Do Higher Radiation Doses with Concurrent Chemotherapy in the Definitive Treatment of Esophageal Cancer Improve Outcomes? A Meta-Analysis and Systematic Review

Abstract

For non-operable, localized esophageal carcinoma (EC), definitive concurrent chemoradiotherapy (dCCRT) is usually the standard treatment approach. Currently, the dCCRT radiation dose recommended by National Comprehensive Cancer Network (NCCN) is 50.4 Gy, which is primarily based on results of the Radiation Therapy Oncology Group (RTOG)85-01 and 94-05 randomized trials. However, the optimal radiation dose in this scenario remains controversial. Radiation dose escalation has been proposed as a technique to obtain higher local-regional control (LRC) and survival rates, notably in Asian countries. Additionally, with advances in radiotherapy techniques, questions have been raised as to whether dose escalation utilizing computerized tomography (CT)-based radiotherapy approaches (including 3-D, IMRT and proton therapy) could achieve improved outcomes with less toxicity compared to older approaches from the 2-D era. The aim of the study is to investigate the effects and safety profile of radiation dose escalation utilizing computerized tomography (CT) based modern techniques (including 3-D, IMRT, SIB-IMRT and proton therapy) in the definitive treatment of patients with EC with dCCRT. Studies published prior to 15 February, 2020 comparing radiation dose and disease-related outcomes in nonoperable EC patients were included. All relevant studies utilizing CT-based radiation planning, comparing high-dose (≥ 60 Gy) versus standard-dose (50.4 Gy) radiation for patients with EC were analyzed for this meta-analysis. Eleven studies including 4946 patients met the inclusion criteria, including 4775 (96.5%) ESCC patients, 142 EAC patients and 30 patients with other histology. The high-dose group demonstrated a significant improvement in local-regional failure (LRF) (OR 2.199, 95% CI 1.487-3.253; P<0.001), two-year local-regional control (LRC) (OR 0.478, 95% CI 0.309-0.740; P = 0.001), two-year overall survival (OS) (HR 0.744, 95% CI 0.657-0.843; P<0.001) and five-year OS (HR 0.683, 95% CI 0.561-0.831; P<0.001) rates relative to the standard-dose group. In addition, there was no difference in grade≥ 3 acute radiation-related toxicities and treatment-related deaths between the groups. The study demonstrated that compared to the standard radiation-doses, dose-escalated (≥60Gy), CT-based radiotherapy techniques may improve ultimate survival in patients with inoperable ESCC under the premise of controlling the rate of toxicities, and represents the first meta-analysis comparing high versus standard radiation doses utilizing CT-based/modern radiotherapy techniques. Our results support this approach as well as the multiple ongoing randomized trials further evaluating this strategy.