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.

Heterogeneous FDG-guided dose-escalation for locally advanced NSCLC (the NARLAL2 trial): Design and early dosimetric results of a randomized, multi-centre phase-III study.

BACKGROUND AND PURPOSE: Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy (tumour) and 74Gy (lymph nodes), was pursued and compared to standard 66Gy/33F plans. MATERIAL AND METHODS: Dose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue. RESULTS: The median dose-escalation in FDG-avid areas was 93.9Gy (tumour) and 73.0Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5Gy (GTV-T) and 81.3Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74Gy due to escalation. CONCLUSIONS: FDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans.

Monte Carlo calculations support organ sparing in Deep-Inspiration Breath-Hold intensity-modulated radiotherapy for locally advanced lung cancer.

BACKGROUND AND PURPOSE: Studies indicate that Deep-Inspiration Breath-Hold (DIBH) is advantageous over Free-Breathing (FB) for locally advanced lung cancer radiotherapy. However, these studies were based on simplified dose calculation algorithms, potentially critical due to the heterogeneous nature of the lung region. Using detailed Monte-Carlo (MC) calculations, a comparative study of DIBH vs. FB was therefore designed. MATERIAL AND METHODS: Eighteen locally advanced lung cancer patients underwent FB and DIBH CT imaging and treatment planning with the Anisotropic-Analytical-Algorithm (AAA) for intensity-modulated-radiotherapy or volumetric-modulated-arc-therapy using 66Gy in 33 fractions. All plans were re-calculated with MC. RESULTS: Relative to FB, the total lung volume increased 86.8% in DIBH, while the gross tumor volume decreased 14.8%. MC revealed equally under- and over-dosage of the target for FB and DIBH, compared to AAA. For the Organs-At-Risk (OARs), DIBH reduced the mean heart dose by 25.5% (AAA) vs. 12.6% (MC), the total lung V5Gy/V20Gy by 9.0/20.0% (AAA) vs. 11.6/19.9% (MC). CONCLUSIONS: MC calculations revealed (i) that DIBH compared with FB can significantly reduce the dose to the OARs even if the treatment planning is carried out with AAA, and (ii) inferior target dose coverage compared to AAA, irrespectively of FB and DIBH. The dose deviations were similar for FB and DIBH. The observed inferior target dose coverage relates therefore to the treatment planning algorithm rather than breathing technique.