Long-Term Outcomes and Toxicity in Esophageal Cancer Patients after Neoadjuvant or Definitive Concurrent Chemotherapy with Proton Beam Therapy

Abstract

Proton-beam therapy (PT) is increasingly utilized over three dimensional-conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) photon irradiation for the treatment of various malignancies due to better toxicity reduction. We investigated the long-term outcomes and toxicity in esophageal cancer (EC) patients treated with PT as part of their neoadjuvant concurrent chemoradiation followed by surgery (nCRT) or definitive concurrent chemoradiation (dCRT) treatment regimen. All consecutively treated, American Joint Committee on Cancer 7th edition clinical stage I-IV EC patients from 2006 to 2022 were retrospectively analyzed. Standard RT dose for most patients was 50.4 Gy/28 fractions. nCRT patients had surgery within 4 months post-RT. Kaplan-Meier method was used to determine overall survival (OS), locoregional recurrence-free survival (LRRFS) and distant metastatic-free survival (DMFS). Acute and chronic RT-related toxicities were graded with Common Terminology Criteria for Adverse Events version 4.0. There were 510 EC PT patients: 204 (40%) had nCRT and 306 (60%) had dCRT. Most lesions were located in the lower esophagus, of adenocarcinoma histology and treated with passive scatter PT. Overall median follow-up was 72 months. Median, 3- and 5-year OS for all patients were 43 months, 54.1% and 44.9%, respectively. Median LRRFS and DMFS were not reached. Esophagitis was the most common grade ≥3 (G3+) toxicity (59 patients; 28.9%, including a G4 and a G5 toxicity), followed by nausea (29 patients; 14.2%) and esophageal stricture (26 patients, 12.7%). With nCRT, median, 3- and 5-year OS were 80 months, 64.7% and 56.1%, respectively, while the median LRRFS and DMFS were not reached again. Their most common G3+ toxicity was esophagitis in 14 patients (6.9%) followed by nausea (8 patients; 3.9%). An nCRT patient developed G4 RT pneumonitis. Pathological complete response (pCR) was observed in 58 patients (28.4%). Surgery-related pulmonary, cardiac and gastrointestinal complications were reported in 38 (18.6%), 40 (19.6%) and 43 (21.1%) patients, respectively. dCRT patients had a median follow-up of 65 months, and median, 3- and 5-year OS of 32 months, 46.7% and 37.0%, respectively. Although the median LRRFS was not reached, the median DMFS was 74 months. The most observed dCRT G3+ toxicity was esophagitis (45 patients, 22.1%: including both G4 and G5 patients) and then esophageal stricture (23 patients, 11.3%). A dCRT patient developed G4 fistula. To our knowledge, this is the largest single-institutional study on EC long-term outcomes and toxicity using PT. Our cohort reveals good outcomes and mostly mild CRT-related toxicities. Trimodality nCRT with protons demonstrates excellent outcomes relative to the CROSS trial (49.4 months) with identical pCR rate (29% in CROSS) and similar toxicity profile. nCRT with protons should be studied rigorously in the current randomized phase III trial NRG GI006.