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

Abstract

IMPORTANCEEffective 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 PARTICIPANTSA phase 1/2, single-arm trial was conducted in 46 patients from April 28, 2010, to April 9, 2015), 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.

A multicenter prospective phase III clinical randomized study of simultaneous integrated boost intensity-modulated radiotherapy with or without concurrent chemotherapy in patients with esophageal cancer: 3JECROG P-02 study protocol

“…Compared with a recent phase I/II trial of chemoradiotherapy with SIB radiotherapy for unresectable locally advanced EC (95% PGTV/PTV = 63.00 Gy/50.40 Gy/28 f, EQD2 = 64.31 Gy), our study had a better median OS, lower 1-year local recurrence rates, and similar 1-year OS and 1-year local recurrence rates (21.5 months, 30%, and 78.3% respectively) [36]. However, all of these studies require long-term follow-up.…”

“…In contrast, the SIB-IMRT dose for the primary treatment area is controversial. The fractionated dose varies from 1.8 to 2.8 Gy; the total dose, from 62.5 Gy to 70 Gy; and the number of fractions, from 25 to 36, which re ects a wide variation [37][38][39] [24]. However, in the above study, the patients treated with this dose range (2.2-2.25 Gy/62.5-66 Gy/25-30 f) may be highly selected, for example, patients in whom the primary tumor was not sensitive to treatment, especially patients with EC who showed insigni cant tumor regression during radiotherapy; or no signs of ulcer perforation without T4 stage.…”

Sequential boost of intensity‐modulated radiotherapy with chemotherapy for inoperable esophageal squamous cell carcinoma: A prospective phase II study

“…This may be because the distant metastasis rate was low (28.4%), and most distant metastases (72.0%) were combined with local‐regional recurrences. Another radiation dose escalation method, simultaneous integrated boost (SIB), has also been explored; local control of 67.5%‐78.6% was reported . However, local control of ESCC was not improved by SIB, compared with standard dose .…”

Prognostic Significance of Baseline Neutrophil Count and Lactate Dehydrogenase Level in Patients With Esophageal Squamous Cell Cancer Treated With Radiotherapy

“…The planning target volume (PTV) encompassed the CTV plus a 0.5-1 cm margin. All patients received simultaneous integrated boost (SIB) radiotherapy, which had been reported in a recent phase 1/2 trial conducted by Chen et al (26). The prescribed dose was 60-66 Gy to GTV in 28-30 fractions, five fractions per week, and at least 50.4 Gy to CTV in 28 fractions, five fractions per week.…”