A Happy New Year to the ESTRO biology community; 2025 is going to be a splendid year. We are returning to Vienna for the annual meeting in May, for which we have received more abstracts (3439) for the biology track than ever before.
As well as the biology pre-meeting course, we have a collaborative event between the biology committee and the urology focus group with a pre-meeting course on bladder cancer. Treatment of bladder cancer provides an excellent model of radiobiology in action. Bladder cancer is more common in biological men compared with women, but women often have a worse prognosis. Although this may be related to environmental factors and occupational exposures, biological differences may be involved. Men and women have different sex chromosomes, and exhibit differences in metabolism and immune biology that may affect cancer development as well as response to treatment and prognosis. Professor Laure Marignol will discuss the intriguing aspects of sex, biology, and bladder cancer.
Treatment paradigms can be associated with the six Rs of radiobiology: radiosensitivity, repair, reactivation of the immune response, reoxygenation, repopulation and redistribution. Muscle-invasive bladder cancer has intrinsic radiosensitivity and responds to radiotherapy alone. Bladder cancer exhibits damage-repair mutations to DNA- that are associated with response to radiotherapy. MRE11, an important DNA damage-signalling protein, and ERCC1, which is critical to nucleotide-excision repair, are of particular interest. It has proved challenging to find a robust way to measure these biological biomarkers. There are issues with how to score immunohistochemistry and inter-observer variation. This means that people are focused on transcriptomic biomarkers, which are more robust and reproducible, although more resource-intensive and expensive.
The immune tumour microenvironment is important in bladder cancer, with checkpoint inhibitors used to treat metastatic bladder cancer. Many trials are testing the use of radiotherapy with immunotherapy and results of these trials are eagerly awaited.
Bladder cancer is one of the few for which there is evidence from a randomised controlled trial that reoxygenation or hypoxia modification improves clinical outcomes. The bladder carbogen and nicotinamide (BCON) study, which was first published in 2010, has been updated with long-term outcomes to 10 years. Hypoxia modification with high-dose oxygen (carbogen) and the nicotinamide vitamin (CON) combined with radiotherapy improves overall survival and local control rates compared with the use of radiotherapy alone. Hypoxia biomarkers, whether they be simple histological parameters such as necrosis, protein expression of, e.g., carbonic anhydrase 9, a bespoke hypoxia transcriptomic signature, or molecular subtypes, can be used to stratify patients by response to CON. This data is compelling and paves the way for a prospective biomarker qualification trial.
Repopulation and redistribution underpin dose and fractionation within radiotherapy protocols. It is difficult to model the impact of these aspects of radiobiology in the clinic. Two of the largest randomised controlled trials for bladder cancer, BC2001 and BCON, compared radiotherapy with radiotherapy plus radiosensitisation using two different dose/fractionation protocols. One was a conventional fractionation that delivered 64Gy in 32 fractions and the other, a moderate hypofractionation protocol that delivered 55Gy in 20 fractions. In a meta-analysis of data for individual patients, outcomes were compared between the two protocols. Moderate hypofractionation was found to be superior to conventional fractionation for loco-regional control. This suggests that bladder cancer is sensitive to specific radiotherapy fractions and is impacted by overall treatment time. We have always assumed that the alpha/beta ratio for bladder cancer is high, but this finding challenges this paradigm or implies that repopulation and redistribution are more important for the radiotherapy response in bladder cancer.
All of us are motivated by seeing improved patient outcomes, and it is empowering to understand how science underpins these improvements. Attendance at #ESTRO25 will enable us to continue these discussions. Come and join the pre-Congress meetings and the biology meet and greet. See you there!
Professor Ananya Choudhury
Department of Clinical Oncology
The Christie NHS Foundation Trust and University of Manchester
Manchester, UK
ananya.choudhury@nhs.net