Chronomodulated Chemotherapy; or Everything Wrong With Medical Research

[Esquire]

I'm working on some allied subjects lately (at my job) and thought this was simultaneously too neat not to share and too infuriating a soapbox not to stand up on. I'm interested to hear people's reactions to and/or thoughts on the subject.

Chronomodulated chemotherapy (chronotherapy, for short) basically consists of taking advantage of patient's individual circadian rhythms (sleep cycles, most usually, and the less obvious processes that go into them) in order to make treatments more effective, less toxic, or both. The idea is that you time treatments such that the biological pathways that carry drugs to where they need to go in the body (tumor cells) are maximally open and the pathways that make, for example, your hair fall out and your stomach malfunction are minimally open. There's all sorts of need logistics being worked out to support this - programmable timed injectors, personalization of chronotherapy regimens based on individual rhythm variation, different (and different from non-cancerous cells) rhythms in different cancers, etc. The inspiration is interesting, too - Francis Levi, the French physician who invented it, claims to have gotten the idea from listening to somebody talking about qi flows in traditional Chinese medicine.

There's been numerous clinical trials, especially in Europe and Asia, and the results are uniformly and overwhelmingly positive: essentially in all cases and all cancers studied, chronotherapy hugely increases life expectancy, decreases serious negative effects, and generally kicks cancer's ass: some of the studies find 200% effect sizes; you can literally live twice as long with, say, brain cancer if your oncologist administers the same drugs slightly differently.

What makes me mad is that this is not a new idea. The foundational animal trials came out in the 1950s, I think; Levi started publishing in the mid-1970s, and at this point probably dozens of Phase III trials have been concluded and, across all those thousands of patients and tens of thousands of natural-experiment and animal datapoints none of them (that I've seen) has ever had any negative reaction to chronotherapy (as opposed to standard chemotherapy) whatsoever. The U.S. oncological community has basically just missed the whole development of the field, with God knows how many unnecessary dead patients as a result, never mind improved survival times and quality of life for those who would have died anyway. I can't make sense of it, except as some bizarre product of academic and organizational siloing, and I think we're approaching the point where not making chronotherapy the standard procedure is actually a violation of medical ethics. Thoughts, questions, suggestions for ways forward? I'm particularly interested in what you all think of my presentation of the issue; I'm not always the best at avoiding jargon.

[Esquire]

Addendum: I can put together a more detailed literature review if anybody's interested; I'm doing the research for work anyway and it wouldn't be hard to collate everything.

[Zixinus]

So why IS chronotherapy not an adapted practice? What is preventing the practice from being adopted? It upsets the figures of the insurance company or what? Is there doubt about its effectiveness in the US medical community?

[Esquire]

No data exist which shed useful light on the subject - again, that I've been able to find, anyway. My personal theory is that it's an academic and administrative siloing issue; the people who read French and German oncology journals and the people who make treatment schedules (or work schedules, more probably) simply don't ever sit down and talk about this sort of thing. Chronotherapy will, obscenely, be impossible to implement until 100% of stakeholders are fully convinced of its necessity, because any one of (oncologists, administrators, medical union reps, etc.) being less than full-throatedly in favor will result in failure. Policy inertia is a powerful thing.

In case you couldn't tell, I'm having a bit of a crisis of confidence re: research practices generally; I gave a speech something like the OP to a room full of oncology fellows and residents and got blank stares in return. See above; this is neither new nor obscure, globally speaking, and yet there's no dissemination/implementation progress in this country.

[mr friendly guy]

Is it a logistical issue?

I imagine if the chemo needs to be administered outside of office hours, its difficult to do in an outpatient setting. You would obviously need some type of device which I can't imagine will be cheap (assuming the chemo is not the oral variety). The alternative to do it as an inpatient may make it logistically easier, ie staff can administer the chemo, but it also has its own problems. For example not all nurses can handle chemo (assuming its not a tablet form), there is also the risk of having less doctors around out of office hours even in a hospital so if there is a reaction it could be a bigger problem, or you have the oncology team on site after hours and pay them more, as well as paying for the extra hospital stay.

It would be interesting to see a cost benefits analysis of this.

[Broomstick]

So why IS chronotherapy not an adapted practice? What is preventing the practice from being adopted? It upsets the figures of the insurance company or what? Is there doubt about its effectiveness in the US medical community?

My guess is that a LOT of acute/intensive medicine is done on a timeline/schedule convenient to the doctor(s) or institution and not to the patient. Based largely on observing family members go through various medical adventures including most recently my spouse and chemotherapy for his cancer.

Mind you, cancer therapy is in many ways tailored to the individual patient, but it's all done on time schedules set by the doctors/institutions. The infrastructure is simply not set up to accommodate the patient's circadian rhythms.

[Broomstick]

I imagine if the chemo needs to be administered outside of office hours, its difficult to do in an outpatient setting. You would obviously need some type of device which I can't imagine will be cheap (assuming the chemo is not the oral variety). The alternative to do it as an inpatient may make it logistically easier, ie staff can administer the chemo, but it also has its own problems. For example not all nurses can handle chemo (assuming its not a tablet form), there is also the risk of having less doctors around out of office hours even in a hospital so if there is a reaction it could be a bigger problem, or you have the oncology team on site after hours and pay them more, as well as paying for the extra hospital stay.

Chemo is insanely toxic shit. It requires a whole separate set of equipment - some chemo agents will dissolve normal medical tubing, it can cause chemical burns to skin, it requires special gloves (I bought some for when I was doing home care for my husband while he was on chemo - all his bodily fluids from tears to spit to piss to sweat because toxic to some degree for several days after a treatment), it requires separate cleaning linens, separation of trash... The personnel who mix it, handle it, and administer it require training specific to it. They DO use "devices" during the administration, IV pumps, sometimes more than one if multiple agents are used at once. When my husband received it as an inpatient they had oncology-specifc and trained nurses administer it, not the regular floor nurses or aides.

So I expect there are logistical/staffing problems at work here.

[Esquire]

This is from my phone, so I apologize for the lack of proper quotation. Basically, yes; it's a pure logistics issue (that's my interpretation, anyway). People with access to/command of cutting-edge literature aren't generally in the position to make systematic changes, and vice-versa; additionally there simply aren't as many medically-inclined neurobiologists (&etc, this is a complex subfield) as we'd need.

Broomstick, quite right on all counts; I'll expand on technological supports for chronotherapy practices later, but basically the state of the art right now appears to be individually-programmed computer-controlled drug injectors for chronotherapy regimens; with sufficient pre-treatment study, individual circadian rhythm, biopathway, and other data can be usefully integrated. A triumph of (extremely rudimentary) personalizalso,

Also, from this thread and Venting - I'm profoundly sorry to hear about your family's misfortunes, and if I can help in any way I'd consider it an honor. If nothing else, please feel free to let me know if you'd like any more in-depth information on your husband's condition, I've had some experience with your side of the situation and I found more and better information helpful.

[mr friendly guy]

@Broomstick

When I say devices I am thinking of IV pumps. If we ever get to home administration I imagine it would have to have something preloaded, and easy to transport to the patient's house and preprogrammed for a particular agent. This of course would require some work to set up.

[Alyrium Denryle]

Addendum: I can put together a more detailed literature review if anybody's interested; I'm doing the research for work anyway and it wouldn't be hard to collate everything.

Do it.

No data exist which shed useful light on the subject - again, that I've been able to find, anyway. My personal theory is that it's an academic and administrative siloing issue; the people who read French and German oncology journals and the people who make treatment schedules (or work schedules, more probably) simply don't ever sit down and talk about this sort of thing. Chronotherapy will, obscenely, be impossible to implement until 100% of stakeholders are fully convinced of its necessity, because any one of (oncologists, administrators, medical union reps, etc.) being less than full-throatedly in favor will result in failure. Policy inertia is a powerful thing.

In case you couldn't tell, I'm having a bit of a crisis of confidence re: research practices generally; I gave a speech something like the OP to a room full of oncology fellows and residents and got blank stares in return. See above; this is neither new nor obscure, globally speaking, and yet there's no dissemination/implementation progress in this country.

That seems about right to me.

Medical administrators probably don't read actual research journals, let alone in French or German. Practicing doctors probably don't read much outside their native language (they have to prune somehow...) so it is only the medical researchers who read this stuff.

What you might want to do is not just write up a literature review for us (but you should definitely do that), but write one up for JAMA or The Lancet. That, literally everyone will read.

[Broomstick]

Also, from this thread and Venting - I'm profoundly sorry to hear about your family's misfortunes, and if I can help in any way I'd consider it an honor. If nothing else, please feel free to let me know if you'd like any more in-depth information on your husband's condition, I've had some experience with your side of the situation and I found more and better information helpful.

Thank you, but at this point there isn't that much more to do beyond comfort measures. He has a particularly aggressive and fast-moving cancer. The chemo had some use, it did reduce many symptoms caused by the cancer and I believe it extended his life at least a couple months, but not everything can be fixed. IF he can build up some strength he might be a candidate for the new immunotherapy approved last May.

Right now I'm pretty exhausted, but if I decide I want/need more information I'll PM you.

[Broomstick]

Medical administrators probably don't read actual research journals, let alone in French or German. Practicing doctors probably don't read much outside their native language (they have to prune somehow...) so it is only the medical researchers who read this stuff.

Their native language and English... It's been about 20 years since I had a doctor whose first language was English.

Part of the problem of a doctor like my husband's oncologist, who is a very smart, very dedicated physician, is the demands of her patient caseload. It isn't just calculating chemo or radiation doses and administering them - she meets not only with patients but their family as well, educates those under care, provides counseling, battles insurance companies directly at times, provides counseling, encouragement, and condolences as needed.... and she tries to keep up with new treatments which means not only knowing about them but learning how to properly use them. It's a LOT to do. Sure, she has a lot of help and can delegate some of it (education done by a "nurse advocate/navigator", for example) but she's incredibly busy all the time.

What you might want to do is not just write up a literature review for us (but you should definitely do that), but write one up for JAMA or The Lancet. That, literally everyone will read.

^ This.

[Esquire]

When I say devices I am thinking of IV pumps. If we ever get to home administration I imagine it would have to have something preloaded, and easy to transport to the patient's house and preprogrammed for a particular agent. This of course would require some work to set up.

These exist already, or something like them at least - programmable IV injectors are part of the logistical backend for effective chronotherapy. And, in keeping with the theme, have been for decades; it's not really* different from gluing an alarm clock to a pump.

Do it.

Aye aye, I'm swamped through this weekend but I'll see what I can put together next week.

That seems about right to me.

Medical administrators probably don't read actual research journals, let alone in French or German. Practicing doctors probably don't read much outside their native language (they have to prune somehow...) so it is only the medical researchers who read this stuff.

What you might want to do is not just write up a literature review for us (but you should definitely do that), but write one up for JAMA or The Lancet. That, literally everyone will read.

That's the weird thing - I've read at least three Lancet articles on this, one of them a meta-analysis of ~80 studies and several thousand patients - although to be fair I'm not 100% sure I'm thinking of the right journal, so don't quote me there; I've read probably a hundred studies on this and they're starting to blend together. I'm writing the review already - effectively have to for work anyway, why not try for publication? - but I can't shake the feeling that something has gone seriously wrong in the "what amount of evidence is sufficient for implementation"/"how do we tell people what we've discovered effectively" areas. Dissemination and implementation 'science,' if that terminology has entered your field - biology, right?

*Well, contextually-substantially, anyway.

[Esquire]

Their native language and English... It's been about 20 years since I had a doctor whose first language was English.

Now that's some qualitative research I could get funded - who reads what, and in what language? With the relentless march of academic/professional siloing and the significant importing of health care professionals to the U.S. (as far as I can tell accidentally or as an emergent effect of globalization + the bizarre state of medical training a few decades ago), there doesn't seem to be a common vocabulary, or even necessarily a common language, between the very specialists we're supposed to be depending on to coordinate usefully with each other. There isn't, to borrow terminology from any hospital brochure, a 'care team;' there's a whole bunch of care mercenaries. Well-meaning, extremely intelligent and well-trained, certainly, but not generally willing or able to collaborate outside their own specialty. I'm exaggerating for dramatic effect but I fear the underlying point is sound.

Part of the problem of a doctor like my husband's oncologist, who is a very smart, very dedicated physician, is the demands of her patient caseload. It isn't just calculating chemo or radiation doses and administering them - she meets not only with patients but their family as well, educates those under care, provides counseling, battles insurance companies directly at times, provides counseling, encouragement, and condolences as needed.... and she tries to keep up with new treatments which means not only knowing about them but learning how to properly use them. It's a LOT to do. Sure, she has a lot of help and can delegate some of it (education done by a "nurse advocate/navigator", for example) but she's incredibly busy all the time.

Indeed. I'm fairly sure there've been some recent studies on this issue - I'll see if I can remember where I read them, but as I recall the gist was that the very specialization imposed by U.S. medical education (and at the second remove by the perverse incentives of our health insurance system) adds up to net inefficiencies of near-ridiculous proportions.

Right now I'm pretty exhausted, but if I decide I want/need more information I'll PM you.

Completely understandable. As I say, I've been there; happy to help in any way and at any time you like.

[momochan]

On a related note, I read that melatonin has a role in fighting cancer. The immune system is active at night, which may be related to lower levels of insulin and higher levels of melatonin in circulation.
Melatonin production is stimulated by darkness, so anyone who has cancer concerns would be well-advised to keep their bedrooms pre-Industrial Age dark -- such that you cannot see your hand in front of your face. Try blackout curtains, covering digital clocks and other indicator lights, or wearing blindfolds if you can stand them.
Melatonin stimulation can be one piece of the puzzle (preventive rather than curative, to be sure). Totally blind people have been found to have lower rates of cancer: https://www.ncbi.nlm.nih.gov/pubmed/9730026

[mr friendly guy]

Melatonin tablets are available for those who have problems sleeping. Might be worth having a clinical trial with melatonin + standard chemo vs standard chemo.

[Shroom Man 777]

Nautil.us had a really great longform on this. But ye-ah it requires so much customization, most hospitals and practices won't be able to apply it to their numerous patients...

[Esquire]

That's simultaneous true and perversely backwards - what's the goddamn point of the health care system if we're just going to ignore something with (sometimes/potentially; again, lit review forthcoming) between 200% and 400% effect sizes because of glorified scheduling difficulties?

[Broomstick]

Because sometimes reality doesn't let you have a perfect system.

In the late 1970's my mother had to wait four months for an absolutely critical triple bypass operation due to logistical concerns like lack of trained surgeons and few facilities equipped for the surgery. It was supposed to be six months, but enough people ahead of her on the list died to move her up two months.

Well, these days such an operation can be done within hours of diagnosis, great - but it took decades to put sufficient resources in place to make that possible.

Likewise with this - even if everyone agreed tomorrow it was the Thing To Do it would take years to reconfigure the system and rebuild it to accommodate that sheer number of patients needing these treatments.

[Khaat]

We aren't talking building treatment networks that didn't exist at all, just a modification and some training on implementation. Even if it was "new patients only into new protocol as we get up to speed/capacity, expanding as training is completed" it shouldn't be that overwhelming.

Lawyers take CLE (Continuing Legal Education) to keep up to speed, I'm fairly confident doctors do something similar. And not every doctor would need this particular training, just oncologists and those with an interest.

With improved treatment efficacy/success trails show, I don't know if it would be insurance companies, the healthcare industry, or a third party that releases the app to track a patient's circadian rhythms for treatment purposes first.

[Broomstick]

It would require running the entire chemotherapy mixing and delivery system 24/7, 365. It is not set up for that. It would probably require at least twice the number of workers involved in the system right now just for the labor part. I really think you fail to understand the logistics required.

[Khaat]

time treatments such that the biological pathways that carry drugs to where they need to go in the body
...
need logistics being worked out to support this - programmable timed injectors, personalization of chronotherapy regimens based on individual rhythm variation, different (and different from non-cancerous cells) rhythms in different cancers, etc.

Perhaps the initial presentation oversimplifies these logistics.

[Esquire]

time treatments such that the biological pathways that carry drugs to where they need to go in the body
...
need logistics being worked out to support this - programmable timed injectors, personalization of chronotherapy regimens based on individual rhythm variation, different (and different from non-cancerous cells) rhythms in different cancers, etc.

Perhaps the initial presentation oversimplifies these logistics.

It really doesn't; individually-programmable injectors have already been developed and validated across numerous cancers. We're (nearly, anyway) talking about gluing an alarm clock to preexisting machinery and hiring a few extra neurobiologists for the individual analyses. Total cost changes, when one factors in the sheer size of the benefits we're talking about, should be negative if anything. Recall, the foundational studies for this are ~70-80 years old.

EDIT: Per hospital, anyway. Systemic costings might plausibly differ; I'm not as well informed re: care access, etc. across different types of local health care providers.

[Broomstick]

From my somewhat limited experience, chemotherapy rarely takes place in a hospital these days. Certainly, when/where my spouse was undergoing it inpatient hospital chemo was not the norm. Most of it around here takes place in oncology office space.

[Shroom Man 777]

Hey, it WOULD be great if new tech allows rapid chronomodulation via some new fangled doohickey... and it might happen! Stating the incapabilities of the current system isn't mutually exclusive with hoping for and working towards reform and improvements, be they incremental or radical...