Patients were retrospectively deemed suitable for surgery if they were documented to be a surgical candidate and patients were deemed suitable for chemoradiation if they were documented to be suitable or they did not meet our exclusion criteria. In our study, 56% of all patients with MIBC and 84% of medically operable patients were identified as suitable candidates for chemoradiation. This proportion appears to be significantly higher than the 10%−30% reported in previous studies[
3,
15]. This likely reflects our less stringent exclusion criteria compared to other studies which often account for tumour size or grade, presence of lymphovascular invasion and multiplicity for example. Most recent studies have also excluded the presence of any tumour-related hydronephrosis with evidence that it is linked to poorer outcomes[
7,
8,
13,
14], whereas our study excluded only bilateral hydronephrosis. Additionally, we did not assess completion of maximal TURBT[
15,
16]. Given the absence of strong evidence regarding optimal patient or tumour selection for chemoradiation, further research is needed to better identify predictors of favourable response.
Our study determined whether patients had a discussion about their treatment options by the presence of documentation of these discussions in electronic clinic/MDT notes. By nature of this method, the extent and quality of discussions could not be assessed and therefore may not be an accurate representation of patient understanding of their treatment options. Additionally, a proportion of patients may have had an appropriate discussion with a clinician without documentation and thus may be underestimated in our study.
Another limitation of the study was the small sample size. In addition to potentially contributing to the non-statistically significant hazard ratio or effect sizes for overall survival and distant metastatic disease, the small sample size prevented a thorough multivariate analysis adjusting for potential confounding variables other than age and ECOG status. The sample size also prevented assessment of the interactive effects between each of the variables.
Emerging data from neoadjuvant studies combining immunotherapy with antibody–drug conjugates (e.g., EV-303 and RC48-C017)[
17] demonstrate pathological complete response rates of approximately 45%–65% and complete clinical response rates (cCR) that are even higher. These outcomes provide a rationale for an approach in which patients first undergo neoadjuvant systemic therapy and if a cCR is achieved, subsequently receive bladder-preserving treatments such as adjuvant radiotherapy or maintenance systemic therapy.
Conclusion
Chemoradiation is an acceptable alternative treatment of MIBC that should be discussed with all suitable patients. Early referral to radiation oncologists would enable these patients to make a fully informed decision about their treatment options. Our single-centre study revealed that most suitable patients are not given the opportunity to consider bladder preservation treatment. While patient and tumour characteristics often direct the decision to pursue chemoradiation, the impact of these factors on treatment response rates has not been well studied. While translational tissue or blood-based biomarkers evolve to guide treatment decisions in the future, and while upcoming trials of newer drugs in the MIBC setting may influence patient/clinician choices in the future, our current patients with MIBC deserve improved fully informed decision making.
The Author(s) 2026. This article is published by Higher Education Press at journal.hep.com.cn.
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