Efficacy of Function-Adapted Simultaneous Modulated Accelerated Radiation Therapy (FA-SMART) with Concurrent Chemotherapy in Patients with Locally Advanced Non–Small-Cell Lung Cancer: A Phase 2 Prospective Clinical Trial

Abstract

To determine whether the function-adapted simultaneous modulated accelerated radiation therapy (FA-SMART) technique and concurrent weekly chemotherapy can improve treatment efficacy in patients with locally advanced non-small-cell lung cancer (NSCLC). In this single-arm phase 2 study (clinicaltrials.gov Identifier: NCT02573506), we enrolled patients with unresectable stage III NSCLC and an Eastern Cooperative Oncology Group performance status score of 0-1. Split-course thoracic radiotherapy was delivered using FA-SMART technique. Pulmonary function test (PFT) including the percentage-predicted forced expiratory volume in 1 second / forced vital capacity (FEV1/FVC %) and single-breath carbon monoxide diffusing capacity (DLCO %) was performed at baseline and after the interval. Patients were irradiated at 51Gy in 17 daily fractions in the first course. After the interval, patients who had non-progressive disease and an adequate pulmonary function (FEV1/FVC % ≥ 40% and DLCO % ≥ 45%) underwent adaptive re-planning, and were irradiated at 15∼18Gy in 5∼6 daily fractions as a boost. Concurrent chemotherapy consisted of weekly docetaxel and nedaplatin. The primary endpoint was progression-free survival (PFS). The Kaplan-Meier method and log-rank tests were performed for survival analysis. Adverse events were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0). A total of 89 patients were enrolled and analyzed. Eighty-three patients (93.3%) completed two courses of RT at a total dose of 66∼69Gy. The median follow-up was 26 months (range, 12∼51 months) on living patients. Median PFS was 12.0 months (95% CI, 7.8∼16.2 months) and the PFS rates were 47.8% (95% CI, 37.2∼58.4%) at 1 year and 35.0% (95% CI, 24.0∼46.0%) at 3 years. Median OS was 27.0 months (95% CI, 14.3∼39.7 months) and the OS rates were 74.2% (95% CI, 65.2∼83.2%) at 1 year and 43.1% (95% CI, 30.6∼55.6%) at 3 years. Grade ≥3 acute esophagitis was observed in 15(16.9%) patients. Grade ≥3 acute and late pneumonitis was observed in 7(7.9%) and 3(3.3%) patients respectively. DLCO was significantly reduced after the first course of RT (6.62 vs 5.79 mmol/min/kPa, p = 0.016). Patients with better interval DLCO % had significantly better OS (DLCO % ≥80% vs 60-79% vs 45-59% vs <45%, 2-year OS was 72.4% vs 45.3% vs 42.1% vs 0, p = 0.008). Interval DLCO % also correlated significantly with the incidence of grade 3 acute pneumonitis (p = 0.005). The split-course FASMART with concurrent chemotherapy has apparently improved survival with no loss in palliation or increased morbidity in patients with LANSCLC. PFT, DLCO in particular, is a necessary indicator for evaluation of irradiation boost after interval. Patients with favorable lung function after treatment interval would benefit more from intensive CCRT regimen, which should be taken into account for future study design.