Surgery Plus FLOT: A Game Changer for Esophageal Cancer?
Patrick Boland, MD, discussed the practice-changing implications of the phase 3 ESOPEC study comparing FLOT vs CROSS regimens for the treatment of esophageal adenocarcinoma.
Patrick Boland, MD
The phase 3 ESOPEC study (NCT02509286) investigated the best approach for treating esophageal adenocarcinoma that can be surgically removed. The study was a head-to-head comparison of neoadjuvant chemoradiation, or CROSS, vs perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT).
The study found that FLOT resulted in significantly better survival rates compared with CROSS. After a median follow-up of almost 5 years, patients receiving FLOT lived a median of 66 months, while those receiving CROSS lived a median of 37 months. The chance of surviving 3 years was also higher with FLOT (57.4%) compared with CROSS (50.7%). Additionally, FLOT showed a higher rate of complete tumor eradication after treatment.
“I do think these are data that should change practice for a portion of patients now…We saw that in all groups, there was no group that did better with some radiation,” said Patrick Boland, MD, in an interview with Targeted OncologyTM.
In the interview, Boland, associate program director of gastrointestinal (GI) medical oncology at RWJBarnabas Health and Rutgers Cancer Institute, discussed the ESOPEC study and its practice-changing implications for GI oncologists.
Targeted Oncology: What are the FLOT and CROSS regimens? How are they used?
Boland: Right now, there are 2 general approaches for esophagus or [gastroesophageal (GE)] junction adenocarcinoma. In part, it depends on what part of the world you are in. But the major option is between getting radiation initially, with an often-chosen regimen being the CROSS regimen with carboplatin and paclitaxel, and the alternative being chemotherapy. With chemotherapy, we most often, for patients who are fit enough, think of FLOT, which is a 3-drug chemotherapy regimen. For some of these GE junction cancers, if there is a reason not to give radiation, we will give a less intense chemotherapy than FLOT like [leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX)]. The standard of care right now will be FLOT or FOLFOX. There [are] some institutional and provider biases between which to use. [ESOPEC] is really the first head-to-head comparison of these 2 regimens.
There was a study last year, the Neo-AEGIS trial [NCT01726452] that compared CROSS-type chemoradiation to chemotherapy, but the chemotherapy was dominantly more of a chemotherapy doublet, like [flouracil (5-FU)]/cisplatin, they allowed. The study was amended as it was going on to allow some patients to get FLOT, but it was a minority. That study suggested the regimen was similar in terms of efficacy, but it was predominantly comparing a doublet which is no longer the standard of chemotherapy, to CROSS. These [ESOPEC] results were then eagerly awaited to see [if] we were going to see superiority with a better systemic therapy.
What was the design of the ESOPEC trial and who was included?
[ESOPEC] was designed for esophageal adenocarcinomas and enrolled patients with early-stage disease to chemoradiation with carboplatin and paclitaxel vs FLOT. This is a relatively large study in this disease site. I think it was clean and well-designed otherwise. Patients were to have surgery afterwards, and then those in the FLOT arm would get [postoperative] chemotherapy, which is also the standard.
Can you summarize the findings of the study?
There were no major differences between the groups that went on either arm, and when they looked at like delivery of treatment, I think by and large, patients got the treatment that was planned.
One thing that was noted is that in the chemoradiation arm, a little bit under 70% of patients got the full planned chemo doses with the radiation, but 98% got all of the radiation therapy planned. [The investigators] did not give us this data but there may have been a dose or 2 of chemotherapy missed, one would imagine. I would estimate that would not have a huge impact on the results, but hard to say. That is less than we have seen; that is a lower rate of chemo completion in the original CROSS study and some of the other studies. I think it would be nice to see data on that. We saw it in the chemotherapy arm. As expected, patients got [preoperative] chemotherapy and a bit more than half got [postoperative] therapy. This is kind of typical, all these studies, and nothing surprising there.
The top results of the study showed is that in the FLOT arm, we had improvements in survival. The hazard ratio was 0.7 [with] significant improvements in survival. The difference was more than 10% difference at 5 years, almost 12%. The disease-free survival difference after about 3 years was about 15%. It seemed to be persistent there. That is a notable difference for us also. Things like rates of getting good surgery done by R0 resection looked looks similar between the 2. It was certainly no worse with chemotherapy than with FLOT. The pathologic response rate was numerically a little bit better with FLOT. So, it was not lower, which we tend to see more higher rates of [pathologic] response with radiation. I think all those things were highly encouraging.
Do you see these findings changing your practice?
I do think these are data that should change practice for a portion of patients now. We always look at the forest plots, the subset analyses, and try to find things that are perhaps problematic. But we saw that in all groups. There was no group that did better with some radiation. There is a benefit, really, across all groups, but especially younger patients, especially node-positive patients, especially those with T3/T4 tumors, there seem to be a clear advantage with FLOT. FLOT is, if you look at an ounce-for-ounce, more effective, but it is also a tougher regimen to give and to get, and just as a lot of patients do not get it [postoperatively], there are a lot of patients who are not candidates for FLOT [preoperatively].
The median age of patients with esophageal cancers is 68. [The median age of patients] was about 63 on this study. In real life, patients are a little bit older and so a lot of them are not going to tolerate it well, or we are going to have concerns when we are looking at quality of life. I think for older patients, there is still going to be some impetus to give chemoradiation as opposed to FLOT for them.
In the chemoradiation arm, patients did not get nivolumab [Opdivo] there. At least today in practice, patients who do not have a pathologic complete response, which is most of them, are given nivolumab, and we know that nivolumab provides a disease-free survival advantage. We are hopeful it gives us a survival advantage, but we do not know that piece yet. Follow-up with CheckMate 577 [NCT02743494] is going to be important as we figure out how to how to lay all these things out. That, of course, is a year of therapy, but it is a largely innocuous treatment for the majority of patients.
I think it would be nice to know outcomes by location. Sort of some of Siewert I, the more classic esophagus cancer where I think the bias is heavily towards chemoradiation, it would be nice to see whether that that trend that is upheld. I do not have a reason to expect it would not be, but it would be beneficial to see that as we try to convince people to change practice. I think already, Siewert III, we tend to treat like gastric cancers. Siewert II is where the big debate is, but I think a lot more Siewert II patients really should end up proceeding with FLOT now.
