Transcript: Johanna C. Bendell, MD: I think it’s very important to note that especially with gastroesophageal cancers, in general, surgery is very, very important. The surgeon is very, very important in choosing what procedure is done but also in outcomes. Manish, I’m sure you have recommendations around this.

Manish A. Shah, MD: Yeah, absolutely. Let me pause about the D1 and D2 just for a second. One way to conceptualize it is that the immediate lymph nodes next to the tumor are the N1 nodes, or the first-level nodes after the tumor is present. And then the N2 nodes are the ones that are a little more distant. And then N3 are even further along. And so, D1, D2, and D3 dissections are actually removing the N1, N2, or N3 nodes. It makes sense that, depending on the location, the N1, N2, and N3 nodes are a little different. Conceptually it’s the idea of local nodes, more distant nodes, and then more distant nodes.

In the Intergroup 0116 study, as you mentioned, the average nodal dissection was about 6 nodes in that study. And an N1 or D1 dissection should have about 15. Most patients had really what we think of as D0, and less than 10% had a D1 dissection. Following that study, in the follow-up Intergroup study that looked at postoperative 5-FU [5-fluorouracil] and radiation versus postoperative ECX [epirubicin, cisplatin, capecitabin] and radiation, there was no difference in outcome. But what we learned was that the nodal dissections actually didn’t evolve over next 10 years. So we’re basically doing what we’re doing. For that reason, in the United States, we do think that there is a benefit with postoperative radiation as opposed to postoperative chemotherapy, which is practiced more in Japan and Korea and other parts of Asia.

The ARTIST-II study was presented here at ASCO [the American Society of Clinical Oncology Annual Meeting], and that was an important study because it built on the initial ARTIST study, where there was a suggestion that for node-positive patients, the addition of radiation in the postoperative setting might have benefit. This was a large study. It was originally intended to be 900 patients, but it closed at around 600 because of poor accrual. But that’s still a large study. Everyone had node-positive disease, and there was a 3-way randomization to S-1 [tegafur-gimeracil-oteracil-potassium]; S-1 [tegafur-gimeracil-oteracil-potassium] plus oxaliplatin; or S-1 [tegafur-gimeracil-oteracil-potassium], oxaliplatin, and radiation.

What we learned is that SOX [tegafur-gimeracil-oteracil-potassium plus oxaliplatin] is better than S-1 [tegafur-gimeracil-oteracil-potassium], which is very similar to the CLASSIC study, which is capecitabine and oxaliplatin. But the addition of radiation on top of SOX [tegafur-gimeracil-oteracil-potassium plus oxaliplatin]—there’s no added benefit. That’s very similar to the last Intergroup study in which once you intensify chemotherapy, adding radiation doesn’t have benefit. Once you already have radiation, intensifying chemotherapy doesn’t add benefit.

From an algorithm standpoint, for patients with gastric cancer, the preferred approach is perioperative therapy. If we’re able to, we should do FLOT [fluorouracil, leucovorin, oxaliplatin, docetaxel] chemotherapy as a 3-drug regimen. If you’re not able to because of performance status and comorbidities, then oxaliplatin/5-FU [5-fluorouracil] would be the standard perioperative approach. And then if you have surgery first for gastric cancer, at least in the United States we would recommend 5-FU [5-fluorouracil] and radiation as the standard. All the adjuvant chemotherapy studies really didn’t include Western or US patients. So it’s possible to extrapolate, but it’s something to think about.

Johanna C. Bendell, MD: OK. David?

David H. Ilson, MD, PhD: Actually, I contest that, Manish, because that actually doesn’t reflect the NCCN [National Comprehensive Cancer Network] Guideline recommendations. The need for postoperative radiation is really dictated by the quality of the surgery. In the Intergroup trial, 10% of patients had a D2 resection. The only impact of adjuvant therapy was to reduce local recurrence. Clearly, you were making up for inadequate surgery. So if you have a D2 resection, NCCN Guidelines endorse adjuvant chemotherapy. We actually have moved away from giving postoperative radiation in the US if you do adequate surgery.

We now have 3 endorsed approaches. In the West, we prefer pre- and postoperative chemotherapy. We’ll talk about FLOT [fluororacil, leucovorin, oxaliplatin, docetaxel] as the new standard, which has improved outcomes compared with ECF [epirubicin, cisplatin, fluorouracil]. And the CRITICS trial shows no benefit to radiation added to perioperative chemotherapy.

If patients undergo up-front surgery, and they’ve had a D2 resection, we endorse adjuvant chemotherapy alone without radiation. That’s clearly stated in the NCCN Guidelines. We also endorse fluorinated pyrimidine-platinum. And now we have supportive evidence from ARTIST that S-1 [tegafur-gimeracil-oteracil-potassium plus] oxaliplatin for 6 months is just as good as a year of S-1 [tegafur-gimeracil-oteracil-potassium]. We also have recent data from Japan that S-1 [tegafur-gimeracil-oteracil-potassium] plus a taxane for a year is better than S-1 [tegafur-gimeracil-oteracil-potassium].

We really reserve radiation for patients who have had inadequate surgery. So if we have that patient on the Intergroup trial who has the 6 lymph nodes that were resected, that patient should get a fluorinated pyrimidine plus radiation. But we really selectively apply radiation in patients who have really had inadequate surgery. The use of radiation has really fallen out of favor. It is endorsed by the NCCN Guidelines, but there’s an equal endorsement for the use of adjuvant chemotherapy alone if a patient has a D2 resection.

Manish A. Shah, MD: Yeah. I don’t think we’re saying anything that differently because the…

David H. Ilson, MD, PhD: No, but you’re saying you didn’t…. We give chemotherapy alone in the United States if patients have had a D2 resection. We do not give radiation.

Manish A. Shah, MD: The point I was making—but thanks for clearing that up—is that the majority of patients in the United States still don’t get a D2 dissection. In fact, 90% don’t. So I think in the United States, the standard operation is not a D2. As you said, the NCCN Guidelines actually endorse what I’m saying.

Transcript Edited for Clarity