The Efficacy of Neoadjuvant versus Adjuvant Therapy for Resectable Esophageal Cancer Patients: Direct and Indirect Comparisons <i>via</i> Meta-Analysis

Abstract

Background: Inconclusive results are available related to whether chemo/radiotherapy should be administered to resectable esophageal cancer patients before surgery (neoadjuvant therapy) or after surgery (adjuvant therapy). The paper, based on a systematic review of treatment modality to administer chemo/radiotherapy, aims to systematically evaluate the effect of timing of chemoradiotherapy and surgery on the multiple outcomes of resectable esophageal cancer patients. Methods: We performed a comprehensive literature search for clinical trials of neoadjuvant and adjuvant therapy for patients with esophageal cancer. Using meta-analysis, we conducted direct and adjusted indirect comparisons of overall survival, complete resection rate (R0 resection), perioperative mortality, leakage rate and local recurrence in patients with resectable esophageal cancer. Findings: A total of 32 studies involving 7585 patients with esophageal cancer were included in the meta-analysis. Twenty-five randomized controlled studies indirectly compared neoadjuvant/adjuvant therapy and surgery alone, while 5 non-randomized controlled studies and 2 randomized controlled studies directly compared neoadjuvant versus adjuvant therapy. Neoadjuvant therapy followed by surgery, compared with surgery along with adjuvant therapy, showed a significant overall survival advantage in our pooled analysis (HR, 0·86; 95% CI: 0·77-0‧97). Neoadjuvant therapy also demonstrated a lower local recurrence over adjuvant therapy in direct comparison (OR, 0·59; 95% CI: 0·41-0·86) with moderate heterogeneity (P = 0·22, I2 = 33%), whereas a significantly higher R0 resection rate was observed for neoadjuvant therapy (OR, 2·71; 95% CI: 1·86-3·95) without heterogeneity (P = 0·58, I2 = 0%). However, neoadjuvant therapy, compared with adjuvant therapy, significantly increased postoperative mortality in both direct and indirect comparisons (P= 0·02), while no significant differences in postoperative anastomotic leakage were noted between the two treatment modalities (P = 0·82). Interpretation: Comparing neoadjuvant and adjuvant therapy via meta-analysis, we found that neoadjuvant therapy was associated with higher overall survival and R0 resection rate without increasing postoperative anastomotic leakage for patients with resectable esophageal cancer, whereas neoadjuvant therapy was associated with higher perioperative mortality after esophagectomy. There were no differences in postoperative anastomotic leakage between these two modalities. Funding Statement: This work was supported by Sichuan Science and Technology Program (2018HH0150) and Chengdu Science and Technology Board (2017-GH02- 00072-HZ). Declaration of Interests: All authors declare no conflicts of interest. Ethics Approval Statement: This meta-analysis pertained to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.