Adjuvant Radiation Therapy for Positive Surgical Margins in Muscle-Invasive Bladder Cancer: A Case-Based Discussion

1. Introduction

Muscle-invasive bladder cancer (MIBC) is an aggressive malignancy, with radical cystectomy (RC) being the gold standard for curative treatment (1). For patients with T2–4a cN0 M0 urothelial MIBC, cisplatin-based combination neoadjuvant chemotherapy (NAC) is recommended. A meta-analysis showed that, in patients who do not receive NAC, the tumor-bearing bladder should ideally be removed within three months of an MIBC diagnosis. Treatment delays related to NAC do not represent a concern in this context. Furthermore, for patients with high-risk pathological features (pT3b–4 disease, positive lymph nodes, or positive surgical margins) following radical cystectomy, adjuvant radiotherapy (RT) combined with chemotherapy may be considered (2).

Adjuvant RT in locally advanced MIBC targets microscopic pelvic disease and may improve locoregional control and survival. Historical trials from the 1990s demonstrated locoregional control rates as high as 96%. However, this approach was gradually abandoned due to concerns about gastrointestinal toxicity associated with large, non-conformal radiation fields. Advances in RT techniques and the development of international contouring guidelines have since improved bowel sparing and redefined the role of adjuvant RT in this setting (3).

A phase 2 multicenter trial demonstrated that adjuvant external beam radiotherapy (EBRT) after radical cystectomy in high-risk MIBC patients achieved an encouraging 2-year local relapse-free rate of 83% ± 5% while maintaining acceptable toxicity levels, supporting further investigation of its role in clinical practice. On the other hand, the 2-year clinical relapse-free survival (CRFS) was 43%, with a median CRFS of 12 months (95% CI: 3–21 months). The overall survival (OS) and bladder cancer-specific survival (BCSS) rates were 52% ± 7% and 62% ± 7%, respectively (4).

We aim to report a case of an MIBC patient with positive surgical margins (PSMs) and incidental prostate adenocarcinoma, where—due to high-risk features—adjuvant RT was successfully administered to reduce the risk of local recurrence (LR). The treatment was completed without interruption, associated only with mild toxicities, and no evidence of recurrence has been observed at the nine-month follow-up.

2. Case Presentation

A 67-year-old male presented in January 2024 with gross hematuria. Contrast-enhanced pelvic magnetic resonance imaging (MRI) revealed bladder wall thickening up to 9 mm with deformation of the bladder contour and nonhomogeneous enhancement in the right posterolateral wall, suggestive of malignant involvement (Figure 1). The patient was a smoker, with no family history of cancer.

A transurethral resection of the bladder tumor (TURBT) was performed at another medical center, and histopathological examination confirmed muscle-invasive urothelial carcinoma involving the right posterolateral wall of the bladder. However, the patient did not proceed with the recommended diagnostic tests or further treatment following the TURBT. As a result, there was an approximate three-month delay before appropriate oncologic evaluation and management were initiated.

A second pelvic MRI performed in May 2024 demonstrated disease progression, with bladder wall thickening increasing from 9 mm to 11 mm, without evidence of nodal involvement. A computed tomography (CT) scan of the chest and abdomen revealed no distant metastases.

Given the diagnosis of MIBC, the patient began neoadjuvant chemotherapy with four cycles of gemcitabine and cisplatin. During the third cycle of chemotherapy, the patient developed grade 3 hematologic toxicities, including anemia, leukopenia, and thrombocytopenia, which required supportive treatment with Filgrastim and Methylprednisolone. Despite these adverse events, the patient was able to complete all four planned chemotherapy cycles on schedule without dose reductions or delays.

In July 2024, radical cystectomy with pelvic lymph node dissection was performed, and bilateral nephrostomies were placed. Fourteen lymph nodes were removed (six on the left side and eight on the right). Histopathological analysis confirmed high-grade (grade 3) muscle-invasive urothelial carcinoma, staged as pT3a pN0 L0, with a PSMs (R1). According to the report, margin positivity was located at the bladder neck, involving the prostatic urethra and adjacent to the pubic bone, making surgical re-excision technically challenging. Additionally, an incidental finding of prostate adenocarcinoma, Gleason score 6 (3+3), staged as pT2c, was described. Postoperative PSA was undetectable (<0.1 ng/mL).

After the radical cystectomy, the case was discussed in a multidisciplinary tumor board. Although clinical guidelines do not routinely recommend adjuvant RT for MIBC, it was considered in this case due to the high-risk features, such as Grade 3 and PSMs, as well as the high risk of LR associated with these factors. Pelvic MRI was suggested prior to the adjuvant RT, but due to financial constraints, the patient was unable to undergo the MRI.

Adjuvant radiotherapy planning and target volume delineation were performed according to the International Consensus Guidelines for adjuvant radiotherapy after radical cystectomy (5). The clinical target volume (CTV) included the cystectomy bed encompassing the bladder neck, prostatic urethra, and adjacent soft tissues corresponding to the area of positive surgical margins. The nodal CTV included the common iliac, external iliac, internal iliac, presacral, and obturator lymph node regions bilaterally, consistent with consensus contouring guidelines for high-risk muscle-invasive bladder cancer (Figure 2).

Adjuvant RT was administered using the intensity-modulated radiation therapy (IMRT) technique in two phases. Phase I involved irradiation of the tumor bed and the pelvic region with a daily dose of 1.8 Gy in 25 fractions, for a total dose of 45 Gy. Phase II consisted of a boost to the high-risk region, including the prostatic area and surrounding tissues, with an additional 14.4 Gy delivered in 8 fractions of 1.8 Gy each, bringing the cumulative dose to 59.4 Gy.

To ensure more precise treatment delivery, daily cone-beam computed tomography (CBCT) was employed for image guidance during treatment.

After 10 fractions of adjuvant RT, the patient began experiencing Grade 1 gastrointestinal toxicity, including mild nausea and diarrhea. These symptoms were managed conservatively with dietary modifications and the use of loperamide. The patient maintained adequate oral intake, and symptoms remained stable without requiring any interruption in treatment.

At the recent nine-month follow-up, a pelvic MRI demonstrated a favorable outcome, with no evidence of local recurrence. The patient also remains clinically disease-free.

3. Discussion

Radical cystectomy aims for complete tumor removal, but achieving negative margins is not always feasible, especially when tumors invade adjacent structures. The occurrence of PSMs after radical cystectomy for MIBC varies widely across studies, with reported rates ranging from 4% to 15%. PSMs are considered a critical prognostic factor, as they are associated with poorer oncologic outcomes (6). Additionally, incidental prostate cancer is found in approximately 24% of radical cystectomy cases, which may have prognostic significance and impact on postoperative management (7).

Patterns of local relapse after radical cystectomy often involve the cystectomy bed, pelvic lymph nodes, or both, particularly in patients with adverse pathological features such as PSMs, extravesical extension, or lymphovascular invasion. These patterns justify the rationale for considering adjuvant radiotherapy in selected high-risk cases.

The role of adjuvant RT in MIBC, particularly in high-risk postoperative settings, has been historically underexplored. However, recent prospective trials have provided growing evidence supporting its safety and potential oncological benefit. Notably, three clinical trials – the Bladder Adjuvant RadioTherapy (BART) trial, the Egyptian Randomized Controlled Study (RCT) by Zaghloul et al., and the Belgian phase II trial by Fonteyne et al. – have advanced the current understanding of adjuvant RT in this population (3,4,8).

The BART trial, the largest randomized study comparing adjuvant radiotherapy (RT) to observation (Obs) in high-risk urothelial MIBC, demonstrated that severe acute and late toxicities were low and comparable between both arms. Grade 3 toxicity was rare (RT 1.6% vs Obs 4.2%), and no grade 4–5 acute events were reported. Mild gastrointestinal side effects such as diarrhea or enteritis were more frequent in the RT group (grade 2: 17.5% vs 1.1%) but were manageable with supportive care. Late grade ≥3 toxicity rates remained low (RT 8.4% vs Obs 10.5%), and nearly two-thirds of irradiated patients experienced no acute or late adverse effects, underscoring the safety and tolerability of well-planned modern RT (3). Although no grade 5 events were observed in the BART trial, such events have been reported in earlier adjuvant RT studies and must be carefully considered when weighing risks and benefits.

These findings are supported by the Egyptian phase III RCT, which also demonstrated low rates of severe late toxicity with adjuvant RT using image-guided intensity-modulated radiation therapy (IG-IMRT), with <5% incidence of grade ≥3 late adverse effects. Similarly, the Belgian phase II trial reported a 6% rate of acute grade 3 bowel toxicity. However, a relatively higher proportion of grade 2 toxicity was noted, potentially attributable to the older median age of patients (70 years) (4,8).

In the Belgian trial, nearly half of the patients with locoregional failure had recurrence arise specifically in the untreated cystectomy bed, despite negative resection margins. As locoregional control remains the principal aim of adjuvant radiotherapy in high-risk MIBC, the BART trial incorporated the cystectomy bed within the radiation field in all cases—excluding those with a neobladder—following international consensus recommendations. The trial demonstrated an encouraging 2-year local relapse-free rate of 83% ± 5% while maintaining acceptable toxicity levels.

Recently, the GETUG AFU 30 trial (presented at ESTRO 2025) reported on acute toxicity associated with adjuvant radiotherapy in high-risk MIBC patients. The study confirmed that modern IG-IMRT techniques resulted in low rates of severe acute toxicities, supporting the feasibility and tolerability of adjuvant RT in this setting (9).

Across all these trials, the use of IG-IMRT enabled excellent bowel sparing while maintaining adequate target coverage, demonstrating the feasibility and safety of pelvic RT in this context.

Although PD-L1 testing was not performed in our case due to financial constraints, adjuvant immunotherapy remains a valid consideration in high-risk patients, particularly those with PD-L1-positive tumors.

Furthermore, while adjuvant RT has shown promise in improving locoregional control, it has not consistently translated into an overall survival benefit – highlighting the ongoing need for effective systemic therapies to control distant metastases.

4. Conclusion

Managing locally advanced MIBC patients with positive surgical margins after radical cystectomy represents a challenging situation. Although adjuvant RT is not universally recommended in this setting, it may offer benefits in lowering the local recurrence rate. Precision delivery of RT using modern techniques such as IMRT and Volumetric Modulated Arc Therapy (VMAT) is essential, as is symptomatic treatment for toxic events during and after RT. It is essential to ensure a careful balance between the potential benefits of radiotherapy and its associated risks and uncertainties. Further prospective studies and clinical trials are necessary to better define the role of adjuvant RT in MIBC and establish more standardized treatment guidelines.

Abbreviations

BCSS – Bladder Cancer-Specific Survival

BART – Bladder Adjuvant Radiotherapy

CBCT – Cone-Beam Computed Tomography

CRFS – Clinical Relapse-Free Survival

CT – Computed Tomography

CTV – Clinical Target Volume

EBRT – External Beam Radiotherapy

GI – Gastrointestinal

IMRT – Intensity-Modulated Radiation Therapy

IG-IMRT – Image-Guided Intensity-Modulated Radiation Therapy

LR – Local Recurrence

MRI – Magnetic Resonance Imaging

MIBC – Muscle-Invasive Bladder Cancer

NAC – Neoadjuvant Chemotherapy

Obs – Observation

OS – Overall Survival

PSMs – Positive Surgical Margins

RCT – Randomized Controlled Trial

RT – Radiotherapy

TURBT – Transurethral Resection of Bladder Tumor

VMAT – Volumetric Modulated Arc Therapy

pT – Pathological Tumor Stage

pN – Pathological Node Stage

L0 – No Lymph Node Involvement

STATEMENTS

Authors’ contributions: All authors equally contributed to writing the manuscript

Consent for publication: As the corresponding author, I confirm that the manuscript has been read and approved for submission by all named authors.

Conflict of interests: The authors declare no conflict of interest.

Funding Sources: None

Statement of Ethics: The accompanying manuscript does not contain any studies carried out by the authors on humans or animals.

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