When would you treat patients with esophageal adenocarcinoma with neoadjuvant chemotherapy alone such as detailed in the UK MRC OE05 trial?

This is an excellent question with no clear data to provide a direct answer. I think we all acknowledge a) that pre-operative chemotherapy is easier to administer than post-operative chemotherapy and that b) there is zero biological rationale to take the same chemotherapy and split it up before and after surgery. Phase III studies of peri-operative chemotherapy have reported that only about 1/2 of patients are able to initiate or complete post-operative chemotherapy. Therefore, it is tempting to try to give all of the treatment pre-operatively.

I am also going to assume that this question relates to Siewert Type III GE junction and gastric cancer. I NEVER EVER give chemotherapy alone for an esophageal and Siewert Types I/II adenocarcinoma.

The current standard-of-care for gastric cancer must be the FLOT regimen based on the FLOT4 study, which gave 4 cycles before and after surgery. As such, my standard practice is to consider giving most or all of the chemotherapy pre-operatively if there is some evidence of response. This includes clear improvement in cancer-related symptoms as well as improvement in SUV of the primary tumor on PET. This is based on extensive prospective data from the MUNICON study as well as the adaptive design of the closed-for-poor accrual Alliance 021302 study. For tumors that are FDG avid at baseline, I repeat a PET/CT after 3 cycles of FLOT. If there is >35% reduction in mSUV of the primary tumor, I then complete all of the chemotherapy prior to surgery.

OEO5 does raise an important question of how much chemotherapy is needed since there was no difference in survival between 6 vs. 12 weeks of pre-operative chemotherapy (just as adding an anthracycline didn't help, hopefully putting the final nail in the coffin of this regimen). Similarly, only about 60% of patients in the FLOT arm of FLOT4 received all adjuvant treatments, suggesting that the benefits noted in the study come from <8 cycles or 16 weeks of chemotherapy. As such, in patients with clinical or PET response, I consider up to 6-8 cycles, depending on tolerance.

Of course, the one concern about increasing the duration of pre-operative chemotherapy is increased surgical complications. At this time, our anecdotal experience with FLOT (and other 5-FU/platinum regimens) does not suggest such a trend.

Our institutional paradigms are consistent with NCCN guidelines, where we treat Siewert Type I/II tumors as esophageal cancer and Siewert Type III as gastric cancer. The broader perspective is that the R0 resection rate for tumors with significant involvement of the GEJ is only about 70% and chemoradiation may increase this to 90% or more. Therefore, I think adding radiation for these tumors is important.

Now, I don't believe the R0 resection rate for distal esophageal/GEJ tumors has been reported for FLOT4. If it approximates the 90% rate seen in the CROSS study, that may begin to make me consider a chemotherapy-only approach for these tumors.