Introduction

Surgical resection is the cornerstone of treatment for resectable gastroesophageal adenocarcinoma. Nevertheless, the poor prognosis after surgery led to evaluate neoadjuvant strategies. The perioperative chemotherapy (CT) and combined neoadjuvant chemoradiotherapy (CTRT) were demonstrated to improve overall survival (OS) compared to surgery alone in patients with stages II–III adenocarcinoma of the gastroesophageal junction (GEJ) and gastric cancer [1,2,3,4,5,6]. However, which neoadjuvant treatment is best for patients with GEJ tumors remains controversial. The FLOT4 trial showed a significant OS benefit of perioperative CT docetaxel-based triplet (fluorouracil plus leucovorin, oxaliplatin, and docetaxel) plus surgery compared to the ECF/ECX-MAGIC regimen for resectable gastric or GEJ adenocarcinoma [7]. In the CROSS study [3], long-term follow-up results of CTRT combined with surgery compared to surgery alone demonstrated more profound OS benefits in patients with squamous cell carcinomas than in those with GEJ adenocarcinoma. In this setting, the POET study compared the efficacy of preoperative CT vs neoadjuvant chemoradiation with inconclusive results [8]. Therefore, the choice depends mostly on the physician's preferences and the different geographical areas.

This network meta-analysis (NMA) aims to define the preferred neoadjuvant treatment in patients with locally advanced/resectable gastric and GEJ adenocarcinomas including distal esophagus.

Materials and methods

This study followed the PRISMA extension statement for reporting network meta-analysis. We systematically searched online databases including MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for all randomized trials published up to January 2022. For search terms, we used the medical subject headings of (stomach or gastric or esophageal or gastroesophageal) and adenocarcinoma and (neoadjuvant or preoperative or perioperative) and randomized. The inclusion criteria of this study included: (a) randomized phase 2–3 trials, (b) at least 100 patients with localized or locally advanced HER-2 negative GEJ or gastric adenocarcinoma included, (c) trials that compared neoadjuvant or perioperative CT plus or minus RT either each other or with surgery alone, (d) trials that reported OS and/or disease-free survival (DFS) and their respective hazard ratios with 95% confidence interval (HRs, 95%Cis) of the intention-to-treat population with adenocarcinoma only, and (e) articles published in English. We excluded the following: (a) studies that included targeted therapies or experimental agents, (b) trials that included only squamocellular carcinoma, (c) a former version of the same trials, and (d) studies with full-text unavailable. The quality of included studies was assessed using the revised Cochrane risk-of-bias tool for randomized trials (RoB2 tool) by two independent reviews (FP and AC).

The primary outcome was OS; the secondary endpoint was DFS. Heterogeneity between studies was assessed using the Q test and I2 statistics. Fixed effect or random effect model was chosen based on the I2 value (< 50% or > 50%, respectively).

Network meta-analyses were performed under the Bayesian framework using the "gemtc" package (https://gemtc.drugis.org). Fixed effects and consistency models were used in network meta-analyses. Noninformative priors were set, posterior distributions were obtained using 40,000 iterations after 15,000 and 20,000 burnins, respectively, for OS and DFS, and a thinning interval of 10. The network meta-analysis results were reported as HRs with 95% credible intervals (CrIs). The probability of each treatment regarding survival outcomes was ranked according to the HRs and the posterior probabilities. Overall ranks of treatments were estimated by SUCRA P scores which were based solely on the point estimates and standard errors of the network estimates. Treatments with the highest and lowest P scores are considered the best and worst treatments, respectively. Two-sided p < 0.05 indicates statistical significance.

Results

Among 1247 citations retrieved, 14 studies were included in the quantitative synthesis and in NMA (Fig. 1; Suppl. File 1). Characteristics of included studies are described in Table 1. These studies compared neoadjuvant CT with surgery (n = 5), perioperative CT with surgery (n = 4), neoadjuvant CT + CTRT vs neoadjuvant CT (n = 1), neoadjuvant CTRT with surgery alone (n = 3), and neoadjuvant CT with CTRT (n = 1). Studies were published between 2005 and 2021.

Fig. 1
figure 1

Flow diagram of included studies

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Table 1 Characteristics of included studies
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A NMA of 13 studies was performed for OS. Regarding the strategies in indirect comparison with perioperative FLOT, neoadjuvant CDDP/5FU, perioperative ECF as well as CTRT, were significantly associated with worst OS (Suppl. Table 1 and 3; Fig. 2). On the other hand, induction with CDDP/5-FU followed by CTRT and FLOT-based perioperative CT were associated with similar OS and are the regimens associated with best OS (SUCRA score P = 0.45 and 0.41) compared to all others preoperative regimens.

Fig. 2
figure 2

Forest plot of bayesian comparisons for overall survival between various treatments

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A NMA of 12 studies was performed for DFS. The results documented that perioperative FLOT is largely the regimen that led to better DFS (SUCRA score P = 0.62). Neoadjuvant CDDP/5-FU, perioperative ECF, neoadjuvant ECX, neoadjuvant CDDP + 5FU, and CDDP + RT were all associated with worst outcomes compared to perioperative FLOT in Bayesian comparisons (Suppl. Figure 1; Suppl. Tables 2 and 4).

FLOT-based CT and other regimens perform better, despite not significantly, than CROSS-based chemoradiation, in term of DFS and OS.

Discussion

Multimodality treatment is the standard of care for locally advanced esophagogastric adenocarcinoma. The objective of neoadjuvant therapy is to shrink the tumor crucial for radical resection and to eliminate micrometastasis to control distant relapse. Whereas the perioperative CT is currently recognized as a standard treatment in locally advanced gastric cancer by international guidelines, the best neoadjuvant therapy for GEJ adenocarcinoma is still under discussion. The CROSS trial demonstrated the benefit in terms of DFS and OS of neoadjuvant CTRT compared to surgery alone. For this reason, since the first publication, has become the standard of care. Nevertheless, the results of the study were strongly influenced by the more profound effect observed in patients with squamous cell carcinoma, respect to the adenocarcinoma histology [9].

The aim of this NMA was to assess which neoadjuvant treatment regimen was best for patients with gastroesophageal adenocarcinoma. The results of this NMA demonstrated that perioperative CT with FLOT regimen was superior in OS and DFS compared to other pre/perioperative chemotherapies and to combined neoadjuvant CTRT. There are several reasons to explain these significant results. First, the use of docetaxel-based therapies improved OS and DFS more than old regimens (cisplatin + 5FU, ECF or FOLFOX-like), even in the population with GEJ Siewert 1 disease, as demonstrated in the randomized FLOT4-AIO trial [7]. Second, the administration of a systemic treatment might better prevent distant relapses allowing greater OS, compared to CTRT, which is more effective in loco-regional control and in obtaining higher rates of pCR [10]. Third, this meta-analysis included studies with gastric and GEJ adenocarcinoma, where the latter can be compared to a chromosomally unstable variant of gastric cancer from a biological and oncological treatment point of view [11].

Our NMA has several intrinsic limitations and could present some evidence of publication bias. First, we compared the three treatment strategies in general, without considering that there are differences in each type of therapy within individual studies (e.g., CT regimens, radiation therapy techniques and total doses). Second, we included gastric and GEJ adenocarcinomas even if the second ones differ from gastric cancer in the type of surgery due to the different risk of loco-regional disease recurrence, in particular for Siewert 1 and 2 [12, 13]. Third, this is not an individual patients’ data meta-analysis.

Two recent evidences are available, while they are unable to modify the routinely clinical practice, at present. In the phase III Neo-AEGIS study including 377 esophagus and GEJ adenocarcinomas, preliminary results of the non-inferiority of a perioperative strategy (FLOT/ECF-EOX) versus neoadjuvant CROSS were presented. Even if the full text is unavailable and the design modification after FLOT-4 publication, there was no evidence that perioperative chemotherapy was inferior to multimodal therapy but greater pCR rates in the CROSS arm were shown.

In the phase II AGITG DOCTOR trial, patients with resectable esophagus adenocarcinoma and poor response after one cycle of cisplatin and 5FU induction were randomly assigned to receive two cycles of DCF or DCF plus RT. In the DCF plus RT arm, despite OS was inferior compared with responders, improved PFS and loco-regional outcomes were obtained, matching the early responders group. However, it seems difficult to translate these results into clinical practice as the combined CTRT treatment is exclusively offered to non-responders patients.

While the perioperative strategy of GEJ Siewert III and gastric cancer is widely accepted, the optimal treatment of Siewert 1 and 2 remains an open question. Some published meta-analysis did not clarify this dilemma, because most included both randomized and observational studies [10, 14, 15]. Despite these data, head-to-head comparisons are missing and clear conclusions cannot be easily drawn because of differences in study design, patient characteristics, and regional differences in surgical management. Whether GEJ adenocarcinomas should be treated with perioperative FLOT or preoperative combined CTRT is currently being evaluated in the two phase 3 studies ESOPEC (NCT02509286) and TOPGEAR (NCT01924819). The results of ongoing studies could help clinicians to understand which patients are most likely to benefit from each treatment strategy.

Moreover, the addition of immunotherapy or targeted therapies (i.e.: anti-HER2 drugs) to standard perioperative CT (or addition of adjuvant nivolumab after preoperative CTRT and surgery [16]) could further improve outcomes in patients with locally advanced gastroesophageal cancers, therefore, new studies in this setting are strongly needed.

In this context, up to now, perioperative CT (with FLOT-based schedule) may still represent one of the preferred regimen in this disease.