Cancer treatment before 3pm could help patients live longer

Giving cancer immunotherapy earlier in the day could actually prolong survival, according to the first randomized controlled trial on how the timing of such interventions affects patient outcomes.

Our body’s cells and tissues follow 24-hour cycles of activity, known as circadian rhythms, which affect everything from our mood to our metabolism and immune system.

More than a dozen observational studies found that cancer patients who happen to be given checkpoint inhibitors—a type of immunotherapy drug that helps certain immune cells kill cancer—appear to have a significantly lower risk of their condition worsening and leading to death.

but now Francis Levi at Paris-Saclay University in France and his colleagues conducted the first randomized controlled trial of chronotherapy—timing treatment according to circadian rhythms—using a combination of chemotherapy and immunotherapy cancer drugs.

The team recruited 210 people with non-small cell lung cancer, all of whom received four doses of pembrolizumab or sintilimab, two checkpoint inhibitors that work in the same way.

Every three weeks, half of the participants were given a dose before 3:00 p.m., while the rest had it later in the day. Shortly after each dose of immunotherapy, they all received chemotherapy, which kills rapidly dividing cells and is thought to be less affected by chronotherapy than immunotherapy.

These timings were maintained for the first four cycles of their so-called immunochemotherapy. After that, all participants continued to take the same drugs until their tumors got worse or until they no longer responded to the treatment, but they were not given at specific times. Previous studies suggest this focusing on the first four cycles is enough to substantially improve survival outcomes, a team member says Yongchang Zhang at Central South University in China.

The researchers followed the participants for an average of 29 months after the first dose of treatment. They found that those initially treated before 3pm survived an average of 28 months, while those initially treated later in the day survived an average of 17 months. “The effects are absolutely huge,” says Lévi. “It’s almost doubling the survival time.”

“If you compare the results to the landmark trials where the new drugs were approved, those drugs rarely have as much of an effect,” he says. The unnamed Pasquale at the University of Warwick in Great Britain. The design of this study suggests that shifting the timing of cancer treatment actually improves outcomes, he says. “It’s the strongest evidence of causality.”

The benefits may come from the fact that the immune cells targeted by these checkpoint inhibitors, called T-cells, tend to cluster around tumors in the morning before gradually migrating into the circulatory system later in the day, so when you give the immunotherapy earlier in the day, the T-cells are closer to the tumor and thus destroy more of it, Lévi says.

Further work should examine whether delivering cancer therapies at more specific times — say, at 11 a.m., rather than over several hours — has additional benefits, Lévi says. Having a wide window would clearly be more appropriate for busy hospitals, says Innominato.

We also need to discover whether controlling the timing of chemoimmunotherapy cycles after the first four can yield even greater benefits, Lévi says. Optimal timing can also vary between individuals, he says, such as those who identify as morning larks or night owls, whose immune systems can fluctuate significantly throughout the day.

Whether the results apply to different types of cancer is another open question. Innominato expects they will be similar among other cancers that affect the skin and bladder, as they are commonly treated with immunotherapy. But tweaking the timing of immunotherapy is unlikely to work for tumors that typically don’t respond to intervention, such as those affecting the prostate and pancreas, he says.

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