Interim Analysis of a Two-Institution, Prospective Clinical Trial of 4DCT-Ventilation-based Functional Avoidance Radiation Therapy

Abstract

Purpose: Functional imaging has been proposed that uses 4DCT images to calculate 4DCT-based lung ventilation (4DCT-ventilation). We have started a 2-institution, phase 2 prospective trial evaluating the feasibility, safety, and preliminary efficacy of 4DCT-ventilation functional avoidance. The trial hypothesis is that the rate of grade ≥2 radiation pneumonitis could be reduced to 12% with functional avoidance, compared with a 25% rate of pneumonitis with a historical control. The trial employed a Simon 2-stage design with a planned futility analysis after 17 evaluable patients. The purpose of this work is to present the trial design and implementation, dosimetric data, and clinical results for the planned futility analysis.

Methods and materials: Eligible patients were patients with lung cancer who were prescribed doses of 45 to 75 Gy. For each patient, the 4DCT data were used to generate a 4DCT-ventilation image using the Hounsfield unit technique along with a compressible flow-based image registration algorithm. Two intensity modulated radiation therapy treatment plans were generated: (1) a standard lung plan and (2) a functional avoidance treatment plan that aimed to reduce dose to functional lung while meeting target and normal tissue constraints. Patients were treated with the functional avoidance plan and evaluated for thoracic toxicity (presented as rate and 95% confidence intervals [CI]) with a 1-year follow-up.

Results: The V20 to functional lung was 21.6% ± 9.5% (mean ± standard deviation) with functional avoidance, representing a decrease of 3.2% (P < .01) relative to standard, nonfunctional treatment plans. The rates of grade ≥2 and grade ≥3 radiation pneumonitis were 17.6% (95% CI, 3.8%-43.4%) and 5.9% (95% CI, 0.1%-28.7%), respectively.

Conclusions: Dosimetrically, functional avoidance achieved reduction in doses to functional lung while meeting target and organ at risk constraints. On the basis of Simon's 2-stage design and the 17.6% grade ≥2 pneumonitis rate, the trial met its futility criteria and has continued accrual.

Fig. 1.

An example of a 4-dimensional computed tomography—ventilation image overlaid with a standard computed tomography image. The color grading scale represents ventilation values calculated using Equation 1 that have been scaled to a percentage. The bright colors represent functional lung, and the blue and darker tones represent regions of ventilation defect. The presented patient has a ventilation defect in the right upper lobe.

Fig. 2.

An example case of a large difference in dose to functional lung (as measured by 4-dimensional computed tomography—ventilation) between the functional avoidance plan (A) and a nonfunctional plan (B). The computed tomography, 4-dimensional computed tomography—ventilation images, isodose lines, and planning target volume (shown in red) are presented for both plans. The arrows highlight the regions with the most prevalent functional lung sparing.