An orthotopic non-small cell lung cancer model for image-guided small animal radiotherapy platforms

Abstract

Methods:: An orthotopic non-small cell lung cancer model in NMRI-nude mice was established to investigate the complementary information acquired from 80 kVp microcone-beam CT (micro-CBCT) and bioluminescence imaging (BLI) using different angles and filter settings. Different micro-CBCT-based radiation-delivery plans were evaluated based on their dose-volume histogram metrics of tumor and organs at risk to select the optimal treatment plan.

Results:: H1299 cell suspensions injected directly into the lung render exponentially growing single tumor nodules whose CBCT-based volume quantification strongly correlated with BLI-integrated intensity. Parallel-opposed single angle beam plans through a single lung are preferred for smaller tumors, whereas for larger tumors, plans that spread the radiation dose across healthy tissues are favored.

Conclusions:: Closely mimicking a clinical setting for lung cancer with highly advanced preclinical radiation treatment planning is possible in mice developing orthotopic lung tumors.

Advances in knowledge:: BLI and CBCT imaging of orthotopic lung tumors provide complementary information in a temporal manner. The optimal radiotherapy plan is tumor volume-dependent.

Figure 1.

Establishment of single nodule orthotopic NSCLC models. (A) Representative 2D delineated CT images of selected time points after H1299 cell suspension injection in the right lung. Tumors, right and left lung are delineated in red, green and blue, respectively. (B) Macroscopic and histological confirmation of presence of a single tumor nodule in the right lung indicated with an arrow. (C) Tumor quantification over time of a representative orthotopic H1299-wildtype lung tumor. (D) Tumor quantification over time of three orthotopic H1299-luciferase lung tumors: A7, C7, and D8 (presenting a central calcification). (E) Normalized H1299-luciferase (from D) tumor volumes to total right lung volume quantification. NSCLC, non-small cell lung cancer.

Figure 2.

Correlation between tumor volume determined by CBCT and BLI signal intensity over time. (A) Representative CBCT and 180-angle BLI images (overlaid on the white light image of the mouse) over time. (B) Correlation between CBCT-derived tumor volume (mm³) and BLI intensity obtained from the 180-degree angle for three independent H1299-luciferase expressing tumors. CBCT, cone beam CT; BLI, bioluminescence imaging.

Figure 3.

Volume-dependent radiation treatment planning. Representative beam setup in axial plane for four radiation plans: parallel-opposed, equally weighted single angle, static crossing a single lung (Plan 1), crossing both lungs (Plan 2), 2-angle parallel-opposed static (Plan 3), or two equally weighted arc (Plan 4) beams for a H1299 tumor model. Two tumors volumes are shown: volume 1 (4 mm³) with the 3 mm collimator (A) and volume 2 (10.4 mm³) with the 5 mm collimator (C), with their corresponding dose–volume histograms (B, D respectively). PTV, ITV, right lung, left lung, spinal cord and heart are indicated in green, light blue, yellow, pink, dark blue and red, respectively. ITV, internal target volume; PTV, planning targetvolume.