Highlights on gastroesophageal tumors: the comeback of FLOT

There is a consensus on the necessity of multimodal management for locally advanced resectable esophageal cancer. However, whether perioperative chemotherapy with FLOT or neoadjuvant chemoradiotherapy with CROSS (41.4 Gy + carboplatin/paclitaxel) should be applied to patients was a matter of debate [8, 9]. FLOT4 trial did not include patients with esophageal adenocarcinoma and suggested similar efficacy of perioperative FLOT in gastric or gastroesophageal junction location. There were no head-to-head comparisons between these two effective treatment options. Patients were treated based on the institutes’ or physicians’ choice/experience, either with CROSS or FLOT until now.

ESOPEC was designed to be a prospective randomized study to compare FLOT with CROSS for patients with locally advanced adenocarcinoma of the esophagus [2]. Patients with cT2 and cN+ or cT2‑4 and any N without distant metastasis were included in the study. The primary endpoint was overall survival (OS). Between February 2016 and April 2020, 438 patients from 25 German sites were randomized into two treatment arms. Baseline characteristics were well balanced between the two arms: male sex 89.3%, median age 63 (range 30–86) years, cT3/4 80.5%, cN+ 79.7%. R0 resection could be achieved in 94% versus 95% of the patients in the FLOT and CROSS arms, respectively. At a median follow-up of 55 months, median OS was 66 months in the FLOT arm and 37 months in the CROSS arm [1].

Among 359 patients with available tumor regression status, pathological complete response (pCR) was achieved in 16.8% of the FLOT arm and 10% of the CROSS arm.

The primary endpoints of OS and pCR were remarkably improved within the FLOT arm; thus, this treatment modality became the new standard for these patients in the resectable setting. There are some minor issues which should be extracted from the footnotes of the study: although the general population seems to have a great benefit from FLOT, patients with less tumor burden (e.g., clinical T2 tumors) seem to have an equal benefit between FLOT and CROSS. This congress report did not address tolerability. One can assume that CROSS is better tolerated, so this might still represent an option for patients with lower tumor burden without clinical nodal involvement. Another important point is that the ESOPEC study did not represent the current standard with respect to the CROSS arm, since patients after neoadjuvant chemoradiotherapy with residual disease in tumor tissue are candidates for adjuvant immunotherapy [10]. Although we have to avoid cross-trial comparisons, despite a potential improvement in patient outcomes after the integration of adjuvant immunotherapy in the CROSS arm, the expected magnitude of benefit might be less than that observed with FLOT. To sum up, FLOT became the standard treatment option for the majority of patients with resectable esophageal and gastroesophageal cancer.

Again, another highly awaited study was presented at the ESMO 2024 meeting. The very relevant study question was whether patients with resectable gastric cancer would benefit from the addition of radiation therapy to neoadjuvant management. The TOPGEAR study aimed to answer this question and randomized patients with resectable gastric and gastroesophageal junction cancer to either perioperative chemotherapy or chemotherapy plus radiation therapy [5]. The chemotherapy included either three cycles of epirubicin/cisplatin/5-fluorouracil (ECF) or four cycles of FLOT, administered both pre- and postoperatively. The preoperative CRT group received one less cycle of preoperative chemotherapy followed by chemoradiotherapy (45 Gy in 25 fractions of radiation plus infusional 5‑FU), and then the same postoperative chemotherapy. The primary endpoint was OS. Between September 2009 and May 2021, 574 patients were enrolled from 70 sites across 15 countries in Australasia, Europe, and Canada; 288 to the perioperative chemotherapy (CT) group and 286 to the preoperative chemoradiotherapy (CRT) group. Patients receiving radiation therapy achieved a higher pCR rate (16.7% vs. 8.0%) when compared to chemotherapy alone. After a median follow-up of 66.7 months, there was no significant difference in OS or PFS: median OS for the CT group was 49.4 months vs. 46.4 months for the CRT group; median PFS for the CT group was 31.8 months vs. 31.4 months for the CRT group [6]. Preoperative CRT was not associated with increased perioperative treatment toxicity or a higher rate of surgical complications.

The results were interesting, since the improvement in pathological response rate was not translated into extended survival outcomes, which is observed in this setting among the latest large clinical trials [11], thus, putting into question the role of pCR as a predictive parameter for survival. Based on the results of the TOPGEAR trial, neoadjuvant radiation therapy cannot be recommended as a standard procedure for the general patient population. Whether there are any subgroups with potential benefit from radiation therapy remains unclear.

Again, ESMO witnessed the SPACE-FLOT study with a very relevant study question and very interesting findings.

FLOT is an effective treatment for resectable gastroesophageal cancers. However, it is not well tolerated by all patients, and the majority of patients cannot complete the preplanned adjuvant cycles [8]. The question remains whether all patients really need adjuvant treatment, or if this could be skipped in some subgroups. The study group of the SPACE-FLOT trial examined whether the administration of adjuvant FLOT could be guided based on the pathological remission rate [7]. They prospectively collected data from 42 centers across 12 countries. Patients receiving FLOT in the neoadjuvant setting between 2017 and 2022 were included. Pathological response was assessed using validated tumor regression grading (TRG) systems. All TRGs were trichotomized into minimal responders (MR = worst TRG category), complete responders (CR = pathological complete response), and partial responders (PR = all TRG categories between MR and CR). A total of 1887 patients (MR n = 459, CR n = 221, PR n = 1207) were evaluated. The median follow-up was 25.5 months. In all, 82.9% and 75.8% of patients completed all 4 cycles of neoadjuvant and adjuvant FLOT, respectively. Prognostic pathological features were similar between those who did and did not receive adjuvant FLOT. In the MR group, there was no disease-free survival (DFS) difference (hazard ratio [HR] 1.03) between those who did (n = 272) and did not (n = 187) receive adjuvant FLOT. While there was a difference in nonadjusted overall survival (OS; HR 0.73), this became insignificant after adjusting for baseline characteristics (HR 0.96). In the CR group, there was no difference in DFS (HR 0.88) or OS (HR 0.69) between those who did (n = 136) and did not (n = 85) receive adjuvant FLOT. In the PR group (adjuvant FLOT n = 847, no adjuvant FLOT n = 360), adjuvant FLOT induced a significant DFS (HR 0.68) and OS (HR 0.55) benefit.

Despite its prospective setting, SPACE-FLOT did not randomize the patients between treatment or watchful waiting. The aim of the study was to gain information in a real-life setting. However, a very interesting message could be obtained, since patients with complete responses did not benefit from the continuation of FLOT treatment. Despite the nonrandomized design, this information might help clinicians to guide their treatment de-escalation strategies.