Reacción a "Administering immunotherapy and chemotherapy in the morning could improve their effectiveness against lung cancer"

The article presents a retrospective study of patients with advanced non-small cell lung cancer (NSCLC). The randomized clinical trial was conducted with 210 patients and presented two therapeutic approaches:

• 105 patients treated before 3 pm.
• 105 patients treated after 3 pm.

The data show that patients treated in the first time slot, in the morning, had greater tumor-free survival and overall survival than those treated in the afternoon, with similar toxicity.

The work is of high quality and is led by leading scientists in the field. This includes oncologists specializing in chronotherapy, such as Dr. Zhang (Central South University, China), an expert in lung cancer; and Dr. Francis Levi (University of Paris-Saclay), whom we could call one of the pioneers of chronotherapy. and Dr. Scheiermann (University of Geneva), whose contributions to the field focus on describing the molecular mechanisms behind the effect of time of day on immunotherapy administration in preclinical models.

Chronotherapy is not a new therapeutic approach. The pioneering studies of Dr. Halberg in the 1970s and later Dr. Levi already demonstrated that drugs do not act the same way at every time of day. This evidence has taken a long time to gain traction in clinical practice and even in basic science, as chronotherapy has been viewed with some skepticism. We are currently experiencing a golden age in chronobiology and chronotherapy. There is increasing data that strongly supports Heraclitus's saying: "A man does not step into the same river twice," meaning that we are not the same at every time of day.

If we had the ability to take a molecular snapshot (and now we can, thanks to powerful 'omics' technologies) of each of us at different times of day, we would see that we are very different. This means that within a specific time window, we are more efficient at performing certain biological functions. If we translate this to clinical practice, the diagnosis of diseases is also dependent on the time of day. We are witnessing that the treatment of diseases is as well.

Not only is such a difference in response based on the time of day plausible, but it also has an indisputable biological basis. In the case of the study mentioned here, it refers to the efficacy of two of the administered drugs, which are immunotherapeutic agents (sintilimab and pembrozilumab), but this can be extended to other chemotherapeutic agents whose targets may be expressed at a specific time of day, according to molecular mechanisms that occur at a particular time. Dr. Scheiermann, the author of the study, previously described in preclinical models that anti-PD-1 therapy was more effective in the active phase, since ICAM-1, a molecule that helps the drug penetrate tumors, is expressed more during this phase. In other words, there is a time of day when the drug is more likely to reach the tumor because there is an agent that picks it up from the bloodstream and introduces it into the tissue—it's that simple.

We are beings of time, and therefore, not everything happens at any time of day.

This work helps to solidify an idea that is, a priori, easy to implement: that the same drug can be more effective because its activity is enhanced and/or its toxicity reduced if administered at a specific time of day. Of course, each drug and its optimal time of administration will have to be tested on specific tumors and their stages. There is still much to be done, but the window to understanding the molecular mechanisms and their testing and application in the clinic is now a reality.

[Regarding potential limitations] As I mentioned before, much remains to be studied and understood, considering that new studies must be conducted depending on the drug, tumor type, and stage. This study focuses on advanced-stage NSCLC, where several drugs, including sintilimab and pembrozilumab (immunotherapeutic agents), are used for chronomodulation. Therefore, the results cannot be extrapolated to other tumor environments, as each drug and each tumor presents a different chronobiological scenario. Furthermore, data reveal a different response to chronodirected treatments depending on sex, especially in hormone-dependent tumors. The gender dimension must also be considered in therapy, as must the patients' age.

Retrospective trials are necessary, and more hospitals should participate in these types of studies, but an understanding of the molecular mechanisms underlying the outcome is also needed.

Finally, hospitals must be prepared to administer chrono-directed therapy. This will require hospital management to integrate the concept of circadian medicine into their daily practice and implement it in the diagnosis and treatment of diseases.