Marshall Provides Insight on Evolving Treatment Patterns in ESCC

OncologyLiveVol. 23/No. 19
Volume 23
Issue 19

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John L. Marshall, MD, provides an overview of esophageal squamous cell carcinoma and discusses several key updates to the treatment landscape, including putting data in the context of the treatment algorithm.

John L. Marshall, MD

Establishing courses of personalized care for patients with esophageal squamous cell carcinoma (ESCC) has paced behind management of other gastric cancers.1 However, progress has been made with immunotherapy approvals such as nivolumab (Opdivo) in combination with fluoropyrimidine- and platinum-based chemotherapy as well as nivolumab plus ipilimumab (Yervoy) for the first-line treatment of patients with advanced or metastatic ESCC based on data from the phase 3 CheckMate 648 trial (NCT03143153).2

“As we see new approvals occur, we’re getting even more studies, so this landscape has gotten complicated regarding who to give what to,” John L. Marshall, MD, said. “In this patient population, [those with] squamous cell cancers of the esophagus with a metastatic disease, we have good, solid evidence that immunotherapy combined with chemotherapy is going to be the standard of care for first-line therapy. We have subsequent lines of therapy out there for our patients to extend that survival and improve their quality of life.”

In “My Treatment Approach: The Evolving Treatment Landscape of Esophageal Squamous Cell Carcinoma” a 4-episode OncLive Insights® series, Marshall provided an overview of ESCC and discussed several key updates to the treatment landscape including putting data in the context of the treatment algorithm. Further, Marshall shared an overview of how available evidence can be applied to clinical practice to improve patient outcomes.

Below are excerpts from Marshall’s discussion in the series.

A Survey of Patient Presentation, Testing, and Diagnosis

Upper esophageal cancers tend to be squamous cell cancers, and the classic risk factors for that are alcohol, tobacco, etc. Those squamous cell cancers have been declining, at least in Western populations, although they’re still out there. You’ll still see them. If you go a little further down, to the gastroesophageal junction, you get adenocarcinomas. Those are more common in Western populations probably because of reflux and Barrett esophagus, obesity, and other problems such as that.

These are increasingly 2 different cancers, even though for many years we’ve lumped them into 1. To diagnose these cancers, as patients are coming in with dysphagia, you often [use] an endoscopy. Usually, CT scanning is part of the basic staging. The real challenges [in treating] these patients are that they often come in with significant nutrition problems, they have pain, and they require multidisciplinary care.

The location of these tumors is very difficult with regard to surgery. Chemoradiation can be effective for local control, but often it’s a big challenge to patients who have comorbidities and nutritional issues coming in. We recognize that [treating] this patient population can be challenging.

Whenever you identify a patient with squamous cell cancers of the esophagus, it’s critical to do a very solid, basic staging—with imaging, an endoscopic ultrasound, and biopsies. Once you get that tissue, you need to know more than just that it’s squamous cell cancer. Yes, you want to know differentiation and the like, but we do increasingly want to know other biomarkers. We’re testing for microsatellite instability [MSI] in every cancer and looking for immunotherapy choices. We’re looking at PD-L1 expression and we’re looking for HER2 expression. We’re also looking for rare mutations. Increasingly, we’re testing patients for broader profile, but it’s critical in upper GI [gastrointestinal] cancers to test for PD-L1, MSI, and HER2. Those are the ones that are going to be most informative for your patient.

Trends and Disparities in Treatment Approaches for Patients With Locoregional ESCC

If the patient has localized disease with no evidence of spread, maybe lymph nodes in the region, the common strategy is giving a combination of chemotherapy and radiation. The classic regimen that we use is called the CROSS regimen.... The CROSS regimen is carboplatin and paclitaxel given weekly; it’s a pretty easy regimen. You can also give platinum and fluoropyrimidine with radiation. This is long-course radiation, 5 to 6 weeks. That can have a fairly significant response, and for some patients that’s the definitive treatment.

The goal is to try to avoid a surgical approach in those patients. Of course, with chemoradiation, it’s not definitive in many patients. When possible, we sometimes will also do a surgical resection. In patients who have residual disease after that surgical resection, there are times when you give more adjuvant therapy with the advent of immunotherapy in that space in patients who’ve had curative intent chemoradiation, surgery, and residual disease followed by immunotherapy.

Esophageal cancer, squamous cell cancers of the esophagus, are seen in 50-, 60-, 70-year-old individuals. They’re seen in White individuals, in Black individuals, in other races around the world, and in other ethnicities. What we’re looking at, increasingly, is that not everyone has the same outcome.

A recent paper from Savitch et al looked at this. It was published in the Journal of Gastrointestinal Surgery.3 [Results] demonstrated that African American [patients] had a worse outcome than non–African American [patients]. It’s not clear that there’s a biological reason for this, but it’s likely more [about] access to treatment. Because this is a complicated disease, it does require multidisciplinary care. It takes a village. Not everybody has a good village on their side. Particularly in patients who are part of more vulnerable populations, regardless of race, make sure to step up your game as a treatment team because we can level the playing field by helping those patients.

First-line Treatment Approaches and Considerations for Patients With Metastatic ESCC

For patients who have unresectable disease or metastatic disease, which is a high proportion of the patients that we encounter, we have 2 issues. One, we have the plumbing issue of getting the patients eating and swallowing again and maintaining nutrition. If we need supplementation through PEG [percutaneous endoscopic gastrostomy] tubes or TPN [total parenteral nutrition], we do that as needed. Sometimes we place stents. Sometimes we give chemoradiation, even though there’s metastatic disease, to control that local disease. In general, first-line treatments of choice are going to be systemic treatments.

The base is chemotherapy. You can use platinum-taxane, you can use fluoropyrimidine/ platinum. There are 3-drug recipes, but they’re more toxic, they have a higher response rate, and they don’t have an overall outcome benefit. Using 2 drugs tends to be the basic right choice for most patients in the front line.

Then we look at the options for biologics. We test everybody for PD-L1 using CPS [combined positive score], and in those patients with high numbers, there’s pretty good evidence that adding anti–PD-1 therapy to chemotherapy will benefit those patients. There are rare patients with HER2-positive disease who have both HER2 and PD-1 as potential options added to the chemotherapy.

Increasingly, first-line therapy for squamous cell cancers of the esophagus is doublet chemotherapy with checkpoint inhibition, so it’s a 3-drug cocktail in total. These have the best reported outcomes so far in these patient populations. Of course, with any patient, there may be some who aren’t candidates for immunotherapy-type approaches. These are patients who have preexisting autoimmune problems that are going to increase their risk from immunotherapies. But increasingly, there aren’t many individuals who wouldn’t be candidates for immunotherapies.

Insights on Existing and Prospective Second-line Treatment Strategies

Initial lines of therapy are combinations of chemotherapy and immunotherapy. Now you move into subsequent lines of therapy, and there are other drugs: irinotecan, taxane, platinum. There are other approaches with combinations of immunotherapies that are being explored. Beyond that first line, the benefit rate doesn’t manage to stay up or stay high for very long, so we want that optimum first-line treatment of choice if we can.

When I’m thinking about treating a patient in the first line, I like to know the CPS and the PD-L1 score. I have approval regardless of the CPS score, and there are pretty good data that in squamous cell cancers, immunotherapies work. My enthusiasm for immunotherapies certainly goes up with those patients who have CPS greater than 5, or even 10. That’s what I’d start with.

These patients need a response, and in some patients, that immunotherapy also generates a durable response. After I get that initial positive benefit in the first 3 to 4 months, I might back off and—as we do in colorectal cancer—take a maintenance-like approach with immunotherapy and an oral fluoropyrimidine, or just immunotherapy single agent so that then I can rechallenge with a chemotherapy or switch to other cytotoxic drugs through the sequence beyond the first line.

If you have a patient with metastatic or locally advanced squamous cell cancers of the esophagus, you think, “What cards do I have on the table, and when do I play what?” For most patients, that first-line treatment of choice is going to be doublet chemotherapy, and there you have a carboplatin/paclitaxel approach, or fluoropyrimidine and a platinum. We have pretty good evidence that immunotherapy should be added to that in that first-line setting. Whether you then go through a maintenance phase if you have a good response and maintain the immunotherapy or not, most of us would maintain something through there. Ultimately, they’ll progress. If you haven’t used a platinum and a taxane, you certainly still have those as a rechallenge.

The other alternative therapies are limited to things such as irinotecan, or other kinds of platinum that you didn’t give, or fluoropyrimidine if you haven’t brought that in. There aren’t many choices beyond those initial lines of therapy in patients with this disease. You want to get your best bang for your buck early on, so you can get your best initial response and then hold on to that with your other drugs and rechallenge or use drugs you haven’t used in your first-line therapy.

As with all our solid tumors, we use CT scanning, endoscopy, patient symptoms, and sometimes cancer markers to determine if a patient is benefiting from the treatment. It comes down to performance status and CT scanning as the primary way that we’re watching out for patient response and benefit. We always must keep in the back of our [mind] that, sometimes with immunotherapy, we can see an early uptick. I don’t think that’s a very common phenomenon, so we’re looking for tumor regressions or stable disease and improved outcomes. When that begins to turn, it’s usually straightforward to see that, and you know you need to switch treatments.

We’re all working as hard as we can to try to identify new therapies and new approaches for our patients with esophageal cancers, particularly the squamous cell type. This is where it’s important for us to do the broad molecular profiling, not just the 3 that you have to do: MSI, PD-L1, and HER2. We’re looking at new approaches around the other targets and new patterns that may emerge. Certainly, combos of chemotherapy and immunotherapy and combos of immunotherapy are being done. Unlike with some of our GI [gastrointestinal] cancers, where we get into third and fourth lines, with this disease we rarely get past the second line. Begin looking for novel approaches early on in your patients so you have something in your hip pocket if it’s out there for that patient.

John L. Marshall, MD, is chief of the Division of Hematology/Oncology at MedStar Georgetown University Hospital, a professor of medicine and oncology at the Georgetown Lombardi Comprehensive Cancer Center, and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers in Washington, DC.


  1. Rogers JE, Sewastjanow-Silva M, Waters RE, Ajani JA. Esophageal cancer: emerging therapeutics. Expert Opin Ther Targets. 2022;26(2):107-117. doi:10.1080/14728222.2022.2036718
  2. FDA approves Opdivo in combination with chemotherapy and Opdivo in combination with Yervoy for first-line esophageal squamous cell carcinoma indications. FDA. Updated May 31, 2022. Accessed September 19, 2022.
  3. Savitch SL, Grenda TR, Scott W, et al. Racial disparities in rates of surgery for esophageal cancer: a study from the National Cancer Database. J Gastrointest Surg. 2021;25(3):581-592. doi:10.1007/ s11605-020-04653-z
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