Mechanisms of Radiation-Induced Bladder Toxicity in Prostate Cancer Treatment: Correlation of Urinary Biomarkers with Bladder Pathophysiology

Radiation therapy is a life-saving treatment for many prostate cancer patients but is associated with adverse side effects. Due to the close proximity of the prostate to the urinary bladder, unavoidable collateral damage to the bladder from the radiation beams means that bladder injury is common. Radiation injury to the bladder is manifested as urinary symptoms of urgency, frequency, nocturia and incomplete bladder emptying. Symptoms occurring during the radiation therapy period often diminish in severity within 3-6 months. However, intolerable bladder dysfunction can develop months or even years after the radiation therapy is completed. Not only is it currently impossible to predict which patients will develop late bladder toxicity, we do not understand the processes underlying bladder damage caused by radiation therapy.

The goal of our proposed project is to define the mechanisms underpinning radiation generated bladder dysfunction using integrated multi-disciplinary approaches. We are currently recruiting prostate cancer patients who will have radiation therapy, to a research clinical trial. Biomarkers of bladder dysfunction in urine samples will be measured before, during and in the 24 months following treatment. Urinary biomarker levels will be correlated with symptoms of bladder dysfunction and impact on health-related quality of life. The Investigator team have complementary expertise in bladder physiology, radiation biology and clinical treatment of prostate cancer and will develop an animal model of radiation therapy, clinically relevant to treatment of prostate cancer patients. We will assess the impact of radiation therapy at specific time points post-treatment on the urinary behaviour of the animals to assess early and late bladder damage. The work will then progress to the organ, tissue, cellular and molecular level as we use a panel of cell physiology, cell biology and cell imaging methodologies to elucidate the mechanisms driving radiation damage in the bladder. The research will enable us to develop strategies to limit radiation damage to the bladder, enabling us to deliver larger, effective radiation doses to maximise tumour kill and minimise radiation bladder toxicity. The biomarker work will enable us to predict which patients are at risk of irreversible late bladder dysfunction and stratify these patients towards radio-protectant therapy.

Radiation therapy for prostate cancer (PCa) patients is potentially life-saving but is associated with adverse effects. Close proximity of the prostate to the bladder means that unavoidable collateral damage to the bladder commonly leads to bladder dysfunction. Acute effects of radiation induced bladder toxicity (RIBT) during the radiation therapy period often diminish in severity within 3-6 months. However, intolerable bladder dysfunction can develop months or even years after the post-treatment. We cannot currently predict which patients are at risk of late RIBT; furthermore we do not understand the underlying mechanisms.

The proposed project will define the mechanisms underpinning RIBT using integrated multi-disciplinary approaches. We are currently recruiting PCa patients to a research clinical trial. Biomarkers of bladder dysfunction (ATP and neurotrophins) in urine samples will be measured before, during and at follow-up appointments, up to 24 months post-treatment. Urinary biomarker concentrations will be correlated with IPSS/RTOG derived information on bladder toxicity and health-related quality of life. The applicants have complementary expertise in bladder physiology, radiation biology and clinical treatment of PCa. Development of an animal model of clinically relevant, PCa radiation therapy will allow us to assess the manifestation of RIBT during and after radiation at specific time points post-treatment by characterising changes in micturition patterns. The underpinning molecular mechanisms driving cellular remodelling and aberrant contraction will be evaluated employing a panel of cell physiology, cell biology and cell imaging. The research will enable development of strategies to limit radiation damage to the bladder, allowing delivery of larger, effective radiation doses. The biomarker work will enable us to predict which patients are at risk of irreversible late bladder dysfunction and stratify these patients towards radio-protectant therapy.

1. Who will benefit from this research?

The goal of the present proposal is to define the mechanisms underpinning radiation induced bladder toxicity (RIBT), a clinical condition negatively impacting the health and well-being of patients who have received pelvic radiation therapy for prostate cancer. RIBT is an unavoidable consequence of pelvic irradiation representing collateral damage to normal tissues located close to the tumour site.
Prostate cancer is the most common genitourinary cancer in UK men with many patients undergoing radiation therapy and developing RIBT during treatment and months /years after treatment has ended. It is surprising that research in this area has been overlooked and the major research was 20-30 years ago. Progress with prostate cancer treatment now needs to be matched with improved health-related quality of life of prostate cancer survivors.
Successful realisation of the project's objectives will direct development of strategies enabling the delivery of larger, effective radiation doses to maximise tumour kill and minimise radiation bladder toxicity. We envisage that the impact to patients will be medium-term as the proposal will provide essential data on the cellular mechanisms underpinning RIBT. An important next step would be the development of bladder radioprotective agents. This seems feasible given that our pilot work has demonstrated that the radiosensitive region of the bladder is just below the urothelial lining - radioprotective agents could potentially be delivered intravesically prior to treatment.
The promise of better radiation therapy for pelvic malignancies in combination with bladder radioprotection will be welcomed by patients and their families/carers.
International research groups who work on bladder dysfunction will benefit from this research; we will visit key groups in the EU and the USA during the project to share our findings and discuss the impact for urology translational research.
The commercial private sector, e.g. pharmaceutical companies will benefit from the MRC sponsored research. Fresh thinking and novel avenues of research are urgently needed to drive development of RIBT therapies.
Publicity through the University Media and Communications Centre will bring the issue of RIBT to the attention of the public, health care practitioners and provide new hope to individuals, their families and carers.
Local government policy makers regularly visit CCRCB and will see the benefit of investing in research for the wellbeing of a significant proportion of the electorate who are impacted by cancer and RIBT.
The Northern Ireland Bladder Forum comprises urologists and uro-oncologists who meet annually to discuss advances in the field. The PI is part of the Forum and presents recent research advances. Forum members will be keen to drive translation to the clinic.

2. How will they benefit?
RIBT is a highly prevalent condition which in addition to limiting the effective radiation dose to be given to a pelvic tumour, can destroy an individual's quality of life. Social isolation from a debilitating and embarrassing condition often leads to cessation of gainful employment. The project will significantly advance the field by stratifying and defining the mechanisms underpinning radiation bladder dysfunction, providing a scientific platform for follow-on translational research. A realistic time-scale of 5-8 years for a phase 1 trial is ambitious but feasible at this stage.
The UK government's changes to pension age means that many more people are expected to work until at least age 67. Yet, this is the age where prostate cancer is more prevalent with a significant proportion of people who suffer chronic dysfunctional bladder unable to sustain employment. The benefits of the research project, in the medium term will support cancer survivors working for longer and contributing to the economic wealth of the nation with an improved quality of life.