Oncologic Benefit of Adjuvant Chemoradiation after D2 Gastrectomy: A Stepwise Hierarchical Pooled Analysis and Systematic Review

Abstract

Our study aimed to evaluate the benefits of chemoradiotherapy (CRT) after D2 gastrectomy, as compared to adjuvant chemotherapy, alone. PubMed, MEDLINE, Embase, and the Cochrane Library were systematically searched. We applied stepwise analyses that enabled the evaluation of data from randomized controlled trials (RCTs), balanced studies, and all studies separately and in a hierarchical manner. Thirteen controlled studies, including six RCTs involving 2603 patients, were included. Overall pooled analysis revealed a disease-free survival benefit of CRT (odds ratio (OR): 1.264, p = 0.053), which was more evident in the subgroup analysis of RCTs (OR: 1.440, p = 0.006) and balanced studies (OR: 1.417, p < 0.001). Overall survival was insignificantly different in the overall pooled analysis (OR: 1.124, p = 0.347). However, the difference was marginally significant in the subgroup analysis of balanced studies (OR: 1.279, p = 0.055) and significant in the subgroup analysis of studies involving stage ≥III patients only (OR: 1.663, p = 0.005). Locoregional recurrence (LRR) reduction was noted in the overall pooled analysis (OR: 0.559, p = 0.012; pooled rate: 11.3% vs. 18.1%) and was more robust in the subgroup analyses. Grade ≥3 leukopenia was higher in the CRT arm (OR: 1.387, p = 0.004; pooled rate: 26.4% vs. 15.7%). CRT after D2 gastrectomy should be applied for patients with high risk of LRR (e.g., stage ≥ III), along with efforts to reduce leukopenia.

Preserved Versus Preservative-Free Latanoprost for the Treatment of Glaucoma and Ocular Hypertension: A Post Hoc Pooled Analysis

“…The current study is innovative in the ophthalmic literature, by providing a pooled analysis of randomized comparative trials and observational studies. However, similar pooled analyses of randomized and observation studies have been recently published in other fields of medicine without significant concerns that incorporation of observational studies might skew the pooled analysis [ 30 – 32 ]. Similar to the aforementioned studies, our study protocol and statistical analyses (detailed in “ Methods ”) incorporated measures to address heterogeneity between studies and response-surface estimation to accommodate the effect of bias from any cause including study design [ 15 , 30 – 34 ].…”

“…However, similar pooled analyses of randomized and observation studies have been recently published in other fields of medicine without significant concerns that incorporation of observational studies might skew the pooled analysis [ 30 – 32 ]. Similar to the aforementioned studies, our study protocol and statistical analyses (detailed in “ Methods ”) incorporated measures to address heterogeneity between studies and response-surface estimation to accommodate the effect of bias from any cause including study design [ 15 , 30 – 34 ]. Shrier et al have previously addressed the advantages of combining randomized and non-randomized studies, including mitigating limitations of each design and increased sample size [ 15 ].…”

Stepwise-Hierarchical Pooled Analysis for Synergistic Interpretation of Meta-analyses Involving Randomized and Observational Studies: Methodology Development

“…Our team recently published two meta-analyses that used the stepwise-hierarchical method [ 21 , 22 ]. The main results of the two studies showed typical features of the ascending and descending patterns.…”

“…However, several observational studies and small randomized trials have reported the oncologic benefit of radiotherapy [ 25 , 26 ]. Therefore, our team conducted a meta-analysis including randomized and nonrandomized comparative studies to evaluate the disease-free survival benefit of adjuvant radiochemotherapy [ 21 ]. As shown in Figure 3 , the effect size in the pooled analysis for all studies was 1.264 (95% CI 0.997-1.603), and the P value was marginally nonsignificant at P =.053.…”

“… A clinical meta-analysis example of the ascending pattern in the stepwise-hierarchical method based on our previous meta-analysis evaluating the benefits of adjuvant radiochemotherapy after D2 gastrectomy as compared to chemotherapy alone [ 21 ]. The forest plots are newly drawn from the raw data obtained by the authors.…”