Administering immunotherapy in the morning seems to matter. Why?
74 comments
·June 8, 2025raylad
sixo
Amazing. And shameful (for them.)
ch4s3
It’s not shameful, it’s how evidence based medicine works. One case is interesting but not a basis for changing a protocol by itself. Tons of things could have influenced the outcome and you need a proper study to know that.
AbrahamParangi
The razor to use to determine whether something is actually evidenced based under uncertainty is whether you would follow the same policy if it was your own child.
There are many things that are simply uncertain and “untrue until proven otherwise” isn’t an exclusively optimal policy.
wyldfire
Though it could certainly inspire such a study.
echelon
> It’s not shameful, it’s how evidence based medicine works.
Yeah, but I'll bet nothing happened as an outcome of this. No study, no communication to anyone else. That information probably just withered on the vine.
I did a molecular bio undergrad and had classes with a bunch of pre-med students. They had zero interest in the science, just getting A's. They did care about appearance and money, driving cool cars, and dating hot partners. I know my experience is purely anecdotal and not indicative of all doctors, but I came away from my undergrad experience highly unimpressed with our medical feedstock. The only students in upper level electives that cared were the research-track students.
I talk to my doctors regularly about medicinal chemistry and biochem -- they don't know anything. It's embrassing how little they retain or care.
vkou
> And shameful (for them.)
1. A single positive outcome with N=1 should generally not be the basis for making a medical recommendation.
2. It takes a mountain of research work to go from that to a study that you can draw meaningful conclusions from.
3. The hospital is not in the business of doing research, it's in the business of treating patients.
tilne
Regarding 3: Shouldn’t the medical system be optimizing for patient outcomes rather than the business their in?
Regarding the first two: I think the anecdote being from 1995 suggests there would have been time to put together said mountain of research.
I’m not agreeing that this is shameful for the original doctor, but I do think it’s shameful if avenues for potential research are not taken because it’s inconvenient for the hospitals.
vlovich123
I agree n=1 generally isn’t enough, but something like this is easily something you ask for volunteers for as an experiment. There’s 0 risk, you’re taking the same drug. The only reason a given time is selected anyway is for administrative ease not because there’s medical requirements.
chiefalchemist
It shameful in the sense we all know there are circadian rhythms. We know the human body is not uniform from waking to shut eye. With this in mind health care therapies should be intentionally administered at various times - as wide as possible; from that perhaps outcomes will vary. You don’t need a study to look for opportunities to optimize a process.
unnamed76ri
I used to be on a chemo drug and had to take folic acid every day to stop it from doing bad things to me.
I had awful ulcers in my mouth from the chemo drug and had been taking the folic acid in the morning. Through forgetfulness I ended up shifting the folic acid to the afternoon and the ulcers went away and never came back.
tomcam
Thanks for sharing, and I’m very glad you are here to discuss it.
levocardia
Hazard ratio of 0.45 seems implausibly high, especially when it's just the exact same treatment dichotomized to before/after 3pm. My money is on something other than a real circadian effect: either the result of a 'fishing expedition' in the data, or some other variable that incidentally varies by time of day. Maybe breaking randomization, leaving the drugs out for too long at room temp, etc. If you really believe this is an important and biologically plausible effect it should be a top candidate for a replication attempt.
trhway
>some other variable that incidentally varies by time of day.
glucose level? low in the morning, and cancer likes glucose (among other effects of low glucose a cancer site would probably have lower local acidity, and the high local acidity is one of the tools used by cancer to protect and spread itself) .
jmward01
I wonder if other basic processes could be at play here like when patients go to the bathroom. If you do this in the morning they may be more likely to not need that for a while while in the evening they may do that immediately. I'm not saying this is the mechanism, just pointing out that there are a lot of timing dependent things in a person's schedule that could be a factor here. It is a great thing to point out though. I hope a lot more research goes into the idea of timing and integrating medication into a schedule most effectively.
rendaw
I'm doing CedarCure. You're required to not exercise or bath/shower for 2h after taking, which is fairly difficult in the morning, so I asked the doc if I could do it in the evening instead (despite explicit instructions to do it in the morning). The doc said it was fine, confirmed by the pharmacist.
I should know better by now than to trust doctors to act based on research and not gut feeling, but I hope this doesn't mean the last year of taking it was a wash...
iamtheworstdev
a brand new study comes out and you're mad the doctors didn't know about it a year ago?
do you carry any of the blame on yourself since you knew there were explicit instructions but apparently waiting to shower or exercise was too much of an inconvenience for you?
Nevermark
> I could do it in the evening instead (despite explicit instructions to do it in the morning)
Have either you or your doctor identified the reason for the morning recommendation?
Maybe restart consideration of timing there?
Doctors are going to take your practical need to break one part of protocol, to maintain the rest of the protocol, seriously. They can't resolve the practicalities of patients' lives.
detourdog
I looked up CedarCure and what I found is that it is a pesticide. What is the treatment about?
tines
OP is an insect going in for assisted suicide.
iamtheworstdev
looks like a sublingual immunotherapy treatment for allergies to japanese cedar pollen.
rendaw
It's an immunotherapy drug for cedar pollen allergy.
mjevans
Explicitly clear, but otherwise not overly specific, medication instructions would be best.
Say exactly what matters.
E.G. 'Take once a day at a similar time.' VS overly specific but not required 'take in the morning / evening / lunch / some other assumption that doesn't matter.' HOWEVER maybe "Take once a day with your first (full) meal." OR "Take once a day with your primary meal." might make more sense for medications that interact with food.
justsomehnguy
There is always an option what taking it in the evening is magnitudes better than not taking it in the morning at all because you skipped it because you need a shower.
Always remember what you are just an another patient with your own quirks.
tialaramex
For the drug I take every day (Levothyroxine), research found that evening was worse, but the explanation was poor compliance - people forget to do it more often compared to the morning. Same reason the contraceptive pill is less effective than you'd expect in real populations, compliance is poor. If you're the sort of person who can actually take it on time, every day, without fail, it's extremely effective, if you aren't, not so much. The choice to include "dummy" pills is because of improved compliance - remembering to take it every single day on the same schedule is just easier, so adjust the medication not the instructions.
pbhjpbhj
What annoys me here is that these things are hidden - if the patient knows that compliance is better (ie their chance of staying with the medicine and so of getting better) does it really reduce said compliance?
parsabg
I wonder if the same would also be true for immunosuppressants administered for autoimmune conditions. Given they mostly interact with the signaling pathways, I guess in theory they should also be more effective in the morning if there is more immune cell activity going on.
BDGC
If you’re interested in circadian biology, which underlies chronoimmunotherapy, please check out UCSD’s BioClock Studio. We create tutorial videos and other media to teach circadian biology concepts: https://bioclock.ucsd.edu/
egocodedinsol
Here’s a link to the abstract: https://ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.85...
apparently it was prospective and randomized. I’m a little shocked by the effect size.
munchler
This paper was not a retrospective analysis, it was a randomized clinical trial.
egocodedinsol
Yeah I’m checking - I saw several other oncologists suggesting song a separate discussion.
owenthejumper
Sicker patients get emergency treatment in the hospital in the afternoon while healthier ones in the morning in the clinic
georgeburdell
Not a medical doctor. Does this also have implications for other immunotherapy like allergy shots?
more_corn
Because the immune system sleeps at night and wakes up in the morning?
Laaas
Light affects us deeply. Very probably true for more than immunotherapy.
My father was on chemotherapy with fludarabine, a dna base analog. The way it functions is that it is used in DNA replication, but then doesn’t work, and the daughter cells die.
Typically, patients who get this drug experience a lot of adverse effects, including a highly suppressed immune system and risk of serious infections.
I researched whether there was a circadian rhythm in replication of either the cancer cells or the immune cells: lymphocyte and other progenitors, and found papers indicating that the cancer cells replicated continuously, but the progenitor cells replicated primarily during the day.
Based on this, we arranged for him to get the chemotherapy infusion in the evening, which took some doing, and the result was that his immune system was not suppressed in the subsequent rounds of chemo given using that schedule.
His doctor was very impressed, but said that since there was no clinical study, and it was inconvenient to do this, they would not be changing their protocol for other patients.
This was around 1995.