Chemoradiation Followed by Surgery as Standard of Care for Gastroesophageal Junction Cancer

David Ilson, MD, PhD, gastrointestinal medical oncologist, Memorial Sloan Kettering Cancer Center, New York, reviews his presentation from the Great Debates and Updates in Gastrointestinal Malignancies August 2022 virtual meeting.

Dr Ilson discusses key considerations for including radiotherapy in the treatment paradigm for gastric and gastroesophageal junction cancers, arguing that chemoradiation followed by surgery is the standard of care for patients with gastroesophageal junction cancers. For patients with gastric cancers who received good quality surgery, perioperative chemotherapy alone or adjuvant chemotherapy alone are appropriate treatments.

Transcript:

Hi, I'm Dr. David Ilson. I'm a GI medical oncologist at the Memorial Sloan Kettering Cancer Center in New York City. I'm going to review today, a presentation I gave at the recent Great Debates and Updates in Gastrointestinal Malignancies meeting, in August of 2022. The role of radiation therapy and upper GI cancers continues to evolve. And what I reviewed was really the evolving data that suggest more nuances in the treatment of these diseases.

For esophageal cancer, typically, the combination of chemotherapy and radiation followed by surgery has been the most adopted approach in the United States. With positive data from a Dutch trial, establishing weekly carboplatin paclitaxel radiation followed by surgery as a standard of care. This applies both for adenocarcinomas in the esophagus and squamous cancers. For squamous cancers, given the relatively high rate of pathologic complete response, up to 50% or more, there is a consideration for using this regimen as definitive treatment in the non-operative management of esophageal cancer.

Certainly, in patients with adenocarcinoma who have medical comorbidities, or are not thought to be medically operable, definitive chemoradiation with some very selective application of surgery is also a consideration. One of the arguments for chemoradiation is that it intends to result in a higher rate of curative negative margin resection. R0 resection rates tend to be higher, rates of pathologic complete response tend to be higher, and rates of node-negative status tend to be higher. Also, local recurrences of the cancer tend to be reduced significantly compared to the use of surgery alone. Some of the older studies of preoperative chemotherapy without radiation really reinforced the concern with chemotherapy alone as a preoperative treatment, even some contemporary studies have shown inadequate rates of negative margin resection, lower rates of pathologic complete response, and lower rates of node-negative status.

However, the FLOT chemotherapy regimen, the standard perioperative chemotherapy regimen for gastric cancer, has now emerged as a potential treatment option for adenocarcinomas of the esophagus and GE junction. Why is that? Well, certainly the initial positive data from Germany showed superiority for the FLOT regimen over ECF in gastroesophageal junction and gastric cancers with improvements in negative margin resection rates and improvement in survival. So why would we consider preoperative chemotherapy with this regimen? Well, there was a very important study from Ireland called Neo-AEGIS, which was a head-to-head comparison of pre-operative chemotherapy versus chemoradiation. On this trial, the cross-Dutch regimen of carboplatin-paclitaxel-radiation was compared to the ECF regimen. A small percentage of patients did receive the FLOT regimen, because as this trial was conducted, the FLOT regimen became the new standard for preoperative and perioperative chemotherapy. But most of the patients on this Neo-AEGIS trial received ECF, and this was compared to chemoradiation. And, as was expected, the pathologic endpoints all favored chemoradiation over chemotherapy alone: more than a 10% increase in R0 resection rate with chemoradiation, a significantly higher rate of pathologic complete response, and also a significantly higher rate of node-negative patients. However, in the head-to-head comparison of overall survival, there was no difference. So even with all the pathologic endpoints favoring chemoradiation over chemotherapy alone, there was equipoise for survival. This really suggests that preoperative chemotherapy could be a consideration, and that's even in a trial using a potentially less-effective chemotherapy.

The Neo-AEGIS trial, this really argues for more equipoise of chemotherapy versus chemoradiation. And now, with the advent of the FLOT regimen, that could be considered an alternative, a perioperative chemotherapy with FLOT compared to chemoradiation. But again, we know the pathologic endpoints, at least at this point, all favor chemoradiation over chemotherapy.

And, obviously, all patients are not candidates for the FLOT regimen. Some of these patients are older, more debilitated. They may not tolerate this intensive regimen. And certainly, if we have concerns about the surgical outcome. If we have a bulky tumor with extensive nodes, we're worried about getting a negative margin resection, we're worried about local recurrence. In that case, chemoradiation still remains a strong consideration.

What I talked about also, is how to improve the current use of chemoradiation followed by surgery. The biggest advance was the positive data for adjuvant nivolumab in esophageal and gastroesophageal junction adenocarcinomas and squamous cancers. This was a randomized trial of nivolumab added as an adjuvant treatment after patients with esophageal and gastroesophageal junction adenocarcinomas and squamous cancers received chemotherapy and radiation followed by surgery, but they had to have some residual disease present, either in the primary site or in the nodes.

This was a placebo controlled randomized trial of a year of adjuvant nivolumab versus observation. And this study showed median disease-free survival could double, up to 22 months compared to 11 months for no adjuvant treatment. Overnight, this established adjuvant nivolumab as a very promising adjuvant strategy after chemoradiation and surgery in patients that have residual disease. We don't have the overall survival and disease-free survival data yet from this study, but a doubling of disease-free survival is almost certainly going to translate into a survival benefit. And for many of us, it argues for the standard use of chemoradiation followed by surgery, because we now have an active systemic adjuvant treatment after this standard-of-care therapy. Whether or not the addition of adjuvant immunotherapy improves outcome in perioperative chemotherapy, we will have to await the results of ongoing trials. And there are other ongoing trials comparing chemotherapy along with the FLOT regimen versus chemoradiation followed by surgery in esophageal and gastroesophageal junction cancers.

Another strategy I also discussed, was based on the data from CALGB 80803. This was a trial that used PET scan response to direct chemotherapy during chemo, radiation. All patients on the CALGB trial were going to get chemoradiation, and surgery, but they were initially treated with induction chemotherapy. Patients were randomized to get FOLFOX or to get carboplatin paclitaxel weekly. Then, after a period of induction chemotherapy, we looked at response on PET scan. PET responders tend to do better, they have higher rates of pathologic complete response and they have improved outcomes. Patients that are PET non-responders to induction chemotherapy tend to do poorly, with past complete response rates less than 5% and higher rates of R1 resection which trends towards poorer outcome.

This trial allowed a change in chemotherapy. If patients did not respond to their assigned induction treatment, they crossed over to the other treatment regimen. Carbotaxel patients that weren't responding would cross over to FOLFOX during radiation, FOLFOX patients that weren't responding after induction crossed over to carboplatin paclitaxel radiation. And this trial did achieve its primary endpoint, which was to show enhancement of pathologic complete response when we made a change in chemotherapy in PET non-responders. Almost 20% of PET non-responders were pathologic complete responders, much better than the historical control data. And also, the 5-year survival approached 40% which is much better than we would expect with PET non-responders. So, there may be 2 strategies to enhance outcome after chemoradiation and surgery. One is adjuvant nivolumab, which is now an established standard of care. And the other, if we're going to give patients induction chemotherapy, is to use PET scan response to direct the selection of chemotherapy during radiation.

I'm just going to comment briefly on the role of radiation and gastric cancer. This has really fallen out of favor because for gastric cancer, clearly the adequacy of the surgery done determines the need for adjuvant radiation. There was a positive trial 20 years ago in the US where upfront surgery showed that postoperative 5-FU radiation improved outcome. That became initial standard of care. On that trial however, the quality of the surgery was extremely poor. Only 10% of patients had what would be considered a standard-of-care surgery, a D2 resection. The biggest impact of this treatment was in reducing local recurrence. If we look at more contemporary trials with better surgical quality control, certainly those studies from Asia, where everybody gets a D2 resection, local recurrences are less than 5% to 10% and adjuvant chemotherapy alone conveys a benefit. And for perioperative treatment in the West, the regimen of ECF has now been replaced by perioperative FLOT.

Does radiation contribute to the use of perioperative chemotherapy? This was addressed in the CRITICS trial, which looked at perioperative chemotherapy and then, after surgery, patients got either completion of their chemotherapy or adjuvant radiation. And the CRITICS trial showed no benefit for adjuvant radiation after patients received perioperative chemotherapy. About 50% of patients had a D2 resection and 50% had D1. So even with optimal surgical quality control not being 100%, radiation did not add a benefit to perioperative chemotherapy. And there was recently a trial from Asia, looking at D2 resection followed by adjuvant chemotherapy with or without radiation, which showed no benefit after D2 resection and adjuvant chemotherapy with the addition of radiation.

We would really use the application of adjuvant radiation in gastric cancer in patients that have suboptimal surgery. If they have less than a D1 resection with very small lymph node retrieval. The other application of radiation and gastric cancer would be if patients have a positive surgical margin. So different approaches. For esophageal and gastroesophageal junction cancer, I would argue that chemoradiation followed by surgery remains a standard of care. We now have adjuvant nivolumab for a year, which significantly improves outcome. I think the perioperative chemotherapy and the appropriate-selected patient remains an option if you want to avoid the use of radiation. However, in gastric cancer, as long as you have good quality surgery, either perioperative chemotherapy alone without radiation or adjuvant chemotherapy alone without radiation are appropriate treatments. Thanks very much.