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What time is it? Your body knows, based on a carefully calibrated internal clock that turns certain genes off and on throughout the day. And humans have long known that certain medicines are best used at different times of day: caffeine in the morning, to name one.
What if cancer medications, provided at specifically tuned times for individual patients, could work better and reduce side effects?
That’s the hope of scientists working on “chronochemotherapy.” But researchers say that both scientific and practical issues mean the approach isn’t ready for prime time.
“We’re still kind of in the learning curve,” says Jian Campian, MD, a neuro-oncologist at the Mayo Clinic in Rochester, MN.
Time Trials
The challenge with cancer medications is to maximize the killing of cancer cells while leaving healthy ones alive. The body’s natural internal clock could help limit toxicity, says Francis Lévi, MD, an oncologist and researcher at Paris-Saclay University. The trick would be to find a time when healthy cells are protected against the drugs or are able to break them down into something that doesn’t harm them – but while cancer cells can’t do that. Tumor cells often have dysfunctional internal clocks, so they’re likely to be more susceptible to treatment at times when healthy cells are protected, says Lévi.
One cancer treatment where timing seems to make a difference is with the combination of 6-mercaptopurine and methotrexate for certain types of leukemia in children. For example, one study in 1985 found that the 36 children who took the drugs in the morning were 4.6 times more likely to relapse than the 82 kids who took it in the evening. Based on this and other studies, doctors usually recommend taking this pair of meds in the evening.
But for most cancer meds, evidence for an effect of time of day is thin or nonexistent.
Campian and colleagues recently asked whether timing made a difference for the drug temozolomide in people with the brain cancer glioblastoma. They already had data on people who took the drug in the morning or the evening. That’s because Campian was trained to tell patients to take it in the evening, so they could sleep through unpleasant side effects like nausea, but other doctors she worked with suggested taking it in the morning.
When the researchers looked back at 166 of their patients, they saw that the people who took temozolomide in the morning survived longer. That suggests the timing makes a difference, but a looking-back study like this is hardly proof of an effect.
Next, the team started a new study, asking whether it would even be feasible for patients to take their meds on a specific time schedule, and if the drug would work better in the morning. In this small study, among 35 adults with brain tumors, participants recorded when they took meds in a diary, which showed they hit the right time of day more than 90% of the time. The results differed from the previous study, in that people who took the drug in the morning didn’t survive any longer than those who took it in the evening.
With conflicting results from two small studies, it’s an open question as to whether timing temozolomide makes a difference. The next step is to go back into the laboratory to understand better how temozolomide efficacy might vary with circadian rhythms, says collaborator Erik Herzog, PhD, a biologist at Washington University in St. Louis. A much larger study would be necessary to test whether this type of chronotherapy does indeed work in people, and how much of a difference it makes.
Lévi has already tested chronochemotherapy in hundreds of people with colorectal cancer. Half of the 564 people in his trial received the standard treatment, including three medications. The others received the same drugs, but with their IVs timed so two meds would peak early in the morning and one would be at maximum in the afternoon.
The results were mixed. On the positive side, men’s risk of death dropped by 25% on the timed treatment. But among women, the chronochemotherapy increased the risk of earlier death by 38%.
Lévi says the difference may be because circadian rhythms control genes differently in men and women, leading to a 5- to 6-hour difference in response to medications.
Not So Fast
Lévi’s results illustrate a key challenge in chronochemotherapy: How do you know when each person should get their meds? Must the dosing schedule be personalized for each patient?
Sex isn’t the only issue. Some people are morning larks. Others are night owls. Researchers envision using activity monitors on patients’ wrists to figure out their unique schedules before prescribing chronochemotherapy.
Meanwhile, some cancers disrupt the body’s internal clock, which could make a chronochemotherapy approach moot.
There are also practical challenges in providing tightly timed medicine.
You could take oral medications like temozolomide any time you’re awake. But what about drugs that require IVs? It could be possible for hospital inpatients to receive tightly timed therapies at any hour, says Belinda Mandrell, PhD, director of nursing research at St. Jude Children’s Research Hospital in Memphis. Lévi prefers programmable drug pumps that can meter out meds at home.
The bigger challenge, though, is to figure out if chronochemotherapy works at all. Aziz Sancar, MD, PhD, a biochemist at the University of North Carolina in Chapel Hill, has doubts. He says more work in cells and mice should be done before clinical trials in people are appropriate.
“I don’t say it’ll never work,” he says. “I think chronotherapy is not there yet, and I don’t know if it’ll ever be there.”
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