Neoadjuvant FLOT/MAGIC vs. CROSS in Distal Esophageal

[RSAOaky]

I'm at a major academic center and the other day it was suggested that we should start considering neoadjuvant chemo alone for distal esophageal cancers based on this abstract at ASCO. Every single reported metric in the table below was superior for CROSS and yet the conclusion was "the data strongly suggests non-inferiority and equipoise."

When us doom and gloomers talk about the declining indications for radiation it's because of things like this. We're perpetually one successful chemo regimen away from becoming obsolete in an entire disease site. Historical clinical trials would say "FLOT/MAGIC were not superior to CROSS and thus CROSS should remain the standard of care." Unfortunately, nowadays the goalposts have shifted to "non-inferiority" and because of the pressures for academics to publish positive studies we have garbage like this where every metric reported by this abstract other than OS is numerically superior for CROSS and the conclusion is "the data suggests equipoise."

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.4004

Background: The optimum combination curative approach to locally advanced adenocarcinoma of the esophagus and esophago-gastric junction (AEG) is unknown. A key question is whether neoadjuvant multimodal therapy, specifically CROSS (carboplatin/paclitaxel, 41.4Gy radiation therapy), is superior to optimum peri-operative chemotherapeutic regimens including modified MAGIC (epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)) and more latterly FLOT (docetaxel, 5-FU, leucovorin, oxaliplatin). Neo-AEGIS was designed as the first randomised controlled trial to address this question.
Methods: 377 patients with cT2-3N0-3M0 AEG were randomly assigned to CROSS or peri-operative chemotherapy (ECF/ECX/EOF/EOX pre-2018, FLOT option 2019/20) at 24 sites (Ireland, UK, Denmark, France, Sweden). The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. This was modified after the first futility analysis (70 events) to a non-inferiority margin of 5%. Secondary end points included toxicity, pathologic measures of response, and postoperative complications as per the Esophageal Complications Consensus Group (ECCG) definitions and Clavien-Dindo severity grade.
Results: Of 362 evaluable patients, 178 CROSS, 184 MAGIC/FLOT (157/27), 90% were male, median (range) age 64 (35-83), 84% were cT3, and 58% cN1. At a median (range) follow up of 24.5 (1-92) months, at the second futility analysis (60% of planned events), there were 143 deaths, 70 CROSS and 73 MAGIC/FLOT arm, with 3-year estimated survival probability of 56% (95% CI 47,64) and 57% (95% CI 48,65), respectively [(HR 1.02 (95%CI. 0.74-1.42))]. Based on the absence of futility evidenced in this data the DSMB recommended closure of recruitment in December 2020.
Conclusions: This RCT reveals no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy, notwithstanding greater proxy markers of local tumour response in the CROSS arm. Oncologic and operative outcomes were consistent with optimum modern benchmarks. These data strongly suggest non-inferiority and support equipoise in decision making in modern practice

Perioperative Chemo Enough in Esophageal Cancer?

MAGIC/FLOT regimens yielded similar overall survival to multimodal CROSS regimen

www.medpagetoday.com

Just look at the first line of the article reporting this study:
"Perioperative chemotherapy in locally advanced esophageal or gastroesophageal junction (GEJ) adenocarcinoma was not "unacceptably" inferior to neoadjuvant chemoradiotherapy, an interim analysis of the randomized Neo-AEGIS trial suggested."

We're really in the ****ter when "not unacceptably inferior" is the benchmark for changing the standard of care.

---

Members don't see this ad.

 

[medgator]

Chemo doesn't help dysphagia as well. Still getting those referrals

 

[deleted1111261]

Chemo doesn't help dysphagia as well. Still getting those referrals

? They are getting surgery.

 

[communitydoc13]

Intentionality and presupposition matter here. If you were told that the two arms were experienced in exactly the same way, to please review the tabulated outcomes that you presented and choose a treatment course, most of us would pick neoadjuvant chemoXRT.

The very premise of this trial, like so many trials evaluating omission of XRT, is that eliminating XRT is a win for patient QOL, cost and overall toxicity even in the face of systemic therapy escalation. More specifically, the trialists are presuming that chemorads is more than a pCR benefit, margin negative benefit, and neutropenia benefit worse than getting FLOT.

Is it? I don't know. But I'm pretty sure the medoncs think FLOT is better than Magic and the comparison has shifted. They will also have other regimens coming down the pipe.

The medoncs have more control of the patients.

This incremental marginalization of XRT is what I have experienced in most sites (lung post-op, endometrial, RP sarcoma, breast, lymphoma, pancreas) over the past 10 years.

 

[Palex80]

But I'm pretty sure the medoncs think FLOT is better than Magic and the comparison has shifted. They will also have other regimens coming down

The issue with NeoAegis is that it allowed several neoadjuvant chemotherapy regimes.
FLOT is superior to MAGIC

There is a completed German trial that compared CROSS to FLOT, but results are pending.

Chemo doesn't help dysphagia as well. Still getting those referrals

Radiation-induced mucositis also doesn't help dysphagia.

 

[RickyScott]

? They are getting surgery.

often have a jtube. Sure, I make the argument in tumor board that FLOT is more toxic than CROSS and that opdivo does not follow FLOT presently, but we will be pushed out of this space over the next 10 years. FLOT vs CROSS is equivalent right now, but very likely a new drug or regimen will be trialed that puts XRT down for good at some point. If FLOT is equivalent, many surgeons would rather operate without xrt.
XRT will be a bit player across GI, not just esophagus: rectal, stomach, pancreas.

BTW: I am starting to fight similar battles in thoracic conference.

 

[communitydoc13]

We know now that FLOT is superior to MAGIC, thus the med oncs will make the argument that only a "pure" FLOT vs. CROSS trial would be able to answer the question.

I agree and that takes time. This trial was largely MAGIC vs chemorads. I think this may be contributing to the following line of thinking by MEDONCS.

"MAGIC is within a reasonable margin of chemorads ---> FLOT>MAGIC --->lets have equipoise now, which means we'll give FLOT as de-facto SOC in those that we think are appropriate".

 

[deleted1111261]

I agree and that takes time. This trial was largely MAGIC vs chemorads. I think this may be contributing to the following line of thinking by MEDONCS.

"MAGIC is within a reasonable margin of chemorads ---> FLOT>MAGIC --->lets have equipoise now, which means we'll give FLOT as de-facto SOC in those that we think are appropriate".

Yep !

 

[medgator]

? They are getting surgery.

Some of them come in pretty bad.... I guess you could put a tube in and wait until the chemo is all done and they go to surgery

 

[medgator]

Radiation-induced mucositis also doesn't help dysphagia.

You mean esophagitis? Usually seeing the mucositis from 5-FU

 

[RickyScott]

anastomotic leak rate seems to be largely equivalent between arms in this very large trial; yet in 60 person MDACC trial of photons vs protons with (garbage) pooled endpt, I thought protons had "less toxicity," largely because there were fewer anastomotic leaks vs photons? by this logic, protons may lead to less anastomotic leaks than no radiation at all? (very very sketchy proton trial)

 

[Palex80]

You mean esophagitis? Usually seeing the mucositis from 5-FU

Esophagitis is mucositis, yes.
I see a lot of esophagitis from RT too.

 

[Palex80]

FLOT vs CROSS is equivalent right now, but very likely a new drug or regimen will be trialed that puts XRT down for good at some point. If FLOT is equivalent, many surgeons would rather operate without xrt.

Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK.​

 

[deleted1111261]

Esophagitis is mucositis, yes.
I see a lot of esophagitis from RT too.

It is a mucosal surface, so yes, it is a mucositis. Most of us just call it esophagitis out this way, but I've seen other literature call it mucositis.

 

[deleted941485]

Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK.​

If it’s not better than CRT, just add more chemo or immuno. Eventually it will be.

I think we all knew how this is going to play out. I guess anal isn’t on their radar yet but I’m sure it will be.

 

[communitydoc13]

Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK.​

This is called being left behind. Still holding out for some really good data that XRT makes IO better.

 

[deleted941485]

This is called being left behind. Still holding out for some really good data that XRT makes IO better.

Med onc crows about the RT toxicity and you won’t see these patients. Non inf will be run and RT will be on the out again.

When was the last time they looked at a non inf with surg?

 

[evilbooyaa]

It takes a med onc who understands what he would want himself and his family to receive in terms of toxicity burden to understand that chemoRT is still the better option for esophageal.

Especially b/c it allows you post-op nivolumab.

Unfortunately lots of med-oncs give into faulty transitive logic and prioritize eliminating the ugly thing that they don't do.
Many a european who delivers RT doesn't care about Radiation b/c clinical oncologist is a thing.

All you can do is a Rad Onc, if you see med oncs pulling stuff like this, is to advocate that every single esophageal cancer patient see you prior to RT and/or be discussed in multi-disciplinary tumor board, where you push the toxicity results of NeoAegis and the ability to receive IT (something only chemoRT patients can do right now, at least until that DANTE trial posted above comes out). But yes, it is not a place where our indication will ever increase, unless we can prove that surgery is not necessary (like in Anal cancer historically, as is being evaluated in rectal cancer now).

Need to re-evaluate the need for surgery in esophageal adenoCA in the setting of better chemo activity, honestly. Most of these patients met out, are they really benefited with the esophagectomy? Med-onc, after having decades of nothing better than Platinum, 5-FU, Doxorubicin, and taxanes, finally has the ability to push the envelope in terms of their efficacy while improving toxicity (not with MAGIC/FLOT, but with IT). It's a golden age for med-onc and there isn't much RT can do. RT already had their golden age w/ IMRT and toxicity reduction. Next golden age of RT.... gotta bank on that FLASH and oligomets.

Surgeons are doing less surgery now, but they're just getting more adventurous with who they offer surgery to before. 80+ yo getting esophagectomy for esophageal adenoCA in 2000? Maybe rare. 80+ yo getting esophagectomy for esophageal cancer in 2022? STANDARD OF CARE!!!!111

Same idea as urologists - lack of PSA testing and rise of AS lead to less low-risk prostates in pathology. Gotta keep the volume up, time to start cutting out the high-risk prostates that historically all were shuffled to RT + ADT.

 

[RSAOaky]

Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK.​

If it’s not better than CRT, just add more chemo or immuno. Eventually it will be.

It's even worse than that. Neither of these arms are the standard of care. It's more like "if you can't prove that chemo is better than chemoRT, prove that more chemo is better than less chemo."

The biggest issue is that once radiation drops out as the standard of care, it's never coming back. We've learned from breast that as systemic control improves locoregional control begins affect survival, but I don't see those trials being done in this day and age.

Intentionality and presupposition matter here.

This is so true and it's quite amazing. If your intention is to prove that we should omit radiation for breast cancer in the elderly, then you'll say the higher rates of recurrence are acceptable. If you want to prove that hypofractionation is equivalent to conventional fractionation for prostate cancer, you'll say the increased risk of GI Toxicity is not clinically significant. If you want to prove that TORS is better than XRT, you'll say that the increased dysphagia/odynophagia noted in clinical trials is "not reflected in our clinical experience." If you want to prove that chemo is better than chemoradiation, you'll look at a trial like this and say that despite every outcome being inferior in the chemo alone arm, the fact that the OS is similar means that chemo is non-inferior.

 

[CaesarRO]

The counterargument to "but the chemo is better today than what was used on trial" is the CHECKMATE 577 trial that added nivo to partial response to the CROSS regimen.

We have had this argument in tumor board as well and pointed out what you have about all the actual numbers favoring chemort and the conclusion being twisted into knots. My take away is if a patient can't get RT for whatever reason (reirradiation?) they have a more toxic alternative that would forego RT.

 

[RickyScott]

If it’s not better than CRT, just add more chemo or immuno. Eventually it will be.

I think we all knew how this is going to play out. I guess anal isn’t on their radar yet but I’m sure it will be.

anal will get rarer w/hpv vaccine. Radiation will be almost completely missing from GI in decade or 2

 

[RickyScott]

The counterargument to "but the chemo is better today than what was used on trial" is the CHECKMATE 577 trial that added nivo to partial response to the CROSS regimen.

We have had this argument in tumor board as well and pointed out what you have about all the actual numbers favoring chemort and the conclusion being twisted into knots. My take away is if a patient can't get RT for whatever reason (reirradiation?) they have a more toxic alternative that would forego RT.

we can argue these trivialities in tumor board, but the fact remains that xrt very likely to be gone after a few more trials.

 

[evilbooyaa]

It's even worse than that. Neither of these arms are the standard of care. It's more like "if you can't prove that chemo is better than chemoRT, prove that more chemo is better than less chemo."

The biggest issue is that once radiation drops out as the standard of care, it's never coming back. We've learned from breast that as systemic control improves locoregional control begins affect survival, but I don't see those trials being done in this day and age.

Well, that's why it's a randomized phase-II. B/c the answer will be then to compare it against ChemoRT --> Surgery --> Nivo if PR, but you know med-oncs are going to run with it and treat as per phase II data.

In the same way HN-002 was a R-PHII where neither arm was SOC, but some are advocating for 60+cis to gross dz in HPV+ dz

 

[fiji128]

We had a discussion about these results the other day in tumor board. If the ESOPEC trail shows at least non inferiority (it's no longer enrolling with an estimated data collection completion date of June 2023) neoadjuvant esophagus RT will become the new gastric RT. I treat about 10 neoadjuvant esophageals a year, will this be 1 or 2 by 2025?

 

[deleted941485]

We had a discussion about these results the other day in tumor board. If the ESOPEC trail shows at least equivalence (it's no longer enrolling with an estimated data collection completion date of June 2023) neoadjuvant esophagus RT will become the new gastric RT. I treat about 10 neoadjuvant esophageals a year, will this be 0 by 2025?

You already know the answer to this question. Why torture yourself?

 

[deleted941485]

anal will get rarer w/hpv vaccine. Radiation will be almost completely missing from GI in decade or 2

Wonder what all those academic GI RO attendings will do with themselves. Just I kidding I don’t care.

Has anyone done an omission of surgery in the last 10 years?

 

[fiji128]

Wonder what all those academic GI RO attendings will do with themselves. Just I kidding I don’t care.

Has anyone done an omission of surgery in the last 10 years?

Talk about how all our circa 2010 GI volume can be replaced with SBRT pancreas and liver.

 

[deleted941485]

Talk about how all our circa 2010 GI volume can be replaced with SBRT pancreas and liver.

Lol. Then run inf trial of 6 immuno drugs plus minus SBRT non inferiority style. Then eliminate it.

These idiots will have 5 patients on treatment

 

[OTN]

Fortunately our surgical oncologists run the esophageal show, and, because they can read, they've all agreed that CROSS is superior to FLOT.

I'm starting to fight the "Neoadjuvant immunotherapy then surgery is better than chemoRT for stage III NSCLC" battle now. Ridiculous to me that we still have surgeons strongly advocating for resection in stage III NSCLC, but it's gaining ground unfortunately.

 

[RickyScott]

Fortunately our surgical oncologists run the esophageal show, and, because they can read, they've all agreed that CROSS is superior to FLOT.

I'm starting to fight the "Neoadjuvant immunotherapy then surgery is better than chemoRT for stage III NSCLC" battle now. Ridiculous to me that we still have surgeons strongly advocating for resection in stage III NSCLC, but it's gaining ground unfortunately.

Exactly the same position.

 

[dieABRdie]

Fortunately here in my community the med oncs stick with CROSS given greater toxicity with FLOT. The last thing they want is to have to go to the hospital...

 

[medgator]

Fortunately here in my community the med oncs stick with CROSS given greater toxicity with FLOT. The last thing they want is to have to go to the hospital...

That's what extenders/APPs are for!

 

[ramsesthenice]

Fortunately here in my community the med oncs stick with CROSS given greater toxicity with FLOT. The last thing they want is to have to go to the hospital...

Fortunately for me, at our academic hub, the medoncs also don't buy this. For most people, 6 cycles of FLOT is way more toxic than chemorads. They won't make the change without data that chemo is better. Thats kinda how its supposed to work right?. If 2 treatments have similar efficacy, we are supposed to go with the one that is less toxic and/or less burdensome for the patient.

That said, even here we are not in the clear yet. They are not blind to the fact that NeoAgis wasn't really a FLOT trial and the door is open to the possibility that if everyone got FLOT it could be better (thinking FOLFIRINOX vs Gem as an equivalent here). If a trial shows true FLOT is more effective than CROSS we are toast unless FLOT + Cross is better than FLOT alone. The closest thing we have to that is Critics and that didn't work out so well.

 

[deleted941485]

I

Fortunately for me, at our academic hub, the medoncs also don't buy this. For most people, 6 cycles of FLOT is way more toxic than chemorads. They won't make the change without data that chemo is better. Thats kinda how its supposed to work right?. If 2 treatments have similar efficacy, we are supposed to go with the one that is less toxic and/or less burdensome for the patient.

That said, even here we are not in the clear yet. They are not blind to the fact that NeoAgis wasn't really a FLOT trial and the door is open to the possibility that if everyone got FLOT it could be better (thinking FOLFIRINOX vs Gem as an equivalent here). If a trial shows true FLOT is more effective than CROSS we are toast unless FLOT + Cross is better than FLOT alone. The closest thing we have to that is Critics and that didn't work out so well.

ESOPEC still waiting on

Plus they can throw all different combos of agents, number of cycles, etc. it’s never ending.

 

[ramsesthenice]

I


ESOPEC still waiting on

Plus they can throw all different combos of agents, number of cycles, etc. it’s never ending.

I mean, its not inherently a bad thing. We are not particularly great at GEJ tumors in terms of outcomes. I have no problem with doing well-powered and designed trials to try to find a better alternative (I'll be opening my own esophageal trial once it gets through the IRB gauntlet). But for gods sake, the bar to changing SOC is high for a reason. Accepting a new SOC because it it isn't "unacceptably inferior" in the absence of any meaningful toxicity benefit is just crazy in my mind.

Acceptably inferior (or not unacceptably inferior if you will) is not inherently wrong as a concept in the right context. Think PORTEC-2. There are more pelvic failures with VBT than WBRT. But the toxicity profile is light years better and since there is no survival difference we uniformly accepted VBT as a SOC. That is not even close to the same as we are talking about with FLOT for GEJ or esophageal tumors.

 

[deleted941485]

I mean, its not inherently a bad thing. We are not particularly great at GEJ tumors in terms of outcomes. I have no problem with doing well-powered and designed trials to try to find a better alternative (I'll be opening my own esophageal trial once it gets through the IRB gauntlet). But for gods sake, the bar to changing SOC is high for a reason. Accepting a new SOC because it it isn't "unacceptably inferior" in the absence of any meaningful toxicity benefit is just crazy in my mind.

Acceptably inferior (or not unacceptably inferior if you will) is not inherently wrong as a concept in the right context. Think PORTEC-2. There are more pelvic failures with VBT than WBRT. But the toxicity profile is light years better and since there is no survival difference we uniformly accepted VBT as a SOC. That is not even close to the same as we are talking about with FLOT for GEJ or esophageal tumors.

This gets back to what’s so crazy about being an RO in the 21st century. It doesn’t matter what we think the SOC should be or what the threshold for changing the standard should be either. All our expertise and data that we know and operate with everyday are immaterial. The only thing that matters is what our referrings think. That’s it. And you can whine and bitch and “oh but the guidelines say” except guidelines can be changed or you can add so many options that it really has the same effect.

 

[RickyScott]

This gets back to what’s so crazy about being an RO in the 21st century. It doesn’t matter what we think the SOC should be or what the threshold for changing the standard should be either. All our expertise and data that we know and operate with everyday are immaterial. The only thing that matters is what our referrings think. That’s it. And you can whine and bitch and “oh but the guidelines say” except guidelines can be changed or you can add so many options that it really has the same effect.

Exactly. If we want to be a player in oncology, need to be able to give drugs

 

[jondunn]

Exactly. If we want to be a player in oncology, need to be able to give drugs

or give radiopharms.

this one is more achievable in the current timeframe MO

 

[RickyScott]

or give radiopharms.

this one is more achievable in the current timeframe MO

would have very minor impact.

 

[jondunn]

would have very minor impact.

compared to giving drugs, sure.

but i do think that giving radiopharms will then give you a bit more control over when you give that same patient ebrt


rad oncs giving drugs in the US is not on the nextt 10-15 forefront, realistically.

 

[RickyScott]

compared to giving drugs, sure.

but i do think that giving radiopharms will then give you a bit more control over when you give that same patient ebrt


rad oncs giving drugs in the US is not on the nextt 10-15 forefront, realistically.

Agreed, but it’s not like radiology in big academic centers will just hand over radiopharm, so if we have to fight, may as well go after something worthwhile.

 

[xrt123]

Agreed, but it’s not like radiology in big academic centers will just hand over radiopharm, so if we have to fight, may as well go after something worthwhile.

Plenty of places have radiation oncologist delivering radiopharma. Currently phase 3 PSMA studies are in front line metastatic and also in 2nd line after ARDT failure/castrate resistant. If these trials are positive it should mean radiation is vital in all stages of prostate cancer.

Seems logical we should push to be involved.why would anyone send these patients to nuc med? Are they going to then send patients that are STAMPEDE trial candidates to you? And then you send back for radiopharma to them. Why not have one person do it all?

 

[RickyScott]

Plenty of places have radiation oncologist delivering radiopharma. Currently phase 3 PSMA studies are in front line metastatic and also in 2nd line after ARDT failure/castrate resistant. If these trials are positive it should mean radiation is vital in all stages of prostate cancer.

Seems logical we should push to be involved.why would anyone send these patients to nuc med? Are they going to then send patients that are STAMPEDE trial candidates to you? And then you send back for radiopharma to them. Why not have one person do it all?

While radonc does deliver radiopharm at some centers, anecdotally they don’t at the main campus of most large academic centers. Of course we should push to be involved.

 

[heartisinradonc]

Is there any evidence any of these protocols are better than definitive RT to 50.4 Gray with concurrent chemo? At least with chemoRT you have an intact oesopahgus when treatment fails. What happened after RTOG 0246?

 

[ramsesthenice]

Is there any evidence any of these protocols are better than definitive RT to 50.4 Gray with concurrent chemo? At least with chemoRT you have an intact oesopahgus when treatment fails. What happened after RTOG 0246?

The problem here is surgeon buy in. Watch and wait took a long time to get surgical buy in for rectal cancer but became a thing once surgeons were convinced that local failures did not compromise survival and result in substantial levels of non-regional spread. The problem I see (and hear about) is that the rectum is anatomically confined and the esophagus is not. There is a much bigger fear that local recurrences have a greater metastatic potential before they are detected in esophageal cancer.

Conceptually, it makes sense. In practice though, I think it’s crap. I probably treat around 10 or so folks a year who I know for medical reasons won’t be going to surgery at all and I can think of a more than a few who either never had complete responses or had a cCR and then had a local recurrence who remained local only failures for well over a year before developing metastatic disease. Given how morbid esophagectomies are and how high we know the pCR rate is, it’s blatantly obvious we are operating on too many people. Besides being better for patients, a non operative scenario would bode well for us (at least for a while). In field response rates (ie CR) with CRT are always going to beat out chemo alone. Even with something like FLOT. We are no where near seeing this become a reality anytime soon. But one can dream.

 

[heartisinradonc]

The problem here is surgeon buy in. Watch and wait took a long time to get surgical buy in for rectal cancer but became a thing once surgeons were convinced that local failures did not compromise survival and result in substantial levels of non-regional spread. The problem I see (and hear about) is that the rectum is anatomically confined and the esophagus is not. There is a much bigger fear that local recurrences have a greater metastatic potential before they are detected in esophageal cancer.

Conceptually, it makes sense. In practice though, I think it’s crap. I probably treat around 10 or so folks a year who I know for medical reasons won’t be going to surgery at all and I can think of a more than a few who either never had complete responses or had a cCR and then had a local recurrence who remained local only failures for well over a year before developing metastatic disease. Given how morbid esophagectomies are and how high we know the pCR rate is, it’s blatantly obvious we are operating on too many people. Besides being better for patients, a non operative scenario would bode well for us (at least for a while). In field response rates (ie CR) with CRT are always going to beat out chemo alone. Even with something like FLOT. We are no where near seeing this become a reality anytime soon. But one can dream.

I completely agree. The last thing that should ever be omitted is RT. Has anyone ever mentioned to the med oncs that their treatment modality contributes approximately 0-4% at most towards a potential cure? Why would they ever have any right to be making judgment upon the merits of our treatment?

 

[ramsesthenice]

I completely agree. The last thing that should ever be omitted is RT. Has anyone ever mentioned to the med oncs that their treatment modality contributes approximately 0-4% at most towards a potential cure? Why would they ever have any right to be making judgment upon the merits of our treatment?

It goes like this: "Cancer X (in this case esophageal) is a systemic disease. Therefore, systemic treatments are needed." While on paper that sounds fine, to keep believing it, you have to ignore the fact that focal chemoradiation has a strong and consistent survival advantage over surgery alone and they have thus far in numerous trials failed to show that chemo alone (even intensified chemo) does not do any better (or even as good if we want to get specific). If the systemic disease argument were really sound, then systemic therapy should not be equivalent to radiation, it should be better. But the systemic disease argument is accepted as gospel in some circles, evidence be damned.

The other thing about this that pisses me off the logic gap. We have a SOC which improves survival but admittedly still isn't great. A decent number of patients still have distant failure. Its not like distant disease control isn't a thing or is unimportant. But rather than trying to replace the SOC, it seems far more logical and meaningful to patients to first try adding to SOC to try to get better rather than equivalent outcomes. If I were on an IRB or study section, I would be much more interested in first seeing if adding good chemo to SOC can even improve distant disease control. If it can't, you already know that at best chemo will be equivalent, but not better than, SOC. In which case, great, half of our patients are still going to die of their cancer. Time to back to the drawing board because we really haven't helped anyone (except for maybe some of the providers). That kind of design would also address the question if we should be talking both modalities instead of either or. Instead, they went with an equivalence design which is pretty much capped at incremental potential from the start. Fortunately, the better designs are out there.

 

[evilbooyaa]

Find a way to intensity chemotherapy while sticking with what works locally in a disease, that with current patterns of care lead to high rates of distant metastatic failure. What a novel ****ing idea. Unfortunate it takes an anonymous misanthrope on the internet to ask the godamn question. Well besides CHECKMATE I guess.

There should be a PACIFIC-style of consolidative IT after definitive chemoRT for unresectable esophageal. Literally lowest hanging fruit for every disease site in the IT space once PACIFIC came out. Maybe there is already, CBA to look for it.

I think the 'concurrent IT' with fractionated RT is likely to be a loser based on CALLA and JAVELIN being negative, with caveat that not all squams/adenos are created equal.

 

[communitydoc13]

"Cancer X (in this case esophageal) is a systemic disease. Therefore, systemic treatments are needed."

Unfortunately we have moved from Halstedian thinking to this. Both wrong. Prevailing thinking among many medoncs (and even some surgeons now) is to treat all solid tumors as systemic disease upfront, selecting for local therapy only in systemic non-progressors.

 

[ramsesthenice]

There should be a PACIFIC-style of consolidative IT after definitive chemoRT for unresectable esophageal. Literally lowest hanging fruit for every disease site in the IT space once PACIFIC came out. Maybe there is already, CBA to look for it.

The bolded is your problem my friend. Potentially resectable patients far outnumber patients who are outright unresectable. The longer a trial goes on, the more expensive it is. On top of that, unresectable patients have more issues with competing mortality. Everyone doling out the cash wants the most immediate ROI they can get. But, since the distant met rate after surgery and SOC approaches 50%, it is very feasible to do an adjuvant IO trial in resected patients. And the trial has already been done. And was positive. Checkmate577:

https://www.nejm.org/doi/full/10.1056/NEJMoa2032125