Investigation of intra-fractionated range guided adaptive proton therapy (RGAPT): (Part II) range-shift compensated on-line treatment adaptation and verification.

We previously proposed range-guided adaptive proton therapy (RGAPT) that uses mid-range treatment beams as probing beams and intra-fractionated range measurements for online adaptation. In this work, we demonstrated experimental verification and reported the dosimetric accuracy for RGAPT.
A STEEV phantom was used for the experiments, and a 3x3x3 cm3 cube inside the phantom was assigned to be the treatment target. We simulated three online range shift scenarios: reference, overshoot, and undershoot, by placing upstream Lucite sheets, 4, 0, and 8 that corresponded to changes of 0, 6.8, and -6.8 mm, respectively, in water-equivalent path length (WEPL). The reference treatment plan was to deliver single-field uniform target doses in pencil beam scanning mode and generated on the Eclipse treatment planning system. Different numbers of mid-range layers, including single, three, and five layers, were selected as probing beams to evaluate beam range measurement accuracy in Positron Emission Tomography (PET). Online plans were modified to adapt to beam range shifts and compensate for probing beam doses. In contrast, non-adaptive plans were also delivered and compared to adaptive plans by film measurements. 
The mid-range probing beams of three (5.55MU) and five layers (8.71MU) yielded accurate range shift measurements in 60 seconds of PET acquisition with uncertainty of 0.5mm while the single-layer probing (1.65MU) was not sufficient for measurements. The adaptive plans achieved an average gamma (2%/2mm) passing rate of 95%. In contrast, the non-adaptive plans only had an average passing rate of 69%. 
RGAPT planning and delivery are feasible and verified by the experiments. The probing beam delivery, range measurements, and adaptive planning and delivery added a small increase in treatment delivery workflow time but resulted in substantial dose improvement. The three-layer mid-range probing was most suitable considering the balance of high range measurement accuracy and the low number of probing beam layers.