Equipment and Instrumentation
The Seattle Cancer Care Alliance Proton Therapy Center (SCCAPTC) is a four-room proton therapy facility  with capabilities to treat patients using PBS and uniform scanning (US). The center is equipped with the IBA Proteus Plus (Ion Beam Applications, Louvain-La-Neuve, Belgium) system. Patients are simulated with a GE Optima 580W CT scanner (GE Healthcare, Waukesha, WI). MOSAIQ (version 2.64) (Elekta Medical System, Sweden) oncology information system is used to deliver and track patient treatments. No patients were involved in this study. For this work, treatment planning and validation was performed with RayStation version 9B (RS) TPS . Depth dose measurements were performed with a commercial microdiamond detector (Type 60019, PTW-Freiburg, Germany) and PC electrometer (Sun Nuclear Corp., Melbourne, FL). Two-dimensional dose profile measurements were made through Gafchromic EBT3 film (Ashland Advanced Materials, NJ) and analyzed through DoseLab software (Varian Medical System, Inc., CA). For end-to-end testing, the phantom localization and set up were performed with planar orthogonal x-ray images that were acquired and analyzed through AdaptInsight Imaging System (Ion Beam Applications, Belgium). Patient-specific 2-D dosimetric measurements were acquired through EBT3 film with analysis performed in OmniPro I’mRT (Ion Beam Applications, Louvain-La-Neuve, Belgium) software.
Design of ocular applicator
Figures 1A and 1B show the schematic and actual picture of the applicator. The applicator is made from brass and is mounted to the smallest snout (10 cm snout) with the same mounting clips used to mount apertures for conventional treatments. The applicator has an built-in acrylic range shifterthat corresponds to a physical thickness of 6.5 cm and water-equivalent-thickness of 7.5 cm. The range shifter is needed as the lowest proton beam energy available at the nozzle exit is 98.5 MeV that corresponds to proton beam range of 7.5 cm in water. A custom patient-specific aperture (Figure 1C) can be mounted at the end of the applicator to enhance lateral dose conformality. The applicator can accommodate a maximum circular opening of 4 cm. The capabilities of the applicator are given in Table 1.
The given applicator was commissioned into a commercial treatment planning system RayStation version 9BSP1. RayStation physics module allows the user to define relevant geometry of the applicator in terms of inner and outer dimensions, and order of beam line elements such as range shifter and aperture.
Depth Dose Comparison
Depth dose measurements for Bragg peaks (single layer monoenergetic scanned fields) were carried out for three different circular apertures of 1.5 (F1.5), 2 (F2), and 3 (F3) cm diameter. These fields are composed of spots of single proton energy arranged in a grid-like pattern with an inter-spot spacing of 0.2 mm in x- and y- directions to achieve a laterally uniform dose distribution. The spot patterns for these fields were created to over-scan the respective aperture size. For each aperture size, three beams were created corresponding to a proton beam range of 2 cm, 4 cm, and 6 cm in water for a total of 9 beams. The measured depth doses were generated from individual point-by-point dose measurements along the central axis with a microdiamond detector.
For comparisons, the measurement geometry for beam and set-up were simulated in the RS TPS through forward planning technique, and calculated depth doses at the central axis were exported. All RS calculations were performed with an MC dose calculation algorithm with a statistical uncertainty of less than 0.5% and an isotropic grid size of 1 mm was used for calculations in the TPS.
Measurements were also made for spread-out Bragg peaks (SOBP) in a water phantom. These beams were generated in the RS TPS through inverse planning by optimizing dose to cylindrical targets and utilizing apertures for sharper lateral dose fall-off. The cylindrical targets of diameters 1.5, 2 and 3 cm were created to have a circular footprint in beams eye view (BEV) corresponding to the aperture sizes of 1.5, 2 and 3 cm respectively. The height and position of the target inside the water phantom were chosen to have two range-modulation combinations: (i) range =2 cm, modulation = 1.5 cm, and (ii) range = 6 cm, modulation = 3 cm. The combination of aperture size, height, and the targets resulted in a total of 6 beams. Once optimized to deliver a uniform dose to the targets, the beams were transferred to Mosaiq and delivered into a water phantom. Like single layer fields, the measured depth doses were generated from individual point-by-point dose measurements along the central axis of each beam with a microdiamond detector.
The analysis for single layer and SOBP beams consisted of point-by-point dose difference between measurements and calculated depth doses. The magnitude of point-by-point dose differences was averaged for all the points along the depth doses and results were considered acceptable if the difference was less than 2%. For SOBP beams, a tolerance of +/-3% was employed for point dose difference at any point along the depth dose except at the distal edge. Additionally, range error between calculated and measured depth doses was evaluated by comparing R80 depths (distal depth corresponding to 80% of maximum) with a tolerance of 1 mm.
2-D profile measurements were also obtained using EBT3 film sandwiched inside proton-compatible solid water for every single layer and SOBP beam from the previous section. For single-layer beams, the measurements were performed at two depths: (i) at the entrance region and (ii) near the Bragg peak. For SOBP beams, the profile measurements were made at the center of SOBP. The irradiated EBT3 films were scanned 24 hours post-exposure on a flatbed scanner (Epson Expression 11000XL, Epson America Inc., California, USA) using 72 pixels per inch of resolution and landscape orientation. A control film that was similarly handled but not exposed was also scanned to obtain net optical density using the red channel. The films were compared to calculated dose profiles from the treatment planning system through gamma index analysis. A dose threshold of 2%, distance tolerance of 1 mm, and low dose threshold of 5% were used. In total, 24 beam profiles were measured and analyzed.
Point Dose Comparison
A comparison of absolute dose output between measured and calculated fields for the single-layer and SOBP fields was performed. For SOBP beams, the point dose measurements were made at the center of the SOBP for all three field sizes. The combination of three field sizes along with two range-modulation sets resulted in a total of 6 measurements. For single-layer uniform fields, the point dose measurements were made at the entrance region at a depth of 5 mm. Like SOBP beams, all three circular field sizes were employed for three ranges i.e. 2 cm, 4 cm, and 6 cm resulting in a total of nine beams. The point dose measurements were performed using a diamond detector cross calibrated against an ADCL calibrated parallel plate chamber. The cross calibration was done at field size of 10 x 10 cm2 using range 16 cm and modulation 10 cm. A tolerance of 2% was used for this analysis.
Although PBS allows for lateral collimation of the beam through the placement of spots conforming to the target extents, it has been shown that a sharper lateral dose fall-off  could be achieved by a patient specific aperture. The use of aperture for PBS adds another layer of complexity for isocenter verification. For double scattering and uniform scanning-based proton therapy, the proton beams over-scan the aperture requiring only the mechanical isocenter of the patient-specific beam modifying devices (aperture and compensators) to coincide with the imaging isocenter. For aperture-based PBS treatments, the congruency of all three isocenters i.e. imaging, mechanical, and proton beam needs to be validated. We performed a film exposure test to measure the discrepancy between all three isocenters and evaluate any changes due to applicator travel along the beam axis. A EBT3 film with fiducials was aligned to the imaging isocenter through the in-room orthogonal x-ray system. Exposure of the film was obtained with a 4 cm aperture in the beam path. The PBS beam consisted of two layers to obtain an aperture outline and central spot alignment on the EBT3 film. The first layers consisted of a low dose uniform lateral profile that over-scanned the 4 cm aperture. The second layer consisted of a single spot of high intensity centered on the central axis. Once exposed, the film allowed the extraction of relative error in all three isocenters: (i) imaging iso at the intersection of fiducials, (ii) mechanical iso at the geometric center of low dose exposure from the first layer and (iii) proton beam iso at the centroid of the single spot exposure from the second layer. The test was conducted for five snout positions corresponding to air gaps: 1 cm, 5cm, 11cm, 15cm, and 20 cm by retracting the snout. The analysis consisted of evaluating relative x- and y- spatial errors between the different isocenters.
End to End test
An end-to-end test was conducted using the clinical protocols of CT simulation, imaging, and treatment delivery. Treatment for ocular targets is conducted in a chair at SCCAPTC as described here . A phantom was constructed out of blue wax  in a cylindrical shape with an insert to place film at 2 cm depth. The phantom was scanned on a GE Optima CT 5580 using the ocular protocol corresponding to a field-of-view of 50 cm and slice thickness of 1.25 mm. A pseudo ocular target of roughly 0.5 cm width, 0.8 cm length, and 0.4 cm depth was created at the depth of 2 cm. A single anterior oblique beam with a custom aperture was inversely optimized to deliver a 50 Gy RBE dose to the target in the RS planning system. The optimized plan was transferred to Mosaiq OIS for treatment delivery. The phantom with a EBT3 film was aligned at the isocenter through the AdaptInsight imaging system. The film was compared to the corresponding dose plane from the planning system using the Gamma Index analysis. A tolerance of 1% dose difference, 1 mm distance-to-agreement, and 10% low dose threshold were used. The absolute dose at the central axis of the field was also measured through a calibrated pin-point ion chamber and compared to corresponding value from the TPS with a tolerance of 3%.
Simulated Lateral and Distal Penumbras
The dose fall-off properties of the proton beam in lateral and distal directions are important for ocular targets that are generally small and have numerous critical OARs in the vicinity. Most ocular specific beamlines have lower proton beam energies (~55- 100 MeV) requiring minimal compensation to produce a clinically relevant beam of range 1-4 cm. By minimizing material in the beam path, these systems can produce relatively sharp lateral and distal dose fall-offs . The lowest PBS beam energy at SCCAPTC is 98.5 MeV which corresponds to the proton beam range of 7.5 cm in water. For treatment of ocular targets, beam energy must be degraded to a clinically relevant range and thus our proposed ocular snout has a fixed range shifter of 7.5 cm WET. Introducing this range shifter in the beam path degrades both distal and lateral penumbra. To compare distal and lateral penumbras presented in this study to available literature [8,11,18], we simulated relevant ocular beams in the TPS with various range-modulation combinations. Seven beams were created to give a uniform dose to a box target of 1.5 cm in diameter. A beam shaping aperture was used to sharpen the lateral penumbra. Distal and lateral penumbra values were calculated from 80% to 20% dose fall-off from the relevant dose planes. A brief comparison between our penumbra values against values from published literature is presented in the discussions section.