which hour? Your body knows, based on a carefully calibrated internal clock that turns certain genes off and on throughout the day. Humans have known for a long time that some medicines are best used at different times of the day: caffeine In the morning, to name a few.
What if cancer pharmaceuticalAt times controlled specifically for individual patients, could it work better and reduce side effects?
That is the hope of the scientists working on “chronological chemotherapy.” But the researchers say that both scientific and practical issues mean the approach is not ready for prime time.
“We’re still kind of on the learning curve,” says Gian Campian, MD, a neuro-oncologist at the Mayo Clinic in Rochester, Minnesota.
The duration of the experiments
The challenge with cancer drugs is to maximize the killing of cancer cells while leaving healthy cells alive. The body’s natural internal clock can help reduce toxicity, says Frances Levy, an oncologist and researcher at the University of Paris-Saclay. The trick is to find a time when healthy cells are protected from drugs or are able to break them down into something that doesn’t harm them – but when cancer cells can’t. Cancer cells often have dysfunctional internal clocks, so they’re likely to be more susceptible to treatment during times when healthy cells are protected, Levy says.
One Cancer treatment Where the timing seems to make a difference is the combination of 6-mercaptopurine and methotrexate for certain types of blood cancer in children. For example, one study in 1985 found that 36 children who took medications in the morning were 4.6 times more likely to relapse than 82 children who took them in the evening. Based on these and other studies, doctors usually recommend taking this pair of medications in the evening.
But for most cancer drugs, the evidence for the effect of the time of day is weak or nonexistent.
Campian and colleagues recently asked if timing made a difference to the drug temozolomide In people with brain cancer glioblastoma. They already had data on people who took the drug in the morning or evening. This is because Campian is trained to tell patients to take it in the evening, so they can sleep due to unpleasant side effects like nausea, but other doctors I’ve worked with have suggested taking it in the morning.
When the researchers looked at 166 of their patients, they saw that the people who took temozolomide in the morning survived longer. That suggests timing makes a difference, but a retrospective study like this hardly proves an effect.
Then, the team began a new study, asking whether it would even be possible for patients to take their medication on a set schedule, and whether the medication would work best in the morning. In this small study, among 35 adults with brain tumors, participants recorded when they took the medications in a diary, showing that they got to 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 more than those who took it in the evening.
With conflicting results from two small studies, it is an open question as to whether the timing of temozolomide makes a difference. The next step is to return to the laboratory to better understand how the effectiveness of temozolomide differs circadian rhythms, says collaborator Eric Herzog, Ph.D., a biologist at Washington University in St. Louis. A much larger study would be necessary to test whether this type of chronotherapy actually works for people, and how much of a difference it makes.
Levy has already tested chronological chemotherapy 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 the intravenous timing, two of the drugs would peak in the early morning and one would be in the late afternoon.
The results were mixed. On the plus side, the men’s risk of dying was reduced by 25% in the given treatment. But among women, chronotherapy a plus Risk of early death by 38%.
The difference may be because circadian rhythms control genes differently in men and women, Levy says, resulting in a 5 to 6 hour difference in response to drugs.
Not so fast
Levy’s findings illustrate a major challenge with chrono-chemotherapy: How do you know when each person should get their medication? Should the dosing schedule be customized for each patient?
Sex is not the only issue. Some people are morning larks. Others are night owls. Researchers envision using activity monitors on patients’ wrists to learn about their unique schedules before prescribing scheduling chemotherapy.
Meanwhile, some cancers disrupt the body’s internal clock, which could make the chronological approach to chemotherapy moot.
There are also practical challenges in providing medicines on time.
You can take oral medications such as temozolomide any time you are awake. But what about drugs that require intravenous administration? It may be possible for hospital inpatients to receive timed treatments at any hour, says Belinda Mandrell, PhD, director of nursing research at St. Jude Children’s Research Hospital in Memphis. Levi prefers programmable drug pumps that can measure medications at home.
However, the biggest challenge is figuring out whether temporal chemotherapy is working at all. Aziz Sankar, MD, PhD, a biochemist at the University of North Carolina at Chapel Hill, has his doubts. He says more work needs to be done in cells and mice than before Clinical trials In suitable people.
“I’m not saying it will never work,” he says. “I think chronotherapy isn’t there yet, and I don’t know if there will ever be.”