First-in-man validation of CT-based stopping-power prediction using prompt-gamma range verification

Purpose & Objective
Currently, the uncertainty in CT-based range prediction is substantially impairing the accuracy of particle therapy. Direct determination of stopping-power ratio (SPR) from dual-energy CT (DECT) has been proposed (DirectSPR) and initial validation studies in phantoms and biological tissues have proven a superior accuracy. However, a validation of range prediction in patients has not been achieved by any means. Here, we present the first verification of CT based proton range prediction in patients, using prompt-gamma imaging (PGI).

Materials & Methods
A PGI slit camera system of improved positioning accuracy, using a floor-based docking station, was developed. Its accuracy and positioning reproducibility were determined with x-ray and PGI measurements. The PGI system was clinically applied to monitor absolute proton ranges for a 1.5 GyE field during hypo-fractionated treatment of 3 prostate-cancer patients using pencil beam scanning (PBS) (Fig. 1). Per patient 3 fractions were monitored. For all monitored fractions, in-room control-CT (cCT) scans were acquired in treatment position enabling PGI-based spot-by-spot range analysis for the actual patient anatomy: The PGI measurements were compared to simulations of the expected PGI signal based on the respective cCT. Three different SPR prediction models were applied in the simulation: A standard CT-number-to-SPR conversion (Std-HLUT), a HLUT optimized with DECT-derived SPR information (Adapt-HLUT), and the directly voxel-wise calculated SPR based on the input from DECT (DirectSPR). To verify range prediction in patients, the histogram of PGI-derived range shifts from all PBS spots was analyzed concerning its Gaussian mean – acting as surrogate for the accuracy of the respective range prediction method. It is independent from random uncertainty contributions (e.g. positioning, statistical uncertainty in shift determination).

Results
The accuracy and precision for global PGI range verification (averaging over multiple spots) was determined to be 0.7 mm (2σ) and 1.3 mm (2σ), respectively. The precision is limited by remaining uncertainties in image registration and positioning reproducibility (1.1 mm, 2σ). Hence, the absolute verification uncertainty of the cumulative mean shift (for 9 monitored fractions) is 0.8 mm (2σ), which is smaller than the range prediction uncertainty for deep-seated tumors (about 10 mm for prostate treatments).
The comparison of the PGI-measured and predicted spot-wise ranges for in total 12000 PBS spots from the 9 analyzed fractions resulted in an range prediction offset of 0.6 mm, 1.3 mm and 4.4 mm, for the DirectSPR, Adapt-HLUT and Std-HLUT approaches, respectively.

Conclusion
The accuracy of PGI-based range verification was improved to enable the worldwide first in-man validation of CT-based stopping-power prediction. The evaluation of the first clinical PGI data for prostate-cancer treatments, systematically acquired within a clinical study, confirms the superiority of DECT-based range prediction in patients.