FLOT vs CROSS in Resectable GEJ Adenocarcinoma: Which Regimen is Best?

April is Esophageal Cancer Awareness Month. This month, Targeted Oncology is highlighting research in the field of esophageal cancer treatment.

Yanghee Woo, MD

Though patients with gastroesophageal junction (GEJ) adenocarcinoma are often treated with neoadjuvant therapy, no guidelines on how to prioritize or decide which regimen to use exist. During the 2024 Society of Surgical Oncology (SSO) Annual Meeting, experts had a debate on the topic to determine which neoadjuvant therapy should be used for these patients.

On the side of the FLOT chemotherapy regimen, which consists of fluorouracil, leucovorin, oxaliplatin, and docetaxel, was Matthew R. Porembka, MD, associate professor, University of Texas Southwestern Medical Center. Arguing in favor of the CROSS chemoradiation regimen of carboplatin and paclitaxel for 5 weeks and concurrent radiotherapy, followed by surgery (chemo XRT), was Yanghee Woo, MD.

In an interview with Targeted Oncology^TM, Woo, surgical oncologist in the Division of Surgical Oncology, associate professor in the Department of Surgery, vice chair of international affairs, director of the Gastroenterology and Minimally Invasive Therapies Program at City of Hope, discussed some factors to consider when choosing between CROSS and FLOT and highlighted ongoing clinical trials looking to determine the best regimen.

Targeted Oncology: Can you provide some background on the debate you were a part of at SSO?

Woo: There was a nice debate on which perioperative therapy we should use for locally advanced gastroesophageal junction adenocarcinomas at the recent SSO [Annual Meeting]. We had a lovely debate. However, I think we were more in agreement than in disagreement. It was not too much of a fight over there, but just a lively discussion about the questions around the best and the most optimal therapy for resectable nonmetastatic gastroesophageal junction adenocarcinoma.

3D rendered medically accurate illustration of esophagus cancer: © Sebastian Kaulitzki - stock.adobe.com

In your experience, what is the current standard neoadjuvant therapy for this patient population?

The debate was talking about FLOT vs CROSS regimens, and I think it brings up the standard of care that was provided for the randomized control trials. The CROSS trial [compared] chemo XRT plus surgery vs surgery alone, which was in 2012. Then FLOT is perioperative, the triple regiment with fluorouracil, leucovorin, oxaliplatin, and docetaxel, which was published in 2017. These 2 regimens have become the standard of care for GEJ adenocarcinoma. However, there are nuances to the studies that were discussed more in detail, and now we have CheckMate 577 [NCT02743494] adding adjuvant nivolumab [Opdivo]. Then we have some evidence about the comparative outcomes of CROSS or CROSS vs perioperative chemo, including [epirubicin, cisplatin plus capecitabine or fluorouracil (Medical Research Council Adjuvant Gastric Infusional Chemotherapy, MAGIC)] plus the FLOT.

In the selection of the perioperative regimen in the resectable locally advanced GEJ adenocarcinoma, we need to consider several things. One is that it is not just the location, but the [microsatellite instability (MSI)]-high status should be considered. These patients should, even though they are not metastatic, their tumor should be evaluated for HER2 status, the MSI-high status, and the PD-L1 status, which will become important in the decision making, not just for the perioperative regiment, but because of the high-risk of recurrence of these locally advanced cancers. We need to know what we are dealing with the potential for systemic recurrences. Then the regimen for surgeons. We want to give the 1 that will give the best chance at an R0 resection, complete removal of not only the primary tumor, but all the lymph nodes that may be positive or show up on a PET scan. Regional control is important for these, and probably the number 1 reason that they recur.

Then, the consideration of how much systemic control can we get from CROSS vs FLOT. Lastly, and the most important, I think we should consider the patient's functional status, as this is important for giving systemic therapy and radiation. It is important when patients are considered for surgery. Some patients may have the ability to receive the perioperative therapy, but if their functional status is poor or becomes very poor, there may be delay in surgery, or they may not be able to tolerate surgery at all.

How do you choose which regimen to use?

[We use] the patient's goals. There are patient-directed therapies where they tell us they do not want surgery ever. Then we need to consider if should we be using some form of both of these regimens that can help them control the local regional disease, as well as the systemic disease without surgery. That does come up more often than you would think, especially in elderly patients.

Could you elaborate on the effectiveness of the CROSS regimen?

Surgeons used to think that we could cure GEJ cancers, and we obviously realized quickly that these patients recur. In search of regimens that would help our patients with GEJ cancers live longer and get better disease control for a durability of time, this regimen took the CROSS trial in 2012 and put the chemo and radiation combination on the map for neoadjuvant therapy. The CROSS trial compared carboplatin and paclitaxel, which are effective systemic treatments for upper GI cancers, 41.4 Gy, and 23 fractions of radiation therapy prior to surgery, in addition to surgery, with surgery alone. The neoadjuvant regimen took 29 days, and the patients waited about 6 weeks and they went to surgery. The bottom line is that chemoradiation before surgery improves survival. This was published in the New England Journal of Medicine, and it changed our practice for GEJ tumors back then.

The CROSS trial included patients, not just with adenocarcinoma, but with squamous cell carcinoma as well. Overall, their survival benefit for adenocarcinoma was an overall median survival of 43 months vs 27 months. Unfortunately, it was very close to being statistically significant, but it was not as significant as for those patients who had squamous cell adenocarcinoma of the esophagus. There was a marked improvement in patients with squamous cell. The 16-month overall survival benefit is real, so despite the nonsignificance, this became standard of care. The study did include 76% of patients with esophageal and only 24% of patients with GEJ tumors, so we need to consider these things when we are sort of evaluating the clinical trial results.

For the inclusion criteria, the patients we studied did not include the very advanced GEJ cancers or [patients with] esophageal cancer who had significant nodal disease. We need to think about what the implications of having nodal disease means, which means that there is a higher risk of systemic recurrence, local regional recurrence in these patients. In terms of overall survival rates, CROSS did a good job with chemoradiation therapy before surgery for our patients vs surgery alone. Additionally in the Journal of Clinical Oncology in 2021, this concern about the overall survival benefit of the CROSS regiment was brought up. The 10-year overall survival benefit for CROSS persisted, and we saw that 38% of the patients who received neoadjuvant therapy plus surgery vs surgery alone remained alive. For surgery alone, only 25% of the patients were alive in 10 years after their surgery, but with the chemo XRT, 38 patients were alive. In this 10-year overall survival benefit, which means that 68% to 75% of these patients had died, and what was notable was that comparing the 2 regimens showed no improvement in isolated distant recurrence control, meaning that with chemo XRT, we fail to control this recurrences or metastases compared with surgery alone. That goes to highlight the strength of the neoadjuvant chemo XRT improving the real R0 rate for surgical resection.

What are the most common adverse effects associated with the CROSS regimen and how are they typically managed?

I think the most common [adverse] effect for the CROSS is that there are patients who get the major common hematologic toxic [adverse] effects in chemoradiation therapy or mild neutropenia, so their white [blood cell] counts go down. It is in a very small percentage of patients, like 2% of patients to 6%. They have a good [adverse] effect profile, they get some nausea, they get diarrhea, and they get some esophagitis, anorexia, and fatigue. These are fairly well managed overall, and I think that is why many practitioners and oncologists liked the CROSS regimen because of the well tolerated [adverse] effects. It is a short duration of 29 days. I think our medical oncologists have access to drugs to increase the neutrophil count and decrease the rate of infection, so this usually does not affect the time to surgery at all for our patients.

Are there any ongoing clinical trials or emerging research findings that might affect the use of CROSS?

There are a few, and I think this is the most exciting area of discussion now. When we were talking about the comparison between the CROSS trial in a neoadjuvant chemo XRT vs perioperative chemotherapy, there was a nice publication of a randomized control trial comparing these head-to-head, the Neo-AEGIS trial [NCT01726452]. It was a randomized phase 3 trial in 24 centers across Europe with patients who are older than 18 who had fairly locally advanced disease, including those who had T2, T3, and N0 and 3 with no metastatic disease. They included both esophageal and GEJ cancers, and they used either modified MAGIC or FLOT vs CROSS. What they found was that there was no difference between the 2 groups. But when we look closely at the study, we learned that 99% of the patients were White, 84% of the patients who had GEJ tumors were actually type 1, so they were esophageal, and they had very few type 3 tumors, which are considered gastric. CROSS did have more complete responders, and FLOT had more grade 3 adverse events.

FLOT is a lot more toxic to the patients. It takes 54 days; you have to give the therapy before. Even though the previous regimens are much better tolerated, the post gastrectomy, esophagectomy, or total gastrectomy tolerance for FLOT is less than 50%. There is vomiting, neutropenia, peripheral neuropathy. The worst for FLOT is the addition of loss of their hair, and for some of the patients, it becomes a factor. That [trial] does not lead us 1 way or the other, but it does give us some more information about the [adverse] effect profiles of each and how we can choose if there will be a trial.

The ESOPEC trial [NCT02509280] will directly compare FLOT vs CROSS, and this began enrollment in January 2016. Hopefully this will start to answer some of the questions. Then 1 study that directly affects our choices between CROSS and FLOT right now is the CheckMate 577 trial. It was a landmark, phase 3 trial comparing adjuvant nivolumab vs placebo in patients who actually underwent the CROSS regimen of chemo XRT.Seventy-one percent of the patients had adenocarcinoma and 40% of the patients had GEJ tumors. This was a well-designed study, which was an answer to a critical question of what do we do with patients that do not have complete responses or have residual tumors after their surgery was complete? They are at higher risk of recurrences and 794 patients were randomized. The intervention group with nivolumab received nivolumab for an additional year after having chemotherapy if they had residual tumor left.

This addition of nivolumab improved the median overall survival to 22 months vs 11 months. What this shows is that this is horrible with only 22 vs 11 months. That also highlights that whatever regimen we have preoperatively and surgery alone plus all of these regiments is still not sufficient. There is no trial comparing FLOT plus adjuvant nivolumab vs CROSS plus adjuvant nivolumab, so there are some questions still pending. Another neoadjuvant or perioperative regimen for these resectable GEJ cancers would be the addition of immunotherapy prior to surgery. The CheckMate 577 showed us after surgery if we gave immunotherapy to some of these patients, it seems like there is a benefit.

There is the MATTERHORN study [NCT04592913] which its initial outcomes were presented at [the European Society of Medical Oncology Annual Congress]. Essentially, MATTERHORN is the first global study, a phase 3 randomized trial, totally double-blinded, where patients got perioperative durvalumab [Imfinzi] plus FLOT in resectable cancers vs FLOT alone. The interim report showed that there was a statistically significant complete path response rate in the patients who received immunotherapy plus FLOT. Adverse events were similar, and they were well tolerated. We need to wait to see if these improved complete response rates prior to surgery actually improve survival, and that is still pending.

One other trial is NEONIPIGA [NCT04006262]. It selected patients with MSI-high esophageal/gastric adenocarcinoma. I think this is the way to go when we are going to be defining how we treat our patients.

For patients with MSI-high gastric cancer, studies have shown that chemotherapy is harmful before surgery. These patients, by having MSI-high tumors, have a good prognosis, and surgery alone is the best compared with chemotherapy. There was no benefit to adding chemotherapy in these patients. However, the question is, what about the addition of neoadjuvant immunotherapy? I think this the trial showed that they are giving [ipilimumab (Yervoy)] and nivolumab in the neoadjuvant setting in patients who underwent surgery and this showed a remarkable path complete response rate of 58%, and 93.7% of the patients are alive at 1 year without relapse, which are good numbers when we compare that to the complete path response rate using perioperative FLOT which was 20%.

Are there any trials similar to NEONIPIGA using perioperative chemotherapy?

We have the INNOVATION trial [NCT02205047]. It is a global, phase 2 trial in HER2-positive gastric cancer. This has 3 arms comparing perioperative chemotherapy, whatever standard of care it is in the country, plus trastuzumab [Herceptin] or adding trastuzumab with pertuzumab [Perjeta]. I think it failed to meet the end point of a 20% better path response rate, but there was a better path the response rate.

Other trials are looking at either neoadjuvant/adjuvant chemotherapy backbone plus immunotherapy, and combinations which I think will help us to learn a little bit more about the importance of immunotherapy in these patients. Personally, I think the adjuvant immunotherapy with perioperative chemotherapy, whether it's chemoradiation or chemotherapy, in patients who have not achieved a complete path response or had no path response, we see a lot of patients with no path responses on a perioperative chemotherapy that are not MSI-high, so in those patients, I think use of adjuvant immunotherapy would be helpful. Of course, it will be based on their MSI-high, PD-L1 status, and HER2 status, as well if we are going to consider adjuvant anti-HER2 therapy.