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Purpose To evaluate the clinical outcomes, toxicity and prognostic factors conditioning survival of reirradiation with Proton therapy for recurrent meningiomas. Methods Recurrent meningioma who failed after radiotherapy were re-irradiated with active scanning proton therapy with a median dose of 54 GyRBE (range 50.4-60 GyRBE). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log rank test was performed to compare the entire survival experience between groups (significant p-value ≤ 0.05). Associations between qualitative variables were analyzed with the Fisher exact test (significant p-value ≤ 0.05). Results Thirty-two patients were re-irradiated with Proton therapy (10 grade I, 22 grade II-III). Median tumor volume at the time of re-irradiation was 43 cc (range 1.2-225.5) and median time from prior RT to reirradiation was 66 months (range 4-288). At a median follow-up of 27 months, 1-yr and 2-yr PFS were 89.4% and 74.5% (1-yr and 2-yr PFS were 100% for grade I, 100% and 76% for grade II, 66% and 50% for grade III). 1-yr and 2-yr OS were 86.6% and 83.0% (2-yr OS were 87% for grade I, 86% for grade II, 66% for grade III). Local recurrence rate was 34% with a median time of recurrence of 13.4 months. Five patients (14%) developed radionecrosis with a median time of 3.4 months from the end of PT (range 3-8.8). Conclusions Re-irradiation with proton therapy seems to be a safe and effective treatment in patients with recurrent meningioma, also for large volume and aggressive lesions (grade II-III).

PURPOSE To investigate MRI myelin water imaging (MWI) by multicomponent T2 relaxometry as a quantitative imaging biomarker for brain radiation-induced changes and to compare it with DTI. METHODS Sixteen patients underwent fractionated proton therapy (PT) receiving dose to the healthy tissue because of direct or indirect (base skull tumors) irradiation. MWI was performed by a multi-echo sequence with 32 equally spaced echoes (10-320 ms). Decay data were processed to identify 3 T2 compartments: myelin water (Mw) below 40 ms, intra-extracellular water (IEw) between 40 and 250 ms, and free water (CSFw) above 250 ms. Both MWI and DTI scans were acquired pre (pre)-treatment and immediately at the end (end) of PT. After image registration, voxel-wise difference maps, obtained by subtracting MWI and DTI pre from those acquired at the end of PT, were compared with the corresponding biological equivalent dose (BED). RESULTS Mw difference showed a positive correlation and IEw difference showed a negative correlation with BED considering end-pre changes (P < .01). The changes in CSFw were not significantly correlated with the delivered BED. The changes in DTI data, considering end-pre acquisitions, showed a positive correlation between fractional anisotropy and the delivered BED. CONCLUSION MWI might detect early white matter radiation-induced alterations, providing additional information to DTI, which might improve the understanding of the pathogenesis of the radiation damage.

To evaluate the feasibility of comprehensive automation of an intra-cranial proton treatment planning.Class solution (CS) beam configuration selection allows the user to identify predefined beam configuration based on target localization; automatic CS (aCS) will then explore all the possible CS beam geometries. Ten patients, already used for the evaluation of the automatic selection of the beam configuration, have been also employed to training an algorithm based on the computation of a benchmark dose exploit automatic general planning solution (GPS) optimization with a wish list approach for the planning optimization. An independent cohort of ten patients has been then used for the evaluation step between the clinical and the GPS plan in terms of dosimetric quality of plans and the time needed to generate a plan.The definition of a beam configuration requires on average 22 min (range 9-29 min). The average time for GPS plan generation is 18 min (range 7-26 min). Median dose differences (GPS-Manual) for each OAR constraints are: brainstem -1.60 Gy, left cochlea -1.22 Gy, right cochlea -1.42 Gy, left eye 0.55 Gy, right eye -2.33 Gy, optic chiasm -1.87 Gy, left optic nerve -4.45 Gy, right optic nerve -2.48 Gy and optic tract -0.31 Gy. Dosimetric CS and aCS plan evaluation shows a slightly worsening of the OARs values except for the optic tract and optic chiasm for both CS and aCS, where better results have been observed.This study has shown the feasibility and implementation of the automatic planning system for intracranial tumors. The method developed in this work is ready to be implemented in a clinical workflow.

PURPOSE To assess the dosimetric advantages of apertures in intracranial single fraction proton radiosurgery. MATERIALS AND METHODS Six neuroma and 10 meningioma patients were investigated. For each patient, six plans were computed, with two spot spacing and three aperture settings (no apertures, 5 and 8 mm margin between aperture and clinical target volume [CTV]). All plans were optimized on the CTV with the same beam arrangement and the same single-field robust optimization (2 mm setup errors, 3.5% range uncertainties). Robustness analysis was performed with 0.5 and 1.0 mm systematic setup errors and 3.5% range uncertainties. CTV coverage in the perturbed scenarios and healthy brain tissue sparing in the surrounding of the CTV were compared. RESULTS Meningiomas were larger and at a shallow depth than neuromas. In neuromas, spot spacing did not affect OAR doses or the robustness of CTV coverage and the apertures reduced brain dose without any significant impact on CTV robustness. In meningiomas, smaller spot spacing produced a reduction in brain V5Gy and improved robustness of CTV coverage; in addition, an 8 mm margin aperture reduced low and medium brain tissue doses without affecting robustness in the 0.5 mm perturbed scenario. A 5 mm margin aperture caused a reduction of plan robustness. CONCLUSION The optimal use of apertures is a trade-off between sparing of low and medium dose to the healthy brain and robustness of target coverage, also depending on size and depth of the lesion.

To comprehensively describe the treatment of mediastinal lymphoma by pencil beam scanning (PBS) proton therapy.Fourteen patients underwent PBS proton treatment in a supine position in deep inspiration breath-hold (DIBH). Three DIBH computed tomography (CT) scans were acquired for each patient to delineate the Internal Target Volume (ITV). Intensity-modulated proton therapy (IMPT) was planned by min-max robust optimization on the ITV, with a 6 mm setup and 3.5% range uncertainties. Robustness analysis was performed and dose coverage was visually inspected on the corresponding voxel-wise minimum map. Layer repainting was set equal to 5 to compensate for cardiac motion. Intra-fraction reproducibility during treatment was assessed by repeated daily DIBH X-ray imaging. Finally, an additional CT was acquired at half treatment to estimate the impact of inter-fraction dosimetric reproducibility.IMPT guaranteed robust mediastinal target coverage and organs-at-risk sparing. However, visual voxel-wise robustness evaluation showed that in five patients a second optimization with focused objectives in the cost-function was necessary to achieve a robust coverage of the target regions at the interface between lungs and soft tissue. In six patients, repainting was not used due to excessive treatment time length and poor patient compliance. Intra-fraction average reproducibility was within 1 mm/1degree. On repeated CT scans, inter-fraction setup errors and/or anatomical changes showed minimal dosimetric differences in CTV coverage.IMPT in DIBH is effective and reproducible to treat mediastinal lymphomas. Caution is recommended to guarantee robust dose delivery to high-risk regions at the interface between lungs and soft tissue.

Prostatectomy, radiotherapy and watchful waiting are the main therapeutic options available for local stage of prostate cancer (PCa). We report our experience on 394 patients affected by prostate cancer primarily treated with high-dose, image-guided, IMRT, focusing on gastrointestinal, genitourinary toxicities and biochemical control. From July 2003 to August 2014, 394 patients were treated with radical high-dose radiotherapy (HDRT) for prostate cancer; the mean total radiation dose was 79 Gy in standard fractions. Hormonal therapy (HT) was administered to 7.6% of low-risk patients, to 20.3% of intermediate-risk patients and to 72% of high-risk patients. Patients were evaluated for biochemical failure, local recurrence (LR) and metastases. Ninety-seven patients (26.65%) developed acute GU toxicity at the medium dose of 25.4 Gy, grade 1 (G1) or grade 2 (G2) in 94 cases. Only 16 patients (4.06%) reported chronic GU toxicity (G1 or G2), and one case developed G3 cystitis. No G3 GI acute and late toxicity were detected. Fifty-six (14.2%) patients experienced LR, 26 (6.6%) developed metastases and 70 patients (17.8%) were deceased. Gleason sum score > 7 was predictive for worse overall survival (GS = 7 was borderline) and for metastasis. No factors resulted predictive for local relapse. HT pre-RT had been demonstrated as a negative predictor for OS and DFS-DM. Data confirm the safety of HDRT for PCa. Treatment was efficient with low toxicity profile. Moreover, continued technologic advancements, as image-guided radiotherapy, could lead to further reduction in toxicity, thus increasing the therapeutic index.

The aim of this Pictorial Essay is to illustrate the metabolic aspect of PET (positron emission tomography) imaging in relation to conventional and advanced MR (magnetic resonance) of brain neoplasms. 10 patients, who performed PET–CT with amino acid tracers and/or FDG were selected from a series of more than 250 cases from a single institution. The selection was made to illustrate and discuss each of the indications reported in the European guidelines. Fusion imaging was obtained merging PET–CT with MR T1-CE (contrast enhanced) and/or T2/FLAIR sequences. The SUVmax of the lesion and the SUVmax lesion to SUVmax background ratio were evaluated. The lesion uptake was also assessed using a five-point visual scale with a range from − 2 to + 2 in relation to basal ganglia uptake. The Hospital Information System (HIS) and the proton therapy data archives have been used for clinical history. For each case, the critical issues were described and the physiopathological correlations were provided to explain the imaging findings. The complexity of illustrated cases demonstrates the need for a multidisciplinary board evaluation to reach a more accurate diagnosis.

To investigate MRI myelin water imaging (MWI) by multicomponent TSixteen patients underwent fractionated proton therapy (PT) receiving dose to the healthy tissue because of direct or indirect (base skull tumors) irradiation. MWI was performed by a multi-echo sequence with 32 equally spaced echoes (10-320 ms). Decay data were processed to identify 3 TMw difference showed a positive correlation and IEw difference showed a negative correlation with BED considering end-pre changes (P.01). The changes in CSFw were not significantly correlated with the delivered BED. The changes in DTI data, considering end-pre acquisitions, showed a positive correlation between fractional anisotropy and the delivered BED.MWI might detect early white matter radiation-induced alterations, providing additional information to DTI, which might improve the understanding of the pathogenesis of the radiation damage.

Background Moderately hypofractionated radiotherapy (RT) currently represents the standard RT approach for all prostate cancer (PCa) risk categories. We performed a systematic review and meta-analysis of available literature, focusing on acute and late genitourinary (GU) and gastrointestinal (GI) adverse events (AEs) of moderate hypofractionation for localized PCa. Materials and methods Literature search was performed and two independent reviewers selected the records according to the following Population (P) Intervention (I) Comparator (C) and Outcomes (O) (PICO) question: “In patients affected by localized PCa (P), moderately hypofractionated RT (defined as a treatment schedule providing a single dose per fraction of 3–4.5 Gy) (I) can be considered equivalent to conventionally fractionated RT (C) in terms of G > 2 GI and GU acute and late adverse events (O)?”. Bias assessment was performed using Cochrane Cochrane Collaboration's Tool for Assessing Risk of Bias. Results Thirteen records were identified and a meta-analysis was performed. Risk of acute GI and GU > 2 adverse events in the moderately hypofractionated arm was increased by 9.8 % (95 %CI 4.8 %–14.7 %; I2 = 57 %) and 1.5 % (95 % CI -1.5 %-4.4 %; I2 = 0%), respectively. Discussion Overall, majority of trials included in our meta-analysis suggested that moderately hypofractionated RT is equivalent, in terms of GI and GU adverse events, to conventional fractionation. Pooled analysis showed a trend to increased GI toxicity after hypofractionated treatment, but this might be related to dose escalation rather than hypofractionation.

Background: Embryonal tumors represent a heterogeneous entity of brain tumors that need a multidisciplinary treatment including cranio-spinal irradiation (CSI), with a known impact on the acute toxicity. Proton therapy (PT) boasts a reduction in acute hematological toxicity. Methods: We retrospectively examined 20 pediatric patients affected by high-risk medulloblastoma and other rare embryonal brain tumors subjected to CSI with PT from September 2016 to April 2020. Before CSI, all patients received induction chemotherapy, and three patients additionally received two high-dose courses with thiotepa, followed by an autologous haemopoietic stem cell transplantation. We recorded the total white blood cell count, absolute neutrophil count, platelets, and hemoglobin levels for all patients during PT. Results: Leucocytes and neutrophils decreased directly after the beginning of treatment, reaching a complete recovery at the end of treatment. Hemoglobin values remained constant over the treatment course. The median platelet value decreased until reaching a plateau around halfway through therapy, followed by a slow increase. No cases of febrile neutropenia or severe infections were reported. No treatment discontinuation due to hematological toxicity was necessary. Conclusions: CSI with PT was proven to be safe in this setting of pediatric patients. Our study showed that despite all patients having undergone chemotherapy prior to irradiation, no serious hematological toxicity was reported at the end of the treatment with PT, and, therefore, no treatment was discontinued or delayed.

Purpose To develop normal tissue complication probability (NTCP) models for radiation-induced alopecia (RIA) in brain tumor patients treated with proton therapy (PT). Methods and materials We analyzed 116 brain tumor adult patients undergoing scanning beam PT (median dose 54 GyRBE; range 36–72) for CTCAE v.4 grade 2 (G2) acute (≤90 days), late (>90 days) and permanent (>12 months) RIA. The relative dose-surface histogram (DSH) of the scalp was extracted and used for Lyman-Kutcher-Burman (LKB) modelling. Moreover, DSH metrics (Sx: the surface receiving ≥ X Gy, D2%: near maximum dose, Dmean: mean dose) and non-dosimetric variables were included in a multivariable logistic regression NTCP model. Model performances were evaluated by the cross-validated area under the receiver operator curve (ROC-AUC). Results Acute, late and permanent G2-RIA was observed in 52%, 35% and 19% of the patients, respectively. The LKB models showed a weak dose-surface effect (0.09 ≤ n ≤ 0.19) with relative steepness 0.29 ≤ m ≤ 0.56, and increasing tolerance dose values when moving from acute and late (22 and 24 GyRBE) to permanent RIA (44 GyRBE). Multivariable modelling selected S21Gy for acute and S25Gy, for late G2-RIA as the most predictive DSH factors. Younger age was selected as risk factor for acute G2-RIA while surgery as risk factor for late G2-RIA. D2% was the only variable selected for permanent G2-RIA. Both LKB and logistic models exhibited high predictive performances (ROC-AUCs range 0.86–0.90). Conclusion We derived NTCP models to predict G2-RIA after PT, providing a comprehensive modelling framework for acute, late and permanent occurrences that, once externally validated, could be exploited for individualized scalp sparing treatment planning strategies in brain tumor patients.

To implement a robust multi-field optimization (MFO) technique compatible with the application of a Monte Carlo (MC) algorithm and to evaluate its robustness. Nine patients (three brain, five head-and-neck, one spine) underwent proton treatment generated by a novel robust MFO technique. A hybrid (hMFO) approach was implemented, planning dose coverage on isotropic PTV compensating for setup errors, whereas range calibration uncertainties are incorporated into PTV robust optimization process. hMFO was compared with single-field optimization (SFO) and full robust multi-field optimization (fMFO), both on the nominal plan and the worst-case scenarios assessed by robustness analysis. The SFO and the fMFO plans were normalized to hMFO on CTV to obtain iso-D95 coverage, and then the organs at risk (OARs) doses were compared. On the same OARs, in the normalized nominal plans the potential impact of variable relative biological effectiveness (RBE) was investigated. hMFO reduces the number of scenarios computed for robust optimization (from twenty-one in fMFO to three), making it practicable with the application of a MC algorithm. After normalizing on D95 CTV coverage, nominal hMFO plans were superior compared to SFO in terms of OARs sparing (p

Proton therapy could minimize the risk of side effects and, therefore, reduce the possible detrimental effect on health-related quality of life (HRQOL) of re-irradiation. The aim of this study was to determine the effect of re-irradiation with active scanning proton therapy on recurrent glioblastoma (GBM) in terms of HRQOL scored by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and EORTC Quality of Life Questionnaire Brain Cancer Module (QLQ-BN20). Thirty-three patients with recurrent GBM were re-irradiated with active scanning proton therapy. Subscales within the EORTC QLQ-C30 include five functional scales, six single-item scales, and global QoL. The BN20 assessed visual disorders, motor function, communication deficit, various disease symptoms, treatment, toxicity, and future uncertainty. The patients completed the questionnaires before starting proton therapy, the last day of proton therapy, and at every follow-up visit until progression of disease. The treatment was associated with improvement or stability in most of the preselected HRQOL domains. Global health improved over time with a maximum difference of six points between baseline and 3-months follow-up. Social functioning and motor dysfunction improved over time with a maximum difference of eight and two points, respectively. We showed a non-significant decrease in cognitive and emotional functioning. Fatigue remained stable during the analysis such as the other preselected domains. Re-irradiation with proton therapy is a safe and effective treatment in patients with recurrent glioblastoma. Proton therapy does not negatively effect on HRQOL, but rather it seems to preserve HRQOL until the time of disease progression.

Introduction: The prognosis of glioma is dismal, and almost all patients relapsed. At recurrence time, several treatment options are considered, but to date there is no a standard of care. The Neurooncology Study Group of the Italian Association of Radiation Oncology (AIRO) collected clinical data regarding a large series of recurrent glioma patients who underwent re-irradiation (re-RT) in Italy. Methods: Data regarding 300 recurrent glioma patients treated from May 2002 to November 2017, were analyzed. All patients underwent re-RT. Surgical resection, followed by re-RT with concomitant and adjuvant chemotherapy was performed. Clinical outcome was evaluated by neurological examination and brain MRI performed, 1month after radiation therapy and then every 3months. Results: Re-irradiation was performed at a median interval time (IT) of 16months from the first RT. Surgical resection before re-RT was performed in 19% of patients, concomitant temozolomide (TMZ) in 16.3%, and maintenance chemotherapy in 29%. Total doses ranged from 9Gy to 52.5Gy, with a median biological effective dose of 43Gy. The median, 1, 2year OS were 9.7months, 41% and 17.7%. Low grade glioma histology (p ≪ 0.01), IT > 12months (p = 0.001), KPS > 70 (p = 0.004), younger age (p = 0.001), high total doses delivered (p = 0.04), and combined treatment performed (p = 0.0008) were recorded as conditioning survival. Conclusion: our data underline re-RT as a safe and feasible treatment with limited rate of toxicity, and a combined ones as a better option for selected patients. The identification of a BED threshold able to obtain a greater benefit on OS, can help in designing future prospective studies.

Background The tumors of many patients with prostate cancer eventually become refractory to androgen deprivation therapy with progression to metastatic castration-resistant disease. Significant advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC) have been made in recent years, and new treatment strategies have recently been made available. The aim of this report was to schematically review all the approved pharmacologic treatment options for patients with mCRPC through 2018, analyzing the efficacy and possible side effects of each therapy to assist clinicians in reaching an appropriate treatment decision. New biomarkers potentially of aid in the choice of treatment in this setting are also briefly reviewed. Methods We performed a literature search of clinical trials of new drugs and treatments for patients diagnosed with mCRPC published through 2018. Results Two new hormonal drugs, abiraterone acetate and enzalutamide have been approved by FDA in 2011 and 2012, respectively for the treatment of patients with mCRPC and have undergone extensive testing. While these treatments have shown a benefit in progression-free and overall survival, the appropriate sequencing must still be determined so that treatment decisions can be made based on their specific clinical profile. Cabazitaxel has been shown to be an efficient therapeutic option in a postdocetaxel setting, while its role in chemotherapy-naive patients must still be determined. Sipuleucel-T and radium-223 have been studied in patients without visceral metastases and have achieved overall survival benefits with good safety profiles. The feasibility and efficacy of combinations of new treatments with other known therapies such as chemotherapy are currently under investigation. Conclusions Drug development efforts continue to attempt to prolong survival and improve quality of life in the mCRPC setting, with several therapeutic options available. Ongoing and future trials are needed to further assess the efficacy and safety of these new drugs and their interactions, along with the most appropriate sequencing.

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 The use of appropriate margins and independent beam directions contribute to plan robustness and robustness analysis may be a part of proton therapy planning even in case of SFO for treatments delivered in one session where a set-up error is systematic. Download : Download high-res image (362KB) Download : Download full-size image

The aim of our Phase II study is to demonstrate the benefits, safety, and tolerance of Orasol Plus, an easy and feasible Lapacho-based medication. Orasol Plus is a nutritional, swallowable solution, useful to support the defenses of the oropharyngeal mucosa. Between January and June 2014, 40 consecutive adult patients affected by head and neck cancer were enrolled. Orasol Plus was administered 3 times a day from the first day till the end of radiotherapy. Primary endpoint was to evaluate tolerance and safety of Orasol Plus; secondary endpoint was to evaluate the effect of Orasol Plus on the incidence of treatment discontinuation. Nearly all patients used Orasol Plus easily till the end of radiotherapy without interruptions. Only 11 (27.5%) patients developed oral mucositis (OM) Grade 2 and only 4 (10%) patients OM Grade 3, no patient developed OM Grade 4. No patient discontinued radiotherapy because of OM. Orasol Plus was well tolerated and the compliance of patients was optimal, mainly due to the fact that it can be swallowed. Data from our study are encouraging and they need to be confirmed by a Phase III study.

Elevated pre-treatment lymphocyte (L) to monocyte (M) ratio (LMR) in peripheral blood has been suggested to correlate with improved survival in some malignancies, but data in the context of pancreatic cancer (PC) is limited. The aim of this study was to evaluate the prognostic significance of LMR before, during and after definitive chemoradiotherapy (CRT) for locally advanced pancreatic cancer (LAPC).We retrospectively reviewed 57 patients with LAPC treated with definitive CRT at a single institution from 2005 to 2013. Complete blood counts were obtained before (TP1), during the third week (TP2) and at the end of CRT (TP3). Univariate analysis (UVA) included gender, age, body mass index, pre-treatment CA19-9, T stage, N stage, induction chemotherapy (ICT), absolute L count (TP1, TP2, TP3), absolute M count (TP1, TP2, TP3), LMR (TP1, TP2, TP3), and relative LMR changes (TP2 ÷ TP1, TP3 ÷ TP1, TP3 ÷ TP2).Median follow-up was 14 months. Twelve patients received ICT. Median LMR was 2.7 (range, 0.8-5.25), 1.4 (range, 0.3-5) and 0.98 (range, 0.3-3.4) at TP1, TP2 and TP3, respectively. Superior PFS was significantly associated with an absolute M count during CRT0.1 (P=0.04) while pre-CRT L count ≥1.1 trended towards significance (P=0.09). Superior OS was significantly associated with change in LMR (TP3 ÷ TP2)0.32 (P0.0001) while pre-CRT LMR ≥2.6 trended towards significance (P=0.06).Factors significantly associated with overall survival (OS) and progression-free survival (PFS) were change in LMR at the end of CRT and absolute M count during CRT. This analysis suggests treatment-time-specific immune system parameters may affect clinical outcomes and warrant continued investigation.

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.

Chordoma is a slow-growing neoplasm arising from remnants of the embryonic notochord. Surgery is recognized as the gold standard approach, however gross total resection is rarely possible for this reason most patients undergo subtotal resection or biopsy followed by radiotherapy. Myasthenia gravis (MG) is neuromuscular autoimmune disorder .The feasibility and safety of radiotherapy and especially of proton therapy (PT) in patients affected by MG has never been adequately documented. We report the case of a patient with lumbar chordoma who was diagnosed of MG just at the beginning of PT.

BACKGROUND 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. MATERIAL AND METHODS 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. RESULTS 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%). CONCLUSION 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.

We report the case of a man affected by renal cell carcinoma with vertebral metastases, who presented a radiological complete response after systemic treatment with everolimus.

BACKGROUND: Protontherapy (PT) could minimize the risk of side effects compared to conventional photon therapy and therefore reduce the possible detrimental effect on QoL of re-irradiation. We report the effect of re-irradiation with active scanning PT of recurrence GBM in terms of quality of life scored by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)--C30 and EORTC Quality of Life Questionnaire Brain Cancer Module (QLQ-BN20) MATERIAL AND METHODS: Between January 2015 and May 2018 twenty-eight patients with recurrence GBM were re-irradiated with active scanning PT. All patients had been previously treated with photon radiotherapy (60 Gy) with concomitant and adjuvant temozolomide (TMZ). Median age and Karnofsky performance status at re-irradiation were 53 years (range, 30–68 years) and 80%, (range, 60–100%), respectively. Target definition was based on CT, MR, and 18F-DOPA PET imaging. All patients received 36 GyRBE (RBE: relative biologic effectiveness) in 18 fractions, with concomitant TMZ in 7 patients (25%). Subscales within the EORTC QLQ-C30 include five functional scales (physical, role, emotional, cognitive, and social), three symptoms scales (nausea, vomiting, and fatigue), six single-item scales (insomnia, appetite loss, constipation, diarrhea, dyspnea, and financial effect of tumor/treatment) and global QoL. The BN20 is specifically developed for brain patients and assessed visual disorders, motor function, communication deficit, various disease symptoms, treatment, toxicity and future uncertainty. The patients completed the EORTC questionnaires before starting PT, the day of the end of PT and every follow-up consult (1-month, 3-months) until progression of disease. RESULTS: Twenty-six patients completed the questionnaires at baseline until progression of disease. The treatment was associated with improvement or stability in most of the preselected HRQOL domains. Global health improved over time with a maximum difference of 6 points between baseline and 3-months follow-up. Social functioning and motor dysfunction improved over time with a maximum difference of 8 and 2 points, respectively. We showed only a small not significance decrease in cognitive and emotional functioning. Interestingly, fatigue remained stable during the analysis such as the other preselected domains. CONCLUSION: Re-irradiation with PT is a safe treatment without a negative effect on HRQOL until the time of disease progression.

BACKGROUND: 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 MATERIAL AND METHODS: 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 RESULTS: 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 CONCLUSION: 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

BACKGROUND: To report preliminary results of active beam scanning proton therapy (PT) for large skull base benign meningiomas. MATERIAL AND METHODS: Thirty-three patients (pts) with large skull base meningiomas were treated with PT between January 2015 and February 2018. Median age was 53 years (range, 28–82) while KPS ranged between 60 and 100 (median 90); 26 were female (79%), and 7 were male (21%). Twelve pts (36%) had histologically proven World Health Organization (WHO) Grade I tumors. In remaining pts diagnosis was based on the typical imaging appearance of benign meningioma. All patients received PT for residual, progressive or non-operable lesions. Newly diagnosed tumors received total dose of 50 GyRBE (RBE: relative biologic effectiveness) while progressing meningiomas 54 GyRBE. All the treatments were delivered at 2 GyRBE per fraction. Treatment planning was based on morphological magnetic resonance imaging (MRI) with contrast enhancement medium administration. All pts received also 68-Ga-DOTATOC-PET. Any area of contrast enhancement on MRI was used to identify the gross tumor volume. We used the pathological distribution of 68Ga-DOTATOC in brain tissue to identify the so-called Biological Tumor Volume. Gross tumor volume ranged from 21 to 107 cc. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.0. Median follow-up time was 9 months (range, 3–37). RESULTS: All pts completed the treatment without breaks. Acute side effects include grade 1 (21%) and grade 2 (9%) skin erythema, grade 1 (9%) and grade 2 (9%) alopecia, grade 1 (48%) fatigue, grade 1 (6%) and grade 2 (15%) conjunctivitis, grade 1 (15%) pain, grade 1 (15%) blurred vision, grade 1 (15%) headache, and grade 2 (15%) skin hyperpigmentation. One pt experienced grade 3 pain. There were no further grade 3 or higher acute toxicities. Late side effects include grade 1 (9%) and grade 2 (9%) alopecia, grade 1 (21%) fatigue, grade 1 (9%) and grade 2 (6%) headache, grade 1 (6%) dizziness, grade 1 (6%) blurred vision, grade 1 (6%) and grade 2 (6%) pain, grade 1 (6%) dry eye, and grade 1 (15%) skin hyperpigmentation. One pts experienced grade 3 pain. There were no further grade 3 or higher late toxicities. One pts (3%) with cavernous sinus meningioma experienced complete obstruction of intracavernous carotid artery with mild transient symptoms that resolved in few days and brain tissue ischemia detected at MRI (grade 2). Before irradiation this pts already had a meningioma-related near-complete obstruction of the intracavernous carotid artery and received a vascular surgery evaluation. Currently, absolute tumor control is 100%. Moreover, relief of symptoms recorded before irradiation occurred in 24% of pts. CONCLUSION: PT is feasible and safe treatment for pts with large skull base benign meningiomas. Longer follow-up is necessary to assess definitive efficacy.

The present phase II study aimed to evaluate the tolerance and safety of Dixentil, a nutritional supplement based on zinc with the addition of prebiotics (galacto-oligosaccharides), tyndalized probiotics (Lactobacillus acidophilus and L. casei) and vitamins B1, B2 and B6, and nicotinamide), given as prophylaxis to patients undergoing pelvic radiotherapy and its efficacy in the prevention and reduction of radiation-related gastrointestinal disorders.Forty consecutive patients who were candidates for pelvic radiotherapy received Dixentil before starting and during radiotherapy. The primary end-point was to evaluate the safety and tolerance of Dixentil. Secondary end-points were incidence and severity of radiation-induced diarrhea and number of patients who discontinued radiotherapy because of diarrhea.Radiation-induced enteritis occurred in 17 patients, grade I and grade II diarrhea was documented in 14 and 3 patients respectively; no grade III or IV diarrhea was observed. Radiotherapy was discontinued due to treatment-induced enteritis only in two patients for 6 days.Use of Dixentil is an easy, safe, and feasible approach to protect patients against the risk of radiation-induced diarrhea.

10-year data from the European Organisation for Research and Treatment of Cancer trial 22911 have been published, reigniting the debate regarding postoperative radiotherapy for prostate cancer. These data show that adjuvant radiotherapy significantly improves biochemical progression-free survival and local control compared with a 'wait-and-see' policy, supporting the 5-year follow-up data.