Perioperative FLOT chemotherapy for locally advanced esophageal adenocarcinoma: from ESOPEC to daily practice—a retrospective cohort study

Introduction

Background

In the treatment of locally advanced esophageal adenocarcinoma, neoadjuvant chemoradiotherapy (nCRT) followed by surgery and perioperative chemotherapy have been propagated for the last decade. nCRT is most frequently based on the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS)-scheme (carboplatin/paclitaxel with 41.4–45 Gy), endorsed by the results of the CROSS publications (1-3).

Alternatively, efficacy of perioperative chemotherapy using the FLOT-scheme (5-fluorouracil, leucovorin, oxaliplatin, docetaxel) was supported by the FLOT-4 trial (4).

Comparison between CROSS nCRT and FLOT chemotherapy remained matter of debate (5,6). However, publication of the ESOPEC-trial, a randomized controlled trial comparing CROSS-scheme nCRT and FLOT-scheme chemotherapy, demonstrated a significant difference in median overall survival (OS) (37 versus 66 months respectively) (7). This even led to an interim update of current guidelines (8).

Rationale and knowledge gap

While these results are promising, discussion continues how to interpret these results. Underperformance of the CROSS-arm in ESOPEC, namely pathologic complete response rate and OS, is often used as an argument to diminish the survival gap. However, this argument is countered by inclusion of larger and lymph node positive tumors (9).

Ultimately, the discussion comes down to translation of clinical trial results to clinical practice, where patients may have poorer performance status or higher stage tumors, ultimately affecting the outcomes. Moreover, data is lacking whether the extent of completion of the perioperative FLOT-regimen influences the long-term outcome of patients with esophageal cancer.

Objective

Therefore, this study aimed to validate the survival results of both the FLOT-4 and ESOPEC-trials in daily practice setting and to assess the importance of treatment continuation in patients with locally advanced esophageal and gastro-esophageal adenocarcinoma treated with the intent to receive perioperative FLOT and surgery. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0895/rc).

Methods

Ethical statement

This study is a retrospective cohort study using a prospectively constructed database. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Research Ethics Committee of UZ/KU Leuven (reference: S70369) and individual consent for this retrospective analysis was waived.

Patients

All consecutive patients with esophageal carcinoma treated in the University Hospitals Leuven between 01/01/2017 and 31/12/2023 were collected. Patients with a locally advanced adenocarcinoma, staged cT1/2N+ or cT3/4N0/+ according to the American Joint Committee on Cancer TNM staging system, eighth edition, were included (10). Intention to treat was perioperative chemotherapy using FLOT and surgery.

Patients with histology other than adenocarcinoma, treatment other than perioperative chemotherapy followed by surgery, chemotherapy schemes other than FLOT and distal gastric cancer were excluded.

Staging

Patients underwent esophagogastroduodenoscopy with biopsies. For most patients, a combination of 18-fluorodeoxyglucose positron emission tomography with computed tomography (CT) scan or with separate chest-abdominal CT-scan was performed. Staging laparoscopy was performed on indication.

Perioperative chemotherapy

Perioperative chemotherapy was administered using the FLOT-schedule. This consisted of four 2-week cycles of chemotherapy preoperatively, followed by surgery and finalized by four more 2-week cycles of chemotherapy. Dosages are fluorouracil at 2,600 mg/m² of body surface area, leucovorin at 200 mg/m², oxaliplatin at 85 mg/m², and docetaxel at 50 mg/m².

Surgical procedures

Esophagectomy with partial or total gastrectomy through a transthoracic approach was performed in all patients. As previously described, open technique was a left thoracoabdominal approach with intrathoracic anastomosis or combined right thoracotomy and laparotomy with cervical anastomosis (11,12). For the minimally invasive technique, a right thoracoscopy, laparoscopy and cervical anastomosis was performed. Procedural details have also been described previously (13,14). Independent of surgical approach, an extensive two-field lymphadenectomy was used as standard with en bloc peritumoral resection (abdominal D2 resection). Surgeon’s preference and time of surgery determined the choice of surgical technique.

Pathological examination

Pathological tumor length, (y)pT-, N- and M-staging, number of lymph nodes examined, number of positive lymph nodes, extracapsular lymph node invasion, lympho-vascular and perineural invasion, Mandard tumor regression grade (TRG) and R-status were extracted from pathological reports. Based on the definition of the College of American Pathologists, R1 was defined as tumor cells present at the cut edge of the specimen. In this context, CRM <1 mm was considered R0, based on previous research from our group, demonstrating that CRM <1 mm was not an independent prognosticator for OS nor DFS survival, both in neoadjuvant nCRT as primary surgery setting (15-17). Mandard tumor regression grade was classified according to the Mandard’s tumor regression scheme (18).

Follow-up

Postoperative follow-up consults were scheduled every 3 months for the first year, followed by every 6 months for the first 5 years and finally a yearly follow-up. At each point of follow-up clinical evaluation was provided. Furthermore, follow-up with imaging was scheduled every 6 months for the first 3 years and then every year a CT-scan or a CT-scan with 18-fluorodeoxyglucose positron emission tomography was performed.

Treatment continuation

Three groups were defined based on treatment continuation. PRE patients started preoperative chemotherapy but never made it to surgery. PRE-SURG patients continued with surgery after preoperative chemotherapy but did not receive any postoperative chemotherapy. PRE-SURG-POST patients continued after preoperative chemotherapy and surgery with at least one postoperative cycle of chemotherapy.

Statistical analysis

Primary outcome was OS for the overall cohort, as well as stratified by treatment continuation. OS was defined as the time between diagnosis and death from any cause or censoring. Secondary outcomes included event-free survival (EFS), stratified according to treatment continuation. Events were defined as either locoregional progression or new distant disease during neoadjuvant treatment or recurrences after treatment.

Comprehensive Complication Index and the Clavien-Dindo classification were used to define postoperative complications (19). Pearson’s chi-squared test was used to compare observed and expected frequencies for several variables over the three groups. Survival was estimated using Kaplan-Meier curves and multivariable analysis was performed using Cox regression models. Descriptive statistics were used: means and medians for respectively normally and non-normally distributed continuous variables. P values smaller than 0.05 were considered significant. IBM SPSS Statistics software, version 29, was used for all analyses.

Results

Patient characteristics

A total of 144 consecutive patients were included. Most tumors (n=117, 81.3%) were located at the gastro-esophageal junction (GEJ) and were clinically staged as high T-stages [cT3 (n=120, 83.3%), cT4 (n=14, 9.7%)] and lymph node positive [cN1 (n=37, 25.7%), cN2 (n=60, 41.7%), cN3 (n=19, 13.2%), total cN+ (n=116, 80.6%)].

Of those who continued to surgery (n=125), the vast majority underwent an open transthoracic esophagectomy (n=118, 94.4%) and all patients had an extensive lymph node dissection performed (median number of 28 and 33 resected lymph nodes in PRE-SURG and PRE-SURG-POST patients respectively).

Major postoperative complications (Clavien-Dindo grade ≥3B) occurred in 18 patients (14.4%). There was one in-hospital death, and 90-day mortality was 2.4% (n=3). Microscopically complete resection (R0) was achieved in 120 patients (96.0%). Tumor differentiation grade was mostly moderate (n=41, 32.8%) to poor (n=73, 58.4%). Adenocarcinoma containing signet ring cells was present in 31 patients (31/144, 31.1%). Pathological complete response after preoperative FLOT was achieved in 11 patients (8.8%) and complete tumor regression (Mandard TRG 1) in 15 patients (12.0%).

Baseline patient characteristics and definitive pathological examination results are respectively shown in Tables 1,2.

Treatment continuation

A flowchart of treatment continuation is shown in Figure 1. Nineteen patients (13.2%) started FLOT but were not referred for surgery (PRE). The predominant reason for treatment discontinuation was disease progression in eight out of 19 patients.

Figure 1 Flowchart of treatment continuation. PRE: started preoperative chemotherapy but never made it to surgery; PRE-SURG: continued with surgery after preoperative chemotherapy but did not receive any postoperative chemotherapy; PRE-SURG-POST: continued after preoperative chemotherapy and surgery with at least one postoperative cycle of chemotherapy. FLOT, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel.

One-hundred twenty-five patients (86.8%) underwent surgery and 96 (76.8%) started postoperative FLOT (PRE-SURG-POST). Nineteen patients (15.2%) did not receive any FLOT in the postoperative setting (PRE-SURG). Reasons for treatment discontinuation are shown in Table 3.

Ten patients had different postoperative chemotherapy schemes. Out of the 96 patients who started their postoperative FLOT, 73 patients (76.0%) finished at least 4 (complete) cycles of FLOT. Additionally, 6 patients finished 4 cycles of FLOT but without oxaliplatin in 1 or 2 cycles.

Details on postoperative chemotherapy, including different therapy schemes and completion of postoperative FLOT-cycles are shown in Table 4.

OS

Median follow up was 24.1 months (IQR, 13.0–42.5 months). For the overall cohort, median OS was 53.3 months [95% confidence interval (CI): 30.2–76.5]. OS was 88.4% at 1 year, 69.0% at 2 years and 57.1% at 3 years (Figure 2A).

Figure 2 Overall survival of (A) all patients with esophageal adenocarcinoma treated with perioperative FLOT chemotherapy with surgery, (B) stratified according to treatment continuation. PRE: started preoperative chemotherapy but never made it to surgery; PRE-SURG: continued with surgery after preoperative chemotherapy but did not receive any postoperative chemotherapy; PRE-SURG-POST: continued after preoperative chemotherapy and surgery with at least one postoperative cycle of chemotherapy. FLOT, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel.

Median OS for PRE patients was 12.9 months (95% CI: 11.1–14.7) and 13.0 months (95% CI: 5.6–20.5) for PRE-SURG patients. Median OS for PRE-SURG-POST patients was not reached but significantly higher than both other groups (P<0.001) (Figure 2B).

Compared to PRE-SURG-POST patients, PRE patients had a hazard ratio (HR) of 5.86 (3.08–11.15; P<0.001) and PRE-SURG patients had a HR of 3.74 (1.87–7.46; P<0.001).

For patients with pathological complete response (ypT0M0, n=11), OS was 100% at 1-, 2- and 3-year, and 85.7% at 4- and 5-year.

EFS

Similarly, median EFS for the whole group was 21.3 months (95% CI: 12.8–29.9) (Figure 3A). EFS was 71.2% at 1 year, 48.5% at 2 years and 42.4% at 3 years.

Figure 3 Event-free survival of (A) all patients with esophageal adenocarcinoma treated with perioperative FLOT chemotherapy with surgery, (B) stratified according to treatment continuation. PRE: started preoperative chemotherapy but never made it to surgery; PRE-SURG: continued with surgery after preoperative chemotherapy but did not receive any postoperative chemotherapy; PRE-SURG-POST: continued after preoperative chemotherapy and surgery with at least one postoperative cycle of chemotherapy. FLOT, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel.

Median EFS was 29.6 months for PRE-SURG-POST patients, compared with 12.4 months (95% CI: 8.8–15.9) for PRE-SURG patients (P=0.06) and 7.7 months (95% CI: 1.0–14.4) for PRE patients (Figure 3B).

Compared to PRE-SURG-POST patients, PRE patients had a HR of 4.63 (2.57–8.34; P<0.001) and PRE-SURG patients had a HR of 1.8 (0.94–3.47; P=0.08).

Discussion

Key findings

This study aimed to validate the survival of both the FLOT-4 and ESOPEC-trials in daily practice and to assess the importance of completion of multimodality therapy in patients with locally advanced esophageal and gastro-esophageal adenocarcinoma treated with the intent to receive perioperative FLOT and surgery.

Our results demonstrated a median OS of 53.3 months and EFS of 29.6 months for the whole group. Tumors were large, locally advanced and lymph node positive with only moderate to poor differentiation grade. Treatment continuation was a major challenge, as 13.2% of patients only had preoperative chemotherapy, 15.2% ended treatment after surgery and of those who reached postoperative chemotherapy 30.2% was not able to receive their postoperative FLOT-chemotherapy as initially intended (n=32; n=10 receiving different regimen and n=22 not completing 4 full cycles).

Strengths

Current discussion is centered on under- or overperformance of both groups in ESOPEC and ultimately on translation of ESOPEC results into daily practice.

This current study can shed some light on both questions. Our daily practice OS results were in line with both the FLOT-4 and ESOPEC-trials; median OS was 53.3 months in our group, 66 months in ESOPEC and 50 months in FLOT-4 (4,7). Considering our group included poor prognosis tumors {predominantly large, high T-stage [(cT3 (n=120, 83.3%), cT4 (n=14, 9.7%)], lymph node positive [(cN1 (n= 37, 25.7%), cN2 (n=60, 41.7%), cN3 (n=19, 13.2%)], GEJ tumors with moderate to poor differentiation grades), these survival results are encouraging.

Comparison with similar research

Without direct comparison in this current series, we look at previously published OS results for CROSS. The original CROSS-trial had a median OS of 43.2 months and a 10-year OS of 36% (2,3). A study by our own group resulted in median OS of 35 months after CROSS, obtained in daily practice, using identical inclusion criteria as the original CROSS-trial (2,20,21). CROSS results in daily practice, obtained from nationwide Dutch data, from centers with a long-standing experience using CROSS, showed an OS of 33.7 months, with a 3-year OS rate of 48.1% (9,21).

In summary, opposed to survival results of the CROSS-trial that do not seem to be reproducible in the daily practice studies mentioned above, our current results of FLOT perioperative chemotherapy do confirm excellent OS results, in a more diverse and poor prognosis population. Additionally, Checkmate-577 results not confirming a significant OS advantage of adjuvant nivolumab after nCRT for adenocarcinoma, does not strengthen the case for CROSS (22,23).

Consequently, these current results confirm the rapid implementation of ESOPEC results in current guidelines and following a more selective approach to the use of CROSS in patients with esophageal adenocarcinoma.

Explanations of findings

Our second focus was treatment discontinuation. Two main reasons stand out: disease progression/resistance and being medically unfit for surgery or postoperative chemotherapy.

For the first group, poor and aggressive tumor biology that escapes preoperative chemotherapy diminishes their prognosis. This is reflected in our additional analysis of OS and EFS stratified by Mandard tumor regression grade. Patients with a good response to neoadjuvant chemotherapy (TRG 1–2) have a significantly better OS and EFS compared to patients with moderate or poor response (TRG 3–5). However, those patients with moderate to poor response still have a survival benefit when comparing to PRE patients who don’t make it to surgery (Figure S1A,S1B). Once more, it confirms the heterogeneity of esophageal cancer and the need to evolve towards more patient-tailored strategies based on comprehensive biospecimen and histopathological biomarkers (24).

A second major cause was being medically unfit for surgery or postoperative chemotherapy. Evidently, the initial functional status of a patient can be a strong predictor of whether this patient will be able to complete the full treatment schedule.

After preoperative chemotherapy (PRE group) 4 patients didn’t undergo surgery because of death or being medically unfit. It is remarkable that for 17 out of 19 patients (in the PRE-SURG group), discontinuation after surgery can be attributed to postoperative complications resulting in prolonged hospitalization, death or deterioration of general condition resulting in being medically unfit to continue treatment (details on reasons for being medically unfit and deterioration of general condition are provided in Table S1).

Minimizing complications should not compromise high quality surgery though, but relies on surgical expertise, enhanced recovery after surgery (ERAS) programs and anesthesiologic techniques (goal-directed therapies). Minimally invasive surgery is often mentioned as a way of minimizing complications. However, in this current series most patients had an open (left thoracoabdominal) approach. The left thoracoabdominal approach was often preferred because of the higher versatility of the technique for these large and extensively N-positive tumors, easier peroperative evaluation of the extension of the tumor and immediate conversion to extended total gastrectomy if needed. Nonetheless, less major postoperative complications were recorded in comparison with the ESOPEC-trial. Additionally, the low rate of R1/R2 resections (6/126 patients, 4.8%), despite a group of large, bulky, lymph node positive tumors, should be considered and corroborates the selected surgical approach.

Implications and actions needed

To minimize treatment discontinuation, perhaps perioperative FLOT chemotherapy should be reserved for patients anticipated to complete the entire schedule after a thorough medical evaluation throughout the entire cycle of pre- and postoperative chemotherapy and perioperative setting.

Limitations

This study also has limitations. Firstly, due to its retrospective character, this study is at risk for selection bias. As previously described, perioperative FLOT chemotherapy was mostly used in our hospital for large, lymph node positive tumors at the GEJ. However, this bias would have a negative impact on prognosis, rather than a positive one.

Secondly, this study does not include a comparison group, also a result of the inclusion criteria. A contemporary comparison group of nCRT or primary surgery patients would inevitably consist of lower graded tumors, thereby interfering with a reliable comparison. Reaching back to a historical cohort would deny recent major evolutions in perioperative management and chemotherapy supportive care.

Thirdly, in a rapidly evolving landscape of esophageal cancer treatment, recent results of the MATTERHORN-trial assessing perioperative FLOT chemotherapy with immune checkpoint inhibitor therapy (durvalumab) shows a significant advantage in EFS compared to perioperative FLOT chemotherapy alone (25). Microsatellite instability (MSI) status was not routinely implemented in our daily practice until 2022, and therefore not available for all patients included in this current study. This limits our ability to assess response on chemotherapy based on MSI status. However, both our current study, MATTERHORN and ESOPEC support the idea of perioperative FLOT chemotherapy as the preferred backbone therapy, now supported by evidence from both a randomized controlled trial setting but also in daily practice.

Conclusions

In summary, perioperative FLOT chemotherapy with surgery offers an encouraging median OS of 53.3 months for patients with locally advanced esophageal adenocarcinoma in an intention-to-treat analysis. A key element to achieve this excellent OS is treatment continuation. Treatment discontinuation is primarily caused by disease progression or being medically unfit. Consequently, a comprehensive and critical patient selection must be applied for this burdensome multimodality treatment schedule. Supportive measures should be aimed at minimizing complications of chemotherapy and surgery to facilitate treatment continuation.

Acknowledgments

Abstract was previously presented at the Belgian Surgical Week 2025, Belgian Week of Gastroenterology 2025 and European Society for Diseases of the Esophagus annual meeting 2025.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0895/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0895/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0895/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0895/coif). F.V.H. reports consulting fees from AMCA. J.D. reports consulting fees from AbbVie, Astellas, AstraZeneca, Bayer, BeOne, BMS, Eisai, MSD, Novartis, Incyte, Ipsen and Roche; speaker fees from Amgen, Astellas, AstraZeneca, Bayer, BeOne, BMS, Eisai, Ipsen, Lilly, MediMix, Merck, MSD, Roche, Servier; as well as travel support from Amgen, AstraZeneca, Ipsen, Servier, Roche. L.D. reports support for a PhD project on esophageal cancer surgery complications. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Research Ethics Committee of UZ/KU Leuven (reference: S70369) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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