Tailoring prostate cancer radiotherapy to body clock could cut long-term side effects

A study by Leicester researchers shows that the timing of radiotherapy treatment may be as important as how it is given for prostate cancer patients.

Researchers at the University of Leicester have discovered that a patient’s genetic makeup and the time of day they receive radiotherapy can work together to influence their risk of developing long-term side effects for treatment of prostate cancer. 

The findings, published in Clinical Cancer Research suggest that a simple change to treatment scheduling, based on a patient’s genetic profile, could help reduce complications such as urinary incontinence and rectal bleeding without diminishing the effectiveness of cancer treatment.

Radiotherapy is highly effective at treating prostate cancer, but some patients experience long-term side effects that can persist for years, including urinary incontinence and rectal bleeding. These complications can have a substantial impact on quality of life long after the cancer itself has been successfully treated.

But new research shows that these side effects are influenced not only by the treatment patients receive, but also by common genetic variations in PER3, a gene involved in regulating the body's circadian rhythm, and by the time of day at which radiotherapy is delivered.

The work undertaken by Leicester researchers alongside European collaborators forms part of the REQUITE study, one of the world's largest prospective radiotherapy side-effect cohorts. 

Using advanced statistical modelling to combine genetic information, detailed records of radiotherapy treatment times and two years of follow-up data on treatment-related side effects, the team were able to identify how patients with different DNA variants in the PER3 gene showed different profiles of side-effect risk for treatment delivered at different times of the day. 

Lead author, Dr Adam Webb, from the University of Leicester’s Division of Genetics and Genome Biology, said: ‘For some groups of patients the difference was striking. 

“We predicted that men carrying a particular PER3 genotype could reduce their risk of urinary incontinence from 15% to 5% by avoiding treatment around midday. 

“However, other groups were either unaffected by treatment time or instead showed most benefit from midday treatment. We saw a similar phenomenon for risk of rectal bleeding which could be reduced from around 11% to 5% for one patient group simply by delivering radiotherapy treatment later in the day.”

The findings build on the team's earlier work in breast cancer, where similar links were observed between circadian rhythm genes, treatment timing and radiotherapy toxicity. 

Professor Chris Talbot, who led the Leicester team, added: “Seeing comparable results in two different cancers strengthens the evidence that the body's internal clock plays an important role in how healthy tissues respond to radiation.”

The discovery opens the possibility of genetically guided chronoradiotherapy: matching the timing of treatment to a patient's genetic profile and biological clock.

“Unlike many precision medicine approaches, this would not require expensive new drugs, new technologies or major changes to radiotherapy delivery. Instead, it could potentially be implemented by scheduling patients at times when they are least likely to experience harmful side effects,” said Professor Talbot.

The researchers stress that further validation studies and clinical trials are needed before treatment schedules are routinely altered. However, the results provide evidence that treatment timing can be personalised using genetic information.

In the future, patients could undergo a simple genetic test before starting radiotherapy. Clinicians could then use that information to recommend the most suitable treatment time, helping to minimise side effects while maintaining cancer control.

This would represent a new form of precision medicine: delivering the same treatment, but at the right time for the individual patient.

Professor Paul Symonds, Emeritus Professor of Clinical Oncology at Leicester, added: “As survival rates for prostate cancer continue to improve, reducing the long-term consequences of treatment is becoming increasingly important. This development could alter clinical practice as even modest reductions in side-effect rates could improve quality of life for thousands of cancer survivors every year.”

The approach could also extend beyond prostate cancer. Because circadian rhythms affect many biological processes involved in radiation response, similar strategies may eventually be used in other cancer types. If confirmed by future studies, genetically guided treatment scheduling could offer a simple, low-cost way of improving cancer care and the quality of life of cancer survivors worldwide.