Perioperative Strategies in Metastatic Gastric Cancer

David H. Ilson, MD: Recently conducted randomized trials have defined new standards of care. In the West, after the publication of the MAGIC trial in the 2000s, perioperative chemotherapy without radiation was the standard. This showed improvement in survival compared with surgery alone. Many of us were never convinced that ECF [epirubicin, cisplatin, 5-flourouracil] or variants were the optimal regimen or that epirubicin really did add a benefit.

German investigators conducted the FLOT4 trial, which was a head-to-head comparison of FLOT [5-fluorouracil, leucovorin, oxaliplatin, docetaxel] versus ECF [epirubicin, cisplatin, 5-flourouracil] or a variant. The FLOT regimen was superior on all outcomes. Most importantly, it translated to about a 9% improvement in 5-year survival compared with ECF [epirubicin, cisplatin, 5-flourouracil]. Also, patients had a higher rate of pathologic response, and there was a higher rate of curative resection—the curative resection rates were improved by about 7% and had a 7% to 8% higher rate of no negative patients. This led to improved surgical outcome, better down-staging, and a modest 9% improvement in 5-year survival, so the FLOT [5-fluorouracil, leucovorin, oxaliplatin, docetaxel] regimen is the new standard for perioperative chemotherapy in the West.

In Asia, trials had looked mostly at adjuvant chemotherapy, postoperative chemotherapy. The standard of care now in Asia is combination chemotherapy after D2 gastrectomy. In Japan, the standard would be 1 year of S-1 [tegafur-gimeracil-oteracil potassium] plus 6 months of docetaxel. A more applicable standard, which could even be applied to Western patients, would be results from the recent ARTIST-II trial from South Korea. This was a postoperative trial in which all patients underwent D2-gastrectomy, and then patients were assigned to 1 of 2 chemotherapy regimens: a year of S-1 [tegafur-gimeracil-oteracil potassium], which was the standard in Japan for many years, or a truncated 6-month treatment with S-1 [tegafur-gimeracil-oteracil potassium]–oxaliplatin. This was only in patients who had node-positive disease. In node-positive disease, 6 months of S-1 [tegafur-gimeracil-oteracil potassium]–oxaliplatin was superior to a year of S-1 [tegafur-gimeracil-oteracil potassium]. That kind of comes in line with adjuvant regimens in the West, where we use a fluorinated pyrimidine plus oxaliplatin. S-1 [tegafur-gimeracil-oteracil potassium]–oxaliplatin is the new standard adjuvant. Previous Korean studies had also suggested that 6 months of capecitabine-oxaliplatin is an appropriate adjuvant treatment. The other issue that the ARTIST-II trial addressed was it randomized patients also to get or not get radiation, and radiation added no survival benefit.

Collectively, these studies show that either perioperative or adjuvant chemotherapy in the setting of good appropriate surgery with D2-gastrectomy, is the standard of care. Radiation does not add a benefit, so chemotherapy alone would be the standard. If we’re going to give it perioperatively, we have evidence that the FLOT [5-fluorouracil, leucovorin, oxaliplatin, docetaxel] regimen is superior. In the postoperative adjuvant setting, 2-drug therapy would be appropriate, either a fluorinated pyrimidine-oxaliplatin or a fluorinated pyrimidine plus docetaxel, based on the Japanese data.

Where does that leave us in terms of incorporating some of the newer targeted agents or immunotherapy drugs in the adjuvant setting? We do know that immunotherapy drugs have a modest signal of activity, that even in PD-L1–positive patients, it’s really a small minority of patients who benefit from these drugs. Because of that, are these drugs really going to have an impact in the adjuvant setting? We know that 50% of patients are PD-L1 negative. Are these drugs really going to have a meaningful impact?

We are awaiting the results of a trial of pembrolizumab added to perioperative chemotherapy. That is the Merck & Co study, in which all patients get perioperative chemotherapy, and patients are randomized to get or not get the inclusion of pembrolizumab. This trial did not select for PD-L1–positive patients or MSI [microsatellite instability]–high patients. One of the criticisms of this trial is that the regimen chosen for perioperative chemotherapy was a fluorinated pyrimidine and a platinum; they did not include a taxane. In the West, we believe we really should use a taxane as a triplet preoperatively. One of the criticisms of that trial is perhaps that perioperative chemotherapy was not optimal. We await the results of this trial, and we’ll see whether there is an impact of combining immunotherapy with perioperative chemotherapy. There also are adjuvant trials ongoing in Asia, looking at immunotherapy as part of a postoperative adjuvant strategy. Then there are some other pilot studies in the West, combining checkpoint inhibitors with perioperative chemotherapy, looking at a signal for activity.

One interesting area that has emerged is MSI as a biomarker in the adjuvant setting. We do know that 5% to 7% of gastric cancers are MSI-high, and there are very provocative data from Asia and Europe that MSI-high patients have a better outcome, even with surgery alone. MSI-high patients have a better survival outcome with surgery alone. A recent pooled retrospective analysis combining Asian and Western studies suggested that in MSI-high patients, they may achieve the same survival with surgery alone than if they get chemotherapy; that chemotherapy did not improve outcome, and there was actually a trend toward inferior survival in MSI-high patients getting adjuvant chemotherapy compared with MSI-high patients getting surgery alone. MSI may emerge as an important biomarker to look for in patients we’re considering for pre- or postoperative chemotherapy in gastric cancer. It may be that these patients are best served with surgery alone, that perioperative or adjuvant chemotherapy may not add a benefit to those patients. Of course, that raises the question, would those patients be candidates for immunotherapy as an adjuvant treatment? Because MSI-high patients are the ones for whom we see the dramatic responses in metastatic gastric cancer. The problem is that it’s a rare subset of patients. It would be hard to design an adjuvant trial that addressed only 5% to 7% of the population. Already these patients have better survival with surgery alone—80%, 85% 5-year survival—so it’s going to be difficult to design a trial to improve on that survival with or without the use of immunotherapy drugs.

Transcript edited for clarity.