AN HOUR is not the same: administering immunotherapy in the morning is different from administering it in the evening. In the sense that the response to treatment is different: in terms of overall survival and progression-free survival. This is suggested by a study published in Lancet Oncology showing how, in patients with metastatic melanoma, checkpoint inhibitors – ipilimumab, nivolumab, or pembrolizumab, alone or in combination – work more when infused during the day than in the late afternoon or evening.
Better before 16.30
The authors of the research (which was funded by the National Institutes of Health, the American Society for Radiation Oncology, the Melanoma Research Alliance, and the Winship Cancer Institute) analyzed information from 299 men and women over the age of 18 and diagnosed. of stage IV melanoma followed at the Winship Cancer Institute of Emory University in Atlanta between 2012 and 2020, drawing them from the MEMOIR – Melanoma Outcomes Following Immunotherapy database. They thus observed that those who had received at least 20% of the infusions after 16.30 had a reduced overall survival compared to those who had received at least 20% of the treatments before that time: the 5-year survival was in fact 49% for the former and 68% for the latter. Disease progression, assessed at one year, was also 40% in patients with multiple evening infusions, and 56% in those with multiple daytime infusions. Finally, for those who had received more administrations after 16.30 the response rate was also lower: 22% versus 34%.
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Less robust immune responses in the evening
The study has several limitations for which the data will need to be confirmed: it is monocentric (i.e. all patients were recruited in a single hospital) and retrospective (retrospective studies bring with them a certain imprecision). “However, the findings are in line with a growing body of evidence indicating that immune responses are less robust when stimulated in the evening,” the authors report. Although prospective studies should be considered on the timing of immunotherapies – they added – “in the context of multidisciplinary management of advanced melanoma, the idea of planning treatments until the early part of the afternoon could be considered”.
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“The study is extremely interesting because it takes up the concept of circadian modulation that was very popular in the seventies and then underwent a drastic downsizing at the end of the eighties”, he comments Paolo Marchetti, oncologist and endocrinologist, scientific director of the IDI-IRCCS in Rome. In those years, many works were published indicating that some drugs undergo a different metabolism depending on the time of administration. Indeed, many studies show that efficacy and toxicity are different according to the circadian rhythm, that is, according to the greater or lesser metabolic activity of the cells according to the time of drug intake. “A phenomenon of this type has never been described in the field of immuno-oncology, but it is certainly the same for the cells of the immune system. As colleagues have speculated, the activity of these cells differs according to the time of day. And this may have determined a different response of patients to the treatments that act precisely on that system “.
Lung cancer: effective immunotherapy in ‘real life’
It must be said that this problem in Italy is not very relevant given that in our country day hospital therapies are usually administered in the morning “, underlines Marchetti:” However, regardless of this aspect, it is an interesting research starting point because it makes us understand that in addition to what we observe there is a world that we still do not know how to interpret but that negatively interferes with the therapeutic opportunities available to patients, even in the presence of extraordinarily effective treatments “.
Lsposoma
This study reopens the issue of evaluating treatments not only in terms of what we see but also in terms of other aspects that we do not take into consideration but which play an important role in oncological treatments, and which are defined as exposome. Exposome is the set of factors that influence our organism and that concern the internal environment in which we are immersed – mutations, DNA transcription mechanisms, etc. – but also the external one: pollution, nutrition and characteristics of the microbiota, styles of life, drugs we take and obviously also the circadian rhythm. We know, for example, that patients who undergo antibiotic therapy and therefore modify their microbiota have a lower response to immunotherapy, the same thing happens with high doses of cortisones. And the different activity of the immune system cells at different times of the day could also have a significant influence. “Today – concludes the oncologist – all our attention is placed on the internal exposome, but the path we must take at this moment is to collect as much information as possible, the most diverse and disparate, on the entire life of our patients, because most likely it is there that the answer to a considerable part of the resistance to treatments could be found “.
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