BTK Gastric Cancer

Hi everyone and welcome back to another episode of Behind the Knife with your surgical oncology team. This is Elizabeth Carpenter, Lexi Adams, Connor Chick, and Dr. Vreeland. Today we'll be discussing gastric cancer. We're pretty excited about this episode because I don't think gastric cancer has actually ever been talked about on Behind the Knife outside of the great oral board review that our own Dr.

Dan Nelson created and we do recommend everyone check that out as well. Yeah, I think gastric cancer is a good topic for behind the knife because it comes up frequently on tests and clinically is actually fairly rare. So people like to test things that are rare to see whether or not you studied. So we'll hopefully get you guys prepped for any tests that you may have oral board scenarios and for real life as well.

But I think it's a very interesting topic just cause it is pretty rare in the United States, but is often tested. Yeah, perfect. So let's dive into a case. Okay. So Lexi, you're seeing a 62 year old man. With a 30 pack year of smoking history and a history of hypertension, he's been referred to you from his primary care doctor

after recently reestablishing care.

He has had four months of deep epigastric pain with early society dyspepsia and a 15 pound weight loss. He's also had occasional dark stools, which he attributes to his iron supplements that his primary care doctor put him on. A year ago for anemia. His last colonoscopy was a year ago, which was only significant for one small tubular adenoma.

His family history is unremarkable, as is his physical exam. What are your next steps? So, after seeing this patient in clinic, I'd order a set of labs, including some nutrition labs, and I'd refer for an EGD. I'm obviously worried about gastric cancer since I'm This is the topic we're discussing, but there's also some other causes that could be peptic ulcer disease, esophageal pathologies, things like esophagitis, or even esophageal cancer as well.

Perfect. So his labs show a mild microcytic anemia, send it for EGD, and there's a fungating ulcerated 2 centimeter mass in the distal stomach, which is biopsied. On final pathology, there's

moderately differentiated adenocarcinoma. So Beth, what's the next step in management now? So this is consistent with gastric adenocarcinoma.

Our next steps would be to stage the tumor. So I'd send the patient for a CT chest, abdomen, pelvis with oral and IV contrast. And I'd also request from our GI colleagues EUS if there's no metastatic disease noted on the CT to assess for depth of tumor invasion and FNA of any abnormal lymph nodes.

Okay, so your CT scan shows a thickened gastric wall, which correlates to the location of the mass described on EGD, and then you see several enlarged perigastric ones. There's no evidence of metastasis. U. S. has performed and there's a lesion invading a subserosal connective tissue. But no invasion of the visceral peritoneum or adjacent structures.

They FNA several abnormal lymph nodes and two of them are positive. So just let's quickly pause and kind of go through some, you know, buzzwords and things that we need to know about gastric cancer. So

Lexi, two histologic subtypes, what are they? So you have the diffuse and the intestinal type the diffuse type is poorly differentiated and often presents in a much later stage and with a worse prognosis.

And then the intestinal type typically presents earlier and typically has a better prognosis. Okay. And then Beth there, you know, I don't really get excited about incidents thing, but for gastric cancer, we have to understand where gastric cancer is super common, where in the world, and then where do the two different subtypes of gastric cancer typically occur.

Gastric cancer is much more common outside of the U S with almost 50 percent of cases in East Asia. So we primarily see this more in Asia than in the United States. The diffuse type is more common, however, in the U S and the intestinal type is more common in Asia. To elaborate on that a bit, you know, if you ever want to talk to a gastric cancer expert, you go to East Asia, right?

There's like a couple in the United States, sure. But there are so many surgeons in Japan and in East Asia have

built their career on gastric cancer because it's so common there. They actually screen patients there just ubiquitously, kind of like we do a colonoscopy because it's so common again. But, you know, you'll read a lot about the difference in outcomes between Western gastric cancer and Eastern gastric cancer.

And there's different debates, like, I remember at SSO years ago, there was some, there was like a whole panel on basically our Japanese surgeons better at operating on gas on gastric cancer, because the outcomes are so much better, but keep in mind that they're treating a different type of gastric cancer.

For the most part, diffuse type gastric cancer is a really bad disease intestinal type. Still not great, but it's, I think the rates of resectability, the rates of, you know, long term survival, all those things are so much better with intestinal type that in my mind, it's almost two different diseases.

So Connor, why don't you talk to us about the risk factors for gastric adenocarcinoma and particularly for intestinal type. Yeah. So in general, chronic inflammation plays a

big role. And that can come from several ideologies. So there's infectious causes like H pylori is probably the biggest one in the West, especially.

And things like EBV, you can have adenominous polyps sort of analogous to what we see in colon cancer. And then there's other things like exposure to nitrates and pickled foods, high salt intake, smoking, obesity, and a diet with ultra processed foods can all play a role. Okay, and then Lexi, you know, beyond these kind of risk factors, talk about genetic causes of gastric cancer and, you know, specifically which kind those patients get.

So about 10 to 15 percent of gastric cancers do have a familial history component. The syndromes that we talk about are, of course, FAP and Lynch syndrome, but also the hereditary diffuse gastric cancer. Beth, do you know which mutation is associated with this? Yeah, it's usually the loss of E cadherin or the CDH1 mutation.

Yeah. And what

other type of cancer comes with that loss of E cadherin? Lobular breast cancer. Right. So, in these patients, what sort of prophylactic surgery do we offer family members with the mutation? We offer a prophylactic total gastrectomy, and that's typically for patients between the ages of 18 and 40 who carry this gene mutation.

Okay. Yeah, there's a kind of interesting sidebar that I like to teach that helps you remember that whole thing about E. cadherin. When you stain a breast cancer cell and you're trying to differentiate between ductile and lobular breast cancer, one of the pathologists always talk about, Beth, that proves that it's lobular breast cancer.

It's kind of like the cells that don't have their, the normal connections anymore. They kind of talk about single file line, but very specifically, they stain for e catherin and they have loss of e catherin. So that's like the sine qua non of lobular breast cancer is a loss of e catherin. So that's an easy way to remember that.

If you can remember that CDH one codes for e catherin, you remember

lobular breast cancer, and they also get diffuse gastric cancer. They talk about that single file, that single file of cancer cells. You see a very similar pattern, diffuse type gastric cancer. So it's not like these cells are clustered around an ulcerated mass like intestinal type, but you get these single files of cancer cells running all through the stomach, which is why you can't.

It's hard, at least to do a limited gastrectomy for diffuse type, because you'll often end up with a positive margin with these random microscopic cells running through the wall of the stomach. And then it. The other thing that's very important for CDH1 mutation is you can do screening EGD all day long, but it doesn't work.

It's just not sensitive for these cancers. So these patients will often have like a T1A cancer or multiple T1A small cancers throughout their stomach. And you can EGD them up and down and do random biopsies and all these things, but you'll still miss cancer. So that's why really it

doesn't matter. You can do an EGD just to make sure they don't have a gastric, you know, an obvious cancer before you operate.

But even when you operate on a patient with a totally normal EGD and random biopsies that are negative, you will still find small cancers in these patients with CDH1. It's very common. So let's get back to our case now that we've reviewed some about gastric cancer. Lexi, can you summarize the findings from our case and help us stage the patient?

Yes. So we have a 62 year old male, the history of smoking, and as his tumor is invading into the subsarosa, but not into the adjacent structures, he'd be T3N1. He has no evidence of metastatic disease. So he'd be consistent with at least stage 2B disease at this point. Perfect. So Beth, how would you proceed?

So I'd present this patient at a multidisciplinary tumor board. And I discussed that as it stands the patient has what appears to be a locally advanced, but resectable tumor. I'd initially recommend a staging laparoscopy. The NCCN recommends

consideration of a staging laparoscopy with biopsy as needed with peritoneal washings to assess the peritoneal cavity and medically fit patients with potentially resectable T1B or higher local regional disease.

When we're considering preoperative chemo rads and or surgery. Yeah. So that's a bit of a controversial area when it comes to gastric cancer. Is there any data to support diagnostic laparoscopy in that setting? Yes. The primary reason for the initial diagnostic laparoscopy is to detect occult metastasis.

So there was a study performed at Memorial Sloan Kettering or MSK for the total of 657 patients. Which what was thought to be receptible gastric cancer who underwent diagnostic laparoscopy and actually 31 percent of patients had metastatic disease based on visual findings but also positive results of cytology.

And we know this is an independent predictor of recurrence after curative intent resection, even if there's no visible implants. Yeah, I mean, I think personally, I think that part of staging

gastric cancer includes laparoscopy, so it should be done up front on all patients, basically T2 or worse, so T2 or above on T staging or any node positive patients, I always do a laparoscopy up front before they start chemo.

Sometimes you get in a situation where the patient sent you and they've already started chemo and you know, it's okay. Just let them keep going with chemo. And then whenever you are done with neoadjuvant, I always do a laparoscopy before I moved any resection. And I try to do it, you know, 10 days before the planned resection, just to give time specifically for washing.

So there's two types of laparoscopy in some ways, a lot of people like for whipples, you'll, for pancreas cancer, you do a laparoscopy kind of as you're starting before you make the big incision. There you're just looking for peritoneal nodules, but because the risk is so high of peritoneal disease and gastric cancer, you want to do washing.

So you, you know, personally, what I do is I just put a leader in the belly and I'll let it sit, wash the bed. You sort of shake the belly around almost like high tech, but the, you know, liquid kind of sit for a little bit and then try to get

somewhere around 70 percent of that liquid back out. And then they spin it down and look for cells.

But that is a little bit of a subtlety to gastric cancer. Laparoscopy is most people do washings as well. And you prefer to do that before chemo. There's a couple of reasons for that. One, even if they clear their cytology with preoperative chemo, their risk of early recurrence is very high. And so you'd rather just know up front so that you can know to either, to basically not offer them curative intent resection or send them maybe for a trial of high tech, things like that.

Which we're not going to get to today. The other thing is that it may change the way that the medical oncologists do chemo So curative intent chemotherapy is very intense for gastric cancer And in a patient who has metastatic disease their quality of life Is going to be better if they back off a little bit on the chemo earlier and so it does change the mindset of the medical oncologist when you have stage four disease So it's always better to know that up front if you can't so back to our case

So the diagnostic laparoscopy and cytology are negative.

The tumor board recommends neoadjuvant chemotherapy. And the results of next gen sequencing are back and there's no targeted limitations. Okay, so we're going to go a little deeper into the data on the next episode, so I don't want to get too crazy here. But Connor, just talk about the role of preoperative treatment in gastric cancer and go into some of the basic trials.

Yeah, so basically any, anybody with clinical T2 or higher or anybody with node positive with clinically node positive gastric cancer is going to get neoadjuvant chemotherapy. So there's two big trials to know for this one is the magic trial. So that was perioperative, epirubicin, FU versus upfront surgery for stage 2 and 3 patients with either gastric or esophageal cancer.

And this study showed an improvement in progression 3 survival and overall survival compared to

surgery alone. The other trial is the FLAT4 AIO trial. But that was some gastric or GE junction tumors. It was a phase 3 trial that compared FLAT4 to the MAGIC regimen. Or to everubicin, cisplatin, or capecitabine.

And they showed an improvement in progression 3 and overall survival in those who got flat 4. And so the regimen is 5 FU, Leucovorin, Oxalaplatin, and Dosotaxel. So, like Dr. Vreeland said, a pretty intense regimen. But it did improve overall survival from 35 to 50 months. And it also improved pathologic response rates.

So, yeah, I mean, basically established the role for perioperative chemo, perioperative chemo versus nothing, and then flop four change the regimen that we use. Interestingly, there has never been a study of adjuvant chemo versus no, right? So the first trial that looked at chemo plus surgery versus surgery alone, just assumed perioperative.

It's very interesting how the

history of these trials affects the standard of care. We have all this debate right now about whether or not you should be using. perioperative or adjuvant chemo for pancreas cancer. But nobody ever asked that question for gastric cancer. Why? Because the first trial that looked at that at chemo did it in a perioperative fashion.

So what if magic had been adjuvant chemo versus surgery alone? Then we would still have this debate for gastric cancer. So I just always find that very interesting that everybody just Accepts that we should give preoperative chemo for gastric cancer, because the 1st study was done that way and yet not for pancreas cancer.

That's a little bit of a sidebar. But flop is a very toxic regimen and was even more toxic. So, you know, it's an interesting regimen. It's short. It's only 4 cycles or 2 months pre op and then 2 months post out. The other thing that if you want to dive into this. If you go read these trials, pay attention to how many patients start and finish their post operative chemotherapy.

The numbers are low. So if you do a total gastrectomy on a

patient and then you would try to get them two more months of slot, it's probably not going to happen. Because again, a total gastrectomy is a huge operation, it takes forever to recover from, and so I actually prefer to try to get a little more of this chemo up front.

Even if they have to drop the tax all and just do full Fox trying to get a full four months pre op is my preference, but that is not the standard of care and lot four has established a standard of care. Yeah. So probably worth mentioning. Humor radiation as well. So in general, it can be considered for gastric cancer more broadly.

It could, it might be more useful when looking at GE junction tumors which are treated in some ways, like esophageal cancers for gastric Generally not as useful when you're talking about a body or a distal tumor, just in terms of toxicity and efficacy and those sorts of things. There are several trials that have looked at this with some mixed results.

Conor, to keep it simple, I, the way I would summarize that is there's really no randomized data that shows benefit to radiation for gastric

cancer. There are some centers that do it. If you're going to do it, you should do a pre op because post op, that area is going to fill with a lot of small intestine, and you're going to end up radiating a lot of small intestine and end up with a lot of toxicity.

So, in general, I don't think radiation has a great benefit. role in gastric cancer. If you're going to do it, do a pre op G junction, there's definitely a rule. So if we get back to our case, our patient completes their new adjuvant chemotherapy. We restage with a C. T. Abdomen pelvis with I. B. And P. O.

Contrast as well as a pet C. T. And there's still no evidence of metastatic disease on resaging. So Lexi, what's your operative plan? Yes, so I would plan on a minimally invasive subtotal gastrectomy with a Roux en Y gastrojejunostomy reconstruction and a spleen sparing D2 lymphadenectomy. The goal would be to have margins of at least 5 centimeters and a lymph node yield of at least 16.

Yeah, I think we're gonna do a journal club on D1 versus

D2 next time. So I'm not, I'm gonna leave that for the next episode. We won't talk about that. I do think it's important to divide in your head the patients that need a total gastrectomy and those that need a distal gastrectomy. They're just in different worlds as far as how morbid the operations are.

So a distal gastrectomy, you know, especially MIS, patients are going to recover very well and do very well to the point where I don't even get super excited about neoadjuvant versus adjuvant chemo because most of these patients will be fine and get to adjuvant chemo. Total gastrectomy, on the other hand, is a life altering operation.

And the ability to tolerate heavy chemo after that operation is so low. So I think that, you know, we lump all this stuff together for gastric cancer, but I do think it's just, you have to separate those two things in your head when you're treating patients because it's such a different a different postoperative course.

So intestinal type that's down in the distal stomach, you know, those patients are just going to do really well after

surgery, but a diffuse type or a really high intestinal where you have to do a total, it's just very different in the morbidity of that operation is very different. I think just to quickly summarize what D one versus D two means for, to set the stage for next time.

So, a D one resection includes all the per gastric lymph nodes, and you also take the greater and lesser momentum. So it's all the per gastric and the pre pyloric lymph nodes. And then once you go into D two dissection, you're tanking. lymph nodes along the branches of the celiac artery. So that's lymph nodes along the left gastric, the common hepatic artery of course at the celiac axis, and then along the splenic artery.

But we typically leave the spleen behind in these resections along with station 10 and most of distal station 11. Yeah, I think what's been learned about D2 dissection is that 11D, which is distal on the splenic artery and the nodes in the splenic hilum are not worth chasing, because that's where you end up the biggest problems.

It's not the

splenectomy, right? It's the distal pancreatectomy. And that's where the morbidity came from. When people were doing D2s that, you know, again, if you look at videos from, you know, Japanese surgeons who are operating on very thin people, and you can like see all the splenic vessels in their splenic hilum, because there's no fat in the way it's probably maybe there.

It's okay to go clear out all those nodes, but the hard reality is an American patients. It's very difficult to get those lymph nodes out without getting into the pancreas. And so the rate of distal pancreatectomy was higher than you would imagine, somewhere on the order of like 15 or 20 percent. And that creates a lot of morbidity.

If you get a pancreatic leak plus an EJ anastomosis, patients can die. And that's essentially where the mortality rate in the D2 patients in the trial that we'll talk about next episode came from. So it's not that, you know, going after the common hepatic and station seven, which is at the base of the left gastric, really not very difficult.

Doesn't add a lot of morbidity.

It's those 11 D it's where you're getting your, the splenic artery dips into the pancreas and you're trying to skeletonize the artery in the parenchyma of the pancreas, or you do a distal pancreatectomy. That's where you get pancreatic leaks and that's where the real morbidity comes from.

Yeah. Thanks Dr. Breland for that. And will the other thing. That we should head on to is so we talked a little bit about the difference between a distal and a total gastrectomy. So, Beth, what about these proximal gastric cancers? What's special about those? You talk us through the classification system and then.

Why we have that classification, like that means. Okay. So what I think you're getting at Connor is the Seward classification system, which is a helpful classification system when you have tumors around the GE junction. So type one is adenocarcinoma of the lower esophagus with the epicenter located within one to five centimeters above the GE junction.

Type two is carcinoma at the cardia of the junction with the tumor epicenter within one centimeter above and two

centimeters below. the G junction. And then finally type three is characterizing tumors between two centimeters and five centimeters below the G junction as well. So these are very helpful in kind of determining how these should be treated as an esophago or gastric cancer based on their anatomic location.

Yeah. So the sewer classification, it's good to memorize that. Right. But what does it actually mean? Essentially a type one, you treat like esophageal cancer type three, you treat like a gastric cancer type two. Nobody really knows what to do. So people generally treat it like esophageal and treat it with chemo radiation, but there's a lot of controversy there.

We have these tumors that we call GE junction. They're around the GE junction, but they're really different entities. Yeah. So Lexi, how has your management changed? If our patient were found on the EUS to have a T1A tumor and then what about a T1B? Yeah, so, small in situ or TIS and T1A tumors, they can be

candidates for definitive endoscopic mucosal or submucosal resection.

That procedure could be considered curative, depending on some risk factors, and that would be depth of penetration, presence of LVI, degree of differentiation. But once it, you hit a T1B tumor, meaning it's penetrated the submucosa, where all the lymphatics lie those patients have to get surgical resection, not endoscopic.

Yeah, the other thing I would add, Lexi, is, you know, I agree with your point about T1b, right? Once you're into where the lymphatics live, you have to do a lymphadenectomy, which means surgery. And then T2, that's when the risk of peritoneal disease goes up. So those are kind of the lines, right? T1a, not worried about lymph nodes, you're not worried about peritoneum, so endoscopic is fine.

T1b, you're worried about lymph nodes, but not as much about peritoneum, although I would probably still start with a laparoscopy, because, you Unfortunately, endoscopic ultrasound is not super accurate on T staging, so often it understages gastric cancer, but once you hit T2, that's when you start worrying about peritoneal disease.

So, back to our previous patient who had a distal gastrectomy. So, he had an unremarkable push up course. He was discharged to home post surgery on day 5, and on final pathology, he has a T3N1 intestinal type gastric adenocarcinoma. It's well differentiated, and he undergoes post operative chemotherapy. So, Beth, how would you surveil this patient moving forward?

So this is based on recommendations from the NCCN guidelines for patients with stage two or three disease. So you want to see them back in clinic every three to six months for one to two years. And then afterwards, every six to 12 months for three to five years you want to get some basic lab work to follow them up as needed as well as an EGD as clinically needed.

You want to get a CT chest, abdomen, pelvis with oral and IV contrast every six months for the first two years. And then annually up to five years. And then you also wanted to, of course, monitor for nutritional deficiency and patients who have undergone surgery and make sure you optimize that as well.

Yeah, I think that

that story is all fine. You know, be aware that these patients are going to recur at some point, right? It's very high risk that they're going to recur. And then we start thinking about and other things. So, you know, in the metastatic setting or the recurrent setting after typical adjuvant therapy.

There are a lot of things in evolution for gastric cancer. So common, they commonly they have her two mutations. So now there's anti her two therapies for gastric cancer. You should be looking for, you know, MSI high and IPD one staining because some patients will benefit from immunotherapy. You know, just keep in mind that that.

Beyond just the typical chemo that we give for gastric cancer, there are a lot of things on the table now. And so once you get beyond the typical things, whether you have metastatic or recurrent disease, you should immediately think of NGS and there may be a lot of targeted therapies available for these patients.

Yeah, thanks for that discussion, Dr. Vreeland. So just in summary, you know, gastric

cancer is not a very common cancer in the west, but its incidence is increasing. And as we've talked about, it can be very challenging to treat. So let's review a quick, a few quick hits before we wrap up. What's the, what's one of the primary familial syndromes associated with diffuse type gastric cancer and which prophylactic operations offered in this population?

Hereditary diffuse gastric syndromes associated with a mutation gene, which is also associated with invasive lobular carcinoma of the breast. Prophylactic gastrectomy is typically offered between the ages of 18 to 40. Great. Beth, what additional therapy is recommended for someone with an advanced gastric cancer with over expression of HER2?

So those are HER2 directed therapies. So therapies such as trastuzumab or Herceptin is the brand name for that. Great. And Lexi, what's the initial management of patients, patients with T1A? T1B and T2 are greater gastric cancers. So T1A patients may be candidates for definitive endoscopic resection.

T1B is when the tumor's invaded the lymphatic, so they might be candidates for upfront surgery but need a lymphadenectomy. Those are also patients you want to think about doing a diagnostic laparoscopy with washings first. And then once you're have T2 disease or higher with any nodal disease, they should be considered for neoadjuvant chemo or chemoradiation prior to resection, and again, undergo that diagnostic laparoscopy first.

I just wanted to bring up one scenario that comes up clinically. Which is a distal cancer that's obstructing, so it's a it's always a very difficult decision about what to do with these patients because you're like, oh, they have first of all, sometimes the gastroenterologist have difficult to get in the U.

S. Scope through it, and so they don't give they can't really give you an accurate T stage. What I would say is that if they're obstructed, it's T four, you know, just assume it's T four. So yeah. That is one scenario where, although the standard of care is clearly preoperative chemotherapy,

where you may do an upfront resection, because the alternative is that you put them on a J tube through all of chemo, and it's just, it's not great.

You know, like, all they can do is J tube feeds and water for comfort through like months of chemo. It's not ideal. So again, if it's very distal and you can do a distal gastrectomy and just a distal gastrectomy, patients tend to do very well. And so I do think that's a scenario where it's not unreasonable to offer upfront surgery and then adjuvant chemo.

But I would always start with a laparoscopy because when they're obstructed, their risk of peritoneal disease is very high. For a T4 tumor, their risk of peritoneal disease is probably over 50%. So always start with laparoscopy with those patients if they have metastatic disease. Lexi, what would you do for them?

Patient, you know, has an obstructing distal gastric cancer. You do laparoscopy, you find a bunch of peritoneal nodules. At that point, I would do a palliative gastrojejunostomy. Yeah, exactly. So just get them to the point where they can eat and then they're on chemo for life, but at least now they can eat food, you know.

So try not to sew to the cancer, you know, try to do it away from the cancer, but usually there's plenty of room. Because we're talking about like antral cancers and you can do a G J to the body. But, yeah, that scenario has come up quite a few times in my career already. And I just think it's something we don't talk enough about.

Yeah, definitely a great point. And then Beth, can you just review which nodal packets are obtained in a D two lymphadenectomy? So D two refers to a combination of lymph nodes along the right and left cardiac lesser and greater curvature, the pyloric nodes along the right gastric artery, and the infra pyloric area.

So that typically stations one through six as well as all of the nodes along the left gastric, common hepatic celiac, and splenic artery. So those are stations seven to 12 with some of those nuances we discussed earlier in the episode. And that's it for Quick Hits. Catch us in a few months for a great journal article review episode discussing D1 versus D2 lymphadenectomies and gastric cancer.