[HN Gopher] Administering immunotherapy in the morning seems to ...
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Administering immunotherapy in the morning seems to matter. Why?
Author : abhishaike
Score : 90 points
Date : 2025-06-08 16:18 UTC (6 hours ago)
(HTM) web link (www.owlposting.com)
(TXT) w3m dump (www.owlposting.com)
| zevets wrote:
| 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 wrote:
| 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 wrote:
| What does randomization mean in this context, and why does it
| fix those problems?
| NhanH wrote:
| Patients are assigned the time for their visits. The time
| itself is randomized
| ajkjk wrote:
| 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 wrote:
| 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 wrote:
| > _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 wrote:
| "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 wrote:
| I guess I'm asking, how do you randomize out the
| confounder in this case.
| ajkjk wrote:
| 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.
| kelnos wrote:
| 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 wrote:
| How does this control for the "alert nurses" variable? In
| that case, patients would do better in the morning,
| regardless of the patient.
| anigbrowl wrote:
| Why would you assume nurses are scheduled on a 9-5 basis?
| simmerup wrote:
| 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 wrote:
| 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 wrote:
| 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 wrote:
| > Yes, maybe morning nurses are fresher and more alert, but,
| again, randomization fixes that
|
| How does randomization fix that?
| finnh wrote:
| exactly. that one clause casts doubt on all the other
| reasoning; randomization controls for patient selection
| bias but not diurnal clinic performance
| gus_massa wrote:
| 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 wrote:
| 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 wrote:
| I can schedule appointments whenever I want. I'm an early
| riser and prefer my appointments first thing in the morning.
| JumpCrisscross wrote:
| > _mid-day appointments as also a luxury for those doing
| well_
|
| Irrelevant to this study given randomization.
| pbhjpbhj wrote:
| 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 wrote:
| 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 wrote:
| The appointment schedule was randomized, so your objection is
| incorrect.
| abhishaike wrote:
| 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 wrote:
| 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 wrote:
| I looked up CedarCure and what I found is that it is a
| pesticide. What is the treatment about?
| rendaw wrote:
| It's an immunotherapy drug for cedar pollen allergy.
| iamtheworstdev wrote:
| looks like a sublingual immunotherapy treatment for allergies
| to japanese cedar pollen.
| tines wrote:
| OP is an insect going in for assisted suicide.
| annoyingnoob wrote:
| https://synapse.inc/medicine/9101/
| justsomehnguy wrote:
| 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 wrote:
| 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 wrote:
| 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 wrote:
| 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 wrote:
| Where did they say they're mad?
| unaindz wrote:
| The last paragraph heavily implies it
| bjornasm wrote:
| They explicitly fault the doctor for not acting on research
| that wasn't available.
| mjevans wrote:
| 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 wrote:
| > 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 wrote:
| 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 wrote:
| 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 wrote:
| Thanks for sharing, and I'm very glad you are here to discuss
| it.
| Laaas wrote:
| Light affects us deeply. Very probably true for more than
| immunotherapy.
| NotGMan wrote:
| 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 wrote:
| 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 wrote:
| >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 wrote:
| 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 wrote:
| This paper was not a retrospective analysis, it was a
| randomized clinical trial.
| egocodedinsol wrote:
| Yeah I'm checking - I saw several other oncologists
| suggesting song a separate discussion.
| raylad wrote:
| 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 wrote:
| Amazing. And shameful (for them.)
| ch4s3 wrote:
| 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 wrote:
| Though it could certainly inspire such a study.
| ch4s3 wrote:
| 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 wrote:
| 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 wrote:
| 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.
| vkou wrote:
| > 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 wrote:
| 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 wrote:
| 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.
| BDGC wrote:
| 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 wrote:
| Sicker patients get emergency treatment in the hospital in the
| afternoon while healthier ones in the morning in the clinic
| georgeburdell wrote:
| Not a medical doctor. Does this also have implications for other
| immunotherapy like allergy shots?
| parsabg wrote:
| 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.
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