PREOPANC Discussion

[Krukenberg]

Can a GI specialist decipher this for me? Big wig med onc at MDACC. At first it seemed to me he was speaking positively about neoadjuvant chemoRT, but then in his reply to a commenter it seems like maybe I misinterpreted?

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[OTN]

Can a GI specialist decipher this for me? Big wig med onc at MDACC. At first it seemed to me he was speaking positively about neoadjuvant chemoRT, but then in his reply to a commenter it seems like maybe I misinterpreted?

I spoke with one of our surgical oncologists after I shared the final publication with him. Main criticism of this trial was that gemcitabine-based chemotherapy is no longer considered the standard of care.

I agree with one of the commenters - some pancreatic cancer patients do benefit from XRT. The challenge is figuring out which ones.

 

[Palex80]

Can a GI specialist decipher this for me? Big wig med onc at MDACC. At first it seemed to me he was speaking positively about neoadjuvant chemoRT, but then in his reply to a commenter it seems like maybe I misinterpreted?

Well, mFOLFIRINOX given as neoadjuvant treatment has shown an OS benefit. The data are not great, but they are there.

So, he's probably advocating that neoadjuvant radiochemotherapy can enhance several endpoints but not OS.

I believe we need to wait a bit more, perhaps we may have some answers this summer from PREOPANC-2

 

[Ray D. Ayshun]

I spoke with one of our surgical oncologists after I shared the final publication with him. Main criticism of this trial was that gemcitabine-based chemotherapy is no longer considered the standard of care.

I agree with one of the commenters - some pancreatic cancer patients do benefit from XRT. The challenge is figuring out which ones.

Is the PREOPANC protocol well-tolerated? If I fit the trial criteria, I'd want it. I'd spend more time pondering whether I want whole breast...

 

[evilbooyaa]

Well, mFOLFIRINOX given as neoadjuvant treatment has shown an OS benefit. The data are not great, but they are there.

So, he's probably advocating that neoadjuvant radiochemotherapy can enhance several endpoints but not OS.

I believe we need to wait a bit more, perhaps we may have some answers this summer from PREOPANC-2

Preopanc-2 will be of value.

I read the initial tweet as "we should stop doing upfront surgery for all pancreatic cancer patients" without a specification on whether it should be neoadjuvant chemotherapy alone or chemo + RT.

But then a reply suggested he believes RT is not needed. For all comers, he is probably right.

Had to google PREOPANC-2, thanks Palex!

Winning arm of PREOPANC-1 will be the 'standard arm': Gem ALONE x 3 with 36/15 during cycle 2, then surgery, then 4 cycles GEM
Experimental arm will be 8 cycles of FOLFIRINOX

Seems unfair to compare a single chemo agent (+ RT) to a 3/4-agent cocktail... in a disease most hallmarked by distant metastatic failure... would be surprised if FOLFIRINOX doesn't win.

I learned something from this discussion, so time to move it to a new thread.

 

[Ray D. Ayshun]

Preopanc-2 will be of value.

I read the initial tweet as "we should stop doing upfront surgery for all pancreatic cancer patients" without a specification on whether it should be neoadjuvant chemotherapy alone or chemo + RT.

But then a reply suggested he believes RT is not needed. For all comers, he is probably right.

Had to google PREOPANC-2, thanks Palex!

Winning arm of PREOPANC-1 will be the 'standard arm': Gem ALONE x 3 with 36/15 during cycle 2, then surgery, then 4 cycles GEM
Experimental arm will be 8 cycles of FOLFIRINOX

Seems unfair to compare a single chemo agent (+ RT) to a 3/4-agent cocktail... in a disease most hallmarked by distant metastatic failure... would be surprised if FOLFIRINOX doesn't win.

I learned something from this discussion, so time to move it to a new thread.

Agree. Do we want to know what's best, or what's best without RT? I've had FOLFIRI. I might go with gem plus RT if the outcomes are the same as FOLFIRINOX as I'm sure its less pleasant with the ox. This has the makings of the standard gyn trial with better LC with RT and better distant control with aggressive chemo, which means chemo wins.

 

[OTN]

If I ever get pancreatic cancer, I'm taking the kitchen sink. There's clearly an RT signal there, and I would hate if I was one of the patients who would benefit and never got it.

 

[deleted1111261]

I’d want preop CRT for myself and would recommend to patients …

 

[jondunn]

i would get FOLFIRINOX. If not responding, and still not resectable, would then take cape-RT.

I would not want to delay the best systemic therapy until after I got a surgery, a surgery that may or may not ever come because I metted out before.


hoping the future is a TNT approach with FOLFIRINOX and some sort of RT.

 

[Ray D. Ayshun]

i would get FOLFIRINOX. If not responding, and still not resectable, would then take cape-RT.

I would not want to delay the best systemic therapy until after I got a surgery, a surgery that may or may not ever come because I metted out before.


hoping the future is a TNT approach with FOLFIRINOX and some sort of RT.

I like the last statement, but I could basically be done with 3 week rt while med onc works through port placement etc as long as their willing to use a peripheral line to give gem.

 

[ramsesthenice]

Alliance is doing another important trial of upfront vs adjuvant FOLFIRINOX for resectable pancreatic cancers (A021806). I think most of us (even the surgeons where I am) are convinced upfront chemo is better tolerated and extremely unlikely to compromise outcomes, but will be good to see in a randomized trial.

Role of RT in more advanced tumors we have to wait and see. With FOLFIRINOX it could go either way. Get better distant control so local control could mean more. But if better chemo gives substantially better local responses too we could be toast. The alliance FOLFIRINOX +/- SBRT for borderline resectable cases didn't bode well for us. https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.3_suppl.377

That said, survival and resection rates in their single-arm TNT with more comprehensive chemorads looked promising in the preliminary analysis: Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer: Alliance for Clinical Trials in Oncology Trial A021101 - PubMed

I bet we end up getting a seat at the TNT table, but it is not a guarantee.

 

[Palex80]

If not responding, and still not resectable, would then take cape-RT.

If not responding, I would take Hyper-CVAD.
Cocaine
Vodka
Adult
Dancers

and forget aout Cape-RT.

Someone posted that wonderful acronym here, years ago, If I am not mistaken. Excellent!

 

[Palex80]

Role of RT in more advanced tumors we have to wait and see. With FOLFIRINOX it could go either way. Get better distant control so local control could mean more. But if better chemo gives substantially better local responses too we could be toast. The alliance FOLFIRINOX +/- SBRT for borderline resectable cases didn't bode well for us. https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.3_suppl.377

There is a small randomized phase II trial running in Australia, testing mFOLFIRINOX or Gem-NabPaclitaxel +/- SBRT in bordeline resectable disease.
The Alliance FOLFIRINOX +/- SBRT was not really +/ SBRT... It was +/- some sort of RT in my humble opinion.
It's quite sad that quality assurance and protocol adherence were not good.

I bet we end up getting a seat at the TNT table, but it is not a guarantee.

Precisely. And unless we deliver high quality data, we are going to lose that seat.

 

[evilbooyaa]

Not to parrot chris crane, but whether you give 50/25-28 or 33/5, it's still not ablative RT. I really don't know that sterilizing margins is a thing in pancreatic cancer. The surgical literature seems to be that the biology that lead to the positive margin leads to the failure, not the fact that a surgeon got a positive margin (because the re-excision based on frozen doesn't really seem to matter).

I think the widespread use of 67.5/15 or 75/25 for unresectable cases is where RT will make it's stand... just requires people willing to do it. Seeing some of those escalated regimens nowadays for liver disease even outside Chris Crane/Parag Parikh...

 

[ramsesthenice]

There is a small randomized phase II trial running in Australia, testing mFOLFIRINOX or Gem-NabPaclitaxel +/- SBRT in bordeline resectable disease.
The Alliance FOLFIRINOX +/- SBRT was not really +/ SBRT... It was +/- some sort of RT in my humble opinion.
It's quite sad that quality assurance and protocol adherence were not good.



Precisely. And unless we deliver high quality data, we are going to lose that seat.

You are correct (as usual). If we do a deep dive, its worse than a negative trial. If anything, survival and resection rates were worse in the RT arm. The fact the RT wasn't consistent was not helping, but that was not the only problem with the trial.

 

[communitydoc13]

but that was not the only problem with the trial.

Functionally an~ 100 person trial. Terrible idea.

 

[ramsesthenice]

If not responding, I would take Hyper-CVAD.
Cocaine
Vodka
Adult
Dancers

and forget aout Cape-RT.

Someone posted that wonderful acronym here, years ago, If I am not mistaken. Excellent!

Thats just CVAD. What makes it hyper-CVAD? All at once?

 

[Palex80]

Thats just CVAD. What makes it hyper-CVAD? All at once?

I like your thinking!

 

[CaesarRO]

To me two things stand out:
1) this is an extremely well tolerated regimen
2) that's a huge benefit in the tail, people talking about median OS miss the point, imo.

Pancreatic cancer is a space with few wins, I see this as a big one.

The radiation is clearly beneficial for ~15% of pts. It would be great to better tease out who that is. Agree the trick will be teasing out FOLFIRINOX vs CRT, but all the pts I've seen get FOLFIRINOX were beaten up real bad.

One I saw as a resident who was still borderline resectable after FOLFIRINOX straight up laughed when I talked about risk of diarrhea with chemoRT, told me it was impossible to have worse diarrhea than he'd already had. He flew through ChemoRT without issues

 

[ramsesthenice]

To me two things stand out:
1) this is an extremely well tolerated regimen
2) that's a huge benefit in the tail, people talking about median OS miss the point, imo.

Pancreatic cancer is a space with few wins, I see this as a big one.

The radiation is clearly beneficial for ~15% of pts. It would be great to better tease out who that is. Agree the trick will be teasing out FOLFIRINOX vs CRT, but all the pts I've seen get FOLFIRINOX we're beaten up real bad.

One I saw as a resident who was still borderline resectable after FOLFIRINOX straight up laughed when I talked about risk of diarrhea with chemoRT, told me it was impossible to have worse diarrhea than he'd already had. He flew through ChemoRT without issues

FOLFIRINOX tends to go better than I would have expected but it’s not a cake walk. Even though they want to get 8ish cycles before RT it’s not unusual to stop after six, radiate, resect, and finish out back. Definitely not something we see with single agent gem or FOLFOX. Don’t sleep on Gem/Abraxane either. That’s strong **** for doublet therapy. Seen more than a few people get switched to FOLFIRINOX from gem/abraxane because of toxicity.

All of it supports your point. Most of the time, we got nothing on the hell oncology puts them through. To be fair though, totally worth it. The data is one of the more striking survival advantages I can recall across the board (ie, palliative, adjuvant…any way you want it).

 

[Radonc90]

This tweet below has more discussion in it.
The tweet is from a co-author himself (Dr Marc Besselink from University of Amsterdam)...

 

[Krukenberg]

This tweet below has more discussion in it.
The tweet is from a co-author himself (Dr Marc Besselink from University of Amsterdam)...

Interestingly I see several prominent surgeons saying RT probably has a role in neoadjuvant treatment, just have to identify the right patients. Hopefully there is will to keep doing trials testing RT as a part of neoadjuvant treatment.

 

[deleted941485]

To me two things stand out:
1) this is an extremely well tolerated regimen
2) that's a huge benefit in the tail, people talking about median OS miss the point, imo.

Pancreatic cancer is a space with few wins, I see this as a big one.

The radiation is clearly beneficial for ~15% of pts. It would be great to better tease out who that is. Agree the trick will be teasing out FOLFIRINOX vs CRT, but all the pts I've seen get FOLFIRINOX were beaten up real bad.

One I saw as a resident who was still borderline resectable after FOLFIRINOX straight up laughed when I talked about risk of diarrhea with chemoRT, told me it was impossible to have worse diarrhea than he'd already had. He flew through ChemoRT without issues

There’s also a preoppanc-3 out there as well which doesn’t appear to use any RT just fiddling with the sequence of FOLFIRINOX

At best you’re looking at comparable cancer outcomes between winning arm of preop panc and FOLFIRINOX with possibly being able to sell preop panc better due to a lower toxicity profile. If the outcomes are the same why risk more tox?

 

[theradiator]

There’s also a preoppanc-3 out there as well which doesn’t appear to use any RT just fiddling with the sequence of FOLFIRINOX

At best you’re looking at comparable cancer outcomes between winning arm of preop panc and FOLFIRINOX with possibly being able to sell preop panc better due to a lower toxicity profile. If the outcomes are the same why risk more tox?

In a community practice, many patients are not candidates for FOLFIRINOX. We should embrace filling the role of neoadjuvant for the non FOLFIRINOX candidate and someone must be working on a Gemcitabine + Abraxane + PREOPANC-like RT schedule.

 

[Palex80]

There’s also a preoppanc-3 out there as well which doesn’t appear to use any RT just fiddling with the sequence of FOLFIRINOX

At best you’re looking at comparable cancer outcomes between winning arm of preop panc and FOLFIRINOX with possibly being able to sell preop panc better due to a lower toxicity profile. If the outcomes are the same why risk more tox?

Indeed, this could work out. It worked out in neoadjuvant esophageal cancer, for instance, with FLOT not being superior to the CROSS-regime according to Neo-AEGIS.

 

[CaesarRO]

Indeed, this could work out. It worked out in neoadjuvant esophageal cancer, for instance, with FLOT not being superior to the CROSS-regime according to Neo-AEGIS.

I also see med oncs arguing Neo-AEGIS means chemo is just as good. My colleagues and I have to actively push back about the lack of benefit with added tox. I think there might be a difference between Europe/US on that front.

Good parallels actually between FOLFIRINOX/PREOPANC and FLOT/NeoAEGIS. The criticism there is only 15% got FLOT, so med onc argues "if CROSS is comparable to worse chemo, our better chemo must be better than CROSS"

 

[deleted941485]

I also see med oncs arguing Neo-AEGIS means chemo is just as good. My colleagues and I have to actively push back about the lack of benefit with added tox. I think there might be a difference between Europe/US on that front.

Good parallels actually between FOLFIRINOX/PREOPANC and FLOT/NeoAEGIS. The criticism there is only 15% got FLOT, so med onc argues "if CROSS is comparable to worse chemo, our better chemo must be better than CROSS"

Any data from esopec?

 

[Palex80]

Any data from esopec?

Accrual completed in April 2020.

 

[ramsesthenice]

Indeed, this could work out. It worked out in neoadjuvant esophageal cancer, for instance, with FLOT not being superior to the CROSS-regime according to Neo-AEGIS.

Sadly, I disagree. The huge difference being that neoadjuvant chemoradiation was already the established SOC in esophageal cancer. In Panc, we are don't have an established foothold yet. I think one of the trials is going to have to show that doublet or triplet chemo + RT is better than doublet or triplet chemo alone (either OS or R0) for us to stay in the SOC game. Despite the fact that local progression is a major cause of severe morbidity and the dominant pattern of progression for up to a third of patients, there is a very strongly held belief that pancreatic cancer is a systemic disease and, by extension, chemo has to be better. Given how much FOLFIRINOX improves survival compared to single agent gem across the board (adjuvant to metastatic) I don't see a realistic scenario in which RT replaces it in people minds. It is going to have to add to it.

Personally, I agree with the toxicity argument. In addition to the acute toxicities, long term neuropathy seems to be quite pronounced as well. But I can tell you from a lot of experience it is hard to get anyone, even NIH study sections with corresponding RFAs, interested in toxicity mitigation studies for aggressive cancers like pancreatic. The montra is "find the cure, then worry about side effects."

 

[Krukenberg]

Sadly, I disagree. The huge difference being that neoadjuvant chemoradiation was already the established SOC in esophageal cancer. In Panc, we are don't have an established foothold yet. I think one of the trials is going to have to show that doublet or triplet chemo + RT is better than doublet or triplet chemo alone (either OS or R0) for us to stay in the SOC game. Despite the fact that local progression is a major cause of severe morbidity and the dominant pattern of progression for up to a third of patients, there is a very strongly held belief that pancreatic cancer is a systemic disease and, by extension, chemo has to be better. Given how much FOLFIRINOX improves survival compared to single agent gem across the board (adjuvant to metastatic) I don't see a realistic scenario in which RT replaces it in people minds. It is going to have to add to it.

Personally, I agree with the toxicity argument. In addition to the acute toxicities, long term neuropathy seems to be quite pronounced as well. But I can tell you from a lot of experience it is hard to get anyone, even NIH study sections with corresponding RFAs, interested in toxicity mitigation studies for aggressive cancers like pancreatic. The montra is "find the cure, then worry about side effects."

Now that nivolumab is part of the pre-op chemoRT paradigm, I don’t see neoAegis moving the needle, at least until someone runs a trial of periop chemo +\- nivo

 

[Palex80]

Sadly, I disagree. The huge difference being that neoadjuvant chemoradiation was already the established SOC in esophageal cancer. In Panc, we are don't have an established foothold yet.

I guess this is a US - European - drift thing again, sorry.

In the hospitals where I have worked, AEG I and the SCC of the esophagus were treated with neoadjuvant chemoradiotherapy, but whenever it was AEG II/III (and of course gastric) the med. oncs always pushed for chemo-only. EOX/Magic in the past, FLOT in the recent years.

I can now point at Neo-AEGIS which was AEG I-III and advocate for CROSS as less toxic.

 

[Palex80]

Now that nivolumab is part of the pre-op chemoRT paradigm, I don’t see neoAegis moving the needle, at least until someone runs a trial of periop chemo +\- nivo

Already happened.

https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.4549

Accrual already complete. It's a large Phase-II, results expected soon.

 

[Krukenberg]

Wheth

Already happened.

https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.4549

Accrual already complete. It's a large Phase-II, results expected soon.

Whether that changes true esophagus RT referrals depends in part on how many Siewart Is are on that trial. My guess is not many.