Health

Does the timing of cancer chemotherapy appointments matter?


What time is it? Your body knows this, based on a carefully calibrated internal clock that turns certain genes on and off throughout the day. And humans have long known that certain drugs are best used at different times of the day: caffeine in the morning, to name one.

What if cancer drugs, given at specific times for each patient, could work better and reduce side effects?

This is the hope of scientists working on “chronochemotherapy”. But the researchers say scientific and practical issues mean the approach isn’t ready for prime time.

“We’re still kind of on the learning curve,” says Jian Campian, MD, a neuro-oncologist at Mayo Clinic in Rochester, MN.

Against the watch

The challenge with cancer drugs is to maximize the destruction of cancer cells while leaving healthy cells alive. The body’s natural internal clock could help limit toxicity, says Francis Lévi, MD, oncologist and researcher at Paris-Saclay University. The trick would be to find a time when the healthy cells are protected from the drugs or are able to break them down into something that doesn’t harm them – but the cancer cells can’t. Tumor cells often have dysfunctional internal clocks, so they’re likely to be more responsive to treatment at times when healthy cells are protected, Lévi says.

One cancer treatment where timing seems to make a difference is the combination of 6-mercaptopurine and methotrexate for certain types of leukemia in children. For example, a 1985 study found that the 36 children who took the drugs in the morning were 4.6 times more likely to relapse than the 82 children who took them in the evening. Based on this and other studies, doctors usually recommend taking this pair of drugs in the evening.

But for most cancer drugs, the evidence for a time-of-day effect is thin or non-existent.

Campian and colleagues recently asked whether timing makes 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 in the evening. That’s because Campian has been trained to tell patients to take it at night, so they can sleep despite nasty side effects like nausea, but other doctors she’s worked with have suggested taking it at night. morning.

When researchers looked at 166 of their patients, they found that people who took temozolomide in the morning survived longer. This suggests that timing makes a difference, but a retrospective study like this is hardly evidence of an effect.

Then the team started a new study, asking if it would even be possible for patients to take their medication on a specific schedule, and whether the medication would work better in the morning. In this small study, among 35 adults with brain tumours, participants noted when they took medication 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 did not survive longer than those who took it in the evening.

With conflicting results from two small studies, the question remains open whether the timing of temozolomide makes a difference. The next step is to return to the lab to better understand how the effectiveness of temozolomide may vary with circadian rhythms, says collaborator Erik Herzog, PhD, a biologist at Washington University in St. Louis. A much larger study would be needed to test whether this type of chronotherapy actually works in people, and what 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 drugs. The others received the same drugs, but with their intravenous injections timed so that two drugs peaked early in the morning and peaked in the afternoon.

The results have been mixed. On the positive side, the men’s risk of death dropped by 25% with the timed treatment. But in women, chronochemotherapy increase the risk of earlier death by 38%.

Levi says the difference may be because circadian rhythms control genes differently in men and women, resulting in a 5-6 hour difference in response to drugs.

not so fast

Lévi’s results illustrate a key challenge in chronochemotherapy: how do you know when each person should receive their medication? Does the dosing regimen need to be individualized for each patient?

Sex is not the only problem. Some people are morning larks. Others are night owls. Researchers plan to use activity monitors on patients’ wrists to determine their unique schedules before prescribing chronochemotherapy.

Meanwhile, some cancers disrupt the body’s internal clock, which could make a chronochemotherapy approach unnecessary.

There are also practical challenges in providing drugs under tight deadlines.

You can take oral medications like temozolomide whenever you are awake. But what about drugs that require IVs? According to Belinda Mandrell, PhD, director of nursing research at St. Jude Children’s Research Hospital in Memphis, it may be possible for hospitalized patients to receive timed therapies around the clock. Levi prefers programmable medication pumps that can dose medications at home.

The biggest challenge, however, is determining if chronochemotherapy works at all. Aziz Sancar, MD, PhD, a biochemist at the University of North Carolina at Chapel Hill, has doubts. He says more work in cells and mice should be done before clinical trials in humans are appropriate.

“I’m not saying it will never work,” he says. “I don’t think chronotherapy is here yet, and I don’t know if it ever will be.”


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