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.

Background and purpose: Recurrent nasopharyngeal carcinoma (NPC) has limited curative treatment options. Reirradiation is the only potential definitive treatment in advanced stages at a cost of substantial severe and often life-threatening toxicity. Proton therapy (PT) reduces irradiated volume compared with X-ray radiotherapy and could be advantageous in terms of safety and efficacy in a population of heavily pretreated patients. We report the retrospective results of PT reirradiation in recurrent NPC patients treated at our Institution Methods: All recurrent NPC patients treated since the beginning of clinical activity entered the present analysis. Clinical target volume consisted of Gross Tumor volume plus a patient-specific margin depending on disease behavior, tumor location, proximity of organs at risk, previous radiation dose. No elective nodal irradiation was performed. Active scanning technique with the use of Single Field Optimization (SFO) or Multifield Optimization (MFO) was adopted. Cumulative X-ray -PT doses were calculated for all patients using a dose accumulation tool since 2016. Treatment toxicity was retrospectively collected. Results: Between February 2015, and October 2018, 17 recurrent NPC patients were treated. Median follow-up (FUP) was 10 months (range 2-41). Median PT reirradiation dose was 60 Gy RBE (range 30.6-66). The majority of patients (53%) underwent concomitant chemotherapy. Acute toxicity was low with no ≥ G3 adverse events. Late events ≥ G3 occurred in 23.5% of patients. Most frequent late toxicity was hearing impairment (17,6%). G2 soft tissue necrosis occurred in two patients. Fatal bleeding of uncertain cause (either tumor recurrence or G5 carotid blowout) occurred in one patient. Kaplan-Meier 18 months Overall Survival (OS) and Local control (LC) rates were 54.4% and 66.6%, respectively. Conclusions: Our initial results with the use of modern PT for reirradiation of recurrent NPC patients are encouraging. Favorable LC and OS rates were obtained at the cost of acceptable severe late toxicity.

Purpose or ObjectiveDose accuracy in presence of heterogeneities and range shifter (RS) modelling are some of the reasons that have made in the last years Monte Carlo (MC) dose calculation algorithm increasingly present in the clinical routine in proton therapy.On the other hand, MC brings with it significantly higher calculation times, especially if you want to do robust optimization/evaluation and/or frequent re-planning.The purpose of this work is to evaluate the last version of the pencil beam (PB7) present in our TPS comparing it with measurements and observe how it behaves with respect to the previous version of the pencil beam algorithm (PB6) and MC. Material and MethodsWe compared the new RayStation 7 pencil beam (PB7) algorithm vs. MC dose engine and the previous one (PB6) clinically implemented so far, in critical conditions such as superficial targets (i.e. in need of range shifter), different air gaps and different gantry angles to simulate both orthogonal and tangential beam arrangements.For every plan the PB7, PB6 and MC dose calculation were compared to measurements using a gamma analysis metrics with passing criteria of 3% of maximum dose, 3mm distal-to-agreement, global approach, and dose threshold of 5%.Measurements were performed with a 2D ion chamber array detector (MatriXX PT, IBA Dosimetry GmbH) placed underneath the following targets: 1)

To report preliminary results of re-irradiation with proton therapy (PT) with or without chemotherapy (CHT) in difficult-to-treat recurrent glioblastoma (rGBM): patients (pts) were selected for PT because of the large tumor size or proximity to dose-limiting organs at risk that previously had received near-maximum dose tolerance during the first radiation course Between January 2015 and January 2018, 34 pts with rGBM were re-irradiated with PT. All pts had been previously treated with Stupp regimen. Twenty-nine (85%) were re-irradiated at first relapse/progression, 5 at the second/third one. Nine pts (26%) were re-irradiated after partial tumor resection. Median (med) age and KPS at re-irradiation were 56 years and 90%, respectively. Med time between prior radiotherapy and PT was 13 months. Target definition was based on CT, MR, and 18F-DOPA PET imaging. Gross Tumor Volume (GTV) included any area of contrast enhancement after contrast medium administration plus any pathological PET uptake regions. Clinical Target Volume (CTV) was generated by adding to GTV a 3-mm margin. Med CTV volume was 47 cc (range, 13–153 cc). All pts received 36 GyRBE in 18 fractions. PT was delivered with or without chemotherapy as follows: eight (23.5%) pts (Group 1) also received concomitant TMZ (75 mg/m2/die, 7 days/week); 4 (12%) pts (Group 2) also received concomitant (as above) and adjuvant TMZ (150–200 mg/m2/die, 5 days/month); 9 (26.5%) pts (Group 3) received PT only; 13 (38%) pts (Group 4) received PT followed by CHT (different regimens/drugs). All pts were treated with active pencil beam scanning PT. Registered side effects were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment response was assessed according to Response Assessment in Neuro-Oncology criteria. Survival and progression-free survival after re-irradiation were calculated from initiation of PT until tumor progression or death (by any cause), using the Kaplan Meier method All pts completed the treatment without breaks. There were no grade 3 or higher acute toxicities. One pts developed TMZ-related grade 1 neutropenia. There were no grade 3 or higher late toxicities. During follow-up five pts (15%) developed radionecrosis (diagnosed at imaging) with mild symptoms controlled with steroids. The med progression-free survival (PFS) was 6.3 months, while 6-month PFS rate was 60%. The med PFS was 6.8, 4.3, 5.4, and 5.5 for Group 1-2-3-4, respectively. Med overall survival (OS) after PT was 10.7 months PT re-irradiation of difficult-to-treat rGBM showed to be feasible and safe even with concomitant and adjuvant chemotherapy administration. Despite the small number of patients of this series and the retrospective nature of the study PFS and OS rates are promising and deserve further evaluation in a larger pts sample to assess the most effective strategy

Introduction: Target volume definition is of critical relevance when re-irradiation is delivered and steep dose gradient irradiation techniques, such as proton therapy (PT), are employed. Aim of the study is to investigate the impact of 18F-DOPA on target volume contouring in recurrent glioblastoma (rGBM) patients (pts) undergoing re-irradiation with PT. MATERIAL AND METHODS: We investigated the differences in volume and relationship of magnetic resonance imaging (MRI)- vs. DOPA PET-derived gross tumor volumes (GTVs) of 14 rGBM pts re-irradiated with PT between January and November 2016. All pts had been previously treated with photon radiotherapy (60 Gy) with concomitant and adjuvant temozolomide. All the pts received morphological MRI with contrast enhancement medium administration and 18F-DOPA PET-CT study. We used the pathological distribution of 18F-DOPA in brain tissue to identify the so-called Biological Tumor Volume (BTV). Such areas were assessed using a tumor to normal brain ratio > 2. Moreover, any area of contrast enhancement on MRI was used to identify the MRI-based GTV (MRGTV). Definitive GTV included MRGTV plus BTV. Clinical target volume was generated by adding to GTV a 3-mm uniform margin manually corrected in proximity of anatomical barriers. CTV was expanded by 4 mm to create planning target volume. All pts received 36 GyRBE in 18 fractions. Mean values of differently delineated GTVs were compared each other by paired Student’s t-test; p < 0.05 was considered significant. To further compare MRGTV and BTV, the overlapping (MRGTV ^ BTV) and the composite (MRGTV U BTV) volumes were calculated, and a concordance index (CI) was defined as the ratio between the overlap and composite volumes. Results: MRGTV (mean 14.9 ± 14.5 cc) was larger than BTV (mean 10.9 ± 9.8 cc) although this difference was not statistically significant. The composite volume (mean 20.9 ± 14.7 cc) was significantly larger than each single volume (p < 0.006). The overlapping volume (mean 5.7 ± 3.3 cc) was quite small compared to each single volume and suggest that relevant part of MRIGTV is not covered by BTV as well as that relevant part of BTV is not covered by MRGTV. In line with such results we recorded also a low CI (mean 0.26 ± 0.2). The PT irradiation of PET-integrated target volumes provided a median progression-free survival (PFS) of 6 months, while the 6-month PFS rate was 57%; median survival after PT was 8.7 months, while 9-month survival rate was 60%. Conclusions: Target volume definition for rGBM undergoing PT re-irradiation may yield significantly differing results depending upon the imaging modality used for target contouring. Our data suggest that 18F-DOPA PET can detect relevant non-enhancing pathological areas outside the conventional MRGTV ultimately yielding to larger volumes to be irradiated. Influence on clinical outcomes deserves further evaluation.

To report preliminary results of re-irradiation with proton therapy (PT) with or without chemotherapy (CHT) in difficult-to-treat recurrent glioblastoma (rGBM): patients (pts) were selected for PT due to the large tumor size or proximity to dose-limiting organs at risk that previously had received near-maximum dose tolerance during the first radiation course. Between January 2015 and January 2017 twenty pts with rGBM were re-irradiated with PT. All pts had been previously treated with Stupp regimen. Fifteen (75%) were re-irradiated at first relapse/progression, five at the second/third one. Six patients (30%) were re-irradiated after partial tumor resection. Median age and Karnofsky performance status at re-irradiation were 56 years and 90%, respectively. Median time between prior radiotherapy and PT was 13 months. Target definition was based on CT, MR, and 18F-DOPA PET imaging. Gross Tumor Volume (GTV) included any area of contrast enhancement after contrast medium administration plus any pathological PET uptake regions. Clinical Target Volume (CTV) was generated by adding to GTV a 3-mm uniform margin manually corrected in proximity of anatomical barriers. Median CTV volume was 47 cc (range, 13-153 cc). All pts received 36 GyRBE in 18 fractions. PT was delivered with or without chemotherapy as follows: four (20%) pts (Group 1) also received concomitant TMZ (75 mg/m2/die, 7 days/week); 3 (15%) pts (Group 2) also received concomitant (as above) and adjuvant TMZ (150-200 mg/m2/die, 5 days/month); 5 (25%) pts (Group 3) received PT only; 8 (40%) pts (Group 4) received PT followed by CHT (different regimens/drugs). All pts were treated with active pencil beam scanning PT. Registered side effects were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment response was assessed according to Response Assessment in Neuro-Oncology (RANO) criteria. Survival and progression-free survival after re-irradiation were calculated from initiation of PT until tumor progression or death (by any cause), using the Kaplan Meier method. All pts completed the treatment without breaks. There were no grade 3 or higher acute toxicities. One pts developed TMZ-related grade 1 neutropenia. There were no grade 3 or higher late toxicities. During follow-up three pts (15%) developed radionecrosis (diagnosed at imaging) with mild symptoms controlled with steroids. The median progression-free survival (PFS) was 6.3 months, while 6-month PFS rate was 60%. The median PFS was 6.8, 4.3, 5.4, and 5.5 for Group 1-2-3-4, respectively. Median overall survival (OS) after PT was 10.7 months. PT re-irradiation of difficult-to-treat rGBM showed to be feasible and safe even with concomitant and adjuvant chemotherapy administration. Despite the small number of patients of this series and the retrospective nature of the study PFS and OS rates are promising and deserve further evaluation in a larger pts sample to assess the most effective strategy.