BTKJournalCl_GastricCA_v3

Hi everyone. Welcome back to another episode from your surgical oncology team. I'm Elizabeth Barbera. I'm from Brooklyn Medical Center. I'm a six year resident there. I'm Lexi Adams. I'm a first year fellow at MD Anderson. I'm Connor Chek, I'm a second year fellow at Ohio State. And I'm Tim Briel, and I'm a surgical oncologist from Brook Army Medical Center.

We hope Dr. Nelson can join us for our next episode. He just recently graduated from an HPV fellowship at MD Anderson, but he's currently moving across the country right now. We'll see him next time. Firstly, we highly recommend you guys check out our most recent clinical challenges episode, which was published on May 23rd.

This episode gives great context for the workup and management about gastric adenocarcinoma, which is going to be super important as we transition today into a discussion about the two trials that really revolutionized the perioperative chemo strategy for this disease. We did have a tough time picking which articles we wanted to talk about today.

There's plenty of papers to discuss with gastric cancer, especially when it comes to discussion of lymphadenectomy approaches, which we did talk about during our last episode. But

ultimately, we picked two trials that are definitely required reading in surgical oncology. The MAGIC trial published in the New England Journal of Medicine in 2006 by Cunningham and colleagues, and the FLOT4 trial published in The Lancet in 2019 by Albatron and colleagues.

These are linked to in our show notes. Connor, do you want to kick off the discussion of the MAGIC trial? Absolutely. So let's talk first about the context of this trial, which was published almost 20 years ago now. So the principal chemotherapy regimen at the time for advanced gastric cancer was ECF, or epirubicin, cisplatin, and 5 FU.

So this regimen had demonstrated improved survival and response rates among patients with advanced G junction cancers or gastric cancers compared to the prior regimen of 5 FU doxorubicin and methotrexate. So the MAGIC trial was designed to investigate whether ECF given before and after surgery improves outcomes.

Beth, can you talk about the methodology of the study? Yeah, absolutely Connor. So in this trial, patients of all ages

were included who had a decent performance status and had biopsy proven adenocarcinoma of the stomach, Or the lower third of the esophagus, and they needed to be stage two or higher. So invading through the muscular propria that was deemed respectable by imaging and or laparoscopy exclusion criteria for the trial included prior chemotherapy or radiotherapy or prohibitive medical comorbidities, which they stratify nicely in the paper patients were randomized to either perioperative chemo and surgery.

So this is approximately 250 patients or surgery alone, and this was 253 patients. Chemo was given of three preoperative and three postoperative cycles. Surgery was scheduled within six weeks after randomization in the surgery alone group, and three to six weeks after the completion of the third cycle of chemo in the peri op chemo group.

The primary endpoint of the study was overall survival, and the secondary endpoint was progression free survival, and these were both measured via the Keppel Meyer method. Additional secondary endpoints the

authors looked at included surgical and pathological assessments of downstaging cure, as well as quality of life.

Lexi, do you want to talk us through the starting results of the trial? Yes. So, patients were randomized between 1994 and 2002, mostly within the UK. And this was in an, although this was an international trial. So to summarize, 250 patients were included in the perioperative chemotherapy group. Out of those if they were able to start chemo, 91 percent of patients were able to complete.

Three cycles preoperatively. Of the patients who then underwent surgery, only 65 percent of patients actually began chemo after surgery, and then the number drops even lower to only about 40 percent of the initial 250 patients actually getting through all six cycles. Reasons for patients to drop out were early death, patient choice, or post op complications.

If you look at the surgery group, 96 percent of those 244 patients

underwent surgery. Surgery was considered curative in 79 percent of patients in, The group that received peri op chemo and only 70 percent in the surgery group. So comparing the groups that got peri optive chemo and just surgery, the postoperative complications, the number of deaths within 30 days and the median hospital stay were actually equivalent between the groups.

Connor, why don't you discuss the survival results? Yeah. So. At a median follow up of about 4 years, the perioperative chemotherapy group had a significantly better progression free and overall survival compared to the surgery first group. And 5 year survival rates were 36 percent for perioperative chemo versus 23 percent for upfront surgery.

Beth, can you help us draw some conclusions from the study and describe some limitations? Yeah, thanks, Connor. So in my opinion, this is a well designed multi center international trial. It was adequately powered and randomized patients to

perioperative chemo versus surgery alone for resectable cancers of the lower esophagus and stomach, and it met its primary endpoint.

Ultimately, conclusions derived from the study demonstrate that anyone with T2 positive or N1 disease should get perioperative or preoperative chemotherapy. And this is interesting because previous studies to this. randomized trial actually included a randomized trial of adjuvant chemotherapy so that showed no survival benefit of post operative chemo.

So let's talk about some limitations of the trial. Only 42 percent of patients completed their post operative treatment, although to some degree this is expected in the setting of a fairly toxic regimen. We also can't draw any definitive conclusions regarding pre versus post operative treatment chemotherapy given it was a combination in the trial.

Interestingly, the authors also acknowledge a few new drugs that were developed during the time of the trial. These include oxaloplatin, which is a key component of the FLOT regimen, which we'll discuss in a moment. Okay. So what are our take home points, Beth? I think you mentioned the big one is, you know,

this was a perioperative chemo regimen.

And, I always bring up when I talk about this, that the history around this is very interesting because as you said, there were some small randomized trials of adjuvant chemo that didn't show much of a benefit. And then this was the first trial that showed real benefit and it was perioperative chemo, meaning pre and post.

And, my theory as to why that's true. Lexi alluded to through some of those numbers, the vast majority of patients who started chemo, 91 percent of the patients who started chemo got through their preoperative chemo post op. Only about 50 percent of patients, or a little less, completed their post op chemo.

So, a lot of the reason that I think peri op works so much better, and one of the big reasons that I'm a huge proponent for neoadjuvant, for gastric and pancreas cancer that requires a Whipple, for cancers that are not only aggressive but require a very large operation, so esophagectomy, Total gastrectomy.

These are massive

operations and patients just don't recover well enough to tolerate full bore chemo. It's the exception, not the rule that a patient undergoes a total gastrectomy and could tolerate chemo, particularly ECF or FLOT, which are very toxic regimens. after that operation. And so I think that's why adjuvant therapy probably would never show a great benefit for patients who need an esophagectomy or a total gastrectomy because it's just so hard to tolerate after that operation if you even get to start it.

And so that, those I think are the key numbers to pay attention to as we go through these two trials is that the vast majority of patients who started their pre op chemo finished their pre op chemo. Of the patients who had surgery. And then we're able to start post op chemo less than half of them complete their post op chemo.

And so I think that's a big take home here is that when you're doing a very big operation for an aggressive cancer, trying to get some chemo on board up front is probably a better option. It's interesting in pancreas cancer that the first trial conco

one that showed a survival benefit for pancreas cancer was an adjuvant.

And then. They, you know, a large perioperative chemo trial has never really been done because it's so hard to enroll because so many people have these thoughts ingrained about whether people should get neoadjuvant or adjuvant, and they don't want to enroll in that trial. So there's an alliance trial ongoing now that hopefully will actually answer this question for us.

Whole different discussion, but. It's just interesting here that the history is that the first trial showing chemo benefited patients with gastric cancer was done in a perioperative fashion. And so that set that as the standard of care from all the way back in 2006. So nobody's ever really questioned the idea of neoadjuvant chemo for for gastric cancer.

Like we have all these debates about pancreatic cancer. At the end, we're going to talk about a retrospective trial that was recently published that asked the question, should we be giving All the chemo up front for gastric cancer. And I think that's an interesting question for the future. You know, we should really talk

about how bad the surgery alone arm did here.

So Lexi, go over the survival numbers again. Yeah. So the dismal outcomes from the magic trial, again, five year overall survival in a surgery alone group was 23 percent versus only 36%, even with perioperative chemo, it's worth it to download this paper and look at the particularly progression pre survival.

Kaplan-Meier curves. If you look at the median progression-free survival in the magic trial for surgery alone. Now again, ECF didn't do that much better, but progression-free survival was about a year. The median was about a year. So if you do a total gastrectomy on a patient, it takes 'em about six months to recover.

And so, maybe they'll get another six months before they recur. It just doesn't make a ton of sense to do surgery alone in these things. And if you're. Thinking that half the patients that get a total gastrectomy and maybe it's even less than that with a total are going to

complete adjuvant chemo.

It's really important to get pre opt chemo. So every once in a while, this scenario comes up where your us will say that it's a T one tumor, but it's like signet ring and diffuse. And they like, couldn't get the scope through the tumor because it's circumferential and they have obstructing symptoms and all these concerning signs that it's clearly a worse tumor than it is.

And, I think it's just, you really have to think hard about operating first on those patients, especially if you're going to have to do a total scan. I think this trial just kind of shows that surgery alone is inadequate for these patients. Patients who get a total gastrectomy in particular, I think, have a low chance of cleaning adjuvant therapy.

So you really should push chemo up front. And most gastric cancers are going to present as a T2 or better, but just don't get tricked by a bad EUS that says it's a T1 when it's clearly not. So, given the poor outcomes and as well as some new drugs on the market this led to a new trial

investigating FLOT, which includes fluorouracil, leucovorin, oxaloplatin, and docotaxel.

And this was used in a randomized open label phase 2 or 3 trial comparing perioperative ECF versus FLOT. And we're going to discuss the phase 3 results of this trial today. Connor, do you want to walk us through the methodology of the trial? Yeah, thanks Lexi. So this was a multi center randomized trial conducted in German centers between 2010 and 2015.

Inclusion criteria were pretty similar to MAGIC. The clinical T2 or greater or node positive resectable GE junction or gastric cancers. The regimens they looked at were 716 ECF, or ECX, which is just Ebrubicin, Cisplatin, and capecitabine, or Zolota. So in total, they randomized 716 patients to perioperative, ECF, or FLOT.

The study protocol tried to control for appropriate surgery based on tumor location, and so they specified that

patients would need an ivory luteus esophagectomy with a thoracic and abdominal lymphadenectomy for CWRT1 tumors. They would need esophageal gastrectomy for CBRT 2 and 3, and then either total or subtotal gastrectomy with D2 and fattenectomy for gastric tumors.

So the primary outcome, interestingly, was changed partway through the trial. Initially, it was disease free survival, but was changed to overall survival at the request of an independent scientific committee. And then secondary outcomes included the rate of R0 resection, disease free survivals surgical complications and perioperative mortality, as well as adverse events.

Beth, can you go over the results of the trial? Ultimately, the breakdown of patients demonstrated a 44 percent stomach site, 33 percent sewer 2 3 site, and 23 to 24 percent who are at one site of malignancy. Most patients had T2 or T3 disease and most were N positive. 98 and 99 percent of patients started ECF and FLOT in

their respective groups.

91 to 90 percent completed all cycles of preoperative chemo in their respective groups. However, 52 and 60 percent of patients in each group started post operative chemo after surgery. 37 percent and 46 percent of patients in each group completed all allocated cycles. The most common reason for discontinuing chemo was disease progression.

Post operative complications were the same in both groups, as was length of stay, re operation rate, and death within 30 days. Super important, grade 3 and grade 4 adverse events were approximately 24 percent in both groups. Which is about a quarter of patients. A super important takeaway is that neither of these regimens are well tolerated.

So ECF is a regimen that is never really used anymore. Interestingly after this trial It was dropped from the like basic recommendations of the NCCN guidelines because FLOT did so much better so you get patients that are older and have gastric cancer and you want to give them

chemo up front, but they may not tolerate flat.

And so if you drop the tax all bath, what's flat called? Full Fox. Full Fox. Yeah. So full Fox is generally kind of the second choice. And that, I think that's a practical approach that a lot of people take is they try to give FLOT. And then if they can't tolerate FLOT, they just drop the tax on and do full Fox.

It's not a ton of chemo. So FLOT 4 is always very confusing, but you know, people talk about cycles. Sometimes they mean a month worth of therapy. Sometimes they mean just a dose. So how many months does it take to get through four cycles of FLOT? Two. Yeah. So each cycle is two weeks long. So it's just two months of chemo pre op.

It's actually not a lot of chemo up front. But even with that it's hard to tolerate. So just to emphasize in the, in this flat trial, each arm only about 40 percent finished all chemo. So again, less than half of patients in each arm who had surgery were then able to tolerate their post operative chemo and finish it.

And only.

A little more than that even started post op chemo. So I think the numbers were around Just about 50 for each arm even started post op chemo So anyway, that's kind of the long and short of being able to tolerate the chemo But then the more important question of this trial is which chemo worked better.

So beth, why don't you cover that? Yeah. So regarding pathologic outcomes, while baseline clinical T and N stages were similar, there is a higher proportion of YPT1 in the FLOT group versus the ECF, as well as N0 49 versus 41 percent FLOT versus ECF. R0 resection was found in 85 percent of FLOT in the FLOT arm versus 78 percent in the ECF arm.

And notably in the phase two study, the results were which we haven't really covered, a pathologic complete response was seen in the FLOT versus ECF group, 16 percent of the time versus 6%. Medium follow up for both groups was 43 months for surviving patients. Finally, for overall survival, which again was the primary endpoint of the study,

there was a significantly increased median overall survival of 50 versus 25 months for FLOT versus ECF.

So Lexi, what conclusions can we draw from the study and what are some limitations of the trial? So, a key point that the authors talk about is that the results of the ECF arm is similar to a more recent study that compares ECX and ECX plus Bev. ECX again being epirubicin, cisplatin, and capecitabine, otherwise known as Zolota.

And those had similar three year survivals to the present study. So, this helps emphasize that the result was not an underperformance of the ECF arm compared to plot. While Blot NECF had different toxic outcomes ultimately there was no increase in toxic deaths, hospitalizations for toxicity, or serious adverse events between the two arms.

As far as limitations for the study, as Connor mentioned before, there was a change in the primary endpoint during the study

and the sample size was calculated from overall survival estimate and even increased to allow a higher theoretical dropout rate. And ultimately, this was requested from an independent source and both of the endpoints were met.

Another limitation in the study that the authors do acknowledge is that it's unclear whether How many of these patients were sewer at one and whether the sewer one patients would have been better treated with a chemo radiation trial, such as in the cross trial. And instead of just with a lot, yeah, it, it's interesting that they say that in this, in that paper, because there is a trial that S.

O. P. E. S. O. P. E. C. trial that was designed to answer exactly that question and was just presented this summer at ASCO. So there's no paper published yet, but it basically shows that for esophageal adenocarcinoma, not squamous, but adenocarcinoma, that the FLOT regimen is probably better than CROSS.

We have to add in this other trial, the CROSS trial, that you should be aware of if you're kind of

wanting to understand gastric and esophageal cancer. The CROSS trial was the big trial that established neoadjuvant chemo radiation for esophageal as a treatment of choice. In that trial, you're getting chemo and radiation at the same time.

It's a pretty toxic regimen of chemo, of carboplatin and paclitaxel plus radiation all at the same time. It's very hard for patients to tolerate. Also, the results from that trial were broken down based on whether the histology was adenocarcinoma versus squamous cell. And what you see is that the majority of the benefit is in squamous cell, and we know that squamous cell carcinomas are much more radio sensitive than than adenocarcinomas.

So there's always kind of been this lingering question of should an esophageal adenocarcinoma actually get the radiation, or it should it get chemo like we treat gastric cancer? That's what this OPEX trial was designed to answer, and it seems that the flat arm won. So probably there will be you know, a kind of changing of the guard there

where we're now treating esophageal cancer as two different cancers based on whether it's es adenocarcinoma or squamous cell carcinoma.

There's some questions there about like where in the esophagus it is and things like that. But certainly for GE junction cancers. adenocarcinoma, I think we'll be treating them as gastric cancer going forward. Dr. Verlin, can you talk a little bit about radiation for gastric cancer because I know that that's certainly in some institutional regimens.

It's funny because I trained at MD Anderson and at MD Anderson, they give radiation for gastric cancer. So I came out of fellowship thinking we should radiate gastric cancer. And then I have this very vivid memory of studying for my surgeon boards and like reading all the trials about gastric cancer.

you know, radiation for gastric cancer. And I was like, this doesn't work, you know, like there's no data that really supports using radiation and gastric cancer. It probably decreases the lymph node burden, as it does with most cancers and certainly has a role in palliation and, Probably has a role

in local control.

There is some data that if you don't do an adequate lymph node dissection, that then adding in radiation is helpful. But I don't think there's any good data to support it in sort of the standard case where you're doing neoadjuvant chemo, just stick with chemo. Just one other point that I think is very interesting whenever I talk about these trials and gastric cancer, if you put up the median overall survival from the magic trial and the Flot four trials.

Now there's all the cautions of cross trial comparison. You're not supposed to do this, but in this case, if you look at overall survival in the magic trial, 23 months for surgery alone, 36 months for ECF, and then you look at the flat for 35 months for ECF versus 50 for flat four. So if you compare the surgery alone arm in the ECF trial to the flat arm in the flat for trial, you go from 23 months.

Of median overall survival to 50 months of median overall survival.

So as much as we want to, kind of be nihilistic real progress has been made, whereas where they were doing surgery alone on gastric cancer in the median overall survival is less than two years. And now with flop four, it's more than four years.

So doubling of median overall survival from surgery alone to flop four. That's real progress. I mean, I think that's things that you can be a little bit less you know, pessimistic about in these aggressive GI cancer. Okay. So I will mention that there was a recent retrospective analysis in the analysis of surgical oncology that looked at total neoadjuvant therapy.

So I think this is a concept that residents should start getting familiar with because I think it's going to become more and more common. So Dr. Song et al, it basically looked at their experience of Total neoadjuvant, meaning they give everything up front and don't rely on any chemo afterwards. Now that regimen typically for the Anderson group consists of either flat or full FOX, followed by chemo radiation, and then surgery.

And I think the key

takeaways are what they found is that almost all patients got through the therapy. 96. 1 percent of patients completed their planned neoadjuvant treatments versus, again, keeping that, keep in mind that number of less than half of patients that will complete all their planned therapy if they plan peri op, right?

They don't get their adjuvant therapy. And so I think that this is a really interesting paper. Again it's single institution, it's retrospective, all these problems. And they acknowledge in the paper that, you know, this needs to be studied further and eventually it'll take a multi institution randomized trial, but yeah.

I really think the idea of a total neoadjuvant approach, especially for a total gastrectomy, distal gastrectomy, total gastrectomy, they're two different animals, just like a Whipple and a distal pancreatectomy are very different. The recovery is very different. So, you know, if you're doing an antrectomy and a lymph node dissection and, you leave Half their stomach patients do really well.

It's not that big of a deal. A total gastrectomy is just such a life changing operation. It takes so long to recover from, but I

think the idea of giving everything you can up front doing total neoadjuvant makes so much sense. So I think that's probably the next kind of evolution in gastric cancer. And for esophageal, I think it gets really complicated with that esopectrial because.

The lot four is a perioperative regimen. It has chemo before chemo after what everybody's been used to in esophagus is cross, which is total neoadjuvant. You give everything up front. And then maybe you try to give like immunotherapy on the backend or something, but you don't typically give chemo after surgery.

And it's very difficult for patients to tolerate chemo after an esophagectomy, just like after a total gastrectomy, it's just such a big operation. It's such a big recovery that I think people in that world are used to giving everything up front and not trying to give everything on the backend. So, you know, just a kind of a bug in, in people's ear that the idea of total neoadjuvant, I think is coming more and more.

We do it now in rectal. I think it's going to come in gastric and esophageal as well. Yeah. Thanks for those comments, Dr. Vreeland. Just to wrap up and provide some key takeaways, I think one

thing I wanted to highlight before we. Talk about the key takeaways from these studies is one of the main reasons that giving all that upfront therapy so important is because the patients who die from gastric cancer, more often than not, they're dying of metastatic disease.

And just for the junior learners listening that's really the key point here is you're, we're not necessarily giving this chemotherapy metastatic disease. That's going to lead to poor outcomes long term. But back to the trials In summary, so the magic trial is important as the 1st phase 3 clinical trial of perioperative systemic therapy and gastric cancer.

Although that specific regimen is no longer used both the. ECF and flat 4 regimens are very toxic. However, we know that ensuring delivery of systemic therapy is very important. Again, flat 4 now is the preferred regimen over with better efficacy and similarly high toxicity. 1 thing to note that we kind of talked about.

It's particularly in the FLOT4 trial is the difference between GE junction and

what we typically think of as gastric cancers. So many times these GE junction cancers, if you talked about with the CROSS trial, those are treated like esophageal adenocarcinoma. So you may see that sort of carbotaxel radiation more often given currently until at least until we see the results of this SOPEC trial published.

But just know that FLOT4 is still the standard for CBRT3 and body or distal gastric cancers. In terms of the toxicity occasionally we'll use Folfox instead of FLOT essentially just eliminating the dose of taxel for patients with suboptimal performance status. And ultimately, the bottom line key takeaway is that perioperative chemotherapy is standard for T2 or greater or node positive gastric and G junction cancers.

Yeah, that's a really good summary of a lot of key takeaways from two very important trials, Connor. Thanks. That's all we've got today, guys, for the most recent Surgeonc episode. Catch us next time, and until then, dominate the day.