Concurrent Chemoradiation of Different Doses (50.4 Gy vs. 59.4 Gy) and Different Target Field (ENI vs. IFI) for Locally Advanced Esophageal Squamous Cell Carcinoma: Results from a Randomized, Multicenter Phase Ⅲ Clinical Trial

Abstract

<h3>Purpose/Objective(s)</h3> Concurrent chemoradiation is standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC), while the optimal regimen of radiotherapy, especially in terms of total dose and planned range of target field, remained unclear. This phase Ⅲ clinical trial was aimed to compare the survival benefits between different total dose and different target field. <h3>Materials/Methods</h3> The clinical trial compared two radiation treatment aspects of total dose and field under two-by-two factorial design. The high radiation dose group (HD) totally received 59.4Gy radiation and standard dose group (SD) received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different radiation plans of clinical target volume (CTV), among which the CTV in IFI group was defined as GTV plus extend margin to the primary tumor and in ENI group CTV was defined as GTV plus the extend margins and the high-risk region of elective nodes. Two cycles of Tegafur/gimeracil/oteracil (S-1) and cisplatin were given with concurrent radiotherapy. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI) by simple randomization (1:1:1:1 ratio). The planned sample size was 147 in each arm (588 totally). The primary endpoint was overall survival (OS) and the second endpoints included progression-free survival (PFS) and objective response rate (ORR). All statistical analysis was performed according to intention-to-treat principle. <h3>Results</h3> The median follow-up period was 47.3 months until December 2021. The median OS were 33.6, 33.9, 41.0 and 28.3 months in HD+ENI, SD+ENI, HD+IFI and SD+IFI groups, respectively. No significant synergistic effect was detected between dose and radiation field in interaction analysis. Compared with SD arms, the HD treatment did not present significantly prolonged OS (HR=0.93, log rank test p value=0.54) but suggested improved PFS (29.1 months to 20.0 months, HR=0.77, log rank test p value=0.023). In subgroup analysis of IFI, the HD treatment was associated with more benefits (HD+IFI arm to SD+IFI arm, HR of PFS is 0.64[0.47-0.84]). In comparison of target field, patients in IFI or ENI group presented similar OS (HR=1.05, log rank test p=0.7) and PFS (HR=1.08, log rank test p=0.5). In the stratified analysis of lymph node status, the ENI treatment suggested benefits compared to IFI in N0 patients (n=108, HR of OS is 0.46[0.24-0.89]). No significant difference in occurrences of severe adverse event was detected in comparisons of dose or field groups. <h3>Conclusion</h3> The HD and SD radiation treatment did not significantly differ in OS, but HD radiation associated with better PFS. The IFI treatment brought similar outcomes to ENI in overall patients, which indicated a reasonable choice for locally advanced ESCC.