Dr. Janjigian:
Hello. Welcome from Diagnosis to Durability: Elevating Outcomes in Gastroesophageal Adenocarcinoma and ASCO Post Roundtable. My name is Dr. Janjigian. I'm a medical oncologist and Chief of GI Oncology Service at Memorial Sloan Kettering Cancer Center in New York. Joining me today are my colleagues, Dr. Daniela Molena, my surgical colleague from Memorial Sloan Kettering, and Dr. Steve Maron, who's a medical oncologist in working together with us.
Our first case will focus on a patient with gastroesophageal adenocarcinoma, really addressing the question of optimal perioperative management. We'll start with a brief discussion of the case, and then we'll take turns highlighting the important aspects of this disease. And this is a pretty typical presentation. A 65-year-old man with history of hypertension and reflux. He presented with progressive dysphagia, solids to liquids, and lost approximately 30 pounds unintentionally in a setting of obesity.
On imaging, he had a CT scan, which showed a thickening GE junction extending into the gastrocardia. And on endoscopy, there was moderately differentiated adenocarcinoma involving the cardia.
So the biomarkers that were done for adenocarcinoma are relatively routine, including MSS assessment, MSI testing was done. The tumor is MSS, HER2-negative using immunohistochemistry, IHC 0, and PD-L1 combined positivity score of 6%, with relatively low claudin overexpression, 10% with two to three plus.
So at this point, Daniela, maybe we can start with you. What are the key features for you of this case that would drive whether or not you would recommend further imaging such as PET scan or perhaps a diagnostic laparoscopy or even endoscopic ultrasound?
Dr. Molena:
Yeah, so we used to do endoscopic ultrasound on all patients for T staging, and we mostly moved away from it because if patient has severe dysphasia and 15-pound weight loss, most likely he has at least a T3 tumor, partially obstructed kind of disease. So I don't know if in today's era the endoscopic ultrasound will help us that much. Definitely a PET-CT. I would want to see the extension of disease on PET-CT, although I find that there is a little bit of a over-estimation of extension to the stomach side with PET. But PET-CT is mostly important to exclude metastatic disease, other organs.
And then staging laparoscopy, I think we're using a lot more freely these days. If the tumor involves the cardia and extended down the GE junction at least a couple of centimeters, I think that's an important test. You don't want to miss peritoneal disease, and no other imaging testing would allow you to determine that. We also look in our own cases and patients, even with just esophageal disease that had sickle cell histology or poor differentiation, those patients sometime can have peritoneal disease even though there is no gastric extension. So all those data are important for staging.
Dr. Janjigian:
And are there any cases or specific situations where you would say, "I really don't need a laparoscopy"?
Dr. Molena:
Yeah. I think if there is just esophageal disease and there is no cardiac involvement or minimal extension below the GE junction and a patient that had a well-differentiated tumor, I don't think that that will help us or is needed to start treatment.
Dr. Janjigian:
Okay. Steve, now to you, it's really nice that all of the biomarkers that we would consider standard were done in this patient. Are you satisfied with the extent of the information? What do you look for in these reports when they come in and there are other additional tests that you order routinely in your clinic?
Dr. Maron:
Yeah, great question. When it's localized disease, I think the most important thing to get first is the MMR testing, and that's because I would treat them totally differently if this was MSI high or MMR-deficient disease.
That said, when somebody's coming to my clinic with just a CT scan or just an endoscopy, I don't quite know yet whether it's a stage III or stage IV. And so I think it's important to get the IHC biomarkers that we have here, so MMR or two, PD-L1 and CLDN18.2 just in case it's metastatic.
And for any patient with locally advanced disease, I would also get next-generation sequencing of the tumor and potentially also of the plasma as well at the same time. And a lot of that's because you never know when you're going to get tissue or whether there's enough tissue to do it. And once you have treated somebody, then testing the blood is unfortunately going to have a very high false-negative rate.
Dr. Janjigian:
And do you wait for the return of the PD-L1 or MMR? This patient is quite symptomatic. How do you practically approach these cases?
Dr. Maron:
So in general now, due to FDA mandate, we have to wait for DPYD testing as well. We're spoiled in our institution with a turnaround time of about 4 business days. And so usually in that time, I can get the MMR testing as well as the DPYD testing, which gives me then time to place a mediport and do any other diagnostic studies that remain before starting them.
If I was really in a pinch and somebody had a near obstruction and I was trying to avoid an intervention like a feeding tube, which would potentially compromise a future surgery, then in those cases, I'd have a risk-benefit discussion about treating with fluoropyrimidine-based therapy, whether it's FOLFOX or FLOT, while awaiting further testing. And nowadays, I think it is defensible since almost all roads point to immune checkpoint blockade to also include a PD-1 inhibitor as well if I were to do that in a pinch.
Dr. Janjigian:
Great. Very important points. So the PET scan was done and showed localized disease, local advanced tumor with primary tumor FDG-avid and single gastropatic lymph node, no distant metastasis. And as Dr. Molena mentioned, often we look specifically for presence of retroperitoneal or supraclavicular lymph nodes because sometimes they're occult and not visible on CT scan, but the PET scan does help bring that up.
And so the patient was seen in a medical oncology clinic. And because of his overall fitness and ability to tolerate treatment, the recommendation was made for preceding with MATTERHORN perioperative paradigm, which is durvalumab once every 4 weeks, combination with FLOT every two weeks.
So I think it's important to review this data, but from surgical perspective, Dr. Molena is actually one of the major surgical PIs on this study. What is the general acceptance of this paradigm in the surgical community so far, at least among the esophageal surgeons?
Dr. Molena:
It's a good question. I think that for many, many years, we had used a combination of chemotherapy and radiation for most of GE junction and esophageal cancers, and with mixed response. We all have known that the chemo used in those regimens are not really strong chemo, and most of these patients will recur in a distant site. And so the micrometastatic control is really key for long-term survival.
And so I think that we change paradigms pretty quickly, not just in big academic centers. We're doing this regimen for a while now, but I've seen all my colleagues, my friends talking about having changed, then moved away from radiation and using this paradigm with the perioperative chemotherapy and immunotherapy.
I think there is still a little bit of concern regarding the adjuvant portion of the treatment. We know that these surgeries are big surgeries, and we see these patients coming back for postoperative visit. They're just starting to get better, they're recovering, and it is a lot for them to go back in a high and strong regimen like FLOT again. So I think hopefully in the future we'll have better paradigm that are more strongest in the neoadjuvant and a little lighter in the postoperative period. But I think that this is very well accepted today and very well liked.
Dr. Janjigian:
That's great to hear. Steve, I know you've been using FLOT for many years now, so tell us some of the practical tips. This 65-year-old, your typical obese patient with some hypertension, nutritionally compromised, probably lost at least 5% or 10% of their body weight before they even met you. How do you get them safely through FLOT, or can you get them safely through FLOT? And what are some of the approaches that you use to do that?
Dr. Maron:
We've been using this for a really long time, and I think our experience with it has taught us that it's really important to counsel patients to use antiemetics early, that they work better for nausea and vomiting. I give all my patients prochlorperazine, ondasetron, and olanzapine as well, and basically say, "Take the prochlorperazine and ondasetron as needed. And the olanzapine, if you're still having breakthrough nausea, start taking that at least for the first several days in the evening." I find that really helps. I think early intervention, giving additional IV hydration helps as well, if somebody's struggling during those first few days.
I don't typically give dexamethasone the day before and the days after as was done in the original protocol. I haven't really found that to be needed, but if people are struggling, it's something that I also can add.
And then also recognizing that you really just have to get people through it. And so if you need a dose reduction, I think it's important to do so because I look at it as more of a marathon than a sprint. And especially in the adjuvant setting, I will almost certainly do a dose reduction based on how they're recovering. And with that, nearly all of my patients are able to get through all eight cycles.
Dr. Janjigian:
I think that's a great point. And practically, a patient like this who's already nutritionally compromised and may not be well hydrated and having difficulty staying hydrated, I think hydration at disconnect is a great advice for all, so we schedule hydration at disconnect.
But also in a patient like this, you could consider starting with lower doses. We often drop the bolus of liquorine, but also reduce oxaliplatin if you're concerned about their functional status. And again, I think it's better to deliver three drugs with a dose reduction than go for a full dose FOLFOX, for example, or even carboplatin/paclitaxel with radiation where you know systemically that's a suboptimal regimen.
So good news, this patient had a great response. Whoever the oncologist was did a great job getting them through all perioperative therapy.
And the MATTERHORN study does show that over the last however many years, the community of oncologists globally have become more adept at delivering FLOT regimens because the delivery in neoadjuvant setting was clearly near 100%. And even in adjuvant setting, it was more than half of the patients were able to complete the whole entire year of adjuvant therapy.
So getting back to our patient, this is a ypT1N0 tumor; 15 negative lymph nodes were sampled, and he had a residual 1B cancer. So I think by our MATTERHORN criteria, this would be considered as major pathologic response. And we know from MATTERHORN data that complete responders and major pathologic responders, this is a paper that was recently submitted for publication. They have an even higher likelihood of a cure, and long-term event-free and overall survival is quite excellent.
And so it's important to be able to give these wins to the patients so you can tell them there's a high probability you're cured. And then you know that they're going to ask, and often the oncologists and the surgeons have to deal with this question—and maybe I'll start with Dr. Molena and then have Dr. Maron also answer—"Well, if you resected my cancer and there's such a great response, why do I need additional therapy in adjuvant setting?" So Daniela, how do you answer that usually?
Dr. Molena:
I get that question all the time. And I actually have to say that that's an easy answer. When there is a great response, you know that chemo worked for that tumor, it's easy to convince the patient to say, "Listen, we got to do whatever we can for avoiding this cancer to come back. We know your tumor is sensitive to the treatment you had. And so we know that this standard treatment has brought a really good outcome overall." And so it's kind of easier to convince them.
I find it really hard to convince them to do more when the response is not so good. And I always tell the patient to wait, wait as long ... and maybe you don't like that I tell this to the patient, but I always tell them, I'd rather them to recover from their surgery and be in good physical condition so they can finish their adjuvant treatment.
Dr. Janjigian:
I think that's a great advice, and we stay the same. I agree with you totally.
Dr. Molena:
They start too soon, because then they start too soon, they can't eat, they start vomiting, and then they quit, and then they don't do anything. So I think I always coach them, and usually I reach out. We are very collegial and we talk about, "Hey, he's lower than others. Let's wait a couple extra week before starting him or her."
Dr. Janjigian:
Steve, other views or thoughts on this?
Dr. Maron:
I mean, it makes me think back to SPACE-FLOT and you had nearly 2,000 patients, where they retrospectively divided patients into whether they had a complete response, minimal response, or a partial response. And so it's almost like a Goldilocks scenario, where if there's no response, it probably didn't work, you're not going to get much benefit. If you had a complete response, there wasn't too much to add. And for that group in the middle, which actually was a pretty large population, they clearly had a survival benefit with the addition of the adjuvant therapy. So for those patients where I see any degree of benefit, I congratulate them on the benefit and say, "We have data that for treating the cells that we don't see, since everything that we saw is removed, I think this is going to be beneficial for prolonging your life, assuming we can safely do so."
Dr. Janjigian:
And when do you tell them ... How do you monitor them and for surveillance maybe in the last minute or so in terms of monitoring their organ function, imaging, B12 deficiencies, and so forth?
Dr. Maron:
So while patients are still getting therapy, I'm generally seeing them for each cycle of triplet chemotherapy and then once every 4 weeks when they're getting the adjuvant durvalumab for those 12 months of adjuvant. I'm typically checking their CBC/CMP as well as TSH for each of those subsequent months due to the risk of hypothyroidism with the durvalumab. Beyond the completion of therapy for the first 2 years, I'm generally seeing them every 3 months with labs in a clinical visit with CT scanning every 6 months per guidelines. And then we do typically do an endoscopy after 1 year just to see how Dr. Molena's handiwork looks, make sure that it's patent without any evidence of recurrence, which we rarely see locally. And then for years 3 through 5, I'm generally doing an annual scan with clinical visits and labs every 6 months.
Dr. Janjigian:
So great case. Thank you for that discussion. So for case one, the key clinical takeaways is that FLOT is the preferred systemic therapy for management of early-stage and localized gastroesophageal adenocarcinoma. And now we have definitive evidence that addition of perioperative neoadjuvant chemoimmunotherapy with FLOT-durvalumab irrespective of PD-L1 status improved survival. And this case really well describes this and outcomes for our patient.
We also know that adjuvant chemotherapy is most beneficial in patients with degree of response to neoadjuvant therapy, which this patient had, and sometimes we need dose reduction in deescalation to make the treatment delivery feasible. Surveillance is crucial due to 70% recurrence occurring in the first 2 years. And of course, having a great surgeon with an effective lymph node dissection is important part of this approach, and we recommend at least 15 to up to 30 lymph nodes preferred for the resection.
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in gastroesophageal cancer or visit us at ascopost.com. Thank you.
