Prospectively scored pulmonary toxicities in non-small cell lung cancer: Results from a randomized phase II dose escalation trial.

PURPOSE: Prospectively scored radiation pneumonitis (RP) observed in a national, randomized phase II dose-escalation trial for patients with locally advanced non-small cell lung cancer (NSCLC) was investigated. METHODS: Patients with stage IIB-IIIB histologically proven NSCLC were treated with concomitant chemo-radiotherapy (oral Vinorelbine 3times/week) at 60 Gy/30fx (A-59pts) and 66 Gy/33fx (B-58pts) from 2009 to 2013 at five Danish RT centers. Grade 2 RP (CTCAEv3.0) was investigated with univariate analysis for association with clinical and dosimetric parameters, including dyspnea and cough at baseline and during RT. Multivariable logistic regression and Cox regression with regularization were used to find a multivariable model for RP ≥ G2. RESULTS: Despite a tendency of higher mean lung dose in the high-dose arm (median[range] A = 14.9 Gy[5.8,23.1], B = 17.5 Gy[8.6,24.8], p = 0.075), pulmonary toxicities were not significantly different (RP ≥ G2 41%(A) and 52%(B), p = 0.231). A Kaplan Meier analysis of the time to RP ≥ G2 between the two arms did not reach statistical significance (p = 0.180). Statistically significant risk factors for RP ≥ G2 were GTV size (OR = 2.091/100 cm3, p = 0.002), infection at baseline or during RT (OR = 8.087, p = 0.026), dyspnea at baseline (OR = 2.184, p = 0.044) and increase of cough during RT (OR = 2.787, p = 0.008). In the multivariable logistic regression and the Cox regression analysis, the deviances of the most predictive models were within one standard deviation of the null model. CONCLUSION: No statistical difference between the high- and low dose arm was found in the risk of developing RP. The univariate analysis identified target volume, infection, dyspnea at baseline, and increase of cough during RT as risk factors for RP. The number of patients was too small to establish a statistically sound multivariable model.

A randomized phase II trial of concurrent chemoradiation with two doses of radiotherapy, 60Gy and 66Gy, concomitant with a fixed dose of oral vinorelbine in locally advanced NSCLC.

INTRODUCTION: In order to test the best performing radiation dose with a convenient chemotherapy schedule of an oral formulation of radio-sensitizing vinorelbine in inoperable locally advanced non-small cell lung cancer (NSCLC), we performed a randomized phase II trial based on a "pick the winner" design. METHODS: After 2 cycles of neoadjuvant chemotherapy, 117 patients with NSCLC stage IIB-IIIB in performance status 0-1 were randomized to radiotherapy 60Gy/30 fractions or 66Gy/33 fractions concurrent with a fixed dose of oral vinorelbine 50mg administered 3 times weekly. The primary endpoint was local progression free interval. A scheduled FDG-PET-CT-scan was performed 9months after randomization. The study was registered at ClinicalTrials.gov (NCT 00887783). RESULTS: Both arms were well tolerated. The local progression free interval at 9months was 54% in the 60Gy arm and 59% in the 66Gy arm (log rank test p=0.55). There was no statistically significant difference in overall survival. The median survival was 23.3 and 23.7months in the 60 and 66Gy arm, respectively. No significant difference in toxicity was observed. CONCLUSION: Both 60 and 66Gy administered concomitant with oral vinorelbine showed similar local control and overall survival, and was well tolerated. The pick the winner design choose 66Gy as the winning arm.

Acute esophagitis for patients with local-regional advanced non small cell lung cancer treated with concurrent chemoradiotherapy.

PURPOSE: Esophagitis is common in patients treated with definitive radiotherapy for local-regional advanced non small cell lung cancer (NSCLC). The purpose of this study was to estimate the dose-effect relationship using clinical and dosimetric parameters in patients receiving intensity modulated radiotherapy (IMRT) and concomitant chemotherapy (CCT). METHODS: Between 2009 and 2013, 117 patients with stages IIB-IIIB NSCLC were treated in a multicenter randomized phase II trial with 2 cycles of induction chemotherapy followed by IMRT and CCT. The esophagitis was prospectively scored using the Common Toxicity Criteria 3.0. Clinical and dosimetric variables were analyzed for the correlation with grade ⩾2 esophagitis through logistic regression. RESULTS: Grade 2 esophagitis was experienced by 31 (27%). All models including gender, institution, a dosimetric parameter and a position parameter were significantly associated with esophagitis. The two models using the relative esophagus volume irradiated above 40 Gy (V40, OR=2.18/10% volume) or the length of esophagus irradiated above 40 Gy (L40, OR=4.03/5 cm) were optimal. The upper part of esophagus was more sensitive and females experienced more toxicity than men. CONCLUSION: V40 and L40 were most effective dosimetric predictors of grade ⩾2 esophagitis. The upper part of esophagus was more sensitive.