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 · 2h ago
Amazing. And shameful (for them.)
ch4s3 · 2h 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 · 1h ago
Though it could certainly inspire such a study.
ch4s3 · 1h 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 · 1h 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 · 26m ago
Even simple studies are expensive and difficult. You need IRB approval, data collection and organization, staff to go 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 · 2h 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 · 1h 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.
vlovich123 · 1h 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.
unnamed76ri · 4h 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 · 4h ago
Thanks for sharing, and I’m very glad you are here to discuss it.
levocardia · 3h 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 · 2h 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) .
jmward01 · 4h 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.
rendaw · 4h 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...
iamtheworstdev · 4h 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 · 4h ago
Where did they say they’re mad?
bjornasm · 3h ago
They explicitly fault the doctor for not acting on research that wasn't available.
unaindz · 3h ago
The last paragraph heavily implies it
Nevermark · 3h 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.
mjevans · 3h 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.
detourdog · 4h ago
I looked up CedarCure and what I found is that it is a pesticide. What is the treatment about?
tines · 4h ago
OP is an insect going in for assisted suicide.
iamtheworstdev · 4h ago
looks like a sublingual immunotherapy treatment for allergies to japanese cedar pollen.
rendaw · 4h ago
It's an immunotherapy drug for cedar pollen allergy.
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 · 4h 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 · 3h 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?
apparently it was prospective and randomized. I’m a little shocked by the effect size.
munchler · 3h ago
This paper was not a retrospective analysis, it was a randomized clinical trial.
egocodedinsol · 3h ago
Yeah I’m checking - I saw several other oncologists suggesting song a separate discussion.
BDGC · 2h 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 · 1h ago
Sicker patients get emergency treatment in the hospital in the afternoon while healthier ones in the morning in the clinic
Laaas · 3h ago
Light affects us deeply. Very probably true for more than immunotherapy.
zevets · 4h 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 · 4h 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 · 4h ago
What does randomization mean in this context, and why does it fix those problems?
The same thing it means in every context: that (with enough samples) you can control for confounders.
tines · 4h 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 · 3h 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 · 2h 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 · 2h ago
I guess I'm asking, how do you randomize out the confounder in this case.
ajkjk · 2h 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.
kelnos · 4h 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 · 4h ago
How does this control for the "alert nurses" variable? In that case, patients would do better in the morning, regardless of the patient.
d_tr · 3h 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".
anigbrowl · 3h ago
Why would you assume nurses are scheduled on a 9-5 basis?
simmerup · 3h 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 · 3h 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 :)
NhanH · 4h ago
Patients are assigned the time for their visits. The time itself is randomized
gus_massa · 2h 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?
leereeves · 4h ago
> Yes, maybe morning nurses are fresher and more alert, but, again, randomization fixes that
How does randomization fix that?
finnh · 4h ago
exactly. that one clause casts doubt on all the other reasoning; randomization controls for patient selection bias but not diurnal clinic performance
abhishaike · 3h 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
majormajor · 4h 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.
pbhjpbhj · 3h 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 · 2h 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.
JumpCrisscross · 3h ago
> mid-day appointments as also a luxury for those doing well
Irrelevant to this study given randomization.
detourdog · 4h ago
I can schedule appointments whenever I want. I'm an early riser and prefer my appointments first thing in the morning.
munchler · 3h ago
The appointment schedule was randomized, so your objection is incorrect.
NotGMan · 3h 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.
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.
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.
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.
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.
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) .
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...
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?
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.
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.
Always remember what you are just an another patient with your own quirks.
apparently it was prospective and randomized. I’m a little shocked by the effect size.
> 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.
The same thing it means in every context: that (with enough samples) you can control for confounders.
I think you're correct that randomising patient assignments doesn't control for provider-side confounders. Curious if the study also randomised nursing assignments.
Whether or not they controlled for nurse-alertness is something you'd have to read the paper (or assume the researchers are intelligent) for.
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.
How many patients dropped out? (Or requested a schedule change) Do they count like live or dead?
How does randomization fix that?
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
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.
Believe they are being treated like robots. Maybe even literally like gears rented by the hour, not even robots.
Irrelevant to this study given randomization.
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.