BTK_ESOPEC

Hi, and welcome to another journal review in Thoracic Surgery with your Swedish Thoracic surgery team. I'm Chloe Hanson. I'm a third year general surgery resident, currently in my research year here at Swedish, and I'm joined by my extremely esteemed attendings, Dr. Brian Louis and Dr. Peter White. Howdy do hello today be the last Swedish thoracic surgery podcast contribution to behind the knife for this journal club, we are discussing the highly awaited e OPEC trial.

Published in January of this year, which examines perioperative chemotherapy versus preoperative chemoradiation in esophageal adenocarcinoma. This paper is the most recent in a series that have been examining the best treatment regimen for esophageal and esophagal gastric junction cancers. But before we get into the details, Brian, can you help set the stage for how this paper fits in with the other studies that have been completed?

Absolutely. We've all heard of the cross trial and the magic

trials, but let's take a quick refresh at several of these studies that led towards e opec. The magic trial was the first, and it was published in 2006, and this examined perioperative chemotherapy versus surgery alone for patients with predominantly gastro carcinoma, but had a number of GE junction cancers in there.

They found a survival benefit in patients who received perioperative chemotherapy. The regimen used in this trial was Epi Rubicon, cisplatin and fluoro UIL given prior to surgery with four cycles, then surgery, then four cycles after. And what this trial really did for GE Junction cancers was it established that there was a potential role for perioperative chemotherapy in GE junction cancers.

All right. Then in 2012 there's a Dutch trial called the Cross Trial that compared neoadjuvant chemoradiation plus surgery to surgery alone in patients with

esophageal adenocarcinoma or squamous cell carcinoma. And this showed that preoperative chemo radiotherapy with carboplatin and paclitaxel plus radiotherapy with a dose of 41.4 gray.

Followed by surgery led to an overall superior survival curve than surgery alone. One of the findings of this study that the benefit for survival was driven more so by the squamous cell cancer population and somewhat less from the adenocarcinoma population. Next came the German Flo four trial, which is published in 2019.

Which examined two chemotherapy regimens, comparing fluoro, uracil, lorrin, oxaliplatin, and docetaxel or flott versus the magic res regimen in patients with esophageal esophagal gastric junction in gastric adenocarcinoma. Flo demonstrated a 15 month improvement in overall survival with 50 months compared to

35 months for the magic regimen.

This cemented flaw as a preferred perioperative chemotherapy regimen for gastric and gastroesophageal adenocarcinoma. The more recent trial was neo ais, which was published in 2023, but was stopped early due to a fertility interim analysis. It compared cross as a trimodality therapy with preoperative chemoradiation against perioperative chemotherapy with the magic regimen up to 2018.

And then switched to Flo in 2018 because of the German trial, it demonstrated equivalency with regards to overall survival in patients with esophageal or EG junction carcinoma, but it was ultimately underpowered because of the switch to Flo late in the trial. And this led to early termination of. Yeah, so we've talked about a few different chemotherapy regimens so far.

Most recently is flott. The other was the regimen with the cross trial which used carboplatin and

paclitaxel. So flott is fairly strong chemotherapy. It does have a higher associated toxicity rate. It can be more difficult for patients to tolerate and then ultimately complete, especially those that are older.

The chemotherapy regimen in the cross trial is almost more of a radio sensitizing agent tends to be much better tolerated and more patients were able to complete this compared to flock. And it's one of the things that we'll talk about as we move forward with these studies. So if you were following along, we've compared plot four with magic, the cross regimen with magic, but we have not yet discussed a completed study of the cross regimen with the Flo regimen, which leads us to the EPEC trial.

Alright, I think we have a good idea of the impetus behind the trial, so let's jump into the methods. Yeah, so the EPEC trial is a German trial that examined adult patients with clinical T two to T four A or node positive lower esophageal and EGJ

adenocarcinoma. These were patients with an ECOG status of zero two with no previous chemotherapy or radiation.

Their primary endpoint was overall survival at three years. And to highlight this as a difference between the cross trial it excluded squamous cell carcinoma and only focused on the esophageal and EGJ adenocarcinoma. And remember, in the cross trial the improved survival benefit and the improved pathologic complete response.

Was seen higher for squamous cell carcinoma compared to adenocarcinoma. And some of this drive, the overall benefit that was seen in the cross trial. Also, the cross trial had excluded patients with T four A disease whereas these T four a size tumors were included in e opec. Good point. There are some other key differences between cross and epec protocol, which may also impact the conclusions we're able to draw from their results.

So CT imaging was performed prior to

randomization to confirm there was no metastatic disease. Note here that in the US a PET scan as part of initial evaluation would also be standard. Patients were then randomized to two arms flop plus surgery versus preoperative chemo radiation plus surgery. The flaw arm consisted of four cycles of chemotherapy every two weeks, followed by surgery, then an additional four cycles of chemotherapy every two weeks.

The second arm was the official cross protocol, which is Carboplatin plus Paclitaxel once daily and 41.4. GRA of radiation Surgery was then performed four to eight weeks after completing four cycles of slot, or four to eight weeks after the last dose of preoperative chemoradiation. Length of follow-up was three years after the last patient was assigned to trial.

So we have some results up to five years. However, we gotta remember that their primary endpoint was three year survival. The other item, Chloe, to remember is that, as you said in the cross protocol, 41 grave, a radiation was used. But

clinically, most groups are using 50.4 graver radiation as a modified cross protocol in most standard US cancer centers.

And so that's a big important point to remember. Yeah, and part of that is the definitive radiation dose for the treatment is the 50 40 gra. And so that helps cover patients that may never get to surgery because now they've had a definitive dose of radiation. Now let's move on to the results. So Chloe, let's walk us through some of the pertinent demographics from table one.

Yeah, so they enrolled a total of 428 patients from 2016 to 20 20, 221 patients in the flaw arm and 217 patients in the pre-op chemoradiation arm. Overall, these patients were mostly male and mostly had an ECOG SAS of zero or one baseline characteristics were mostly balanced. However, the Flo arm had slightly more patients with the T four tumor and the pre-op chemo RADS arm had more patients with nodal disease.

Yeah, and then with regards to treatment in the Flo Group,

87% had received all four cycles of therapy prior to surgery. However, only 53% completed the full four cycles of adjuvant. Flo after surgery. This speaks to the difficulty of the adjuvant chemotherapy after recovering from surgery, as well as some of the inherent side effects of flos and the potential challenges.

38% of patients in the flat arm did not receive any adjuvant chemotherapy after surgery in the cross arm of the EPEC trial. 67% received complete five cycles of chemotherapy before surgery, and 88% of patients received the complete 41 gray of a radiation. This is one of the places where the cross arm of the PEC trial does worse in comparison to the same arm in the true cross trial, where 91% received full treatment compared to 67% in the same arm in the EPEC trial.

Moving on to their primary

endpoint. The overall survival at three years was 57% in the flaw arm and 50% in the pre-op chemoradiation arm with a hazard ratio of 0.7 favoring flaw. In the five year data, the overall survival was 50% in the flaw arm and only 38% in the pre-op chemoradiation arm. The median overall survival was 66 months in the flat arm and only 37 months in the pre-op chemo RADS arm.

A difference of 29 more months in median survival for the flaw arm. Yeah, that's a pretty significant difference in both the five year outcomes as well as the median overall survival. Brian, remind us what were the similar statistics that were reported in the pre-op chemo radiation arm of the cross trial?

So in the cross trial, they reported overall survival at 58% at three years. 47% at five years. And also in the neo ages trial, it was 57% at three years. So there's some discrepancy between the E OPEC results and the other two trials for the

same treatment arm. As we mentioned earlier, remember, e OPEC does not include squamous cell carcinoma, which typically is a good response to chemoradiation.

And 23% of patients on the cross all had squamous cancer, which is one reason for the discrepancy in these numbers. It's interesting to look at the OPEX subgroup analysis. They demonstrated a better response with flaws versus chemoradiation with male patients, younger patients, patients with a lower ECOG score, patients with a higher T score, particularly T three to four, and those with node positive disease.

This definitely gives the sense of those that are younger, stronger, and with more aggressive cancers would tend to do better with flock as a more aggressive chemotherapy regimen compared to chemoradiation. Chloe, tell us a little bit about the secondary endpoint of disease progression in recurrence.

They report that progression-free survival at three years was 51% in the flaw arm and

35% in the pre-op chemoradiation arm. In an intention to treat analysis. This includes patients who were found to have distant mets before the start of therapy, of which the pre-op chemo radiation arm had more, still fairly significant.

Yeah. Then in terms of type of progression in the flaw arm, there was more isolated local regional progression while the pre-op chemoradiation arm had more patients with distant metastasis. It seems like this makes intuitive sense as radiation is good at controlling local disease and the stronger chemotherapy in the Florida arm would be better at controlling systemic disease.

I wonder if that's really the case. Yeah, Brian, it seems like there's clearly more to it. 'cause if you look at the pathologic endpoints, both groups had similar rates of R zero resection. And we might have expected a higher rate of R zero with the addition of radiation. Also, when we look at the response rate with the pathologic specimens, there's a difference in the complete response,

and you would've thought that the addition of radiation would've boosted the pathologic complete response in the cross arm.

But Chloe, can you tell us about that? As a reminder, pathologic complete response or PCR is defined as no residual invasive cancer in the surgical specimen after resection. So they report a 16.7% path CR in the flat arm and only a 10% path CR in the pre-op chemoradiation arm. This is pretty low. That path CR seems fairly low for the pre-op chemoradiation arm.

What was it in the cross trial, the reported PCR for adenocarcinoma in the cross trial in the chemoradiation arm was 23%. Why do you think there is such a discrepancy? Chloe, it may be related to a few different factors. One of them is the inclusion of the T four A tumors in the E OPEC trial. These are presumably gonna be larger.

Though it only accounts for about 5% of tumors that were within the cross regimen arm of the e

OPEC trial. A second reason, it may be related to fewer patients in the preoperative chemo radiotherapy arm, and e OPEC completing the full therapy. So in E opec, only 67% completed it, whereas it was 91% within the cross trial.

Lastly, when you look at nodal disease, there was an overall higher percentage of patients with nodal disease within the e OPEC trial, and that's the preoperative chemo radiotherapy arm of the IS OPEC trial, which is 81.6%, whereas that same arm in the cross trial, it was lower at 65%. Then when you look at post resection nodal disease, as you'd expect even after resection, nodal disease percentage was higher in the chemo radiotherapy arm of the IS OPEC trial at 45% versus that same arm in the cross trial at 31%.

These are considerations of the differences

between these trials. Um, but it is a little bit tough to make direct comparisons because of the way and the nature that these trials were run. Well, that's a lot of data. Peters, let's now go over the safety and side effect outcomes in the two arms. Chloe, can you summarize, as we mentioned previously, flaw is typically challenging with higher serious and severe adverse events compared to the cross regimen.

The serious adverse event rate was 47% in the flaw arm compared to 41% in the pre-op chemoradiation arm. While severe adverse events, which is grade three or higher, at a rate of 58% in the flaw arm and 50% in the cross arm, the most common serious adverse event in both treatment arms was pneumonia. The most common severe, which is grade three or higher adverse event, was neutropenia in the flaw arm and leukopenia in the preoperative chemoradiation.

So essentially more side effects and adverse events in the flaw arm. Which is something that

we see and are concerned about clinically in practice as well, right? There was also a difference in estimated 90 day postoperative mortality with 3.1% in the flaw arm and 5.6 in the pre-op chemoradiation arm.

But as this was an estimate from Survival curves, we can't draw statistical comparison. Alright, so that's a lot of data. You may have to go back and listen to it a few times to fully cover it, but let's now summarize and give some highlights. E OPEC is a phase three randomized controlled trial. It examines surgically resectable, lower esophageal, and esophagal gastro junction adenocarcinoma.

It compared the regimens of four cycles of induction flo plus surgery, plus an additional four cycles of adjuvant Flo versus preoperative chemo radiotherapy plus surgery. Overall, the findings demonstrated an improved three and five year survival in patients

receiving FL therapy with a median overall survival of 66 months in the flat arm compared to 37 months in the cross arm.

There is a lot to talk about here. This trial reported fairly significant survival benefit to flock over preoperative chemo radiotherapy, but there are some considerations. Dr. Louie, what do you think? Yeah, so firstly, e OPEC is for adenocarcinoma only, and while there is a subset, some subset analysis adenocarcinoma across this creates some limits to directly compare cross regimens in each of these.

E opec. Most patients had a performance status of zero to one with a median age of 63 with the toxicity associated with Flo. It may be more challenging to get ECOG two patients or octogenarians through the complete regimen of fl. Even in ES opec, only 53% of patients completed the four cycles of flock after surgery.

And these studies are generally the best case scenario.

In real life, this may be even tougher. And we've actually been discussing moving these cycles of flaw to all before surgery. So we have often given all eight cycles upfront. Peter, what are your thoughts? Yeah I definitely agree with that.

You've mentioned already when you look back at the Flop four study, they also had a pretty low completion rate. Only 46% of patients had completed all eight cycles. And there are several studies showing a higher completion rate if you move those cycles before surgery in potentially a total induction treatment regimen.

Although when you think about it, even though only 53% of patients completed the adjuvant plot. We still saw a significant benefit when they were all grouped together over preoperative chemo radiotherapy. So even with that potential downside with the way the study was done, we saw the benefit, and we touched on this before, but to highlight the discrepancy of the path CR rate for preoperative

chemoradiation of E OPEC compared to the cross trial, it was 10% in the same e OPEC trial arm versus 23% in the same cross trial arm.

Though when you compare it to neo ages, the pathologic complete response was 12%. So more similar to what we've seen in e opec. This is one of the critiques that we hear about the e OPEC trial saying, well, maybe the trial just wasn't done in the same manner because the PATH CR rates were so different.

But we talked about some of the differences in terms of larger tumor sizes and more nodal disease. So that may also give some explanation as to why we see that discrepancy. Additionally, Anis opec, they tended to be higher stage patients because of that. And the authors also point out this as a difference between the studies as a potential explanation.

Chloe, is there anything you also wanted to point out? So we mentioned this before, but the preoperative chemo rats arm had more distant recurrence than the flaw arm, which

again goes back to flaw being a superior systemic treatment, um, to compared to the cross regimen. So based on the ES OPEC data, it does appear that there is a clear superiority when we do perioperative floss compared to preoperative chemoradiation for esophageal and GE junction adenocarcinoma.

But Brian is there ever a case when you would actually prefer the cross regimen to Flo? You know, Peter, there's a few ways to sort of think about the answer to that question. The first point I think is, is most important is that surgical resection, regardless of these two regimens, is the most important aspect or modality that need to get to.

So the key goal is to make sure that if you're using flawed or cross, that you still get to surgery. And if you make the patient so sick that they can't get to surgery, that becomes a problem. And this is where we get to with some of the supplementary group analysis. As, as you've mentioned before, for the benefit of Flo was driven by patients who are under 60 good

ECOG performance status, higher T stage, and more nodal disease.

So in those patients, I'm more likely to push for flock, but those patients in the PEC trial who had higher ECOG scores who were older than 70, might have had lower stage disease. The hazard ratios crossed one. So those are folks that clinically I might give cross to because I just need to simply get them through to surgery and these folks probably do equally as well.

Now, the other two things that we should point out are that based on Checkmate 5, 7, 7, but we, which we previously discussed in the behind the knife journal review, that adds nivolumab after chemoradiation, followed by surgery. And in the current US model, we cannot give and don't always get approval for adjuvant nivolumab, and that's not been studied in the EPEC trial.

The second I item that we mentioned before is the true cross regiment has 41 graver radiation, and most of us have moved to

50.4, which potentially adds different advantages after using this higher radiation dose. Though that's not been truly fully studied. Yeah, and of course we have to mention, we as surgeons all know it, but we're not the ones who are actually giving these chemotherapy drugs.

There may be many institutions where the oncologists drive these decisions for perioperative care and systemic therapy. But I'd really encourage all the surgeons out there have those conversations, talk to the oncologists because our experience with seeing how patients are before surgery, after they've had flaw versus chemoradiation, as well as talking to them about the nuances of the care, it really gets them excited and they almost always really appreciate our input.

So hope you'll use some of the things you've learned with this to talk to your oncologist about it. Thanks for listening to another Swedish Thoracic Surgery Journal review. I really hope you've taken away some nuggets to impress your attendings with your in-depth knowledge of the Issa Effect trial.

After this podcast, there's gonna be a new thoracic surgery group who's gonna continue making amazing thoracic content. We want to say that it's been an absolute pleasure to be involved with the behind the knife over the last four years. Yeah, Peter, it's been a fantastic experience learning how to generate content, do podcasts, and we hope to see all of you at future thoracic and foregut meetings.

This is Swedish thoracic surgery. Over and out now go out and dominate, dominate the day.