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S1 is one of them: a better capecitabine. 43 </p> 44 <h2> 45 What is S1? 46 </h2> 47 <p> 48 S1 is the muy sexy common name of a drug manufactured by Taiho 49 Pharmaceutical in Japan. (It did get a brand name a few years after it 50 went to market: âTeysunoâ). 51 </p> 52 <p> 53 It is a combination of three drugs, all in a pill. 54 </p> 55 <p> 56 The first is a prodrug, called tegafur or ftorafur (âFTâ in many 57 papers), that converts to 5-fluorouracil (5-FU) in the body. 58 Capecitabine, the only oral 5-FU agent we use in the US, is also a 5-FU 59 prodrug. 60 </p> 61 <p> 62 The second is gimeracil, a drug that inhibits the enzyme 63 dyhydropyrimidine dehydrogenase (DPD). This reduces tegafur breakdown in 64 the GI tract, which allows it to make its way into the bloodstream. 65 (Patients with inherent DPD deficiency cannot break down drugs in this 66 family once they make it into the bloodstream, leading to potentially 67 lethal side effects from 5-FU and itâs cousins - gimeracil is only 68 creating a local DPD deficiency in the gut. Brilliant.). 69 </p> 70 <p> 71 The third is oteracil, which prevents 5-FU activation in the GI 72 tract, reducing off-target local adverse effects (capecitabine has 73 horrible GI side effects in many patients). Also brilliant. 74 </p> 75 <p> 76 <img src="/images/s1-is.png" alt="The FU drugs, including S1"> 77 </p> 78 <p> 79 This is a very rationally conceived drug. Using a prodrug with a 80 companion that lets it survive long enough to be absorbed lets us use an 81 oral formulation. Oral is so much more convenient than a pump the 82 patient has to wear for a couple of days (and which sometimes 83 malfunctions in strange ways). In capecitabine we already have an oral 84 5-FU agent that works. However, many of the adverse effects of 85 capecitabine are local to the GI tract, leading to dose reductions or 86 drug switch in many cases, so combining something like capecitabine with 87 something that reduces badness in this location also makes a lot of 88 sense. 89 </p> 90 <p> 91 This rationality bears out in clinical practice as well (this is not 92 always the case - a popular saying amongst clinical trialists is âthe 93 road to hell is paved with biological plausibility.â The majority of 94 ideas that work out well in a petri dish or animal model do not work out 95 at all when we try them in humans. Hence clinical trials.). Trial after 96 trial have established S1 as the standard of care in many relevant 97 regimens in Asia, pretty much any situation where we would use 98 infusional 5-FU or capecitabine in the US. (Iâm sure thereâs nuance 99 here, but it appears generally true.) S1 works well, is easier to give, 100 and is better tolerated. 101 </p> 102 <h2> 103 So why donât we have it in the US? 104 </h2> 105 <p> 106 Good. Question. 107 </p> 108 <p> 109 Itâs not that it has been completely ignored by researchers in the 110 West, as youâll see. The Europeans can get it. And Iâm sure Taiho would 111 love to expand their market to the US. 112 </p> 113 <p> 114 Truthfully, I canât say I know all the reasons. These things are 115 complex and the FDAâs reasons are not always readily apparent or written 116 clearly (though they often are - I have equally strong respect and 117 disdain for that particular agency, but the trend in my feeling is 118 toward respect. I used to feel only disdain. The more I learn what and 119 how they do All The Things, the more I see a bunch of humans really 120 trying to do their best, rationally to the extent possible, in difficult 121 situations, with many conflicting interested parties). 122 </p> 123 <p> 124 The clearest reason that S1 is a Big Deal in Asia but unknown here is 125 a difference in the prevalence of certain versions of enzymes that 126 convert the tegafur to 5-FU. 127 </p> 128 <p> 129 <em>Aside: Iâm going to use the terribly imprecise terms âAsianâ and 130 âWesterner.â The studies in this area use the terms âAsianâ and 131 âCaucasian,â which is worse, as in, âeven more wrong than the 132 alternative I chose.â There is huge genetic and biologic variability 133 within and across the places we call âAsiaâ and âThe West,â and, if 134 humans do anything, humans migrate. This biped was made for walkinâ, and 135 thatâs just what it do. Donât take these terms too seriously.</em> 136 </p> 137 <p> 138 Folks from Asian countries tend to have a set of CYP2A6 polymorphisms 139 that lead to much slower conversion of this particular drug, or, more 140 appropriately said (Taiho is a Japanese company, after all), Westerners 141 tend to have a CYP2A6 reality that makes them convert tegafur too damn 142 fast. Dose-finding studies correspond well with the known differences in 143 enzymes: the recommended daily dose in Asia is 40mg/m2 twice a day, 144 whereas the Western dose is 30mg/m2 twice a day. 145 </p> 146 <p> 147 There are other findings from the dosing studies that donât precisely 148 line up with differences in processing after absorption. The most severe 149 toxicity in Asian populations is bone marrow suppression, whereas it is 150 GI toxicity in Western populations. I donât know why the oteracil 151 doesnât pull its weight in the guts of Westerners. Then again, it might 152 be entirely unrelated to oteracil, I have no idea. 153 </p> 154 <h2> 155 The Dutch, as usual, are leading the way 156 </h2> 157 <p> 158 The most interesting study to-date using S1 in Westerners was done in 159 the Netherlands and published as the â<a href="https://doi.org/10.1093/annonc/mdx122">SALTO Study</a>.â 160 </p> 161 <p> 162 (S1 has approvals in Europe, though for a much shorter list of 163 indications compared with Japan and China, so folks governed by the EMA 164 can get it and play around, whereas there is no provision at all for 165 getting it in the US outside of clinical trial - it has orphan 166 designation but is not approved for anything) 167 </p> 168 <p> 169 They looked at 161 patients who qualified for 5-FU-based monotherapy 170 for metastatic colorectal cancer. Combination drug therapy is the 171 standard of care frontline therapy in the metastatic setting, but 172 monotherapy is a reasonable option for older and more frail patients, 173 which is who this trial enrolled. They were randomized to S1 vs 174 capecitabine, and compared efficacy as well as rates of adverse effects. 175 Efficacy was comparable, and most adverse effects were also comparable, 176 with the notable exception of hand-foot syndrome. The rates of this were 177 45% in the S1 group, vs 73% in the capecitabine group. They were also 178 better able to maintain dose intensity in the S1 group, which is a good 179 surrogate for the <em>je ne sais quoi</em> of all the little things that 180 being on therapy does to a person but arenât fully captured in the other 181 metrics. Though hand-foot syndrome is not a lethal problem, it can be a 182 huge quality-of-life problem, particularly when the point of therapy is 183 palliative in the first place. 184 </p> 185 <p> 186 The same group also published a <a href="https://doi.org/10.1080/0284186X.2016.1278459">retrospective</a> 187 on 52 patients who had hand-foot syndrome on capecitabine and were 188 switched to S1, which they then tolerated beautifully. The graph below 189 is from this paper. âBeforeâ is on the left, and âafterâ is on the 190 right. The difference is stark. 191 </p> 192 <p> 193 <img src="/images/s1-cape-hfs.jpg" alt="HFS improves significantly after switching from capecitabine to S1"> 194 </p> 195 <h2> 196 Why Iâd love to have S1 in the US 197 </h2> 198 <p> 199 One tough part of my job is telling somebody who wants to continue 200 therapy but isnât tolerating the âeasiestâ form of therapy, even after 201 dose reduction and maximizing supportive care, that their only options 202 are to continue to push forward with the poorly tolerated therapy (to a 203 degree - Iâm not afraid to say no and refuse to prescribe if I feel like 204 Iâm hurting someone), or stop cancer-directed therapy altogether. I love 205 hospice and the services it provides, and many patients are relieved to 206 make this move, but a significant portion are not. Having another option 207 in the armamentarium, something else to try for the patient who wants to 208 try something, especially in such a commonly used class of drugs, would 209 be great. S1 has clear benefit for patients who have an indication for 210 5-FU-based therapy but have developed significant hand-foot syndrome, 211 and I would use it in this situation if I had it on formulary. 212 </p> 213 <p> 214 Also, though I practice in âthe West,â not everyone here hails from 215 the Caucasus 216 </p> 217 <p> 218 <em>âHarumph,â he roared, suddenly on his feet and staring down at 219 me, his tweedâs elbow patches straining as he assumed the pose of a 220 portly academic Superman, âmost Caucasians do not, in fact, hail from 221 the Caucasus. Very few do. That was proto-eugenic Neo-Platonic foolery. 222 If you use the term Caucasian, you have to accept the fallacious 223 philosophy upon which it was built, and you are equally obligated to 224 accept the terms from which it is inextricable, namely âCaucasoid,â 225 âMongoloid,â âNegroid.â Good sir, I do not believe this was your purpose 226 nor desire. If you must use an imprecise term, at least let it be one of 227 the cardinal directions, which are not unladen but are not actively 228 destructive of scientific and societal progress, good sense, morality, 229 and decency.â The final word was given in a whisper.</em> 230 </p> 231 <p> 232 so having S1 as an up-front option for folks of Asian ancestry would 233 be nice - itâs a clearly better drug in Asian countries, and I doubt it 234 was the ground underfoot that made the difference. 235 </p> 236 <p> 237 An idea related to this, with perhaps more biological justification 238 than a nebulous definition of ancestry, would be to deploy CYP2A6 239 screening of some sort to select folks who may most benefit from S1 240 rather than capecitabine. 241 </p> 242 <p> 243 This could be done in several ways, all of which have precedence in 244 other types of screening and at some centers. Ideally youâd do trials to 245 determine if any of these actually pan out (see above, on the path to 246 hell). Theyâre all extrapolations. 247 </p> 248 <p> 249 One option would be to screen all patients with known Asian ancestry, 250 as is done in some centers for various indications (e.g. GPD deficiency 251 screening for patients of African descent prior to starting potentially 252 problematic drugs). 253 </p> 254 <p> 255 Another would be to screen only those who have had dose-limiting GI 256 intolerance to capecitabine, to make an argument that perhaps they would 257 tolerate S1 better. (Though, in reality, if S1 was suddenly available 258 and someoneâs GI adverse effects were particularly horrendous on 259 capecitabine, Iâd probably talk with the patient about it and try it if 260 they want, rather than what I might normally do, which would be to try 261 infusional 5-FU or a drug from a different class, depending on the 262 specifics of the situation. I think an empiric approach would be 263 appropriate, as it wouldnât require fancy testing which may or may not 264 actually be predictive, and is what we do most of the time with other 265 cognate drugs, even if they have class-effect toxicities - some folks 266 just tolerate Drug A better than Drug B). 267 </p> 268 <p> 269 A third option would be to screen everyone to try and find folks with 270 compatible CYP2A6 to select for up-front S1. This is expensive. Only 271 fancy places do population-wide pharmacogenomics (etc.) in practice, and 272 there are deep debates about how much good this actually does. But hey, 273 cool if you can get it, especially if you have data to back it up, but 274 even then make youâd have to make sure you donât take it without a grain 275 or six of salt. 276 </p> 277 <p> 278 As it is, even if I wanted to test out some of these ideas, or see if 279 the Dutch prospective study replicates, Iâd have to go through an insane 280 approval process, and it would be expensive and time consuming. If the 281 drug was approved and available, studies like the Dutch retrospective 282 become almost trivially easy. 283 </p> 284 <p> 285 One day. Maybe when the Big Boss of the FDA starts reading my blog 286 and sends me a golden goose for my genius, along with a Christmas basket 287 full of S1 and Cadbury. (Thatâs how it works, right?) 288 </p> 289 <h2> 290 Until next time 291 </h2> 292 <p> 293 This kind of thing is one of my favorites, a thoroughly enjoyable 294 line of inquiry - what drugs are out there that I canât get? What 295 inspiration is there to be had from the practice patterns of other 296 countries? Would those drugs and patterns work here - why or why 297 not? 298 </p> 299 <p> 300 It pairs nicely with my obsession with the histories of therapies for 301 cancers. Love me a critical genealogy,* love me some heteroglossia and 302 unfinalizability. Butler and Bakhtin ftw. 303 </p> 304 <hr> 305 <p> 306 * I idly wondered if there had been much movement on that term, which 307 I got at least thirdhand from Judith Butler, and it looks like thereâs 308 going to be a cool book coming out in the next year or two: <a href="https://absolute-disruption.com/a-genealogy-of-genealogy/">A 309 Genealogy of Genealogy</a> 310 </p> 311 </main> 312 <div id="footnotes"></div> 313 <footer></footer> 314 </div> 315 </body> 316 </html>