Administering immunotherapy in the morning seems to matter. Why?

https://www.owlposting.com/p/the-time-of-day-that-immunotherapy

115•abhishaike•9h ago

Comments

zevets•7h ago

This is bad science. Patients schedule when they go to immunotherapy appointments. People who go in the morning are still working/doing things, where once you get _really_ sick, you end up scheduling mid-day, because its such a hassle to do anything at all.

vhanda•7h ago

From the article -

> this paper was not a retrospective study of electronic health records, it was a randomized clinical trial, which is the gold standard. This means that we’ll be forced to immediately throw away our list of other obvious complaints against this paper. Yes, healthier patients may come in the morning more often, but randomization fixes that. Yes, patients with better support systems may come in the morning more often, but randomization fixes that. Yes, maybe morning nurses are fresher and more alert, but, again, randomization fixes that.

tines•7h ago

What does randomization mean in this context, and why does it fix those problems?

NhanH•7h ago

Patients are assigned the time for their visits. The time itself is randomized

ajkjk•7h ago

https://en.wikipedia.org/wiki/Randomized_controlled_trial

The same thing it means in every context: that (with enough samples) you can control for confounders.

tines•7h ago

Supposing that patients did better in the morning because, say, the nurses were more alert, no matter how many samples you take you'll find the patients do better in the morning. How does "more samples" help control for confounders rather than just confirm a bias?

JumpCrisscross•7h ago

> How does "more samples" help control for confounders rather than just confirm a bias?

I think you're correct that randomising patient assignments doesn't control for provider-side confounders. Curious if the study also randomised nursing assignments.

ajkjk•5h ago

"more samples" is not what controls for confounders. Controlling for confounders is what controls for confounders, which you can only do with enough samples that you can randomize out the effect of the confounder.

Whether or not they controlled for nurse-alertness is something you'd have to read the paper (or assume the researchers are intelligent) for.

tines•5h ago

I guess I'm asking, how do you randomize out the confounder in this case.

ajkjk•5h ago

I imagine that that particular confounder is not possible to eliminate via randomization. Perhaps you collect a bunch of data on nurse awakeness--day shift vs night-shift, measuring alertness somehow, or measuring them on other activities known to be influenced by alertness--and then ensure your results don't correlate with that.

There is also the mechanistic side: if you have lots of plausible mechanism for what's going on, and you can detect indicators for it that don't seem to correlate with nurse alertness, that's a vote against it mattering. Same if you have of lots of expertise on the ground and they can attest that nurse alertness doesn't seem to have an affect. There are lots of ways, basically, to reach pretty good confidence about that, but they might not be as rigorous as randomized assignments can be.

bravesoul2•24m ago

Have every dose be observed by another doctor?

kelnos•7h ago

Patients in the study are randomly assigned to the early group or the late group. They don't get to schedule their own appointments for whatever time of day they want.

tines•7h ago

How does this control for the "alert nurses" variable? In that case, patients would do better in the morning, regardless of the patient.

anigbrowl•7h ago

Why would you assume nurses are scheduled on a 9-5 basis?

simmerup•7h ago

Why do you think you're going to poke holes in a research article when you've clearly only just heard of the concept and havent even read the article

tines•6h ago

If I thought I could poke holes in the research, I wouldn't be posting on HN. I'm asking questions to learn because obviously I don't understand :)

d_tr•6h ago

Based on these graphs and the differences in outcomes they show, you are not talking about "alert vs less alert" nurses but about "nurses doing their job vs nurses basically slowly killing dozens of patients".

leereeves•7h ago

> Yes, maybe morning nurses are fresher and more alert, but, again, randomization fixes that

How does randomization fix that?

finnh•7h ago

exactly. that one clause casts doubt on all the other reasoning; randomization controls for patient selection bias but not diurnal clinic performance

gus_massa•5h ago

How many dose this treatment has? How many between them?

How many patients dropped out? (Or requested a schedule change) Do they count like live or dead?

majormajor•7h ago

I always have seen mid-day appointments as also a luxury for those doing well (at least professionally/financially). If you have to go first thing in the morning, it's often because your boss wants you in relatively early and won't let you take time mid-day. If you're in a position where you can go in at 2PM and not have to sacrifice sleep to do so, that feels healthier.

Given the highly-evident strong circular nature of the body, a hypothesis that it has something to do with that seems highly likely, certainly worth following up on.

detourdog•7h ago

I can schedule appointments whenever I want. I'm an early riser and prefer my appointments first thing in the morning.

JumpCrisscross•7h ago

> mid-day appointments as also a luxury for those doing well

Irrelevant to this study given randomization.

pbhjpbhj•6h ago

Surely your boss legally has to let you attend a health appointment? Though they might not have to pay you. That seems like a very basic workers right, the sort of thing you'd have a general strike over if it didn't exist??

mjevans•6h ago

The most vulnerable, at least among those who have a job at least, often have the most draconian restrictions on when and what they can do.

Believe they are being treated like robots. Maybe even literally like gears rented by the hour, not even robots.

munchler•6h ago

The appointment schedule was randomized, so your objection is incorrect.

abhishaike•6h ago

Writer of the article here: randomization fixes most of this, but the other commenters are correct in that doesnt fully account for the clinic performance (e.g. nurse performance, which does dip during the night according to the literature). I previously thought it wasn't a major issue for clinical trials, since a separate team independent from the main ward are giving the drugs, but there isn't super strong evidence to support that. I will update the article to admit this!

This said, I am inclined to believe that this isn't a major concern for chronotherapy studies, since I haven't yet seen it being raised in any paper yet as a concern and the results seem far too strong to blame entirely on 'night nurses make more mistakes'. Fully possible that that is the case! I just am on the other side of it

rendaw•7h ago

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...

detourdog•7h ago

I looked up CedarCure and what I found is that it is a pesticide. What is the treatment about?

rendaw•7h ago

It's an immunotherapy drug for cedar pollen allergy.

iamtheworstdev•7h ago

looks like a sublingual immunotherapy treatment for allergies to japanese cedar pollen.

tines•7h ago

OP is an insect going in for assisted suicide.

annoyingnoob•7h ago

https://synapse.inc/medicine/9101/

justsomehnguy•7h ago

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•7h ago

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•6h ago

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?

iamtheworstdev•7h ago

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?

tomcam•7h ago

Where did they say they’re mad?

unaindz•6h ago

The last paragraph heavily implies it

bjornasm•6h ago

They explicitly fault the doctor for not acting on research that wasn't available.

mjevans•6h ago

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.

Nevermark•6h ago

> 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.

jmward01•7h ago

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.

unnamed76ri•7h ago

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•7h ago

Thanks for sharing, and I’m very glad you are here to discuss it.

Laaas•7h ago

Light affects us deeply. Very probably true for more than immunotherapy.

NotGMan•7h ago

Perhaps it's due to overnight fasting, that people in the morning don't eat yet/as much?

Autophagy is increased during fasting, it usually takes 3 days of water fasting to fully ramp up to its maximum, so no food overnight might just slightly start it up.

I watched a youtube video of guy who did low carb and fasted at least 24h before and after chemo (or even 48h, forgot which) and he didn't experience the negative side effects of chemo as much.

levocardia•6h ago

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•5h ago

>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) .

egocodedinsol•6h ago

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•6h ago

This paper was not a retrospective analysis, it was a randomized clinical trial.

egocodedinsol•6h ago

Yeah I’m checking - I saw several other oncologists suggesting song a separate discussion.

raylad•6h ago

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.

sixo•5h ago

Amazing. And shameful (for them.)

ch4s3•5h ago

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.

wyldfire•4h ago

Though it could certainly inspire such a study.

ch4s3•4h ago

Sure, but someone needs to fund, organize, and conduct the study. If you're not at a research hospital it's not as easy for a one off case to generate a study.

vlovich123•4h ago

This is a fairly innocuous change the doctor should be organizing on their own to publish a pilot study. In terms of funding very little would be required since you’re just making a small adjustment to when an existing drug regimen is happening which you already isn’t a controlled factor requiring FDA oversight or anything.

_qua•3h ago

Even simple studies are expensive and difficult. You need IRB approval, data collection and organization, staff to do those things. It seems simple from the outside but making it happen takes time, effort, and money which then means also applying for grants which is a process in and of itself.

echelon•1h ago

It's no wonder biology hasn't even entered into the punch-card phase.

When I did my bio undergrad I was keenly aware our bodies are just scaled up molecular machines. I was hoping for a future where we'd grow MHC-neutral clonal bodies for organ harvesting.

Nope. We're in the stone age.

_qua•46m ago

Move fast and break things in human medicine means unethical researchers maim and kill people, often marginalized people. Nazis, Japanese experimenting on prisoners, Tuskegee airmen syphilis experiments, Cincinnati radiation experiments and many others stand as testament to what ambitious unethical scientists will do to further their knowledge and career. Thus we have strict guardrails that slow down how we do things.

echelon•32m ago

We've been able to clone mammals for 30 years and haven't acted on it. We're still toying with molecular systems beyond the limit of detection.

Clone humans. Cut off their brain stem during development. Turn off cephalization signals for good measure. Scale it up to industrial scale.

Research problems solved.

We'd have every study at our fingertips. We'd have organs and tissue and blood for everyone.

We could possibly even do whole head transplants and cure all non-blood, non-brain cancers.

But we're playing in the sand.

more_corn•2h ago

Or you could consider if there’s reason to believe there’s a causal relationship, if there is you could change your protocol (offer it in the evening as an option), measure the improvement, publish the result and simultaneously improve your patient outcomes and move science forward.

daveguy•57m ago

That's why doctors publish case studies all the time -- to inspire larger scale and statistically sound studies.

AbrahamParangi•2h ago

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.

echelon•1h ago

> 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•5h ago

> 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•4h ago

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.

vkou•2h ago

Yes, it should.

But cost is also important to patients. Or it would be in any universe that made sense.

vlovich123•4h ago

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.

vkou•2h ago

Its not easy to ask if it messes with staff scheduling.

chiefalchemist•2h ago

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.

bravesoul2•30m ago

What's the p value? 0.5?

BDGC•5h ago

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/

owenthejumper•4h ago

Sicker patients get emergency treatment in the hospital in the afternoon while healthier ones in the morning in the clinic

georgeburdell•3h ago

Not a medical doctor. Does this also have implications for other immunotherapy like allergy shots?

parsabg•2h ago

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.

more_corn•2h ago

Because the immune system sleeps at night and wakes up in the morning?

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