The trillions of cells in the human body run to the rhythm of an ever-ticking clock. This internal timepiece is known as the circadian rhythm, where "circadian" stems from the Latin words "circa diem," meaning "around a day." In roughly 24-hour cycles, the functions of the body's tissues fluctuate, and throughout the day and night, these oscillations in activity affect everything from blood pressure levels and hormone production to immune cell activity and energy metabolism.
Evidence suggests that cancer also tunes its activity to the circadian rhythm and that our internal clock influences how the body breaks down and reacts to drugs. These observations raise an important question: Does it matter what time of day you get cancer treatment? For instance, is there an optimal time to get chemotherapy when the treatment would be the safest and most effective?
The short answer is yes, probably. However, the field of "cancer chronotherapy" — aimed at figuring out how to optimally sync cancer treatment to the circadian rhythm — is still in its early days.
"I think it has huge potential, honestly," Katja Lamia, an associate professor of molecular medicine at Scripps Research in California, said of cancer chronotherapy. "I think that people don't really appreciate how much of a difference it can make, what time certain drugs are given."
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Past research by Lamia's lab demonstrated that the rate at which the liver processes metformin, a widely used type 2 diabetes drug, varies in time with the circadian rhythm in mice. A different study involving mice and human cells suggested that circadian clocks may broadly regulate how quickly the body breaks down drugs by helping control which drug metabolism-related genes are switched "on" or "off" at a given time. This affects how quickly mice metabolize ketamine, and thus how long the rodents stay asleep when given the anesthetic, the team found.
In the realm of cancer, Lamia's lab is currently investigating why circadian rhythm disruptions — such as those seen in night-shift workers — have been linked to an increased risk of cancer in observational studies. This risk may be related to the circadian rhythm's role in regulating the rate at which cells detect and repair damage in their DNA, the team suspects.
Several lines of evidence support the idea that circadian rhythm disruptions raise the risk of cancer, but the exact mechanisms driving this link still need to be uncovered, and they may vary among cancer types, according to a review published in March 2023 in the journal Trends in Cell Biology.
In addition, other research suggests that, once cancer is present in the body, its ability to metastasize, or spread, appears to fluctuate in daily cycles and may be regulated by the circadian rhythm. For example, breast cancer may be more likely to metastasize at night, while prostate cancer and multiple myeloma (a cancer of the white blood cells) may be most likely to spread during the day, according to a statement.
Since the 1980s, various research groups have conducted human studies of timed cancer therapies, aimed at finding the sweet spot where the patient experiences as few side effects as possible but gets the maximum benefit from their treatment.
According to the Trends in Cell Biology review, several studies of timed chemotherapy for metastatic colorectal cancer have shown success. Patients given an infusion of one chemotherapy drug during the day and another at night experienced fewer side effects and slightly increased survival times, compared with patients on a standard dosing schedule. Similarly, decreases in side effects were seen in ovarian cancer patients in a comparable trial, and improvements in survival time have been seen in trials with patients with acute lymphoblastic leukemia (a cancer of the blood and bone marrow) or glioblastoma (a type of brain cancer).
Notably, not all studies of timed chemotherapy have had positive results. For example, "some studies in patients with colorectal and ovarian cancer do not support previous research," the review noted.
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There have also been timed trials of immunotherapy, which works by lowering the invisibility cloak that cancer uses to hide from the immune system while also revving up the body's immune response.
In one study, melanoma patients received immunotherapy infusions either before 4:30 p.m. or after, and those in the earlier group had a "nearly doubled" overall survival times compared with the latter group. In a different trial involving non-small-cell lung cancer patients, those given immunotherapy before 12:45 p.m. "had quadrupled median progression-free and overall survival" times compared to those treated later in the day. These results are particularly interesting because immunotherapies hang around in the body for some time, so it's not entirely understood why the timing of administration seems to matter, the review authors noted.
Although these trials hint at the promise of cancer chronotherapy, much more research is needed before cancer doctors and researchers will be fully convinced of the concept, Lamia told Live Science. "We haven't gotten to where chemotherapy cancer experts are totally convinced," she said. "I think it's going to take a large clinical trial, which hasn't really been done yet."
The review authors wrote that, "although the idea of chronotherapy has brought much excitement, it is still viewed with caution owing to its historical partial success rate." To "fully unleash its potential on the clinical side," scientists will need to better understand how the circadian rhythm influences cancer progression, at a genetic and cellular level. For instance, researchers need to better understand how the internal clock controls the proliferation and release of metastasis-driving tumor cells into the bloodstream.
Lamia noted that more research is also needed to understand how a person's sex influences their optimal timing for cancer treatment, as some studies indicate that a person's sex may be a key factor to consider. There's also a broader question of how conditions in hospitals, which tend to be unfavorable for sleep, affect a patient's circadian rhythm and their cancer prognosis, she added.
In short, "we're still in early days" for cancer chronotherapy, Lamia said. Scientists have yet to uncover all the nuances of how the effects of different cancer drugs, designed to target distinct tumor types, might vary depending on the time of day they're given to patients.
"I think the potential impact of this area is really high," Lamia told Live Science. "But it's so complicated that it's going to take a lot of work to get to where we can really implement changes."
