Background

The prevalence of gastric cancer has decreased over the several decades, but it is still a common malignancy and the fourth leading cause of cancer-related death worldwide [1]. Although the treatment strategy varies geographically, perioperative chemotherapy, adjuvant chemotherapy, or adjuvant chemoradiotherapy are the treatment options that can be used as adjuncts to surgery [2,3,4]. In Asia, the preferred method is surgery with D2 dissection followed by adjuvant chemotherapy. In Europe, on the other hand, perioperative chemotherapy is usually done. Adjuvant chemoradiotherapy has been the cornerstone of adjuvant therapy since the pivotal Int 116 trial; however, results of the recent adjuvant chemoradiotherapy (CRT) trials in patients with D2 dissected gastric cancer were negative, thus questioning the role of adjuvant chemoradiation [3, 4].

Many studies have found that the presence of R1 resection, lymph node involvement, diffuse histology, lymphovascular invasion, tumor grade, and resection type are associated with poor disease-free survival in gastric cancer patients [5,6,7,8].

According to Lauren’s classification, gastric cancers are histologically classified as diffuse and intestinal subtypes [9]. These two subtypes exhibit many differences in epidemiology, biology, and prognosis.

In this study, we aimed to assess the benefit of adjuvant CRT according to Lauren’s histological classification by conducting a meta-analysis of phase III trials that reported disease-free survival (DFS) outcomes according to histological subtype.

Method

Literature search

We performed this meta-analysis following the Preferred Items for Systematic Reviews and Meta-Analysis guidance.

We systematically searched the PubMed database for published clinical trials from inception until April 4, 2022. The inclusion criteria were as follows: (1) phase III clinical trial evaluating the role of adjuvant radiotherapy in operable gastric cancer, (2) hazard ratio (HR) for disease-free survival (DFS), (3) separate reporting for the intestinal and diffuse subtypes, and (4) only English-language studies. The exclusion criteria were as follows: (1) articles other than clinical trials (real-world data, commentaries, reviews, and opinion papers); (2) studies without separate reporting for Lauren subtypes; and (3) lack of data regarding HRs.

Two authors independently extracted the available data (HCY and DCG), and any discrepancies were resolved by the senior author (OD). The following data was extracted for the included studies: year of the study, study arms, sample size, study arms, and HR for DFS in the intestinal and diffuse subtypes The risk of bias was evaluated with the Risk of Bias Tool v.2.

Our search strategy retrieved a total of 743 records. Of the 743 records, 39 articles (phase 3 clinical trials and randomized trials) with full texts were evaluated, and after duplicates were removed, 31 articles were evaluated. Twenty-nine of the articles were excluded: lack of DFS outcomes (N:11), neoadjuvant chemoradiotherapy (N:9), other primary tumors (N:3), recurrent disease treatment (N:2), phase 2 trial (N:2), no D2 surgery (N:1), and article not in English (N:1). Two articles were included in the systematic review. The PRISMA diagram for article selection is shown in Fig. 1.

Fig. 1
figure 1

PRISMA flow diagram

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Meta-analysis

The primary objective was to evaluate the benefit of adjuvant radiotherapy according to intestinal and diffuse subtypes. The meta-analysis was conducted using the generic inverse variance with a fixed-effect model, considering the low degree of heterogeneity across studies. The principal summary measure was the HR with a 95% confidence interval (CI).

We conducted meta-analyses with the Review Manager software, version 5.3 (The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark), and considered p values below 0.05 statistically significant.

Result

Our search strategy retrieved a total of 743 records. Of the 743 records, 2 articles were included in the systematic review. The PRISMA diagram for article selection is shown in Fig. 1.

The ARTIST and ARTIST 2 studies were included in the analysis. Table 1 outlines the main characteristics of both trials. A total of 1004 patients were included in the two studies. Of these patients, 328 had intestinal-type tumors, 534 had diffuse-type tumors, and 142 had mixed or unclassified tumors.

Table 1 Characteristics of the ARTIST and ARTIST-2 trials
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Meta-analysis including the two studies showed that adjuvant CRT did not improve DFS in gastric cancer patients treated with D2 surgery in the entire patient population (HR: 0.70 (0.62–1.02), p. 0.07). However, the benefit of CRT varied with the histological subgroup. Adjuvant CRT significantly prolonged DFS in intestinal-type gastric cancers (HR: 0.58 (0.37–0.92), p = 0.02), but no DFS benefit was observed in patients with diffuse gastric cancer (HR: 0.91 (0.67–1.22), p = 0.52) (Fig. 2).

Fig. 2
figure 2

Meta-analysis of the association between histological type and disease-free survival (DFS) in localized-stage gastric cancer

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Discussion

Our study showed that adjuvant CRT improved DFS in patients with intestinal-type gastric cancer but not in those with diffuse-type gastric cancer after D2 dissection.

Int 116 was the first randomized phase III trial showing the benefit of adjuvant CRT in patients with gastric cancer, but most of these patients had D0 or D1 surgery [10]. Although the trial was overall positive, updated OS analysis showed that the OS benefit of CRT was limited to patients with intestinal-type GC. This was an unplanned subset analysis, and the histologic type was unknown in 23% of the patients in this trial. The authors stated that it was not known whether the difference in DFS benefit was random or depended on biology; however, subsequent trials suggested that this effect was not random.

We could not include this study in our meta-analysis because we did not have the subgroup analysis of DFS according to histology in this study. The CRITICS trial compared the efficacy of adjuvant CT vs. CRT in patients with gastric cancer treated with neoadjuvant CT [11]. In the per-protocol analysis of the patients who started the assigned postoperative treatment, which was about 60% of the whole study population, CRT was worse than CT in terms of 5-year OS.

There was no difference between CT and CRT in patients with diffuse-type gastric cancer in this study. CT performed better in intestinal-type tumors. The study’s differences were that all of the patients had received neoadjuvant CT, and postoperative CRT was not added to but instead replaced adjuvant CT.

ARTIST1 and ARTIST2 trials were designed to assess the benefit of adjuvant CRT in addition to adjuvant CT in patients with gastric cancer treated with D2 surgery [3, 4]. In ARTIST1, subgroup analysis showed lower recurrence rates with CRT in patients with node-positive tumors [3]. Subsequently, ARTIST2 was initiated in node-positive tumors, which did not show any benefit from CRT [4]. However, subgroup analysis of both trials showed a strong signal of benefit with CRT in patients with intestinal-type tumors, and our meta-analysis confirmed these findings. Current NCCN guidelines do not recommend adjuvant CRT for people who have had their gastric cancer removed but did not get any treatment before surgery.

The inclusion of only two phase 3 clinical trials in our study is our most important limitation, and it also prevented us from evaluating other prognostic parameters.

We suggest that patients with diffuse-type tumors definitely do not need CRT, but those with intestinal-type tumors may still derive some benefit from adjuvant CRT, and this issue should be investigated in future trials.