Results of a Phase 1/2 Trial of Chemoradiotherapy With Simultaneous Integrated Boost of Radiotherapy Dose in Unresectable Locally Advanced Esophageal Cancer

Abstract

Importance: Effective treatment options for locally advanced esophageal cancer are limited, and rates of local recurrence after standard chemoradiotherapy remain high.

Objective: To evaluate toxic effects, local control, and overall survival rates after chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose to the gross tumor and nodal disease for patients with unresectable locally advanced esophageal cancer.

Design, setting, and participants: A phase 1/2, single-arm trial was conducted in 46 patients from April 28, 2010, to April 9, 2015 (median follow-up, 52 months [range, 2-86 months]), at a tertiary academic cancer center. Outcomes of the study patients were compared with those of 97 similar patients treated at the same institution from January 10, 2010, to December 5, 2014, as part of the interim analysis. Statistical analysis was performed from December 15, 2018, to February 12, 2019.

Interventions: Chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose (50.4 Gy to subclinical areas at risk and 63.0 Gy to the gross tumor and involved nodes, all given in 28 fractions) with concurrent docetaxel and capecitabine or fluorouracil.

Main outcomes and measures: Toxic effects, local (in-field) control, and overall survival rates.

Results: All 46 patients (11 women and 35 men; median age, 65.5 years [range, 37.3-84.4 years]) received per-protocol therapy, as intensity-modulated photon therapy (39 [85%]) or intensity-modulated proton therapy (7 [15%]); 11 patients (24%) ultimately underwent resection. No patients experienced grade 4 or 5 toxic effects; the 10 acute grade 3 toxic events were esophagitis (4), dysphagia (3), and anorexia (3) and the 3 late grade 3 toxic events were all esophageal strictures. The actuarial local recurrence rates were 22% (95% CI, 11%-35%) at 6 months, 30% (95% CI, 18%-44%) at 1 year, and 33% (95% CI, 20%-46%) at 2 years. Overall, 15 patients (33%) experienced local failure, at a median interval of 5 months (range, 1-24 months). The median overall survival time was 21.5 months (range, 2.3-86.4 months). Exploratory comparison with a 97-patient contemporaneous institutional cohort receiving standard-dose (non-simultaneous integrated boost) chemoradiotherapy showed superior local control (hazard ratio, 0.49; 95% CI, 0.26-0.92; P = .03) and overall survival (hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .02) in the group that received chemoradiotherapy with a simultaneous integrated boost.

Conclusions and relevance: These findings suggest that chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose for locally advanced esophageal cancer is well tolerated, with encouraging local control, and thus warrants further study.

Trial registration: ClinicalTrials.gov identifier: NCT01102088.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Welsh reported receiving research support from GlaxoSmithKline, Bristol-Meyers Squibb, Merck, Nanobiotix, Mavu Pharmaceuticals, and Checkmate Pharmaceuticals; serving on the scientific advisory board for RefleXion Medical, MolecularMatch, OncoResponse, CheckMate, Mavu Pharmaceuticals, and Alpine Immune Sciences; being cofounder of Healios Oncology, MolecularMatch, and OncoResponse; serving as an advisor to AstraZeneca, Merck, MolecularMatch, Incyte, Aileron, and Nanobiotix; and holding patents for MP470 (amuvatinib), MRX34 regulation of PDL1, and XRT technique to overcome immune resistance (MD Anderson Cancer Center has a trademark for RadScopal). No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram of the Trial

Figure 2.. Local Recurrence Rate of the Study Population

A, Local recurrence in all patients. B, Local recurrence by histologic findings. Survival at 12 months was 32% in patients with adenocarcinoma (n = 22) and 29% in patients with squamous cell carcinoma. C, Local recurrence by nodal status. Survival at 12 months was 29% in patients with negative lymph nodes (n = 14) and 32% in patients with positive lymph nodes (n = 31). D, Local recurrence by radiotherapy type. Survival at 12 months was 33% in patients who received intensity-modulated (photon) radiotherapy (n = 39) and 14% in patients who received intensity-modulated proton therapy. Death was used as a competing risk. SCC indicates squamous cell carcinoma.

Figure 3.. Overall Survival of the Study Population

SCC indicates squamous cell carcinoma; SIB, simultaneous integrated boost.