Proton therapy for intracranial meningioma: a single-institution retrospective analysis of efficacy, survival and toxicity outcomes.

PURPOSE: To report the outcomes of a large series of intracranial meningiomas (IMs) submitted to proton therapy (PT) with curative intent. METHODS: We conducted a retrospective analysis on all consecutive IM patients treated between 2014 and 2021. The median PT prescription dose was 55.8 Gy relative biological effectiveness (RBE) and 66 GyRBE for benign/radiologically diagnosed and atypical/anaplastic IMs, respectively. Local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), overall survival (OS), and radionecrosis-free survival (RNFS) were evaluated with the Kaplan-Meier method. Univariable analysis was performed to identify potential prognostic factors for clinical outcomes. Toxicity was reported according to the latest Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: Overall, 167 patients were included. With a median follow-up of 41 months (range, 6-99), twelve patients (7%) developed tumor local recurrence after a median time of 39 months. The 5-year LRFS was 88% for the entire cohort, with a significant difference between benign/radiologically diagnosed and atypical/anaplastic IMs (98% vs. 47%, p < 0.001); this significant difference was maintained also for the 5-year OS and the 5-year DRFS rates. Patients aged ≤ 56 years reported significantly better outcomes, whereas lower prescription doses and skull base location were associated with better RNFS rates. Two patients experienced G3 acute toxicities (1.2%), and three patients G3 late toxicities (1.8%). There were no G4-G5 adverse events. CONCLUSION: PT proved to be effective with an acceptable toxicity profile. To the best of our knowledge this is one of the largest series including IM patients submitted to PT.

Optimizing b-values schemes for diffusion MRI of the brain with segmented Intravoxel Incoherent Motion (IVIM) model.

PURPOSE: To define an optimal set of b-values for accurate derivation of diffusion MRI parameters in the brain with segmented Intravoxel Incoherent Motion (IVIM) model. METHODS: Simulations of diffusion signals were performed to define an optimal set of b-values targeting different perfusion regimes, by relying on an optimization procedure which minimizes the total relative error on estimated IVIM parameters computed with a segmented fitting procedure. Then, the optimal b-values set was acquired in vivo on healthy subjects and skull base chordoma patients to compare the optimized protocol with a clinical one. RESULTS: The total relative error on simulations decreased of about 40% when adopting the optimal set of 13 b-values (0 10 20 40 50 60 200 300 400 1200 1300 1400 1500 s/mm2 ), showing significant differences and increased precision on D and f estimates with respect to simulations with a non-optimized b-values set. Similarly, in vivo acquisitions demonstrated a dependency of IVIM parameters on the b-values array, with differences between the optimal set of b-values and a clinical non-optimized acquisition. IVIM parameters were compatible to literature values, with D (0.679/0.701 [0.022/0.008] ·10-3 mm2 /s), f (5.49/5.80 [0.70/1.14] %), and D* (8.25/7.67 [0.92/0.83] ·10-3 mm2 /s) median [interquartile range] estimates for white matter/gray matter in volunteers and D (0.709/0.715/1.06 [0.035/0.023/0.271] ·10-3 mm2 /s), f (7.08/7.84/21.54 [1.20/1.06/6.05] %), and D* (10.85/11.84/2.32 [1.38/2.32/4.94] ·10-3 mm2 /s) for white matter/gray matter/Gross Tumor Volume in patients with skull-base chordoma tumor. CONCLUSIONS: The definition of an optimal b-values set can improve the estimation of quantitative IVIM parameters. This allows setting up an optimized approach that can be adopted for IVIM studies in the brain.

The impact of particle radiotherapy on the functioning of cardiac implantable electronic devices: a systematic review of in vitro and in vivo studies according to PICO criteria.

The number of oncological patients who may benefit from proton beam radiotherapy (PBT) or carbon ion radiotherapy (CIRT), overall referred to as particle radiotherapy (RT), is expected to strongly increase in the next future, as well as the number of cardiological patients requiring cardiac implantable electronic devices (CIEDs). The management of patients with a CIED requiring particle RT deserves peculiar attention compared to those undergoing conventional photon beam RT, mostly due to the potential generation of secondary neutrons by particle beams interactions. Current consensus documents recommend managing these patients as being at intermediate/high risk of RT-induced device malfunctioning regardless of the dose on the CIED and the beam delivery method used, despite the last one significantly affects secondary neutrons generation (very limited neutrons production with active scanning as opposed to the passive scattering technique). The key issues for the current review were expressed in four questions according to the Population, Intervention, Control, Outcome criteria. Three in vitro and five in vivo studies were included. Based on the available data, PBT and CIRT with active scanning have a limited potential to interfere with CIED that has only emerged from in vitro study so far, while a significant potential for neutron-related, not severe, CIED malfunctions (resets) was consistently reported in both clinical and in vitro studies with passive scattering.

MRI-based radiomics signature for localized prostate cancer: a new clinical tool for cancer aggressiveness prediction? Sub-study of prospective phase II trial on ultra-hypofractionated radiotherapy (AIRC IG-13218).

OBJECTIVES: Radiomic involves testing the associations of a large number of quantitative imaging features with clinical characteristics. Our aim was to extract a radiomic signature from axial T2-weighted (T2-W) magnetic resonance imaging (MRI) of the whole prostate able to predict oncological and radiological scores in prostate cancer (PCa). METHODS: This study included 65 patients with localized PCa treated with radiotherapy (RT) between 2014 and 2018. For each patient, the T2-W MRI images were normalized with the histogram intensity scale standardization method. Features were extracted with the IBEX software. The association of each radiomic feature with risk class, T-stage, Gleason score (GS), extracapsular extension (ECE) score, and Prostate Imaging Reporting and Data System (PI-RADS v2) score was assessed by univariate and multivariate analysis. RESULTS: Forty-nine out of 65 patients were eligible. Among the 1702 features extracted, 3 to 6 features with the highest predictive power were selected for each outcome. This analysis showed that texture features were the most predictive for GS, PI-RADS v2 score, and risk class; intensity features were highly associated with T-stage, ECE score, and risk class, with areas under the receiver operating characteristic curve (ROC AUC) ranging from 0.74 to 0.94. CONCLUSIONS: MRI-based radiomics is a promising tool for prediction of PCa characteristics. Although a significant association was found between the selected features and all the mentioned clinical/radiological scores, further validations on larger cohorts are needed before these findings can be applied in the clinical practice. KEY POINTS: • A radiomic model was used to classify PCa aggressiveness. • Radiomic analysis was performed on T2-W magnetic resonance images of the whole prostate gland. • The most predictive features belong to the texture (57%) and intensity (43%) domains.

Intravoxel incoherent motion as a tool to detect early microstructural changes in meningiomas treated with proton therapy.

PURPOSE: To assess early microstructural changes of meningiomas treated with proton therapy through quantitative analysis of intravoxel incoherent motion (IVIM) and diffusion-weighted imaging (DWI) parameters. METHODS: Seventeen subjects with meningiomas that were eligible for proton therapy treatment were retrospectively enrolled. Each subject underwent a magnetic resonance imaging (MRI) including DWI sequences and IVIM assessments at baseline, immediately before the 1st (t0), 10th (t10), 20th (t20), and 30th (t30) treatment fraction and at follow-up. Manual tumor contours were drawn on T2-weighted images by two expert neuroradiologists and then rigidly registered to DWI images. Median values of the apparent diffusion coefficient (ADC), true diffusion (D), pseudo-diffusion (D*), and perfusion fraction (f) were extracted at all timepoints. Statistical analysis was performed using the pairwise Wilcoxon test. RESULTS: Statistically significant differences from baseline to follow-up were found for ADC, D, and D* values, with a progressive increase in ADC and D in conjunction with a progressive decrease in D*. MRI during treatment showed statistically significant differences in D values between t0 and t20 (p = 0.03) and t0 and t30 (p = 0.02), and for ADC values between t0 and t20 (p = 0.04), t10 and t20 (p = 0.02), and t10 and t30 (p = 0.035). Subjects that showed a volume reduction greater than 15% of the baseline tumor size at follow-up showed early D changes, whereas ADC changes were not statistically significant. CONCLUSION: IVIM appears to be a useful tool for detecting early microstructural changes within meningiomas treated with proton therapy and may potentially be able to predict tumor response.

Intensity modulated radiation therapy boost in locally-advanced cervical cancer in the absence of brachytherapy.

OBJECTIVE: Standard treatment in locally-advanced cervical cancer is external beam radiotherapy concomitant with platinum-based chemotherapy, followed by brachytherapy. The goal of our study was to determine whether an intensity modulated radiation therapy (IMRT) boost is feasible in patients unfit for brachytherapy. METHODS: We retrospectively analyzed data of 25 patients unfit for brachytherapy with median age 55 years (range, 30-82) with locally-advanced/metastatic cervical cancer who underwent external beam radiotherapy to pelvis ±para-aortic lymph nodes and sequential IMRT boost between July 2014 and December 2017. Total dose of 45-50.4 Gy in 25-28 fractions (1.8 Gy/fraction) was administered to the cervix, uterus, parametria, ovaries, vaginal tissues (based on vaginal extension), involved lymph nodes, or relevant draining lymph-nodal groups. Para-aortic nodes were included if involved at radiological staging or if common iliac nodes were positive. The IMRT boost included all residual tumor after external beam radiotherapy identified on MRI. The Kaplan-Meier method was used to calculate 2 years' overall survival, 2 years' progression-free survival, and 2 years' local control. Overall survival- and progression-free survival were calculated considering the starting of radiotherapy or neo-adjuvant chemotherapy if prescribed, while local control was calculated from the end of radiotherapy. RESULTS: Median radiation dose to pelvis ±para-aortic lymph nodes was 50.4 Gy (45-50.4), boost treatment was homogeneously performed to a total dose of 25 Gy in five fractions every other day.After a median follow-up of 26 months (range, 4-77), tumor persistence at cervix at 6 months from the end of radiotherapy or local recurrence occurred in five women (20%), eight (32%) experienced a further distant progression (two of them had also tumor persistence). Two-year local control and overall survival rates for all stages were 78% and 67%, respectively. According to Common Terminology Criteria for Adverse Events v.4 scoring criteria, 10 patients experienced gastrointestinal and/or genitourinary grade G1-2 acute toxicity. G2 rectal late toxicity requiring laser-coagulation was registered in two patients, there were no gastrointestinal and/or genitourinary acute or late toxicities≥G3. CONCLUSION: The combination of external beam radiotherapy and brachytherapy remains the standard of care, however our preliminary data show the feasibility of IMRT boost in terms of toxicity with promising results in terms of local control and overall survival.

Correction to: Late toxicity of image-guided hypofractionated radiotherapy for prostate: non-randomized comparison with conventional fractionation.

Unfortunately, the denomination of the IEO was incorrectly published in the affiliation of this original.

Late toxicity of image-guided hypofractionated radiotherapy for prostate: non-randomized comparison with conventional fractionation.

PURPOSE: To evaluate the incidence and predictors for late toxicity and tumor outcome after hypofractionated radiotherapy using three different image-guided radiotherapy (IGRT) systems (hypo-IGRT) compared with conventional fractionation without image guidance (non-IGRT). METHODS AND MATERIALS: We compared the late rectal and urinary toxicity and outcome in 179 prostate cancer patients treated with hypo-IGRT (70.2 Gy/26 fractions) and 174 non-IGRT patients (80 Gy/40 fractions). Multivariate analysis was performed to define predictors for late toxicity. 5- and 8-year recurrence-free survival (RFS) and overall survival (OS) were analyzed. RESULTS: Mean follow-up was 81 months for hypo-IGRT and 90 months for non-IGRT group. Mainly mild late toxicity was observed: Hypo-IGRT group experienced 65 rectal (30.9% G1/G2; 6.3% G3/G4) and 105 urinary events (56% G1/G2; 4% G3/G4). 5- and 8-year RFS rates were 87.5% and 86.8% (hypo-IGRT) versus 80.4% and 66.8% (non-IGRT). 5- and 8-year OS rates were 91.3% and 82.7% in hypo-IGRT and 92.2% and 84% in non-IGRT group. Multivariate analysis showed that hypo-IGRT is a predictor for late genitourinary toxicity, whereas hypo-IGRT, acute urinary toxicity and androgen deprivation therapy are predictors for late rectal toxicity. Advanced T stage and higher Gleason score (GS) were correlated with worse RFS. CONCLUSIONS: A small increase in mild late toxicity, but not statistically significant increase in severe late toxicity in the hypo-IGRT group when compared with conventional non-IGRT group was observed. Our study confirmed that IGRT allows for safe moderate hypofractionation, offering a shorter overall treatment time, a good impact in terms of RFS and providing potentially more economic health care.

The role of particle radiotherapy in the treatment of skull base tumors.

The skull base is an anatomically and functionally critical area surrounded by vital structures such as the brainstem, the spinal cord, blood vessels, and cranial nerves. Due to this complexity, management of skull base tumors requires a multidisciplinary approach involving a team of specialists such as neurosurgeons, otorhinolaryngologists, radiation oncologists, endocrinologists, and medical oncologists. In the case of pediatric patients, cancer management should be performed by a team of pediatric-trained specialists. Radiation therapy may be used alone or in combination with surgery to treat skull base tumors. There are two main types of radiation therapy: photon therapy and particle therapy. Particle radiotherapy uses charged particles (protons or carbon ions) that, due to their peculiar physical properties, permit precise targeting of the tumor with minimal healthy tissue exposure. These characteristics allow for minimizing the potential long-term effects of radiation exposure in terms of neurocognitive impairments, preserving quality of life, and reducing the risk of radio-induced cancer. For these reasons, in children, adolescents, and young adults, proton therapy should be an elective option when available. In radioresistant tumors such as chordomas and sarcomas and previously irradiated recurrent tumors, particle therapy permits the delivery of high biologically effective doses with low, or however acceptable, toxicity. Carbon ion therapy has peculiar and favorable radiobiological characteristics to overcome radioresistance features. In low-grade tumors, proton therapy should be considered in challenging cases due to tumor volume and involvement of critical neural structures. However, particle radiotherapy is still relatively new, and more research is needed to fully understand its effects. Additionally, the availability of particle therapy is limited as it requires specialized equipment and expertise. The purpose of this manuscript is to review the available literature regarding the role of particle radiotherapy in the treatment of skull base tumors.

Microstructural parameters from DW-MRI for tumour characterization and local recurrence prediction in particle therapy of skull-base chordoma.

BACKGROUND: Quantitative imaging such as Diffusion-Weighted MRI (DW-MRI) can be exploited to non-invasively derive patient-specific tumor microstructure information for tumor characterization and local recurrence risk prediction in radiotherapy. PURPOSE: To characterize tumor microstructure according to proliferative capacity and predict local recurrence through microstructural markers derived from pre-treatment conventional DW-MRI, in skull-base chordoma (SBC) patients treated with proton (PT) and carbon ion (CIRT) radiotherapy. METHODS: Forty-eight patients affected by SBC, who underwent conventional DW-MRI before treatment and were enrolled for CIRT (n = 25) or PT (n = 23), were retrospectively selected. Clinically verified local recurrence information (LR) and histological information (Ki-67, proliferation index) were collected. Apparent diffusion coefficient (ADC) maps were calculated from pre-treatment DW-MRI and, from these, a set of microstructural parameters (cellular radius R, volume fraction vf, diffusion D) were derived by applying a fine-tuning procedure to a framework employing Monte Carlo simulations on synthetic cell substrates. In addition, apparent cellularity (ρapp ) was estimated from vf and R for an easier clinical interpretation. Histogram-based metrics (mean, median, variance, entropy) from estimated parameters were considered to investigate differences (Mann-Whitney U-test, α = 0.05) in estimated tumor microstructure in SBCs characterized by low or high cell proliferation (Ki-67). Recurrence-free survival analyses were also performed to assess the ability of the microstructural parameters to stratify patients according to the risk of local recurrence (Kaplan-Meier curves, log-rank test α = 0.05). RESULTS: Refined microstructural markers revealed optimal capabilities in discriminating patients according to cell proliferation, achieving best results with mean values (p-values were 0.0383, 0.0284, 0.0284, 0.0468, and 0.0088 for ADC, R, vf, D, and ρapp, respectively). Recurrence-free survival analyses showed significant differences between populations at high and low risk of local recurrence as stratified by entropy values of estimated microstructural parameters (p = 0.0110). CONCLUSION: Patient-specific microstructural information was non-invasively derived providing potentially useful tools for SBC treatment personalization and optimization in particle therapy.

Evaluation of endocrinological sequelae following particle therapy performed on anterior skull base lesions in the adult population.

Background: Radiotherapy has increasingly assumed a central role in the multidisciplinary treatment of skull base lesions. Unfortunately, it is often burdened by relevant radio-induced damage to the pituitary function and the surrounding structures and systems. Patients who were treated with radiotherapy around the sellar region especially have a high risk of developing radio-induced hypopituitarism. Particle therapy has the potential advantage of delivering a higher radiation dose to the target while potentially sparing the sellar region and pituitary function. The aim of this study is to evaluate the pituitary function in adult patients who have undergone hadron therapy for anterior skull base lesions involving or surrounding the pituitary gland. Methods: This is a retrospective, observational, and noncontrolled study. We evaluated pituitary and peripheral hormone levels in all patients referring to National Center for Oncological Hadrontherapy, Pavia, Italy for anterior skull base tumors. Furthermore, we performed a magnetic resonance imaging for every follow-up to evaluate potential tumoral growth. Results: We evaluated 32 patients with different tumoral lesions with a mean follow-up of 27.9 months. The mean hadron therapy (HT) dose was 60 ± 14 Gray, with a mean dose per fraction of 2.3 ± 2.1 Gray. Six patients were treated with carbon ions and 26 with protons. Pituitary hormone alteration of some kind was reported for six patients. No patient experienced unexpected severe adverse events related to particle therapy. Conclusion: Particle radiotherapy performed on anterior skull base lesions has proved to cause limited damage to pituitary function in the adult population.

The Role of Carbon Ion Therapy in the Changing Oncology Landscape-A Narrative Review of the Literature and the Decade of Carbon Ion Experience at the Italian National Center for Oncological Hadrontherapy.

BACKGROUND: Currently, 13 Asian and European facilities deliver carbon ion radiotherapy (CIRT) for preclinical and clinical activity, and, to date, 55 clinical studies including CIRT for adult and paediatric solid neoplasms have been registered. The National Center for Oncological Hadrontherapy (CNAO) is the only Italian facility able to accelerate both protons and carbon ions for oncological treatment and research. METHODS: To summarise and critically evaluate state-of-the-art knowledge on the application of carbon ion radiotherapy in oncological settings, the authors conducted a literature search till December 2022 in the following electronic databases: PubMed, Web of Science, MEDLINE, Google Scholar, and Cochrane. The results of 68 studies are reported using a narrative approach, highlighting CNAO's clinical activity over the last 10 years of CIRT. RESULTS: The ballistic and radiobiological hallmarks of CIRT make it an effective option in several rare, radioresistant, and difficult-to-treat tumours. CNAO has made a significant contribution to the advancement of knowledge on CIRT delivery in selected tumour types. CONCLUSIONS: After an initial ramp-up period, CNAO has progressively honed its clinical, technical, and dosimetric skills. Growing engagement with national and international networks and research groups for complex cancers has led to increasingly targeted patient selection for CIRT and lowered barriers to facility access.

The POLO (Partially Omitted Lobe) approach to safely treat in-breast recurrence after intraoperative radiotherapy with electrons.

OBJECTIVES: The aim of this study is to evaluate feasibility of salvage 4-week hypofractionated whole breast radiotherapy (WBRT) in patients with in-breast recurrence after receiving intraoperative radiotherapy with electrons (IOERT) for primary breast cancer (BC). METHODS: BC patients who had repeated quadrantectomy underwent modified WBRT with intensity-modulated radiotherapy using Helical Tomotherapy to underdose the IOERT region. This approach, called POLO (Partially Omitted Lobe), excluded the IOERT volume from receiving the full prescription dose. RESULTS: Nine patients were treated with this approach, receiving 45 Gy in 20 fractions. A simultaneous integrated boost of 2.5 Gy in 20 fractions was delivered in 6/9 patients. Dose constraints and planning objectives were reported. No severe toxicity was reported while local control and overall survival were 100%. CONCLUSION: The POLO approach is technically feasible and capable to achieve a significant reduction of radiation dose delivered to the previous treated IOERT area. ADVANCES IN KNOWLEDGE: The study demonstrates the technical and dosimetric feasibility of conservative salvage whole breast radiotherapy, while sparing the area already treated with IORT, in patients with in-breast recurrence.

Particle Radiotherapy for Skull Base Chondrosarcoma: A Clinical Series from Italian National Center for Oncological Hadrontherapy.

BACKGROUND: The standard treatment for skull base chondrosarcoma (SB-CHS) consists of surgery and high-dose radiation therapy. Our aim was to evaluate outcome in terms of local control (LC) and toxicity of proton therapy (PT) and carbon ion (CIRT) after surgery. MATERIALS AND METHODS: From September 2011 to July 2020, 48 patients underwent particle therapy (67% PT, 33% CIRT) for SB-CHS. PT and CIRT total dose was 70 GyRBE (relative biological effectiveness) in 35 fractions and 70.4 GyRBE in 16 fractions, respectively. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5). RESULTS: After a median follow-up time of 38 months, one local failure (2%) was documented and the patient died for progressive disease. Overall, 3-year LC was 98%. One (2%) and 4 (8%) patients experienced G3 acute and late toxicity, respectively. White-matter brain changes were documented in 22 (46%) patients, but only 7 needed steroids (G2). No patients had G3 brain toxicity. No G4-5 complications were reported. We did not find any correlation between high-grade toxicity or white-matter changes and characteristics of patients, disease and surgery. CONCLUSIONS: PT and CIRT appeared to be effective and safe treatments for patients with SB-CHS, resulting in high LC rates and an acceptable toxicity profile.

Radiomics and Dosiomics for Predicting Local Control after Carbon-Ion Radiotherapy in Skull-Base Chordoma.

Skull-base chordoma (SBC) can be treated with carbon ion radiotherapy (CIRT) to improve local control (LC). The study aimed to explore the role of multi-parametric radiomic, dosiomic and clinical features as prognostic factors for LC in SBC patients undergoing CIRT. Before CIRT, 57 patients underwent MR and CT imaging, from which tumour contours and dose maps were obtained. MRI and CT-based radiomic, and dosiomic features were selected and fed to two survival models, singularly or by combining them with clinical factors. Adverse LC was given by in-field recurrence or tumour progression. The dataset was split in development and test sets and the models' performance evaluated using the concordance index (C-index). Patients were then assigned a low- or high-risk score. Survival curves were estimated, and risk groups compared through log-rank tests (after Bonferroni correction α = 0.0083). The best performing models were built on features describing tumour shape and dosiomic heterogeneity (median/interquartile range validation C-index: 0.80/024 and 0.79/0.26), followed by combined (0.73/0.30 and 0.75/0.27) and CT-based models (0.77/0.24 and 0.64/0.28). Dosiomic and combined models could consistently stratify patients in two significantly different groups. Dosiomic and multi-parametric radiomic features showed to be promising prognostic factors for LC in SBC treated with CIRT.

Particle Beam Therapy Tolerance and Outcome on Patients with Autoimmune Diseases: A Single Institution Matched Case-Control Study.

It is unclear whether autoimmune diseases (ADs) may predispose patients to higher radiation-induced toxicity, and no data are available regarding particle therapy. Our objective was to determine if cancer patients with ADs have a higher incidence of complications after protons (PT) or carbon ion (CIRT) therapy. METHODS: In our retrospective monocentric study, 38 patients with ADs over 1829 patients were treated with particle therapy between 2011 and 2020. Thirteen patients had collagen vascular disease (CVD), five an inflammatory bowel disease (IBD) and twenty patients an organ-specific AD. Each patient was matched with two control patients without ADs on the basis of type/site of cancer, type of particle treatment, age, sex, hypertension and/or diabetes and previous surgery. RESULTS: No G4-5 complications were reported. In the AD group, the frequency of acute grade 3 (G3) toxicity was higher than in the control group (15.8% vs. 2.6%, p = 0.016). Compared to their matched controls, CVD-IBD patients had a higher frequency of G3 acute complications (27.7 vs. 2.6%, p = 0.002). There was no difference between AD patients (7.9%) and controls (2.6%) experiencing late G3 toxicity (p = 0.33). The 2 years disease-free survival was lower in AD patients than in controls (74% vs. 91%, p = 0.01), although the differences in terms of survival were not significant. CONCLUSIONS: G3 acute toxicity was more frequently reported in AD patients after PT or CIRT. Since no severe G4-G5 events were reported and in consideration of the benefit of particle therapy for selected cancers, we conclude that particle therapy should be not discouraged for patients with ADs. Further prospective studies are warranted to gain insight into toxicity in cancer patients with ADs enrolled for particle therapy.

Potential role of functional imaging in predicting outcome for patients treated with carbon ion therapy: a review.

OBJECTIVE: Carbon ion radiation therapy (CIRT) is an emerging radiation technique with advantageous physical and radiobiologic properties compared to conventional radiotherapy (RT) providing better response in case of radioresistant and hypoxic tumors. Our aim is to critically review if functional imaging techniques could play a role in predicting outcome of CIRT-treated tumors, as already proven for conventional RT. METHODS: 14 studies, concerning Magnetic resonance imaging (MRI) and Positron Emission Tomography (PET), were selected after a comprehensive search on multiple electronic databases from January 2000 to March 2020. RESULTS: MRI studies (n = 5) focused on diffusion-weighted MRI and, even though quantitative parameters were the same in all studies (apparent diffusion coefficient, ADC), results were not univocal, probably due to different imaging acquisition protocols and tumoral histology. For PET studies (n = 9), different tracers were used such as [18F]FDG and other uncommon tracers ([11C]MET, [18F]FLT), with a relevant heterogeneity regarding parameters used for outcome assessment. CONCLUSION: No conclusion can be drawn on the predictive value of functional imaging in CIRT-treated tumors. A standardization of image acquisition, multi-institutional large trials and external validations are needed in order to establish the prognostic value of functional imaging in CIRT and to guide clinical practice. ADVANCES IN KNOWLEDGE: Emerging studies focused on functional imaging's role in predicting CIRT outcome. Due to the heterogeneity of images acquisition and studies, results are conflicting and prospective large studies with imaging standardized protocol are needed.

Investigating DWI changes in white matter of meningioma patients treated with proton therapy.

PURPOSE: To evaluate changes in diffusion and perfusion-related properties of white matter (WM) induced by proton therapy, which is capable of a greater dose sparing to organs at risk with respect to conventional X-ray radiotherapy, and to eventually expose early manifestations of delayed neuro-toxicities. METHODS: Apparent diffusion coefficient (ADC) and IVIM parameters (D, D* and f) were estimated from diffusion-weighted MRI (DWI) in 46 patients affected by meningioma and treated with proton therapy. The impact on changes in diffusion and perfusion-related WM properties of dose and time, as well as the influence of demographic and pre-treatment clinical information, were investigated through linear mixed-effects models. RESULTS: Decreasing trends in ADC and D were found for WM regions hit by medium-high (30-40 Gy(RBE)) and high (>40 Gy(RBE)) doses, which are compatible with diffusion restriction due to radiation-induced cellular injury. Significant influence of dose and time on median ADC changes were observed. Also, D* showed a significant dependency on dose, whereas f consistently showed no dependency on dose and time. Age, gender and surgery extent were also found to affect changes in ADC. CONCLUSIONS: These results overall agree with those from studies conducted on cohorts of mixed proton and X-ray radiotherapy patients. Future work should focus on relating our findings with clinical information of co-morbidities and thus exploiting such or more advanced imaging data to build normal tissue complication probability models to better integrate clinical and dose information.