A Phase 3, Multicenter, Randomized Trial To Evaluate The Symptomatic And Quality Of Life Improvements In Lung Cancer Patients Receiving External Beam Radiation With Or Without High Dose Rate Intraluminal Brachytherapy

Uncontrolled studies suggest that the addition of HDRILB to EBR may improve palliation for patients with metastatic or locally advanced NSCLC. The purpose of this study was to evaluate the addition of HDRILB to EBR in a multicenter randomized trial. Patients with symptomatic stage 3 or 4 NSCLC with endobronchial disease from 8 centers who are not candidates for radical chemo radiation were randomized to EBR (20 Gy in 5 daily fractions or 30 Gy in 10 daily fractions) or EBR plus HDRILB (14 Gy in 2 fractions over two weeks). The primary outcome was the proportion of patients who achieved symptomatic improvement in patient-reported lung cancer symptoms defined as a 10 point improvement (on a 100 point scale) for overall lung cancer symptoms on the Lung Cancer Symptom Scale (LCSS) at 6 weeks following randomization. Secondary outcomes included improvement in individual lung cancer symptoms and the LCSS summary score, symptom progression free and overall survival. Patients were assessed at 6 week intervals following randomization up to 18 weeks and then every 8 weeks. For the primary analysis treatment arms were compared using an exact conditional test stratified on pre-treatment LCSS score (<50, >50), prior chemotherapy (yes or no) and center. Change in LCSS scores from baseline were compared on a general linear model. Time to event outcomes were estimated using the Kaplan-Meier method and compared using the Cox regression test. The planned sample size was 250 patients based on detection of symptomatic improvement from 40 to 60% with a two-sided α of 0.05 and 80% power. Between October 2011 and April 2016, 134 patients were randomized: 67 to each arm. The study was closed early due to low accrual. The mean age was 69.8 years, 57% were male, 87% had ECOG score < or = 2 and 67% had metastatic disease. Seven patients in the EBR arm and 6 patients in the EBR+HDRILB arm had grade 3 acute (<6 weeks) radiation toxicity (commonly fatigue); 1 patient in the EBR arm had grade 4 late (>6 weeks) toxicity (febrile neutropenia) and 3 patients in the EBR+HDRILB arm had grade 3 late radiation toxicity (2 cases of bronchitis and 1 case of pneumonitis). At six weeks 19 patients (28.4%) in the EBR arm and 20 patients (29.9%) in the EBR+HDRILB arm experienced a 10 point improvement in lung cancer symptoms (P = 0.84). Small between group differences in mean change scores (0.2-0.3 standard deviations) in favor of EBR+HDRILB were observed for overall symptoms, individual symptoms and the LCSS summary score but they were not statistically significant. No significant differences between groups were observed in progression free [HR = 0.68; 95% CI = 0.34, 1.35; P = 0.27) or overall survival [HR = 1.06; 95% CI = 0.73, 1.55; P = 0.77). EBR plus HDRILB was well tolerated. Small improvements were seen in symptom relief with the combined therapy, but they did not reach statistical significance. Further research is necessary before recommending HDRILB in addition to EBR for palliation of lung cancer symptoms.