Perioperative chemotherapy with 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) for esophagogastric adenocarcinoma: ten years real-life experience from a surgical perspective

Langenbeck's Archives of Surgery (2023) 408:81 https://doi.org/10.1007/s00423-023-02822-7 RESEARCH Perioperative chemotherapy with 5‑FU, leucovorin, oxaliplatin, and docetaxel (FLOT) for esophagogastric adenocarcinoma: ten years real‑life experience from a surgical perspective Leila Sisic1 · Nerma Crnovrsanin1 · Henrik Nienhueser1 · Jin‑On Jung1,2 · Sabine Schiefer1 · Georg Martin Haag3 · Thomas Bruckner4 · Martin Schneider1 · Beat P. Müller‑Stich1 · Markus W. Büchler1 · Thomas Schmidt1,2 Received: 7 July 2022 / Accepted: 26 January 2023 © The Author(s) 2023 Abstract Purpose According to the results of FLOT4 trial, perioperative FLOT chemotherapy improved overall survival (OS) in locally advanced, resectable esophagogastric adenocarcinoma (EGA) compared to perioperative ECF/ECX. We report reallife data 10 years after introduction of perioperative FLOT at our institution. Methods Survival of 356 consecutive EGA patients (cT3/4 and/or cN + and/or cM1) who underwent curative surgical resection was retrospectively analysed from a prospective database. A total of 263 patients received preoperative chemotherapy according to FLOT protocol and 93 patients received an epirubicin/platinum/5FU-based regimen (EPF). Propensity score matching (PSM) according to pretretment characteristics was performed to compensate for heterogeneity between groups. Results Median OS did not differ between groups (FLOT/EPF 52.1/46.4 months, p = 0.577). After PSM, survival was non-significantly improved after FLOT compared to EPF (median OS not reached/46.4 months, p = 0.156). Perioperative morbidity and mortality did not differ between groups. Histopathologic response rate was 35% after FLOT and 26% after EPF (p = 0.169). R0 resection could be achieved more frequently after FLOT than after EPF (93%/79%, p = 0.023). Conclusion Overall survival after perioperative FLOT followed by surgery is comparable to clinical trials. However, collective real-life application of FLOT failed to provide a significant survival benefit compared to EPF. In clinical reality, patient selection is triggered by age, comorbidity, tumor localization, and clinical tumor stage. Yet matched analyses support FLOT4 trial findings. Keywords Adenocarcinoma · Esophageal cancer · Gastric cancer · Histopathological regression · Perioperative chemotherapy Introduction Leila Sisic and Nerma Crnovrsanin contributed equally to this work. * Thomas Schmidt 1 Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany 2 Present Address: Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, 50937 Cologne, Germany 3 Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, 69120 Heidelberg, Germany 4 Institute for Medical Biometry (Imbi), University Hospital Heidelberg, 69120 Heidelberg, Germany Over the past decades, treatment of esophagogastric adenocarcinoma (EGA) has developed from mere tumor resection to sophisticated multimodal treatment strategies, in order to overcome limitations of surgery alone by improving local resectability as well as systemic tumor control [1–9]. In Western countries, where more than 70% of junctional and gastric adenocarcinomas are diagnosed in advanced stages [10], perioperative chemotherapy has become standard treatment for locally advanced EGA [11, 12] after 2006 based on the results of the MAGIC trial [1]. Hence, perioperative triplet epirubicin-, platinum-, and fluorouracil-based chemotherapy regimens (EPF) became state of the art in treating locally advanced EGA. Results of the MAGIC trial later were confirmed by the French FNCLCC/FFCD trial using 13 Vol.:(0123456789) 81 Page 2 of 15 a platinum/fluoropyrimidine doublet therapy [2]. Despite these advances, outcome of EGA patients remained unsatisfactory. A new combination consisting of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) was first evaluated in metastatic EGA and proved to be highly active [13–15]. Thereupon, a phase II/III randomized controlled trial (RCT) was conducted comparing perioperative FLOT to perioperative anthracycline-based triplet chemotherapy with epirubicin, cisplatinum, 5-fluorouracil/capecitabine (ECF/ECX) for treatment of locally advanced EGA. The FLOT4 trial showed a significantly higher complete pathologic response (pCR) rate of 16% after FLOT compared to 6% after ECF/ ECX [16] and revealed increased OS in the FLOT group compared to the ECF/ECX group (50 vs. 35 months median) [17]. These results internationally defined FLOT as the new standard perioperative chemotherapy protocol for treatment of EGA. However, data from real-life application of perioperative FLOT chemotherapy in clinical practice is scarce. This is the first study to report real-life experience on perioperative FLOT compared to anthracycline-based triplet chemotherapy (EPF). The aim of this single-center retrospective study was to investigate, whether the results of the FLOT4 trial can be reproduced in a heterogeneous patient population with comparable results in a real-life environment. Methods Langenbeck's Archives of Surgery (2023) 408:81 Comorbidity The American Society of Anaesthesiologists (ASA) Physical Status Classification System was applied in order to assess medical comorbidities and the perioperative risks of patients [18–20]. Pretreatment comorbidities of patients were assessed by experienced anesthesiologists and surgeons. The following conditions, which were clinically judged pertinent to perioperative risk assessment, were considered severe: decompensated renal insufficiency, decompensated cardiac insufficiency, liver cirrhosis, status post (s/p) myocardial infarction, s/p valve replacement, s/p stroke, s/p carotid stenosis, severe coronary heart disease, complicated diabetes mellitus, chronic pancreatitis, chronic obstructive pulmonary disease (COPD), or lung emphysema. Pretreatment staging Initial staging comprised upper endoscopy including biopsies with or without endoscopic ultrasound and computerized tomography (CT) of the chest and upper abdomen for all patients. Clinical tumor stage and localization were assessed according to the 8th edition of the UICC (Union for International Cancer Control) staging system. As for the cN category, it was only differentiated between cN0 and cN + according to lymph node diameter, shape, and contrast enhancement. The cM category was evaluated by CT or biopsies. Study design and patient population This study included patients with primary EGA who underwent elective surgery in curative intent at the University Hospital of Heidelberg, Department of Surgery between August 2010 and April 2018. Inclusion criteria were locally advanced primary tumor (cT3/4) and/or nodal positive disease (cN +) and/or distant metastasis (cM1) according to pretherapeutic clinical staging. Patients with distant metastasis (cM1) presented with oligo-metastatic disease and underwent surge (...truncated)