Radiotherapy Use in Muscle-Invasive Bladder Cancer: Review of the Guidelines and Impact of Increased Awareness in Patient Referral at a Tertiary Center in Belgium

Introduction

Neo-adjuvant chemotherapy, followed by surgery, and in case of high-risk residual disease, adjuvant immunotherapy, is recognised as standard of care treatment for muscle-invasive bladder cancer (MIBC).¹ The role of radiotherapy (RT) in the management of MIBC is more frequently debated. Despite being one of the cancers with the most frequent evidence-based indications for RT, its actual utilization in the treatment of bladder cancer remains limited.² In Belgium, for instance, an important gap was observed between the optimal and actual use of RT in bladder cancer patients.³ In 2017, a survey conducted among Belgian urologists, medical oncologists and radiation oncologists confirmed the underutilization of RT in MIBC in all treatment settings. This survey suggests that providing an overview of the available guidelines can increase awareness of RT’s role in MIBC.⁴ Since then, our tertiary institution has made several efforts to raise awareness about RT as a treatment option for MIBC patients. These efforts include increasing research on RT for MIBC (including conducting the aforementioned survey) and giving more attention to RT as a MIBC treatment option at our multi-disciplinary tumor board meetings. The current study aims to provide a critical overview of the RT indications in MIBC as currently recommended by several guidelines. The study also aims to evaluate whether the raised awareness about the role of RT in MIBC impacted the use of RT in MIBC in daily practice at a tertiary center.

Materials and Methods

Guideline Review

We identified the most recent guideline versions of the European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), the National Comprehensive Cancer Network (NCCN), and the National Institute for Health and Care Excellence (NICE).^5–8 Also, the collaborative guideline of the American Urological Association, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology (AUA/ASCO/ASTRO/SUO) was included in this review.⁹ The full-text documents were compared and guideline modifications (if updated) since our previous assessment in the survey of 2017 were evaluated.

Pattern of Care Analysis

After approval by our Ethics Committee (Ghent University Hospital: ONZ-2022-0209), we retrospectively reviewed the medical charts of MIBC patients treated with RT at Ghent University Hospital between 1 January 2012 and 31 December 2021. Due to the retrospective nature of the study, the Ethics Committee waived the requirement for written informed consent. Patient data was maintained with confidentiality. Before analysis, all confidential patient information was removed. The ethical principles established by the Declaration of Helsinki were respected. Patient characteristics (age and sex), disease characteristics (histology, stage according to UICC TNM Classification 8 edition) and treatment characteristics (start/stop date, total dose, total number of fractions, concomitant treatment, and trial inclusion) were collected. Treatment practice was evaluated in the curative and palliative setting. The curative setting consists of patients treated with primary RT, adjuvant RT, perioperative RT (patients treated with neoadjuvant RT followed by bladder-sparing surgery and brachytherapy) and with RT for local recurrent disease. For patients treated with primary RT, the reason for referral to the RT department was extracted from the patients’ electronic health record. Predefined reasons were patient preference (patient could choose between RT and surgery, and opted for RT), medical preference (patient was suitable for surgery, but the multidisciplinary tumor board preferred RT), and inoperability (patient was not suited for surgery). The palliative setting consists of patients treated with RT to palliate symptomatic pelvic or extra-pelvic disease and patients treated with metastasis-directed radiotherapy (MDRT), ie, metastatic disease treated with high-dose radiotherapy with the intent to eradicate individual metastatic lesions. Frequency of RT use for each indication was evaluated per year between the first (2012–2016: Group A) and second (2017–2021: Group B) 5-year period of the analyzed decade. 2017 was chosen as cut-off to compare the pre- and post-survey period. As reference, the number of newly registered MIBC patients at our hospital during these 2 periods was obtained from the Cancer Registry. Further, patient, disease, and treatment characteristics were compared between the 5-year periods. Continuous variables were compared using the independent sample t-test and categorical variables with the Chi-square test. Statistical significance was reached at p ≤ 0.05 in all tests performed. Data were analyzed by SPSS statistics 28 (IBM SPSS, Chicago, IL).

Results

Guideline Review

In Table 1–3, an overview of the role of RT in MIBC as recommended by the current guidelines is presented. Characteristics of the consulted guidelines, including the system used for evidence and recommendation grading, are summarized in Supplementary Table 1.

Table 1 Overview of the Role of RT as Primary Treatment for MIBC, as Recommend by the Consulted Guidelines

Table 2 Overview of the Role of RT in MIBC in the Neoadjuvant, Adjuvant and Recurrent Treatment Setting, as Recommend by the Consulted Guidelines

Table 3 Overview of the Role of RT as Palliative Treatment in MIBC, as Recommend by the Consulted Guidelines

Pattern of Care Analysis

Between January 2012 and December 2021, a total of 221 unique patients were treated for MIBC at our department of radiation oncology. The number of patients treated with RT increased with 39% between the first (Group A: N=109) and second (Group B: N=151) 5-year period. The number of newly registered MIBC patients at our hospital increased between the same periods with 26% (2012–2016: N=72 and 2017–2021: N=91) (note: registration of bladder cancer patients was based on the TNM-classification at initial diagnosis and was not updated in case of disease progression or recurrence). An overview of the number of MIBC patients treated with RT per 5-year period is shown in Table 4. Comparison of the patient, disease and treatment characteristics per 5-year period is shown in Table 5.

Table 4 Number of Patients Treated with Radiotherapy per Treatment Setting per 5-Year Period, Ie, (2012–2016) and (2017–2021)

Table 5 Comparison of the Patient, Disease and Treatment Characteristics Between (2012–2016) and (2017–2021), Univariate Analysis

Curative Setting

During the analyzed decade, one hundred and seventeen MIBC patients received RT with curative intent. An overview of the number of patients per type of treatment, per year, is shown in Figure 1.

Figure 1 Overview of the absolute number of muscle-invasive bladder cancer patients treated with radiotherapy (RT) in the curative setting, per type of treatment, per year.

Primary RT

Fifty-one MIBC patients were treated with primary RT, of whom 19 with and 32 without concurrent chemotherapy. Between 2012 and 2016, only 7 patients were referred for primary RT. The majority was referred because of inoperability (5 out of 6 patients with a known reason for RT referral) as shown by Figure 2. All of these patients were also deemed unfit for radiochemotherapy and received therefore RT-alone (25 × 1.8Gy to the bladder with a sequential boost of 5 × 5Gy to the tumor site). After 2017, forty-four patients were referred for primary RT and most patients were referred for RT because of patient or medical preference (29 out of 41 patients with a known reason for RT referral) (Figure 2). Patients fit for radiochemotherapy received 20 × 2.6Gy (2017–2020) or 20 × 2.75Gy (from 2021 on) to the bladder with concurrent gemcitabine. As of 2017, almost all patients deemed unfit for radiochemotherapy received ultra-hypofractionated RT (6 × 6Gy to the bladder, once weekly) (N=19).

Figure 2 Reason of referral for primary radiotherapy, percentage of patients per reason, per year. The absolute number of patients treated with primary radiotherapy per year (N) is reported under the corresponding year on the x-axis.

Neo-Adjuvant/ Adjuvant/ Peri-Operative RT

Fifty patients received RT in the post-operative setting of whom 84% received adjuvant RT as part of a clinical trial (study enrolment between August 2014–October 2020). All patients were treated with 25 × 2Gy to the pelvic lymph node areas at risk ± the cystectomy bed (in case of a positive surgical margin). Ten patients were treated with peri-operative radiotherapy consisting of low-dose neo-adjuvant RT (3 × 3.5Gy) to the tumor site followed by a partial cystectomy and post-operative brachytherapy (60Gy, pulse dose rate 0.5Gy per pulse, 1 pulse per hour). Apart from this peri-operative treatment, no patients were treated with neoadjuvant RT.

Local Recurrent Disease

Six patients who developed a locoregional recurrence post-cystectomy were treated with radical RT to obtain maximal locoregional control, ie, 25 × 2Gy to the pelvic lymph node areas at risk with a simultaneous integrated boost (65–70Gy) to the recurrence.

Palliative Setting

Thirty-three patients received palliative RT for pelvic disease, of whom 12 because of locoregional recurrence after their cystectomy. Of the patients treated for pelvic disease 13 and 20 patients received a multi-fraction, ie, 10 × 3Gy or 5 × 4Gy, and single fraction ie, 1 × 7Gy or 1 × 8Gy, RT schedule, respectively. A total of 186 extra-pelvic lesions, divided over 110 patients, were treated with RT. Of these patients, seventy-four patients were treated with a palliative scheme, ie, 1 × 8Gy or 10 × 3Gy or 5 × 4Gy, mostly because of symptomatic disease. Thirty-six patients received MDRT (most used schedules were 3 × 8Gy or 3 × 10Gy), of whom 23 within clinical trials.^10,11 The number of MIBC patients treated with palliative RT, per type of treatment, per year is shown in Figure 3.

Figure 3 Overview of the absolute number of MIBC patients treated with radiotherapy (RT) in the palliative setting, per type of treatment, per year.

Discussion

The absolute number of new bladder cancer patients with an RT indication is predicted to increase in the immediate future. In several countries, bladder cancer is expected to settle in the top 5 most frequent cancers according to evidence-based indications.² Underutilization of RT in the field of bladder cancer has been observed in Belgium and this inevitably leads to denying a potential treatment option to bladder cancer patients.³ An important step in adherence to clinical guidelines is the awareness of the actual guidelines. Agreement between and clarity of guidelines are key for adopting and adhering to guidelines in daily practice.¹²

In the primary setting, all guidelines recommend radiotherapy in combination with a radiosensitizer, ie, trimodality therapy or multi-modality treatment, as an alternative treatment option for selected MIBC patients, especially in those patients unsuitable for cystectomy or seeking an alternative to cystectomy. Several guidelines still list criteria to select optimal candidates for multi-modality treatment (MMT) (Supplementary Table 2). It is important to emphasize that many of these criteria are known to be prognostic factors and should not be considered as absolute contra-indications. Patients who do not meet these selection criteria will also have a poorer prognosis when treated with cystectomy. At this moment, there is no strong evidence for one MIBC treatment to be superior to the other. This is best translated in the recommendation of the NICE guidelines, stating that a choice between cystectomy and MMT needs to be offered after a full discussion between patient, urologist, radiation-oncologist and clinical nurse specialist. Important adaptations have been made, since our previous review (survey of 2017), in favour of MMT. As indicated in Table 1, modifications in the EAU and ESMO recommendations now indicate that patient preference may influence treatment. A small but notable difference in the phrasing of the EAU recommendation is the change of “highly selected” to “selected” patients. Also, the NCCN guideline changed its recommendation for MMT from category 2A to category 1. At our center, we observed an increase in overall RT use for MIBC patients during the last few years. We attribute this raise in RT use to an increased awareness of optimal use of RT in MIBC patients. One of the measures taken at our center, was the advocacy of MMT, ie, radiochemotherapy, as bladder-sparing alternative for surgery. Consequential, more fit patients, also eligible for radiochemotherapy, were referred to our RT department. Meanwhile, patient preference has become the main reason for primary RT instead of inoperability.

Regarding the use of RT-alone as primary treatment, some discrepancies between guidelines were noted. The AUA/ASCO/ASTRO/SUO and EAU both strongly recommend against offering RT-alone as curative treatment. However, the EAU guideline, as well as the NCCN guideline, mentions that RT-alone could be considered in patients unfit for cystectomy or concurrent chemotherapy. The ESMO and NICE guidelines discuss RT-alone only as a palliative treatment strategy. Undertreatment in older MIBC patients is well documented, and high cancer-specific mortality in this elderly population indicates that omitting active treatment in patients unfit for RC or MMT, is not always justified.^13–15 RT-alone used in a hypofractionated scheme, ie, 6 × 6Gy, is safe and seems to provide a better local disease control than a purely palliative treatment.¹⁶ Since we implemented this hypofractionated scheme at our center, the use of RT-alone increased. We suspect that this could possibly indicate a more active treatment attitude in this often undertreated group.

Currently, the role of neoadjuvant RT seems to be very limited and is only discussed by the EAU and NCCN guidelines. Based on a meta-analysis showing no overall survival benefit when using neoadjuvant RT, the EAU guideline strongly recommends against offering pre-operative RT for operable patients.¹⁷ The NCCN guideline briefly mentions that low-dose pre-operative RT prior to a partial cystectomy can be considered. At our center, neoadjuvant low-dose RT was used a few times in preparation for bladder-sparing surgery followed by brachytherapy. This is in accordance with the Dutch guidelines last updated in 2019.¹⁸ These guidelines state that despite favourable reported outcomes, the level of evidence for this treatment strategy is limited and should only be considered in strictly selected MIBC patients (cT1-3aN0M0, solitaire tumor ≤3 cm located outside the trigonum/bladder neck, no carcinoma in situ and/or severe urinary complaints).¹⁸

In the adjuvant setting, both EAU and NCCN guidelines state that there are only limited data for the use of radiotherapy following cystectomy. Both guidelines cite a Phase II trial that compared adjuvant chemotherapy vs adjuvant chemoradiation.¹⁹ This trial showed an improvement in local relapse-free survival, with low rates of late-grade ≥3 toxicity. Based on these results, the EAU and NCCN guidelines conclude that adjuvant RT can be considered in case of high pathological risk for local recurrence. In contrast, the ESMO guideline mentions that there is no role for adjuvant RT in high-risk patients and further states that these patients have been included in adjuvant immunotherapy trials. Interestingly, patients with a positive resection margin were excluded from the adjuvant immunotherapy trials. A Belgian phase II trial reports that only 3 out of 14 patients with a positive resection margin developed a locoregional failure after adjuvant RT (median follow-up of 18 months).²⁰ This suggests the importance of adjuvant RT in patients with a positive resection margin. Currently, the role of adjuvant RT is further investigated in 2 Phase III trials (GETUG-AFU30 (NCT03333356) and BART trial (NCT02951325)), both including patients with a positive margin.

Patients with a locoregional recurrence have a poor prognosis and often experience debilitating symptoms.²¹ Patients treated for recurrence showed a better survival than those without treatment (1-year survival: 27% vs 2%).²² Both the EAU and NCCN guidelines recommend RT as a treatment option for recurrent disease. At our center, few patients received RT for recurrent disease. A possible explanation for this is a reduction in the number of locoregional relapses, through the use of adjuvant RT and/or immunotherapy in high-risk MIBC patients. Further, almost all guidelines recommend RT as a means to palliate 1 or more of following local symptoms in patients unsuitable for curative disease: haematuria, lower urinary tract symptoms, pelvic pain. No guideline specifically discusses the role of RT as treatment of symptomatic distant metastases. This, despite the well-established role of RT in the treatment of uncomplicated painful bone metastases.²³ There is limited evidence that MDRT can achieve durable disease control in selected patients with minimal metastatic disease.²⁴ Currently, only the EAU guideline briefly mentions a potential role for RT as metastasis-directed therapy. The increased MDRT use at our center was mainly induced by the treatment of patients with MDRT as part of a Phase 1 and Phase 2 trial running between 2016 and 2020 at our hospital.^10,11 In the absence of stronger evidence, the role for MDRT outside of clinical trials remains limited. The role of MDRT in oligometastatic bladder cancer is further evaluated in the ongoing EFFORT-MIBC trial.²⁵

There are some limitations to this study. Review of the guidelines was not a systematic review. The pattern of care analysis was a single-center retrospective analysis. Observed changes in treatment frequency are based on absolute numbers of patients. Therefore, the reported changes in treatment practice must be interpreted with caution. However, the observed increase in overall RT use was more pronounced than the increase in newly registered MIBC patients at our hospital.

Conclusion

International guidelines recommend MMT as an alternative to cystectomy, but differ in patient selection. Patient preference is gaining importance in several guidelines. Our single-center experience suggests that increased awareness of MMT as a treatment option can lead to an increase in its use, particularly by including patient preference as a reason for referral. Adjuvant RT for MIBC is currently not well established, and ongoing trials may provide more clarity. RT is recommended for palliating local symptoms in patients ineligible for curative treatment, but guidelines do not discuss its use for symptomatic metastases. The role of MDRT outside of clinical trials remains limited.