Aims To assess the robustness and to define the dosimetric and NTCP advantages of pencil-beam-scanning proton therapy (PBSPT) compared with VMAT for unresectable Stage III non-small lung cancer (NSCLC) in the immunotherapy era. Material and methods 10 patients were re-planned with VMAT and PBSPT using: 1) ITV-based robust optimization with 0.5 cm setup uncertainties and (for PBSPT) 3.5 % range uncertainties on free-breathing CT 2) CTV-based RO including all 4DCTs anatomies. Target coverage (TC), organs at risk dose and TC robustness (TCR), set at V95%, were compared. The NTCP risk for radiation pneumonitis (RP), 24-month mortality (24MM), G2 + acute esophageal toxicity (ET), the dose to the immune system (EDIC) and the left anterior descending (LAD) coronary artery V15 < 10 % were registered. Wilcoxon test was used. Results Both PBSPT methods improved TC and TCR (p < 0.01). The mean lung dose and lung V20 were lower with PBSPT (p < 0.01). Median mean heart dose reduction with PBSPT was 8 Gy (p < 0.001). PT lowered median LAD V15 (p = 0.004).ΔNTCP > 5 % with PBSPT was observed for two patients for RP and for five patients for 24 MM. ΔNTCP for ≥ G2 ET was not in favor of PBSPT for all patients. PBSPT halved median EDIC (4.9/5.1 Gy for ITV/CTV-based VMAT vs 2.3 Gy for both ITV/CTV-based PBSPT, p < 0.01). Conclusions PBSPT is a robust approach with significant dosimetric and NTCP advantages over VMAT; the EDIC reduction could allow for a better integration with immunotherapy. A clinical benefit for a subset of NSCLC patients is expected.

Proton therapy (PT) represents an advanced form of radiotherapy with unique physical properties which could be of great advantage in reducing long-term radiation morbidity for cancer survivors. Here, we aim to describe the whole process leading to the clinical implementation of consolidative active scanning proton therapy treatment (PT) for mediastinal lymphoma. The process included administrative, technical and clinical issues. Authorization of PT is required in all cases as mediastinal lymphoma is currently not on the list of diseases reimbursable by the Italian National Health Service. Technically, active scanning PT treatment for mediastinal lymphoma is complex, due to the interaction between actively scanned protons and the usually irregular and large volumes to be irradiated, the nearby healthy tissues and the target motion caused by breathing. A road map to implement the technical procedures was prepared. The clinical selection of patients was of utmost importance and took into account both patient and tumor characteristics. The first mediastinal lymphoma was treated at our PT center in 2018, four years after the start of the clinical activities. The treatment technique implementation included mechanical deep inspiration breath-hold simulation computed tomography (CT), clinical target volume (CTV)-based multifield optimization planning and plan robustness analysis. The ultimate authorization rate was 93%. In 4 cases a proton–photon plan comparison was required. Between May 2018 and February, 2021, 14 patients were treated with consolidative PT. The main clinical reasons for choosing PT over photons was a bulky disease in 8 patients (57%), patient’s age in 11 patients (78%) and the proximity of the lymphoma to cardiac structures in 10 patients (71%). With a median follow-up of 15 months (range, 1–33 months) all patients but one (out-of-field relapse) are without evidence of disease, all are alive and no late toxicities were observed during the follow-up period. The clinical implementation of consolidative active scanning PT for mediastinal lymphoma required specific technical procedures and a prolonged experience with PT treatments. An accurate selection of patients for which PT could be of advantage in comparison with photons is mandatory.

Stereotactic radiosurgery (SRS) is an important treatment option for intracranial lesions and several photon-SRS techniques have been developed. Proton therapy (PT) has special characteristics that allow normal tissues to be spared better as well as greater homogeneity than with the use of photons, but limited data are available for proton-SRS. Nowadays, PT-SRS is delivered only with passive scattering technique while active pencil beam scanning (PBS) that is considered the most advanced proton technique has not been reported for SRS treatments yet. Here we report early clinical outcomes of PBS PT SRS. Between June 2017 and January 2019, 14 patients (pts) with 20 lesions underwent PBS PT SRS at our institution. Median age was 62 years (range, 28–87). Median Karnofsky performance status was 90 (range, 70–100). Six were male. Tumors included 16 meningiomas (MG) and 4 vestibular schwannomas (VS). Median GTV was 1.05 cc (range, 0.2–2.71). Dose prescription was 12 Gy radiobiologic equivalent (RBE) in one fraction for VS and 15 GyRBE in one fraction for MG. Pts were immobilized using a frameless system: Type-S proton overlay and Type-S proton mask (CIVCO medical solutions, Kalona, IA, USA) together with Moldcare headrest (Q-Fix systems, Avondale, PA, USA). All pts were treated with PBS PT using 2–3 fields with single field optimization technique, and using min-max robust robust optimization (2 mm setup errors, 3.5% range uncertainties), with a Monte Carlo algorithm and 1 mm grid size. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 4.0. Median follow-up (FU) was 9 months (range, 3–22). All pts completed the treatment with excellent compliance and no side effects were registered during the procedure. Registered acute side effects include grade 1 (14%) fatigue, grade 2 (7%) headache, and grade 2 (28%) alopecia. There were no grade 3 or higher acute toxicities. Registered late side effects include grade 1 (7%) headache, and grade 1 (14%) alopecia. There were no grade 3 or higher late toxicities. Currently, absolute tumor control is 100% regardless the type of tumor. Despite the short FU radiological reduction was registered in 9 lesions (45%). PBS PT SRS is a feasible and safe treatment in pts with MG or VS. A high radiological response rate was observed. Longer FU is necessary to assess definitive safety and efficacy.

To assess the advantages of apertures in intracranial stereotactic radiosurgery (SRS) delivered with proton pencil beam scanning (PBS). We selected 12 patients, for a total of 20 target volumes (16 meningiomas and 4 neuromas), previously treated with PBS SRS without apertures. Dose prescriptions for meningiomas and neuromas were 15 and 12 GyRBE, respectively. All meningiomas were superficial and a range shifter (RS) was needed for treatment, while for neuromas it did not. A plan with apertures was optimized for each target volume with same beam direction, cost-function, beam parameters as for the clinical plan without apertures.All plans were optimized on the CTV with Single Field Optimization technique, using min-max robust optimization (2mm setup errors, 3.5% range uncertainties), with a Monte Carlo algorithm and a 1mm grid size. Plans with and without apertures were compared in terms of target coverage (V99, V95, D1) and sparing of the healthy brain tissue within 2cm of the CTV (HBT) (V10, V12, Dmean and D1). In meningiomas, skin sparing was scored via Dmean. Average values were compared with t test and p < 0.05 was considered significant. Results are summarized in table 1. The target coverage was very similar with and without apertures. The distance from CTV to aperture needed to achieve target coverage ranged from 5 to 9 mm. Plans with apertures allowed a reduction in both skin mean dose (range 0.3-2.2 GyRBE) and HBT V10, V12, and mean dose. Considering meningiomas and neuromas separately, the HBT sparing was significant only for meningiomas, where it ranged from 0.9 to 9.1cc for V10 and from 0.4 to 6.0 cc for V12. Apertures are beneficial in intracranial SRS with PBS, in particular for shallow targets such as meningiomas. In deeper lesions where the use of RS is not necessary, such as neuromas, they do not seem to bring an advantage.Abstract 3776; Table 1Main DVH indexes and t test results for mean between all twenty, meningioma and neuroma plans. Dosimetric values selected useful for the evaluation of the planning technique are shown.VolumeValuesALL CASESMENINGIOMA CASESNEUROMA CASESwithout APAPt.testwithout APAPt.testwithout APAPt.testCTVV99% (%)99,499,60,02699,499,50,03299,699,70,104V95% (%)100,0100,00,070100,0100,00,048100,0100,00,196D1% (GyRBE)14,815,60,29515,116,20,14713,413,40,133HBTV10GyRBE (cc)7,65,60,0019,36,80,0001,00,80,079V12GyRBE (cc)4,83,60,0026,04,60,0010,10,10,126D1% (GyRBE)12,712,60,00613,513,40,0079,69,50,044Dmean (GyRBE)4,53,50,0004,83,30,0004,63,90,049SKINDmean (GyRBE)5,24,10,0005,24,10,000--- Open table in a new tab

Positron emission tomography (PET) is one of the most mature techniques for monitoring in ion beam therapy. PET allows to reconstruct the β+ activity generated in the patient by the nuclear interaction of the ions. Taking advantage of the spatial correlation between positron emitters created along the ions path and the dose distribution, it is possible to perform a quality control of the treatment. Usually, to reconstruct the activity generated within the irradiated volume, standard 3D PET reconstruction techniques are implemented. In this work, we explore a new reconstruction method (Straight Forward Reconstruction) particularly useful for reconstructing activity distribution generated by mono-energetic pencil beams. The method was validated by measuring the produced activity distribution with the DoPET system. Irradiations performed with mono-energetic pencil beams on phantoms mimicking human tissues were used for this study. Both reconstruction methods reach an accuracy in the reconstruction of the activity distribution width of the order of 1.5 mm for 2⋅108 primaries.

Purpose (1) To compare the dosimetric effect of setup error and range uncertainties with the effect of using two dose calculation algorithms (Pencil Beam (PB) vs. Monte Carlo (MC)) on protontherapy treatment plans, and (2) To assess which uncertainties affect the most the difference between the nominal and actual dose distribution. Methods 12 treatment plans designed for clinical treatment at the Proton Therapy Centre in Trento were selected, covering four anatomical sites: brain, head and neck, chordoma of the spine, and craniospinal axis. The plans, which were initially optimized with the PB algorithm, were recalculated with MC with a statistical uncertainty of 1%. Then, we evaluated the effect of geometrical (setup) and range uncertainties on the planned dose distribution with an in–house software. This software simulates 8 setup errors and 2 range errors (16 calculations per plan in total), in order to estimate near worst-case scenarios for target volume and organs at risks (OAR). We evaluated the differences between MC vs. PB distribution and the robustness of PBS plans using the same dosimetric indices used to optimize the plan (e.g. D1 and D99 for the target volume D1 for serially responding complications, etc.). Results In Table 1, we show CTV and OAR dosimetric indices for the plans optimized with PB, then recalculated with MC, and also the worst-case scenario after robustness analysis. CTV D99 in MC plans are smaller than in PBS plans. Furthermore, except for plans of intracranial treatments, MC dose distributions are in general worse than the worst-case scenario (Fig. 1). Consequently, sparing of OARs with MC is obtained. For instance, the lacrimal gland mean dose is lower by 9% and 50% in MC vs PB for the static case and the worst case scenario, respectively. Conclusions In 2 out of the 4 disease sites we studied, the effect of using two dose calculation algorithms is greater than the effect of setup error and range uncertainties especially in CTV coverage. Considering MC as a gold standard, the minimum dose to the CTV isn’t guaranteed when plans are designed with PB. (1) To compare the dosimetric effect of setup error and range uncertainties with the effect of using two dose calculation algorithms (Pencil Beam (PB) vs. Monte Carlo (MC)) on protontherapy treatment plans, and (2) To assess which uncertainties affect the most the difference between the nominal and actual dose distribution. 12 treatment plans designed for clinical treatment at the Proton Therapy Centre in Trento were selected, covering four anatomical sites: brain, head and neck, chordoma of the spine, and craniospinal axis. The plans, which were initially optimized with the PB algorithm, were recalculated with MC with a statistical uncertainty of 1%. Then, we evaluated the effect of geometrical (setup) and range uncertainties on the planned dose distribution with an in–house software. This software simulates 8 setup errors and 2 range errors (16 calculations per plan in total), in order to estimate near worst-case scenarios for target volume and organs at risks (OAR). We evaluated the differences between MC vs. PB distribution and the robustness of PBS plans using the same dosimetric indices used to optimize the plan (e.g. D1 and D99 for the target volume D1 for serially responding complications, etc.). In Table 1, we show CTV and OAR dosimetric indices for the plans optimized with PB, then recalculated with MC, and also the worst-case scenario after robustness analysis. CTV D99 in MC plans are smaller than in PBS plans. Furthermore, except for plans of intracranial treatments, MC dose distributions are in general worse than the worst-case scenario (Fig. 1). Consequently, sparing of OARs with MC is obtained. For instance, the lacrimal gland mean dose is lower by 9% and 50% in MC vs PB for the static case and the worst case scenario, respectively. In 2 out of the 4 disease sites we studied, the effect of using two dose calculation algorithms is greater than the effect of setup error and range uncertainties especially in CTV coverage. Considering MC as a gold standard, the minimum dose to the CTV isn’t guaranteed when plans are designed with PB.

Purpose To evaluate plan robustness against set up and range uncertainties on a radiosurgery plan for a small volume meningioma. Methods and materials A single proton therapy fraction of 14GyRBE was prescribed. 3 posterior beams were planned and 3 different scenarios were generated with single field optimization (SFO): 1.uniform dose prescribed to the CTV; 2.uniform dose prescribed to the PTV; 3.uniform dose prescribed to the CTV with robust optimization assuming 2 mm as maximum patient position uncertainty and 3% as range uncertainty. Another beam arrangement (scenario 4) including one posterior and 2 lateral field was planned using the robust optimization options of scenario 3. Each nominal plan was recomputed moving the isocenter on vertices of a cube of side length 3 mm, centered at the planning isocenter and applying a density perturbation of +-3%. The DVH for the CTV and for the brain tissue were collected. The volume of CTV receiving a dose greater than 1400cGyRBE (V1400) and the dose to 5 cc of brain tissue were compared for the nominal plan and the worst case scenario. Results The DVH for CTV and brain tissue are shown in Fig. 1. V1400 and the dose to 5 cc of brain tissue are presented in Tab. 1. V1400 of the CTV is between 96 and 99% for all nominal plans, in the worst case V1400 drops to 54% for scenario 1 and remains greater than 80% for the other scenarios where a margin was used in planning. In scenario n.4 beams arrangement contributes to the robustness of V1400. Conclusion To evaluate plan robustness against set up and range uncertainties on a radiosurgery plan for a small volume meningioma. A single proton therapy fraction of 14GyRBE was prescribed. 3 posterior beams were planned and 3 different scenarios were generated with single field optimization (SFO): 1.uniform dose prescribed to the CTV; 2.uniform dose prescribed to the PTV; 3.uniform dose prescribed to the CTV with robust optimization assuming 2 mm as maximum patient position uncertainty and 3% as range uncertainty. Another beam arrangement (scenario 4) including one posterior and 2 lateral field was planned using the robust optimization options of scenario 3. Each nominal plan was recomputed moving the isocenter on vertices of a cube of side length 3 mm, centered at the planning isocenter and applying a density perturbation of +-3%. The DVH for the CTV and for the brain tissue were collected. The volume of CTV receiving a dose greater than 1400cGyRBE (V1400) and the dose to 5 cc of brain tissue were compared for the nominal plan and the worst case scenario. The DVH for CTV and brain tissue are shown in Fig. 1. V1400 and the dose to 5 cc of brain tissue are presented in Tab. 1. V1400 of the CTV is between 96 and 99% for all nominal plans, in the worst case V1400 drops to 54% for scenario 1 and remains greater than 80% for the other scenarios where a margin was used in planning. In scenario n.4 beams arrangement contributes to the robustness of V1400.