commit 15baea2ab74a7bb0c79bc6d4e76c77fb713426b6
parent 6f0f7522f16b007d9130056bd663a28a2799eabb
Author: Beau <cbeauhilton@gmail.com>
Date: Fri, 29 Mar 2024 14:41:22 -0500
add post on S1
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diff --git a/site/posts/pp-tech-infra.md b/site/posts/pp-tech-infra.md
@@ -86,8 +86,8 @@ With the research I do and am interested in continuing,
a university infrastructure adds little,
where it isn't actively working against me,
and I'd rather pay my salary, which will be much bigger, from taking care of people in clinic
-than working through the weekend
-(when I may also still be on call for the hospital) to meet grant deadlines.
+than working through the weekend to meet grant deadlines
+(while I may also still be on call for the hospital).
The university infrastructure is great for basic and clinical science,
and some flavors of data science,
diff --git a/site/posts/s1.md b/site/posts/s1.md
@@ -0,0 +1,228 @@
+# Drugs we can't get: S1
+
+<time id="post-date">2024-03-29</time>
+
+<p id="post-excerpt">
+ There are a number of interesting drugs used in the global market that,
+ for one reason or another, do not have FDA approval and are therefore inaccessible
+ in the US, at least outside of clinical trials. S1 is one of them: a better capecitabine.
+</p>
+
+## What is S1?
+
+S1 is the muy sexy common name of a drug manufactured by Taiho Pharmaceutical in Japan.
+(It did get a brand name a few years after it went to market: "Teysuno").
+
+It is a combination of three drugs, all in a pill.
+
+The first is a prodrug, called tegafur or ftorafur ("FT" in many papers),
+that converts to 5-fluorouracil (5-FU) in the body.
+Capecitabine, the only oral 5-FU agent we use in the US, is also a 5-FU prodrug.
+
+The second is gimeracil, a drug that inhibits the enzyme dyhydropyrimidine dehydrogenase (DPD).
+This reduces tegafur breakdown in the GI tract, which allows it to make its way into the bloodstream.
+(Patients with inherent DPD deficiency
+cannot break down drugs in this family once they make it into the bloodstream,
+leading to potentially lethal side effects from 5-FU and it's cousins -
+gimeracil is only creating a local DPD deficiency in the gut. Brilliant.).
+
+The third is oteracil, which prevents 5-FU activation in the GI tract,
+reducing off-target local adverse effects
+(capecitabine has horrible GI side effects in many patients).
+Also brilliant.
+
+
+
+This is a very rationally conceived drug.
+Using a prodrug with a companion that lets it survive long enough to be absorbed
+lets us use an oral formulation.
+Oral is so much more convenient than a pump the patient has to wear for a couple of days
+(and which sometimes malfunctions in strange ways).
+In capecitabine we already have an oral 5-FU agent that works.
+However, many of the adverse effects of capecitabine are local to the GI tract,
+leading to dose reductions or drug switch in many cases,
+so combining something like capecitabine
+with something that reduces badness in this location also makes a lot of sense.
+
+This rationality bears out in clinical practice as well
+(this is not always the case - a popular saying amongst clinical trialists
+is "the road to hell is paved with biological plausibility."
+The majority of ideas that work out well in a petri dish or animal model
+do not work out at all when we try them in humans. Hence clinical trials.).
+Trial after trial have established S1 as the standard of care in many relevant regimens in Asia,
+pretty much any situation where we would use infusional 5-FU or capecitabine in the US.
+(I'm sure there's nuance here, but it appears generally true.)
+S1 works well, is easier to give, and is better tolerated.
+
+
+## So why don't we have it in the US?
+
+Good. Question.
+
+It's not that it has been completely ignored by researchers in the West,
+as you'll see.
+The Europeans can get it.
+And I'm sure Taiho would love to expand their market to the US.
+
+Truthfully, I can't say I know all the reasons.
+These things are complex and the FDA's reasons are not always readily apparent or written clearly
+(though they often are -
+I have equally strong respect and disdain for that particular agency,
+but the trend in my feeling is toward respect.
+I used to feel only disdain.
+The more I learn what and how they do All The Things,
+the more I see a bunch of humans really trying to do their best,
+rationally to the extent possible,
+in difficult situations,
+with many conflicting interested parties).
+
+The clearest reason that S1 is a Big Deal in Asia
+but unknown here
+is a difference in the prevalence of certain versions of enzymes
+that convert the tegafur to 5-FU.
+
+*Aside: I'm going to use the terribly imprecise terms "Asian" and "Westerner."
+The studies in this area use the terms "Asian" and "Caucasian," which is worse,
+as in, "even more wrong than the alternative I chose."
+There is huge genetic and biologic variability within and across the places we call "Asia" and "The West,"
+and, if humans do anything, humans migrate. This biped was made for walkin',
+and that's just what it do.
+Don't take these terms too seriously.*
+
+Folks from Asian countries tend to have a set of CYP2A6 polymorphisms
+that lead to much slower conversion of this particular drug,
+or, more appropriately said (Taiho is a Japanese company, after all),
+Westerners tend to have a CYP2A6 reality that makes them convert tegafur too damn fast.
+Dose-finding studies correspond well with the known differences in enzymes:
+the recommended daily dose in Asia is 40mg/m2 twice a day,
+whereas the Western dose is 30mg/m2 twice a day.
+
+There are other findings from the dosing studies
+that don't precisely line up with differences in processing after absorption.
+The most severe toxicity in Asian populations is bone marrow suppression,
+whereas it is GI toxicity in Western populations.
+I don't know why the oteracil doesn't pull its weight
+in the guts of Westerners.
+Then again, it might be entirely unrelated to oteracil,
+I have no idea.
+
+## The Dutch, as usual, are leading the way
+
+The most interesting study to-date using S1 in Westerners
+was done in the Netherlands
+and published as the "[SALTO Study](https://doi.org/10.1093/annonc/mdx122)."
+
+(S1 has approvals in Europe,
+though for a much shorter list of indications compared with Japan and China,
+so folks governed by the EMA can get it and play around,
+whereas there is no provision at all for getting it in the US outside of clinical trial -
+it has orphan designation but is not approved for anything)
+
+They looked at 161 patients who qualified for 5-FU-based monotherapy for
+metastatic colorectal cancer.
+Combination drug therapy is the standard of care in this setting,
+but monotherapy is a reasonable option for older and more frail patients,
+which is who this trial enrolled.
+They were randomized to S1 vs capecitabine,
+and compared efficacy as well as rates of adverse effects.
+Efficacy was comparable,
+and most adverse effects were also comparable,
+with the notable exception of hand-foot syndrome.
+The rates of this were 45% in the S1 group,
+vs 73% in the capecitabine group.
+They were also better able to maintain dose intensity in the S1 group,
+which is a good surrogate for the *je ne sais quoi*
+of all the little things that being on therapy does to a person
+but aren't fully captured in the other metrics.
+Though hand-foot syndrome is not a lethal problem,
+it can be a huge quality-of-life problem,
+particularly when the point of therapy is palliative in the first place.
+The same group also published a [retrospective](https://doi.org/10.1080/0284186X.2016.1278459)
+on 52 patients
+who had serious hand-foot syndrome on capecitabine
+and were switched to S1, which they then tolerated beautifully.
+
+
+
+
+## Why I'd love to have S1 in the US
+
+One tough part of my job is telling somebody
+who wants to continue therapy
+but isn't tolerating the "easiest" form of therapy,
+even after dose reduction and maximizing supportive care,
+that the only option remaining is hospice.
+They can continue to push forward with the poorly tolerated therapy
+(to a degree - I'm not afraid to say no if I feel like I'm hurting someone),
+or they can stop therapy altogether.
+I love hospice and the services it provides,
+and many patients are relieved to make this move,
+but a significant portion are not.
+Having another option in the armamentarium,
+something else to try for the patient who wants to try something,
+especially in such a commonly used class of drugs,
+would be great.
+S1 has clear benefit for patients who have an indication for 5-FU-based therapy
+but have developed significant hand-foot syndrome,
+and I would use it in this situation if I had it on formulary.
+
+Also, though I practice in "the West,"
+I treat a diverse population.
+Having S1 as an up-front option for folks of Asian ancestry
+would be nice -
+it's a clearly better drug in Asian countries,
+and I doubt it was the ground underfoot that made the difference.
+
+Related to this,
+with perhaps more biological justification than a nebulous
+definition of ancestry,
+would be to deploy CYP2A6 screening of some sort
+to select folks who may most benefit from S1 rather than capecitabine.
+This could be done in several ways,
+all of which have precedence in other types of screening
+and at some centers.
+Ideally you'd do trials to determine if any of these
+actually pan out (see above, on the path to hell).
+They're all extrapolations.
+One option would be to screen all patients with known Asian ancestry,
+as is done in some centers for various indications
+(e.g. GPD deficiency screening for patients of African descent
+prior to starting potentially problematic drugs).
+Another would be to screen only those who have had
+dose-limiting GI intolerance to capecitabine,
+to make an argument that perhaps they would tolerate S1 better.
+(Though, in reality, if S1 was suddenly available
+and someone's GI adverse effects were particularly horrendous on capecitabine,
+I'd probably talk with the patient about it and try it if they want,
+rather than what I might normally do,
+which would be to try infusional 5-FU or a drug from a different class,
+depending on the specifics of the situation.
+I think an empiric approach would be appropriate,
+as it wouldn't require fancy testing which may or may not actually be predictive,
+and is what we do most of the time with other cognate drugs).
+A third option would be to screen everyone
+to try and find folks with compatible CYP2A6
+to select for up-front S1.
+This is expensive.
+Only fancy places do population-wide
+pharmacogenomics (etc.) in practice,
+and there are deep debates about how much good this actually does.
+But hey, cool if you can get it,
+especially if you have data to back it up,
+but even then make you'd have to make sure you don't take it without a grain or six of salt.
+
+## Until next time
+
+This is one of my favorite lines of inquiry -
+what drugs are out there that I can't get?
+What inspiration is there to be had from the practice patterns of other countries?
+Would those drugs and patterns work here - why or why not?
+
+It pairs nicely with my obsession with the histories of therapies for cancers.
+Love me a critical genealogy,* love me some heteroglossia and unfinalizability.
+Butler and Bakhtin ftw.
+
+\* I idly wondered if there had been much movement on that term,
+which I got at least thirdhand from Judith Butler,
+and it looks like there's going to be a cool book
+coming out in the next year or two: [A Genealogy of Genealogy](https://absolute-disruption.com/a-genealogy-of-genealogy/)
