Researchers at The Christie NHS Foundation Trust have published one of the largest studies to date exploring whether the time-of-day cancer patients receive immunotherapy could influence how well treatment works.
The study, published in the British Journal of Cancer, analysed outcomes for 2,631 patients with advanced cancer who received immune checkpoint inhibitors at The Christie between January 2018 and December 2023.
The findings suggest patients who received most of their immunotherapy treatments earlier in the day experienced longer overall survival than those whose treatments were predominantly given later in the day.
However, researchers stress that the findings should be interpreted with caution and do not prove that morning treatment directly causes improved outcomes.
Professor Paul Lorigan, consultant medical oncologist at The Christie and senior author of the study, said: "The most important message from this research is that there appears to be a signal worth investigating further.
"Our findings suggest that patients receiving immunotherapy earlier in the day may have better outcomes than those receiving treatment later in the day. But this was a retrospective study, so we cannot conclude that timing alone is responsible."
Immune checkpoint inhibitors have transformed treatment for many cancers over the past decade by helping the body's immune system identify and attack cancer cells. However, doctors have long known that responses to immunotherapy vary significantly between patients and cancer types.
Increasingly, scientists are exploring whether circadian rhythms, the body's internal biological clock, may influence how the immune system functions and responds to treatment. Previous research has suggested that time of day can affect immune responses in areas ranging from vaccination to cancer therapy.
The Christie study is the largest single-centre analysis yet undertaken in this area. Researchers examined patients with advanced lung cancer, melanoma, kidney cancer, head and neck cancer and urothelial cancer who received immunotherapy either alone or in combination with other treatments.
Across the overall patient population, those classified in the ‘early’ treatment group had a median overall survival of 21.4 months compared with 13.1 months in the ‘late’ treatment group.
The association remained significant even after researchers used advanced statistical methods designed to reduce some of the biases that can affect retrospective studies.
Professor Lorigan said: "One of the strengths of this study is its size and the fact that we saw a broadly consistent pattern across several different tumour types.
"We also worked hard to account for known sources of bias and took external statistical advice. But there will always be limitations in studies that look back at existing patient data."
The researchers highlighted several possible explanations for the findings which will need further investigation.
Patients who are more unwell may require additional clinical review before treatment and therefore receive appointments later in the day. Travel difficulties, socioeconomic factors, frailty and other patient characteristics may also influence appointment times and outcomes independently of treatment timing.
Professor Lorigan said: "The timing of treatment could be linked to many factors beyond biology. It could reflect differences in a patient's health, their ability to travel, hospital scheduling systems or a range of other influences. Those are exactly the questions we need future studies to address."
Researchers also believe individual biology may prove important.
"Some people are naturally morning people, and some are evening people," said Professor Lorigan. "It may be that different patients respond differently according to their own biological rhythms. We simply don't know yet."
The Christie team is seeking funding for prospective randomised research designed to test the hypothesis under tightly controlled conditions. Working with colleagues at the University of Southampton and Cardiff University, researchers hope to study the question in patients with melanoma and haematological cancers. The programme would also include laboratory and translational research aimed at understanding any biological mechanisms that might explain the findings. A funding application for the next phase is currently under consideration.
The researchers stressed that patients should continue attending immunotherapy appointments as scheduled while further studies are undertaken and should not assume that a morning appointment would necessarily provide additional benefit.
"We are not advocating a change in how we treat people at present," Professor Lorigan said. "As with many observations in medicine, we now have a strong signal, but we still need rigorous evidence before changing clinical practice.
"If future research confirms these findings, any change would likely involve only the first 3 or 4 cycles of immunotherapy treatment. That means it could potentially be delivered through relatively straightforward scheduling changes, without major disruption to services or significant additional cost."
He added: "What makes this question particularly interesting is that, if the effect ultimately proves to be real, it could potentially improve outcomes without requiring a new drug, additional treatment or increased toxicity."
"But we are not there yet. The next step is to test this properly."
The study concludes that while the findings provide further evidence supporting a possible relationship between immunotherapy timing and patient outcomes, a large prospective randomised trial will be required to determine whether altering treatment schedules can genuinely improve survival.
Key facts
Analysis of 2,631 patients treated with immunotherapy at The Christie between 2018 and 2023.
Largest study of its kind to date according to the authors.
Median overall survival was 21.4 months for patients receiving most treatments earlier in the day versus 13.1 months for those receiving most treatments later in the day.
Findings span lung cancer, melanoma, kidney cancer, head and neck cancer and bladder cancer.
Authors explicitly state the findings are observational and that randomised trials are required to confirm them.