Better Brain Tumor Outcomes With Morning Rather Than Evening Chemotherapy

“Timing” can make a difference in cancer treatment. This has in fact been studied quite intensively for several years. The 2015 Nobel Prize in Chemistry laureate, Prof. Dr. Aziz Sancar, whose studies showed that DNA repair varies according to our biological clock, brought chronotherapy to the world as a concept. Later, the 2017 Nobel Prize in Medicine was likewise awarded for discovering the biological effects of circadian rhythm. Such basic-science discoveries prompted us to consider how to use our biological clock in cancer treatment. Results from the first clinical studies on this subject have now begun to arrive. 

On 2 March 2021, Neuro-Oncology Advance published a new study showing that patients with the brain tumor glioblastoma had markedly improved disease outcomes when temozolomide chemotherapy was given in the morning rather than in the evening.

The findings come from a single-center retrospective review of glioblastoma patients who had undergone surgery and chemoradiotherapy and were subsequently prescribed maintenance treatment with oral temozolomide.

Overall, patients taking the drug in the morning had median overall survival of about 17 months, compared with 13.5 months when it was taken in the evening.

The difference was more pronounced in a subgroup of 56 patients with MGMT-methylated tumors: median overall survival was about 25.5 months with morning temozolomide and 19.5 months with evening dosing.

Note: MGMT methylation or an IDH mutation in glioblastoma has been associated with a better disease course and better response to treatments.

The researchers stated that both of these operating-system differences were statistically significant.

However, the overall survival difference was not significant in the subgroup of 95 patients with unmethylated tumors (median overall survival of 1.06 years with morning dosing and 1.04 years in the evening).

Although the results contain data from only one center, they make further evaluation of the potential of circadian medicine in glioblastoma worthwhile.

Chronotherapy – A Topic Worth Discussing With Patients

This is an important observation, but the results should be retested in a prospective, multicenter study.

Many brain tumor patients normally take temozolomidie in the evening with an anti-nausea drug and then go to sleep.

Glioblastoma is known as one of the most aggressive cancers, and gaining 6 months of survival is very important. Something as simple as changing the timing of a drug is therefore certainly worth further study. If such a study is planned, patients should be well informed and part of the decision.

Why Is Timing Important in Cancer Treatment?

There are several theories about why morning and evening doses differ: 

One of the study's lead authors, Prof. Dr. Erik herzog, said, "In an earlier study, we found that glioblastoma cell lines in a dish have daily circadian rhythms of sensitivity to temozolomide. This suggests that a daily rhythm can emerge within the tumor."

He explained, for example, that the circadian clock can alter temozolomide-induced DNA damage, the ability of cells to repair DNA damage and even their tendency to undergo apoptosis (programmed cell death).

Daily rhythms in the abundance or activity of DNA repair enzymes such as ATM or MGMT may produce these results. We also know that blood-brain barrier permeability changes with biological rhythm. All these potential circadian mechanisms appear to affect temozolomiidn being more effective when taken in the morning.

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