Does the timing of cancer chemotherapy appointments matter?

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

What if cancer drugs made available to individual patients at specific times could work better and reduce side effects?

That is the hope of the scientists working on “chronochemotherapy”. But researchers say both scientific and practical problems mean the approach isn’t prime-time ready.

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

time trial

The challenge with cancer drugs is to maximize the killing of cancer cells while keeping healthy ones alive. The body’s natural internal clock could help limit toxicity, says Dr. Francis Lévi, oncologist and researcher at the University of Paris-Saclay. The trick would be to find a time when healthy cells are protected from the drugs or can break them down into something that doesn’t harm them – while cancer cells can’t. Tumor cells often have disrupted internal clocks, so they’re likely more susceptible to treatment during 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 childhood leukemia. For example, a 1985 study found that the 36 children who took the medication in the morning were 4.6 times more likely to relapse than the 82 children who took it in the evening. Based on this and other studies, doctors usually recommend taking this drug in the evening.

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

Campian and colleagues recently asked whether timing makes a difference for the drug temozolomide in people with glioblastoma brain cancer. They already had data from people who took the drug in the morning or evening. That’s because Campian was trained to tell patients to take it in the evening so they could survive uncomfortable 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 found that the people who took temozolomide in the morning survived longer. That suggests timing does make a difference, but a retrospective study like this is hardly evidence of an effect.

Next, the team launched a new study, asking if it was even feasible for patients to take their medication on a specific schedule and if the medication worked better in the morning. In this small study of 35 adults with brain cancer, participants kept a journal to record when they took their medication, 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 survived no longer than those who took it in the evening.

Given conflicting results from two small studies, it’s an open question whether the timing of temozolomide makes a difference. The next step is to go back to the lab to better understand how temozolomide’s effectiveness might vary with circadian rhythms, says collaborator Dr. Erik Herzog, 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 how much of a difference it makes.

Lévi has tested chronochemotherapy on hundreds of people with colon cancer. Half of the 564 people in his study received standard care, including three drugs. The others received the same drugs, but their IVs were timed so that two drugs peaked in the early morning and one peaked in the afternoon.

The results were mixed. On a positive note, the men’s risk of death decreased by 25% with the timed treatment. But in women, chronochemotherapy elevated the risk of an earlier death by 38%.

Lévi says the difference could be because the circadian rhythm controls genes differently in men and women, resulting in a 5- to 6-hour difference in drug response.

Not so fast

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

Sex isn’t the only problem. 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 delivering tightly timed medicine.

You can take oral medications like temozolomide anytime you’re awake. But what about medications that require IVs? It could be possible that hospital inpatients are receiving tightly scheduled therapies every hour, says Belinda Mandrell, PhD, director of nursing research at St. Jude Children’s Research Hospital in Memphis. Lévi prefers programmable medication pumps that can dose medication at home.

The bigger challenge, however, is figuring out 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 should be done on cells and mice before human clinical trials are appropriate.

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



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