Local Radiotherapy for Urinary Bladder Cancer in Patients Not Eligible for Curative Treatment

Umeå University248 enrolled

Overview

The goal of this clinical trial is to improve the quality of life and prolong survival in bladder cancer patients unfit for curative treatment. The trial will compare the survival and symptoms of patients randomized to either local radiotherapy in addition to standard of care or standard of care alone. Using modern radiotherapy techniques, including hypofractionation and image-guided treatment adaptation, the aim is to deliver a well-tolerated, time-efficient, and effective treatment strategy for these patients. The trial collaborates with two ongoing exploratory biomarker studies collecting and analyzing potential biomarkers in urothelial bladder cancer. The hope is to provide biomarkers for prognosis and treatment response which is essential to ensure bladder cancer patients individualized treatment in the future, like those with breast and prostate cancer.

Around 700 individuals in Sweden are diagnosed each year with muscle-invasive bladder cancer (MIBC), and a similar number die annually from the disease (SVF RCC 2023). With a median age at diagnosis approaching 76 years (Swedish National Quality Registry for Urothelial Carcinoma), the incidence is expected to rise as the population ages. Due to advanced age and comorbidity, many patients are not eligible for the demanding multimodal treatments used with curative intent. Recently introduced systemic therapies for palliation, such as antibody-drug conjugates and immunotherapy, also require a WHO performance status \<2 and regular hospital-based administration. Consequently, up to 30% of patients receive no tumor-directed therapy at diagnosis (Swedish National Quality Registry for Urothelial Carcinoma). Without treatment, MIBC often progresses rapidly, with a median overall survival of approximately 12 months in this cohort. Symptom burden is substantial, commonly involving pain, bleeding, and urinary tract obstruction, which frequently require repeated hospital admissions late in the disease trajectory. Radiation therapy (RT) is an established curative modality in bladder cancer and is well documented for symptom palliation. In other malignancies, such as prostate cancer, limited radiation doses have been shown to prolong survival and reduce the development of distressing symptoms. Although some studies indicate similar benefits in bladder cancer, a clear survival effect has not been demonstrated, representing an important knowledge gap in the management of a common cancer type. The LORUP project builds on existing translational research infrastructures to address this gap. Its aim is to develop a treatment strategy for MIBC patients unfit for curative therapy, focused on improving quality of life by reducing symptom burden and potentially prolonging survival, while maintaining a low treatment burden and minimal side effects.

Interventions

Local hypo fractionated adaptive radiotherapy and Standard of CareRADIATION

Patients randomized to the radiotherapy (RT) arm will receive external beam radiotherapy to the whole urinary bladder as well as Standard of Care. Intensity-modulated Radiotherapy will be delivered using an adaptive treatment strategy, permitting either: * Plan-of-the-day (PoD) adaptive radiotherapy using a predefined library of plans, or * Online adaptive radiotherapy (oART) with daily re-contouring and re-optimisation to the anatomy of the day. The choice of adaptive strategy (PoD vs oART) and imaging modality (CBCT- or MR-based) is at institutional discretion, provided all protocol-specified target coverage objectives and organ-at-risk (OAR) constraints are met. The prescribed dose is 21 Gy in 3 fractions of 7 Gy, delivered every other day.

Standard of Care (Investigator Choice)OTHER

All applicable palliative treatments associated with the Standard of Care, such as local RT, TURB, systemic anti-tumour treatments or other interventions/treatments applicable according to treating physician are allowed

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Oral and written consent 2. Histologically confirmed MIBC with urothelial component 3. Male or female participants ≥ 18 years old 4. Deemed not to benefit from curative treatment at a multidisciplinary tumour conference (MDT) or having declined curative treatment of their own accord. Exclusion Criteria: 1. Clinical Fragility Scale score ≥8 2. Previous pelvic RT with significant overlap 3. Visceral or bone metastases on CT scan 4. Multiple (\>3) lymph node metastases with a measurement of \>2 cm on CT scan 5. Planed for systemic treatment at the time of inclusion. 6. Local RT to the bladder indicated for the palliation of symptoms at the time of inclusion.

Outcomes

Primary Outcomes

Overall Survival

Time frame: From date of randomization until the date of death from any cause assessed up to a minimum of 36 months

Secondary Outcomes

Disease specific Survival

Time frame: From date of randomization until the date of death by MIBC assessed up to a minimum of 36 months

Progression-free survival

Any symptoms associated with tumor progression, including but not restricted to the AESI of the study.

Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to a minimum of 36 months

Radiological progression-free survival

Defined as; 1. new lesion as compared to baseline and/or 2) increase of longest tumour diameter by 20% as assessed by local investigator.

Time frame: Time from randomization to the date of the first documented radiological progression or death, whichever comes first, assessed up to a minimum of 36 months

Start of systemic anti-tumour treatment

Start of any systemic anti-tumour treatment, such as immunotherapy, tyrosine kinase inhibitors, chemotherapy or antibody-conjugates

Time frame: Time from randomization to start of systemic anti-tumour treatment assessed up to a minimum of 36 months

Health related quality of life, HRQoL

Global HRQoL will be evaluated with the EORTC QLQ C15 PAL questionnaire (C15 PAL). Patients' responses to the QLQ questions will be scored and converted to a numeric scale 1-4, where 1=none and 4=very much, using the standard algorithms provided by EORTC

Time frame: Collected every fourth month throughout follow-up from randomization to 36 months of follow-up or until death of any cause, which ever comes first

Patient reported outcome, PRO

PRO will be evaluated using a study specific self-assessment questionnaire (PRO\_GI-GU) based on the functional scale for urinary problems in patients without urostomy from EORTC QLQ - BLM30 (question 31-37) by the European Organisation for Research and Treatment of Cancer (EORTC) and the functional scale for bowel bothers from the Prostate Cancer Symptom Scale (PCSS) question 21-35,50 (ver. 1, 2013) © Fransson \& Widmark, Umeå, Sweden. The patients' responses are converted to a numeric 0-10 scale, where 0 = none and 10 = very much, using the standard algorithms provided by EORTC and Fransson \& Widmark(PMID:33444529).

Time frame: Collected at every follow up (month 1, 2 and thereafter every 4th month from randomization) until last follow-up visit at 36 months or until death of any cause, which ever comes first

Early adverse events /late adverse event

Differences between the arms in severity and frequency of reported early (within 90 days of EoRT) and late adverse events (after three months of EoRT) according to specified modules from CTCAE v5.0)

Time frame: Collected at every follow up (month 1, 2 and thereafter every 4th month from randomization) until last follow-up visit at 36 months or until death of any cause, which ever comes first

Adverse event of special interest, AESI:

Differences between the arms in reporting of symptoms associated with tumour progression, specifically: Palliative RT Blood transfusion Surgical intervention due to local progression (TURB) Hospitalisation due to bladder tumour Urinary catheter placement (urinary, suprapubic, or nephrostomy)

Time frame: Collected throughout follow-up for a minimum of 36 months or until death of any cause, which ever comes first