A Single-Institution Phase I Feasibility Study of Dose-Escalated IMRT for Non-Operative Locally Advanced Esophageal Carcinoma

Abstract

Concurrent chemoradiation continues to be the standard of care for definitive management of inoperable locally advanced esophageal carcinoma, however outcomes remain poor. Prior attempts to improve outcomes with dose escalation with conventional radiotherapy were limited by increased toxicity, though the role of radiation in that toxicity was unclear. This Phase I study attempted to utilize more conformal radiation with IMRT to achieve improved tolerability of dose escalation. A prospective, single-institution Phase I study was conducted between 2007 and 2013. Patients deemed inoperable by thoracic surgery were treated with concurrent chemoradiation. The primary tumor and involved lymph nodes were treated to 60 Gy in 30 fractions and sites at risk for microscopic disease to 54 Gy with simultaneous integrated boost. Concurrent chemotherapy primarily consisted of cisplatin/5-FU with consolidation chemotherapy offered at the discretion of the treating oncologist. The primary objective was to assess feasibility as determined by a <15% rate of grade 4 or 5 toxicity. Secondary objectives included assessment of overall survival (OS), disease free survival (DFS), and locoregional (LRR) and distant recurrence. A total of 26 patients were enrolled with median follow up of 17.6 months (range 0.1 to 152.0). The majority were male (69%), Caucasian (81%), and AJCC 6th/7th edition Stage III (46%), with tumors in the distal esophagus/GE junction (81%) and adenocarcinoma histology (85%). Twenty-one patients (81%) completed their course of radiation therapy, however, one patient experienced a 195-day break after 30 Gy due to toxicity and non-compliance. Of the 18 patients who received cisplatin/5-FU, only 10 (56%) were able to receive 2 cycles of concurrent chemotherapy due to chemotherapy-related toxicity. The remaining patients received concurrent carboplatin/5-FU (4), FOLFOX (2), carboplatin/paclitaxel (1), or no concurrent chemotherapy (1). Consolidation chemotherapy was administered to 9 patients (35%), the majority (67%) with cisplatin/5-FU. One patient developed grade 4 cardiac toxicity (acute myocardial infarction) and there was one treatment-related death, both during chemoradiation and before receiving 50 Gy. Median survival was 24 months, with a 3-year OS and DFS of 44% and 30%, respectively. The predominate site of failure was distant (54%). LRR occurred in 10 patients (38%), isolated with no distant disease in 4 patients. While the feasibility threshold for the study was achieved, toxicity to therapy was still significant and treatment compliance was relatively poor with outcomes otherwise comparable to historical controls. In the context of the recent ARTDECO, our study further suggests an uncertain role for dose escalation in definitive management of locally advanced esophageal cancer.