Effectiveness of S-1–Based Chemoradiotherapy and S-1 Consolidation in Elderly Patients with Esophageal Squamous Cell Carcinoma: A Multicenter Randomized Phase III Clinical Trial

Abstract

<h3>Purpose/Objective(s)</h3> There has been a steady increase in the incidence of esophageal squamous cell carcinoma (ESCC) among elderly patients. The optimal treatment approach of elderly ESCC patients was still vague. <h3>Materials/Methods</h3> Between March 2017 and April 2020, 339 patients were screened in 10 centers in China; 184 and 146 patients were randomized into the S-1 based chemoradiotherapy followed by S-1 monotherapy (CRT-CT arm) or radiotherapy alone (RT arm). CRT-CT arm consisted simultaneous integrated boost radiotherapy (SIB-RT) (dose, 59.92 Gy/50.4 Gy) in 28 daily fractions administered using intensity-modulated radiotherapy or volumetric modulated arc therapy. S-1 was orally administered (40–60 mg/m2) concurrently with radiotherapy and 4–8 weeks later, for up to four 3-week cycles at the same dose. RT arm performed SIB-RT alone with the same radiotherapy dose. The primary endpoint was overall survival (OS) of the intention-to-treat (ITT) population. <h3>Results</h3> In the ITT population, 63.9% and 24.8% had T3 and T4 stage disease, and 68.8% had nodal metastases. The median OS was 27.8 months in the CRT-CT arm and 20.8 months in the RT arm and the OS rates were 72.5% vs 62.8% at 1 year; 55.2% vs 43.7% at 2 years; 45.5% vs 33.7% at 3 years ((hazard ratio, 0.75; 95% CI, 0.56–0.99; <i>P</i> = 0.041). The median PFS was 19.5 months in the CRT-CT arm and 11.5 months in the RT arm. Time dependent cox regression model revealed Charlson comorbidity index, BMI and cumulative chemotherapy cycles were independent prognostic factors associated with OS. OS and PFS of patients treated with 5–6 cycles of chemotherapy were superior to those of the patients treated with 0 (treated with radiotherapy alone), 1–2 and 3–4 cycles. There was no significant increase in the incidence of toxicities higher than grade 3 in the CRT-CT arm. Grades 4 and 5 toxicities were reported in 2.8% and 2.8%, respectively, of the CRT-CT arm compared with 0% and 4.2%, respectively, of the RT arm <h3>Conclusion</h3> Oral S-1 chemotherapy administered with SIB-RT is highly recommended for elderly patients with inoperable ESCC as an alternative treatment modality that improves survival outcomes with a more favorable side-effects profile.