Radiation treatment planning study to investigate feasibility of delivering Immunotherapy in Combination with Ablative Radiosurgery to Ultra-High DoSes (ICARUS)

Abstract

Purpose: Immune checkpoint inhibitors improve survival in metastatic diseases for some cancers. Multisite SBRT with pembrolizumab (SBRT + Pembro) was shown to be safe with promising local control using biologically effective doses (BEDs) = 95-120 Gy. Increased BED may improve response rate; however, SBRT doses are limited by surrounding organs at risk (OARs). The purpose of this work was to develop and validate methods for safe delivery of ultra-high doses of radiation (BED₁₀ > 300) to be used in future clinical trials.

Methods and materials: The radiation plans from 15 patients enrolled on a phase I trial of SBRT + pembro were reanalyzed. Metastatic disease sites included liver (8/15), inguinal region (1/15), pelvis (2/15), lung (1/15), abdomen (1/15), spleen (1/15), and groin (1/15). Gross tumor volumes (GTVs) ranged from 80 to 708 cc. Following the same methodology used in the Phase I trial on which these patients were treated, GTVs > 65 cc were contracted to a 65 cc subvolume (SubGTV) resulting in only a portion of the GTV receiving prescription dose. Volumetric modulated arc therapy (VMAT) was used to plan treatments BED₁₀ = 360 Gy. Plans utilizing both 6FFF and 10FFF beams were compared to clinical plans delivering BED₁₀ = 112.50 Gy. The target primary goal was V100% > 95% with a secondary goal of V70% > 99% and OAR objectives per the trial. To demonstrate feasibility, plans were delivered to a diode array phantom and evaluated for fidelity using gamma analysis.

Results: All 30 plans met the secondary coverage goal and satisfied all OAR constraints. The primary goal was achieved in 12/15 of the 6FFF plans and 13/15 of the 10FFF plans. Average gamma analysis passing rate using criteria of 3% dose difference and 3, 2, and 1 mm were 99.1 $\pm$ 1.0%, 98.5 $\pm$ 1.6%, and 95.1 $\pm$ 3.8%, respectively.

Conclusion: Novel VMAT planning approaches with clinical treatment planning software and linear accelerators prove capable of delivering radiation doses in excess of 360 Gy BED₁₀ to tumor subvolumes, while maintaining safe OAR doses.

Keywords: SBRT; immunotherapy; treatment planning; ultra-high dose.

FIG. 1

Contracted 65cc planning SubGTV (blue) and contoured GTV volumes (red) for (a) pelvis and (b) liver patients.

FIG. 2

Dose distributions for 6FFF ICARUS plans with a prescribed dose of 90 Gy in three fractions to the 65 cc SubGTV (shaded blue) in three fractions for (a) pelvis patient 02 and (b) liver patient 03.

FIG. 3

Dose profiles for 6FFF ICARUS plans with a prescribed dose of 90 Gy in three fractions to the 65 cc SubGTV in three fractions for (a) pelvis patient 02 and (b) liver patient 03.

FIG. 4

DVHs for 6FFF ICARUS plans for (a) pelvis patient 02 and (b) liver patient 03. The dark blue line represents SubGTV coverage and the red line represents the GTV coverage.