PurposeTo evaluate the safety and efficacy of pencil beam scanning (PBS) proton radiotherapy (RT) in trimodality therapy for esophageal cancer. MethodsThis prospective pilot study was planned to accrue 30 patients with locally advanced esophageal or gastroesophageal junction (GEJ) carcinoma, medically suitable for chemoRT (CRT) followed by esophagectomy. PBS proton RT consisted of 25 fractions, 50 Gy to tumor + 1 cm and 45 Gy to a 3.5 cm mucosal expansion and regional lymph nodes. Chemotherapy was weekly carboplatin (AUC = 2) and paclitaxel (50 mg/m2). At 4-8 weeks after CRT, patients underwent restaging and potential esophagectomy. The primary endpoint was acute grade 3+ adverse events (AEs) attributed to CRT. Overall (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier methodology; local-regional recurrence (LRR) and distant metastases (DM) rates were assessed by cumulative incidence methodology. The Functional Assessment of Cancer Therapy-Esophagus (FACT-E) assessed quality of life. ResultsThirty eligible patients enrolled June 2015-April 2017. Median age was 68 years. Histology was adenocarcinoma in 87% and location was distal esophagus/GEJ in 90%. Stage was T3-4 in 87% and N1-3 in 80%. All patients completed the planned RT dose. Acute grade 3+ AEs occurred in 30%, most commonly leukopenia and neutropenia. Acute grade 3+ non-hematologic AEs occurred in 3%. Esophagectomy was performed in 90% of patients (R0 in 93%). Pathologic complete response rate was 40%. Major post-operative complications (Clavien-Dindo score ≥ III) occurred in 34%. Postoperative mortality at 30 days was 3.7%. Median follow-up was 5.2 years. 5-year outcome estimates were OS 46%, PFS 39%, LRR 17%, and DM 40%. FACT-E scores (medians) were baseline (145), end of CRT (136, p=0.0002 vs. baseline), before esophagectomy (144), 12 months (146), and 24 months (157). ConclusionsPBS proton RT is feasible and safe as a component of trimodality therapy for esophageal cancer.