Neoadjuvant therapy versus upfront surgery in resectable pancreatic cancer according to intention-to-treat and per-protocol analysis: A systematic review and meta-analysis

Abstract

The effectiveness of neoadjuvant therapy (NAT) remains unclear in resectable pancreatic cancer (PC) as compared with upfront surgery (US). The aim of this study was to investigate the survival gain of NAT over US in resectable PC. PubMed and EMBASE were searched for studies comparing survival outcomes between NAT and US for resectable PC until June 2018. Overall survival (OS) was analyzed according to treatment strategy (NAT versus US) and analytic methods (intention-to-treat analysis (ITT) and per-protocol analysis (PP)). In 14 studies, 2,699 and 6,992 patients were treated with NAT and US, respectively. Although PP analysis showed the survival gain of NAT (HR 0.72, 95% CI 0.68-0.76), ITT analysis did not show the statistical significance (HR 0.96, 95% CI 0.82-1.12). However, NAT completed with subsequent surgery showed better survival over US completed with adjuvant therapy (HR 0.82, 95% CI 0.71-0.93). In conclusion, the supporting evidence for NAT in resectable PC was insufficient because the benefit was not demonstrated in ITT analysis. However, among the patients who completed both surgery and chemotherapy, NAT showed survival benefit over adjuvant therapy. Therefore, NAT could have a role of triaging the patients for surgery even in resectable PC.

Figure 1

Flow diagram for identification of selected studies in the meta-analysis.

Figure 2

Anticancer therapy strategies and chemotherapy regimens in NAT and US strategy, respectively in the studies of this meta-analysis.

Figure 3

Meta-analyses of 14 studies on overall survival of NAT versus US using random effects model. NAT strategy had a better OS compared with US strategy in resectable pancreatic cancer (HR 0.80, 95% CI 0.70–0.92, P = 0.002). although the heterogeneity between studies is identified (Chi² = 21.02, P = 0.070, I² = 38%).

Figure 4

Subgroup analysis based on the analytic method of survival data (ITT or PP analysis). The subgroup analysis with PP analysis showed the survival gain of NAT (HR 0.72, 95% CI 0.68–0.76, P < 0.001). However, the studies with ITT analysis did not show the survival gain of NAT (HR 0.96, 95% CI 0.82–1.12, P = 0.610).

Figure 5

(A) Subgroup analysis regarding the delivery sequence showed that the neoadjuvant delivery of anticancer therapy had survival benefit over the adjuvant delivery among the patients underwent surgical resection (HR 0.82, 95% CI 0.71–0.93, P = 0.003) and the heterogeneity between studies was not significant (Chi² = 3.57, P = 0.310, I² = 16%). (B) Sensitivity analysis after excluding the study of Mokdad et al. showed that the trend of survival benefit of NAT still maintained.