The Comparison of FLOT and DCF Regimens as Perioperative Treatment for Gastric Cancer

Gastric cancer is one of the most mortal cancer types and a serious healthcare problem. Resectable cancer has a chance for curative option and gastrectomy plus D2 lymph node dissection is a crucial method for definitive treatment [1]. Gastric cancer is a heterogenous disease and mostly presents with locally advanced or advanced stages.

Perioperative chemotherapy with epirubicin-cisplatin-fluorouracil (ECF) followed by surgery was superior to surgery alone by a trial [2]. Another study concluded that cisplatin- and fluorouracil-based chemotherapy before surgery had better survival rates than surgery alone [3]. Perioperative chemotherapy became a standard option for locally advanced gastric cancer with increased data such as previous trials and guidelines recommending this approach. Various drug combinations were evaluated. In recent years, the combination studies with docetaxel revealed promising results [4]. Docetaxel-cisplatin-fluorouracil (DCF) regimen was used for metastatic setting and could be performed for locally advanced disease, but serious toxicity limited the use, thus ECF was another option [5, 6]. Oxaliplatin was started to use instead of cisplatin and several trials were designed. Docetaxel-oxaliplatin-fluorouracil (TEFOX regimen) was used for advanced disease and provided a curative intent approach for 40% of patients [7]. Another study concluded that the mentioned combination had acceptable toxicity rates [8].

Nowadays, fluorouracil-leucovorin-oxaliplatin-docetaxel (FLOT) combination is used widely. Recently FLOT4 and FLOT-AIO trials showed superiority and better results than ECF and epirubicin-cisplatin-capecitabine regimens and became a standard treatment for resectable locally advanced gastric cancer [9, 10]. The aim of the study was the comparison of current FLOT and historical DCF regimens for efficacy, responses, toxicity, and impacts on survival rates.

The study is a retrospective multicenter cohort study. The medical records of 240 patients diagnosed with locally advanced gastric cancer between August 2013 and March 2023 were analysed. The patients older than 18 years who have received FLOT and DCF chemotherapy regimens perioperatively followed by surgery with D2 dissection were included. Unresectable and metastatic disease, peritoneal involvement, other regimens, and gastroesophageal junction involvement were excluded.

Demographic features, the time of diagnosis, histopathological properties, baseline clinical staging, treatment durations, postoperative responses (according to pathological and baseline clinical staging), presence of relapse, and toxicity were noted. Mentioned parameters were compared for two groups. Overall survival (OS) was calculated as the time from initial chemotherapy to last visit or death date; disease-free survival (DFS) was detected as the time from initial chemotherapy to progression time or last visit date.

IBM SPSS version 25 was used for all statistical analyses. For normal distribution detection, histogram and Kolmogorov-Smirnov test were used. Normally distributed continuous variables were given with mean ± standard deviation, while not normally distributed values were showed with median (minimum-maximum). For categorical comparisons, χ² or Fisher’s exact test were used. For group comparisons of numerical variables, Mann Whitney U test was used. Survival analyses were performed with Kaplan-Meier plots and a Log-rank test, also Cox-regression analysis was done for hazard ratios (HRs). p value was considered as significant under 0.05.

Two hundred and forty patients were included in the study. The median age was 59 (26–80) years. Males were 180 patients (75%). The FLOT group had 103 patients, DCF group had 137 patients. FLOT regimens were started after December 2017; DCF was performed before December 2017. The demographic and disease features were summarised in Table 1. Follow-up periods were longer in the DCF group, and all participants underwent postoperative radiotherapy by historical approach. Eight patients (7.8%) of the FLOT group had received cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with oxaliplatin because baseline diagnostic laparoscopy detected peritoneal involvement.

Pathological complete responses were seen in 8 patients (7.8%) in the FLOT group, while no patients had complete responses in the DCF group (Table 2). There was a statistically significant difference between the pathological response rates in the FLOT group and the pathological response rates in the DCF group (p = 0.001). Relapse was detected in 32 (31.06%) patients in the FLOT group during follow-up, while relapse was detected in 97 (70.8%) patients in the DCF group. The difference between the two groups is statistically significant (p ≤ 0.001). At the same time, 93 (67.8%) patients in the DCF group died during follow-up, while 24 (23.3%) patients in the FLOT group died. The difference between the two groups is statistically significant (p ≤ 0.001).

Median PFS was superior in the FLOT group (p = 0.002, median not reached for [NR-NR] vs. 13.94 months [12.01–19.65] for DCF) (Fig. 1). Median OS was similar between the two groups (p = 0.173 37.8 [37.78–38.81] vs. 30.90 [25.40–36.39] months) (Fig. 2). The follow-up period was affected the survival data. For evaluation 36 months survival FLOT was 63%, while the DCF group was %40 (log-rank test; p = 0.015).

Data on HER2 status, number of lymph nodes removed, and tumour localisation were missing in the DCF group. No significant correlation was found between the number of lymph nodes removed and OS (p = 0.51; HR: 0.98 [0.94–1.03]) and DFS (p = 0.83; HR: 0.99 [0.95–1.03]) in the FLOT group. Again, no significant correlation was found between HER2 positivity and OS and DFS, p = 0.208 and p = 0.184. There was no difference in OS and DFS between the gastroesophageal junction and gastric tumours in the FLOT group, p = 0.509 and p = 0.642.

The present study showed that the perioperative FLOT regimen was more effective than DCF treatment on the prognosis of locally advanced gastric cancer. Few trials that compared FLOT and DCF exist in the literature. Farrokhi et al. [11] evaluated the efficacy of FLOT, ECF, FOLFOX, and DCF treatments for patients with resectable gastric cancer. They concluded that FLOT had 84% objective response rate and provided 39 months of survival. The other regimens were inferior and OS rates were under 28 months.

Gürler et al. [12] assessed the FLOT and DCF in the metastatic setting. This trial showed that FLOT added nearly 3 months to PFS significantly (10.1 vs. 7.4 months), but OS was similar between the two groups. Grade 3–4 adverse events were more common in the DCF group. Hashimoto et al. [13] designed a study that compared FLOT versus oxaliplatin-docetaxel-S1 treatments, the trial is ongoing.

Kianersi et al. [14] compared the neoadjuvant protocols with or without taxanes in Iran. DCF and FLOT were compared to FOLFOX. The median OS was significantly higher in the FLOT group than in the DCF group (20.3 vs. 15.4 months). For all patients, the taxane group had similar results with FOLFOX.

Immune checkpoint inhibitors raised in oncology management recently and neoadjuvant protocols were studied recently. Phase 2 The GERCOR NEONIPIGA study investigated the efficacy of nivolumab and ipilimumab for locally advanced gastric cancer with dMMR/MSI-H. Pathological complete response was 58.6%, and all patients underwent surgery. The result provided promised results as an alternative to chemotherapy [15]. Another phase 2 PANDA trial concluded that neoadjuvant atezolizumab plus chemotherapy provided 70% pathological response and 45% pathological complete response in the gastric and gastroesophageal cancer [16].

Phase 2/3 DANTE/IKF-s633 trial investigated the effect of the addition of atezolizumab to FLOT treatment. Downstaging and complete responses are more common in the chemoimmunotherapy arm, especially PD-L1 positive and microsatellite unstable subgroups [17]. MATTERHORN phase 3 study will investigate the impact of durvalumab addition to FLOT protocol for resectable gastric cancer and will show the result of chemoimmunotherapy [18].

Keynote 585 studied chemoimmunotherapy versus chemotherapy in locally advanced gastric or junction cancers. Different cohorts exist. FLOT cohort was divided into two groups FLOT + placebo versus FLOT + pembrolizumab. Pathological complete response and event-free survival were better in the pembrolizumab arm (13% vs. 2.4%, 45.8 vs. 25.7 months), but OS data were not mature [19].

DCF was a historic regimen, and we used it before 2017 more commonly after new developments and new studies about FLOT regimen [20, 21]. It had some differences such as postoperative chemoradiotherapy from FLOT regimen. By recent data, we do not prefer radiotherapy for D2 dissected gastric cancer patients. The role of radiotherapy is still controversial, some benefit was found and the ongoing discussion may result more obvious in future investigations [22, 23].

The present study has several limitations. Retrospective design limited the quality of data and records. Also, treatment periods and follow-ups were different. Evaluation tools and approaches might vary. But as far as we know, it is the first assessment of the comparison of the mentioned regimens in our population.

The present study concluded that FLOT regimen was standard therapy and superior to DCF regimen as the current guidelines’ suggestions. New combinations and multimodality treatments may change the algorithm. Further prospective trials may be needed.

This study protocol was reviewed and approved by Ankara Bilkent City Hospital Ethics Committee (No.: 2384; date: February 9, 2022). The Ethics Committee stated that informed consent was not required because the study was retrospective.

The authors have no conflicts of interest to declare.

None of the authors of this work received any funding.

Gökhan Uçar, MD (corresponding author), Serhat Sekmek, İrfan Karahan, Yakup Ergün, Özlem Aydın İsak, Sezai Tunç, Mutlu Doğan, Fatih Gürler, Doğan Bayram, Yusuf Açıkgöz, Selin Aktürk Esen, Burak Civelek, Fahriye Tuğba Köş, Öznur Bal, Efnan Algın, Tülay Eren, Gökşen İnanç İmamoğlu, Zuhat Urakçı, Ozan Yazıcı, Nuriye Özdemir, and Doğan Uncu contributed to the conception, revising, and final approval of the version to be published and agree to be accountable for all aspects of the work.

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author. None of the authors of this work receive funding.