Practical Perspectives on Treatment of Advanced Gastric/GEJ Cancers - Episode 6
Minaxi Jhawer, MD: On the tail end of the perioperative study, the MAGIC trial with ECF [epirubicin/cisplatin/fluorouracil], Al-Batran presented in ASCO 2017 a very compelling and game-changing study, the FLOT trial. This was a phase II/III trial looking at epirubicin/cisplatin/5-FU [fluorouracil], the MAGIC ECF regimen, compared with FLOT. FLOT is essentially FOLFOX [leucovorin/fluorouracil/oxaliplatin] without the bolus 5-FU but with a 24-hour infusion of 5-FU. In addition to that, docetaxel, or the T, is added. Patients are given 2 months of chemotherapy with FLOT prior to the surgery and then 2 months after.
What was really impressive was that there was a higher pathological complete response rate with the FLOT regimen, up to 10% to 23% versus 6% in the epirubicin/cisplatin/5-FU regimen. There was reduced grade 3/4 toxicity in the FLOT regimen. The data are still accruing, but it looks like there has been an improvement in survival from 30 to 50 months, which is also a very impressive number, essentially making FLOT the perioperative therapy of choice if the patient can tolerate it. It is a 3-drug regimen. We’re all very aware of what we do when we use 3-drug regimens over 2-drug regimens in terms of toxicity. So for patients who do not tolerate FLOT, I generally give FOLFOX in the perioperative period, which also has good data as a perioperative regimen that works very well.
David Ilson, MD, PhD: For gastric cancer, perioperative chemotherapy without radiation is an accepted global standard of care. Up until recently, the British regimen combining epirubicin, platinum, and 5-FU was the standard chemotherapy. The Germans developed the FLOT regimen, which is modified FOLFOX with an addition of docetaxel, and they had promising phase II data and tolerance from their preoperative studies. They did a head-to-head comparison of FLOT versus ECF or ECX [epirubicin/cisplatin/capecitabine] in over 700 patients with GE [gastroesophageal] junction and gastric cancers, and the primary endpoint was overall survival. The FLOT regimen is given every 2 weeks for 4 cycles preoperatively and 4 cycles postoperatively compared with the standard 3 pre- and postoperative cycles of ECF. This trial was well conducted. Patients had endoscopic ultrasound staging. Many had laparoscopic staging, and the majority had T3 or node-positive cancers. It was about a 50/50 distribution of GE junction and distal gastric cancers.
This was a positive trial. Progression-free survival was significantly improved from 18 to 30 months with FLOT, and median survival was improved from the 30-month range to 50 months with the FLOT regimen. All the other endpoints favored FLOT. There was a slight improvement in the curative resection rate of about 8%, and there were more pathologic complete responses on the FLOT arm. So pretty much every endpoint favored the FLOT regimen. Slightly more patients were node-negative and in an earlier T stage. Putting that together, in an appropriate patient who can tolerate 3-drug therapy, the FLOT regimen has become the new standard. It improved surgical outcomes and response compared with ECF alone. I think for a distal gastric cancer, the FLOT regimen should be the new standard of care. With toxicity management, the doses used on that trial were pretty high, and most patients will require dose reductions or growth factor support, but that can be individualized for each patient.
There are always concerns that dose reduction may compromise efficacy. I’d have to say in 3 decades of practice, I’ve never seen that be the case. Most chemotherapy regimens are dosed much too high and we accept way too significant toxicities. Appropriate dose reductions should probably be made for this regimen to try to minimize toxic effects.
Transcript Edited for Clarity