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Xeroderma Pigmentosum (XP) is a rare genetic disorder with a poor prognosis due to high photosensitivity in affected patients. Herein, we describe the first case of the use of cemiplimab in a patient with XP, a 19-year-old girl presented with locally advanced squamous cell carcinoma of the right periorbital and nasal region. This treatment has been undertaken after a cycle of proton beam radiotherapy. Besides, it is reported a description of the few cases in the literature describing the effectiveness of immunotherapy on skin cancers in XP-patients. This case is in line with those reported, underlining how anti-PD1 monoclonal antibodies may be a promising treatment in this genodermatosis.

Selection criteria to propose neoadjuvant (re)chemoradiation (CHRT) in locally recurrent rectal cancer (LRRC) are required, since re-irradiation is sometimes associated to severe adverse effects. Aim of the present study was to compare chances of R0 surgery and disease-free survival (DFS) in LRRC patients (pts) treated by neoadjuvant (re)CHRT followed by surgery vs. upfront surgery, stratifying pts by each localization of LRRC.LRRC pts treated at the National Cancer Institute of Milan (Italy) were retrospectively divided into two groups: neoadjuvant (re)CHRT vs. upfront surgery. According to our Milan classification, LRRC were categorized as S1, if located centrally (S1a-b) or anteriorly (S1c) within the pelvis; S2, in case of sacral involvement; S3, in case of lateral pelvic wall infiltration.152 pts were candidate for multimodal treatment: 49 (32.2%) by neoadjuvant (re)CHRT and surgery, including 33 re-irradiations, vs. 103 (67.8%) by upfront surgery. No difference was observed in R0 resection rates (respectively 47.6% vs. 51.0%). However, neoadjuvant (re)CHRT followed by surgery improved the DFS (p = 0.028), also in R1 procedures (p = 0.013), compared with upfront surgery. At multivariate analysis, the R+ surgery (p 0.0001) strongly predicted unfavorable DFS, while neoadjuvant (re)CHRT followed by surgery was independently associated to better DFS (p = 0.0197). Stratifying by LRRC localization, the combined approach significantly improved DFS in the S1c (p = 0.029) and S2 (p = 0.004) subgroups compared to upfront surgery, but not in S1a-b and S3 pts.Anterior (S1c) and sacral-invasive (S2) pelvic recurrences significantly benefit in terms of DFS by combination of neoadjuvant (re)CHRT and radical surgery, also after R1 resection.

Background and Summary: The management of endometrial cancer, in an ever-older population with considerable comorbidity, remains a challenge for gynecological and radiation oncologists. Key Message: The present paper reviews literature data on treatment options for endometrial cancer patients unfit for surgery.

Background and purpose The aim was to evaluate dosimetric uncertainties of a mixed beam approach for patients with high-risk prostate cancer (PCa). The treatment consists of a carbon ion radiotherapy (CIRT) boost followed by whole-pelvis intensity-modulated RT (IMRT). Materials and methods Patients were treated with a CIRT boost of 16.6 Gy/4 fractions followed by whole-pelvis IMRT of 50 Gy/25 fractions, with consequent long term androgen deprivation therapy. Deformable computed tomography image registration (DIR) was performed and corresponding doses were used for plan sum. A comparative IMRT photon plan was obtained as whole-pelvis IMRT of 50 Gy/25 fractions followed by a boost of 28 Gy/14 fractions. DIR performances were evaluated through structure-related and image characteristics parameters. Results Until now, five patients out of ten total enrolled ended the treatment. Dosimetric parameters were lower in CIRT + IMRT than IMRT-only plans for all organs at risk (OARs) except femoral heads. Regarding DIR evaluation, femoral heads were the less deformed OAR. Penile bulb, bladder and anal canal showed intermediate deformation. Rectum was the most deformed. DIR algorithms were patient (P)-dependent, as performances were the highest for P3 and P4, intermediate for P2 and P5, and the lowest for P1. Conclusions CIRT allows better OARs sparing while increasing the efficacy due to the higher radio-biological effect of carbon ions. However, a mixed beam approach could introduce DIR problems in multi-centric treatments with different operative protocols. The development of this prospective trial will lead to more mature data concerning the clinical impact of implementing DIR procedures in dose accumulation applications for high-risk PCa treatments.

To investigate the impact of four-dimensional robust optimization (4DRO) on dose delivered to lung cancer patients in pencil beam scanning proton therapy.2 strategies were compared for 20 lung cancer patients, using a different number of breathing phases of the reconstructed 4D computed tomography (CT) included in the plan optimization problem. In the restricted approach combined with gating, only 3 phases close to reference end-exhale were considered instead of the whole breathing cycle. The prescribed dose was 60 Gy(RBE) in 10 fractions. Target coverage (D98%) and dose to healthy tissues were evaluated using Wilcoxon signed-rank test. To assess the robustness against interfractional anatomical and respiratory variations, the optimized plans were recalculated on re-evaluation 4DCTs. To compare the sensitivity of both strategies to interplay effects, we implemented an end-to-end test with a home-made heterogeneous moving phantom and ionization chambers measurements. Robustly optimized plans with prescription doses of 6 Gy(RBE) were delivered in different dynamic conditions.Both 4D robustly optimized plans reached the same target coverage (p = 0.56), while a statistically significant decrease of the homolateral lung dose was observed using the restricted approach (p 0.0001). Plan recalculations within 15 days from the treatment simulation showed the same robustness of target D98% against interfractional variations (p = 0.48), with an average decrease of approximately 3 Gy(RBE). Phantom measurements confirmed the delivery accuracy of the restricted approach (mean dose deviations5%). Higher deviations were found for ungated full 4DRO and larger motion amplitude.The restricted approach combined with gating improved normal tissue sparing and was shown to be more robust to single fraction deliveries and large motion amplitude.

Multiparametric MRI is a remarkable imaging method for the assessment of patho-physiological processes. In particular, brain tumor characterization has taken advantage of the development of advanced techniques such as Diffusion- (DWI) and Perfusion- (PWI) Weighted Imaging, but a thorough analysis of meningiomas is still lacking despite the variety of computational methods proposed. We compute perfusion and diffusion parametric maps relying on a well-defined methodological workflow, investigating possible correlations between pure and diffusion-based perfusion parameters in a cohort of 26 patients before proton therapy. A preliminary investigation of meningioma staging biomarkers based on IntraVoxel Incoherent Motion and Dynamic Susceptibility Contrast is also reported. We observed significant differences between the gross target volume and the normal appearing white matter for every investigated parameter, confirming the higher vascularization of the neoplastic tissue. DWI and PWI parameters appeared to be weakly correlated and we found that diffusion parameters - the perfusion fraction in particular - could be promising biomarkers for tumor staging.

Aims To report oncologic and functional outcomes in terms of tumor control and toxicity of carbon ion radiotherapy (CIRT) in reirradiation setting for recurrent salivary gland tumors at CNAO. Methods From November 2013 to September 2016, 51 consecutive patients with inoperable recurrent salivary gland tumors were retreated with CIRT in the frame of the phase II protocol CNAO S14/2012C for recurrent head and neck tumors. Results Majority of pts (74.5%) had adenoid cystic carcinoma, mainly rcT4a (51%) and rcT4b (37%). Median dose of prior photon based radiotherapy was 60 Gy. Median dose of CIRT was 60 Gy [RBE] at a mean of 3 Gy [RBE] per fraction. During reirradiation, 19 patients (37.3%) experienced grade G1 toxicity, 19 pts (37.3%) had G2 and 2 pts (3.9%) had G3. Median follow up time was 19 months. Twenty one (41.2%) patients had stable disease and 30 (58.8%) tumor progression at the time of last follow up. Furthermore, 9 (18%) patients had G1 late toxicity, 19 (37%) had G2 and 9 (17. 5%) had G3. Using the Kaplan Meier method, progression free survival (actuarial) at one and two years were 71.7% and 52.2% respectively. Estimated overall survival (actuarial) at one and two years were 90.2% and 64%, respectively. Conclusions CIRT is a good option for retreatment of inoperable recurrent salivary gland tumors with acceptable rates of acute and late toxicity. Longer follow up time is needed to assess the effectiveness of CIRT in reirradiation setting of salivary gland tumors.

Background The aim of this study is to evaluate results in terms of local control (LC), overall survival (OS), and toxicity profile and to better identify factors influencing clinical outcome of skull base chordoma treated with proton therapy (PT) and carbon ion radiotherapy (CIRT). Methods We prospectively collected and analyzed data of 135 patients treated between November 2011 and December 2018. Total prescription dose in the PT group (70 patients) and CIRT group (65 patients) was 74 Gy relative biological effectiveness (RBE) delivered in 37 fractions and 70.4 Gy(RBE) delivered in 16 fractions, respectively (CIRT in unfavorable patients). LC and OS were evaluated using the Kaplan–Meier method. Univariate and multivariate analyses were performed, to identify prognostic factors on clinical outcomes. Results After a median follow-up of 49 (range, 6–87) months, 14 (21%) and 8 (11%) local failures were observed in CIRT and PT group, respectively. Five-year LC rate was 71% in CIRT cohort and 84% in PT cohort. The estimated 5-year OS rate in the CIRT and PT group was 82% and 83%, respectively. On multivariate analysis, gross tumor volume (GTV), optic pathways, and/or brainstem compression and dose coverage are independent prognostic factors of local failure risk. High rate toxicity grade ≥3 was reported in 11% of patients. Conclusions Particle radiotherapy is an effective treatment for skull base chordoma with acceptable late toxicity. GTV, optic pathways, and/or brainstem compression and target coverage were independent prognostic factors for LC. Key Points • Proton and carbon ion therapy are effective and safe in skull base chordoma. • Prognostic factors are GTV, organs at risk compression, and dose coverage. • Dual particle therapy and customized strategy was adopted.

Background and summary: Among all vulvar cancers, primary adenoid cystic carcinoma (ACC) of Bartholin’s gland is a very rare tumor characterized by a slow growth, a high local aggressiveness, and a remarkable recurrence rate. Due to its rarity, treatment remains a challenge for oncologists and gynecological surgeons. Key message: The present paper reports clinical, radiological, and histological features of ACC of Bartholin’s gland and reviews the literature data on the treatment options with a particular focus on the potential role of particle radiation therapy.

One of the most important late side-effects of radiation therapy is the development of radiation-induced secondary malignancies. In the last years, this topic has significantly influenced treatment decision-making as the number of long-term cancer survivors has significantly increased with advances in treatment modalities. All efforts are being made to prevent the incidence of tumors induced by radiation. In this review article we summarize the current knowledge about treatment-related secondary cancers with a particular attention to hadrontherapy.

Background/aim Malignant peripheral nerve sheaths tumors (MPNST) are rare, highly aggressive and radioresistant tumors of soft tissue. Carbon ion radiotherapy (CIRT) seems to be an attractive treatment option when surgery is not possible or refused by the patient. The aim of this study was to report our preliminary results (outcomes and toxicity) of CIRT in the treatment of MPNSTs. Patients and methods Our study retrospectively analyzed 13 patients (median age=54 years; range=23-72 years) with MPNST treated with CIRT for a median total dose of 73.6 Gy (relative biological effectiveness) (range=70.4-76.8 Gy) between 2013 and 2016. Results Six local progressions were recorded, with a median local progression-free survival of 23.2 months (range=2.2-45.4 months). Acute toxicities were mild. Late toxicity of grade 2 or more was noted in two patients. Conclusion CIRT yielded good local control with a low rate of acute and late toxicities.

The aim of this study is to evaluate results in terms of local control (LC), overall survival (OS), and toxicity profile and to better identify factors influencing clinical outcome of skull base chordoma treated with proton therapy (PT) and carbon ion radiotherapy (CIRT).We prospectively collected and analyzed data of 135 patients treated between November 2011 and December 2018. Total prescription dose in the PT group (70 patients) and CIRT group (65 patients) was 74 Gy relative biological effectiveness (RBE) delivered in 37 fractions and 70.4 Gy(RBE) delivered in 16 fractions, respectively (CIRT in unfavorable patients). LC and OS were evaluated using the Kaplan-Meier method. Univariate and multivariate analyses were performed, to identify prognostic factors on clinical outcomes.After a median follow-up of 44 (range, 6-87) months, 14 (21%) and 8 (11%) local failures were observed in CIRT and PT group, respectively. Five-year LC rate was 71% in CIRT cohort and 84% in PT cohort. The estimated 5-year OS rate in the CIRT and PT group was 82% and 83%, respectively. On multivariate analysis, gross tumor volume (GTV), optic pathways, and/or brainstem compression and dose coverage are independent prognostic factors of local failure risk. High rate toxicity grade ≥3 was reported in 11% of patients.Particle radiotherapy is an effective treatment for skull base chordoma with acceptable late toxicity. GTV, optic pathways, and/or brainstem compression and target coverage were independent prognostic factors for LC.• Proton and carbon ion therapy are effective and safe in skull base chordoma.• Prognostic factors are GTV, organs at risk compression, and dose coverage.• Dual particle therapy and customized strategy was adopted.

Simple Summary Concurrent chemo-radiotherapy is the standard treatment in anal cancer. Intensity-modulated radiotherapy (IMRT) was proved to reduce severe, acute and late toxicities. Moreover, IMRT techniques allow for the planning and delivery of a simultaneous integrated boost (SIB), with a differential dose per fraction given to selected sub-regions during the same treatment session. This boost modality provides the chance to employ a dose-painted approach with a reduction in overall treatment time that could result in a potential clinical advantage. Since a large variability in dose prescription to the primary tumor and elective or involved lymph nodes can be found in available guidelines and clinical practice, a multicenter analysis was conducted to evaluate the pattern of care and the impact of radiotherapy parameters on clinical outcomes for anal cancer patients treated with IMRT techniques within a national cohort. Abstract A multi-institutional retrospective study was conducted to evaluate the pattern of care and clinical outcomes of anal cancer patients treated with intensity-modulated radiotherapy (IMRT) techniques. In a cohort of 987 patients, the clinical complete response (CR) rate (beyond 6 months) was 90.6%. The 3-year local control (LC) rate was 85.8% (95% CI: 84.4–87.2), and the 3-year colostomy-free survival (CFS) rate was 77.9% (95% CI: 76.1–79.8). Three-year progression-free survival (PFS) and overall survival (OS) rates were 80.2% and 88.1% (95% CI: 78.8–89.4) (95% CI: 78.5–81.9), respectively. Histological grade 3 and nodal involvement were associated with lower CR (p = 0.030 and p = 0.004, respectively). A statistically significant association was found between advanced stage and nodal involvement, and LC, CFS, PFS, OS and event-free survival (EFS). Overall treatment time (OTT) ≥45 days showed a trend for a lower PFS (p = 0.050) and was significantly associated with lower EFS (p = 0.030) and histological grade 3 with a lower LC (p = 0.025). No statistically significant association was found between total dose, dose/fraction and/or boost modality and clinical outcomes. This analysis reports excellent clinical results and a mild toxicity profile, confirming IMRT techniques as standard of care for the curative treatment of anal cancer patients. Lymph node involvement and histological grade have been confirmed as the most important negative prognostic factors.

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&rsquo, 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 &alpha, = 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.

An Eye Tracking System (ETS) is used at CNAO for providing a stable and reproducible ocular proton therapy (OPT) set-up, featuring a fixation light (FL) and monitoring stereo-cameras embedded in a rigid case. The aim of this work is to propose an ETS set-up simulation algorithm, that automatically provides the FL positioning in space, according to patient-specific gaze direction and avoiding interferences with patient, beam and collimator. Two configurations are provided: one in the CT room for acquiring images required for treatment planning with the patient lying on a couch, and one related to the treatment room with the patient sitting in front of the beam. Algorithm validation was performed reproducing ETS simulation (CT) and treatment (room) set-up for 30 patients previously treated at CNAO. The positioning accuracy of the device was quantified through a set of 14 control points applied to the ETS case and localizable both in the CT volume and in room X-ray images. Differences between the position of ETS reference points estimated by the algorithm and those measured by imaging systems are reported. The corresponding gaze direction deviation is on average 0.2° polar and 0.3° azimuth for positioning in CT room and 0.1° polar and 0.4° azimuth in the treatment room. The simulation algorithm was embedded in a clinically usable software application, which we assessed as capable of ensuring ETS positioning with an average accuracy of 2 mm in CT room and 1.5 mm in treatment room, corresponding to gaze direction deviations consistently lower than 1°.

PURPOSE In-beam Positron Emission Tomography (PET) is one of the modalities that can be used for in-vivo non-invasive treatment monitoring in proton therapy. Although PET monitoring has been frequently applied for this purpose, there is still no straightforward method to translate the information obtained from the PET images into easy to interpret information for clinical personnel. The purpose of this work is to propose a statistical method for analyzing in-beam PET monitoring images that can be used to locate, quantify and visualize regions with possible morphological changes occurring over the course of treatment. MATERIALS AND METHODS We selected a patient treated for Squamous Cell Carcinoma (SCC) with proton therapy, to perform multiple Monte Carlo (MC) simulations of the expected PET signal at the start of treatment, and to study how the PET signal may change along the treatment course due to morphological changes. We performed voxel-wise two-tailed statistical tests of the simulated PET images, resembling the Voxel-Based Morphometry (VBM) method commonly used in neuroimaging data analysis, to locate regions with significant morphological changes and to quantify the change. RESULTS The VBM resembling method has been successfully applied to the simulated in-beam PET images, despite the fact that such images suffer from image artifacts and limited statistics. Three dimensional probability maps were obtained, that allowed to identify inter-fractional morphological changes and to visualize them superimposed on the Computed Tomography (CT) scan. In particular, the characteristic color patterns resulting from the two-tailed statistical tests lend themselves to trigger alarms in case of morphological changes along the course of treatment. CONCLUSIONS The statistical method presented in this work is a promising method to apply to PET monitoring data to reveal inter-fractional morphological changes in patients, occurring over the course of treatment. Based on simulated in-beam PET treatment monitoring images, we showed that with our method it was possible to correctly identify the regions that changed. Moreover we could quantify the changes, and visualize them superimposed on the CT scan. The proposed method can possibly help clinical personnel in the replanning procedure in adaptive proton therapy treatments. This article is protected by copyright. All rights reserved.

Background/Aim: Re-irradiation of locally recurrent rectal cancer poses challenges due to the proximity of critical organs, such as the bowel. This study aimed at evaluating the safety and efficacy of re-irradiation with Carbon Ion Radiotherapy (CIRT) in rectal cancer patients with local recurrence. Patients and Methods: Between 2014 and 2018, 14 patients were treated at the National Center of Oncological Hadrontherapy (CNAO Foundation) with CIRT for locally recurrent rectal cancer. Results: All patients concluded the treatment. No G≥3 acute/late reaction nor pelvic infections were observed. The 1-year and 2-year local control rates were, 78% and 52%, respectively, and relapse occurred close to the bowel in 6 patients. The 1-year and 2-year overall survival rates were 100% and 76.2% each; while the 1-year and 2-year metastasis free survival rates were 64.3% and 43%. Conclusion: CIRT as re-irradiation for locally recurrent rectal cancer emerges as a safe and valid treatment with an acceptable rate of morbidity of surrounding healthy tissue.

Background Malignant melanoma of the lower genital tract is a rare disease known to have a poor prognosis. Because of the high rate of distant metastasis and unsatisfactory survival benefit, a more conservative treatment approach, instead of extensive surgery, may be warranted. Gynecological melanoma is a radioresistant tumor, an ideal disease to test the biological efficacy of carbon ion radiotherapy (CIRT). Aim To report our preliminary experience with CIRT in the treatment of gynecological melanoma at the National Center of Oncological Hadrontherapy (CNAO). Patients and methods Between January 2016 and February 2017, four patients were admitted for CIRT at CNAO. A case of cervical melanoma was treated with palliative aim because of large volume macroscopic disease, while three cases of vaginal melanoma were irradiated with a total dose of 68.8 Gy (relative biological effectiveness) in 16 fractions delivered over 4 weeks (4 days a week). Results The age of women ranged between 49 and 72 (median=60.5 years) years. Treatment was well tolerated in all patients and all women completed the scheduled treatment course. During CIRT, toxicity was mild. For patients with vaginal disease, local control was 10.23 and 12.6 months, while that for cervical malignant melanoma was 7.3 months. All patients experienced systemic progression, with median distant metastasis-free survival of 11.7 months. The median overall survival for the whole patient group was 11.41 months. Conclusion In our first experiences, CIRT appears to be a safe non-invasive option for malignant melanoma of the lower genital tract, but more data and longer follow-up are necessary in order to evaluate the effectiveness and late effects.

BACKGROUND AND OBJECTIVES Selection of patients affected by pelvic recurrence of rectal cancer (PRRC) who are likely to achieve a R0 resection is mandatory. The aim of this study was to propose a classification for PRRC to predict both radical surgery and disease-free survival (DFS). METHODS PRRC patients treated at the National Cancer Institute of Milan (Italy) were included in the study. PRRC were classified as S1, if located centrally (S1a-S1b) or anteriorly (S1c) within the pelvis; S2, in case of sacral involvement below (S2a) or above (S2b) the second sacral vertebra; S3, in case of lateral pelvic involvement. RESULTS Of 280 reviewed PRRC patients, 152 (54.3%) were evaluated for curative surgery. The strongest predictor of R+ resection was the S3 category (OR, 6.37; P = .011). Abdominosacral resection (P = .012), anterior exenteration (P = .012) and extended rectal re-excision (P = .003) were predictive of R0 resection. S3 category was highly predictive of poor DFS (HR 2.53; P = .038). DFS was significantly improved after R0 surgery for S1 (P

Background/aim Definitive radiotherapy for bone and soft tissues sarcomas benefits patients deemed unfit for surgery; poor outcomes have been reported with conventional photons, while interesting preliminary results have been described with particle in single-Institution experiences. The aim of the study was to retrospectively evaluate preliminary results of carbon ion radiotherapy (CIRT) in patients with axial bone and soft tissue sarcomas (BSTS) treated with curative intent at the National Center for Oncological Hadrontherapy (CNAO). Patients and methods From January 2013 to September 2018, 54 patients with axial BSTS were treated with CIRT at CNAO. Their median age was 50 years (range=19-79 years), males/females=1.4:1. Tumor site was the pelvis in 50% of cases (n=27), thoracic region in 24% (n=13), cervical spine in 15% (n=8) and lumbar in 11% (n=6). A total of 76% (n=41) of patients had primary disease, while 24% (n=13) had recurrent disease. Before CIRT, surgery was performed in 47% of cases, including positive margins (R1) in 8 patients, and macroscopic residual disease (R2) in 17. Histological subtypes were mainly represented by chondrosarcomas in 39% (n=21) of patients and osteosarcomas in 24% (n=13). Pre-treatment chemotherapy was administered in 40% of cases (n=22); no patient received previous radiotherapy. All treatments were performed with active scanning CIRT for a median total dose of 73.6 Gy (range=70.4-76.8 Gy), in 16 fractions (4 fractions per week). Results Median follow-up was 24 months (range=4-61 months). Four patients were lost to follow-up. Acute toxicities were mild, no >G2 event was reported and no treatment interruption was required. For late toxicity, only G3 neuropathy was detected in 4% of cases (n=2). With a median time to local progression of 13 months (3-35), 15 local failures were observed, resulting in 2- and 3-year local control rates of 67.4% for both. Distant progression occurred in 12 patients, with 1-year progression-free survival (PFS) rate of 97.5%; 2- and 3-year rates were 92.2%. Fifteen patients died resulting in 1- 2- and 3-years overall survival (OS) rates of 87.1%, 75.4% and 64%, respectively. At log-rank test, gross total volume (GTV) >1,000 ml was found to be predictive of local failure (p=0.04), pre-treatment chemotherapy was found to be significantly related to PFS and OS (p=0.02 and p=0.016); also, recurrent disease and distant progression were significantly related to OS (p=0.019 and p=0.0013). Cox proportional-hazards model confirmed that GTV >1,000 ml was related to worse local control (p=0.0010). Conclusion CIRT for axial BSTS resulted in mild toxicity, showing promising results in terms of clinical outcomes. A longer follow-up is warranted.

Meningiomas are mainly benign tumors, though a considerable proportion shows aggressive behaviors histologically consistent with atypia/anaplasia. Histopathological grading is usually assessed through invasive procedures, which is not always feasible due to the inaccessibility of the lesion or to treatment contraindications. Therefore, we propose a multi-parametric MRI assessment as a predictor of meningioma histopathological grading.Seventy-three patients with 74 histologically proven and previously treated meningiomas were retrospectively enrolled (42 WHO I, 24 WHO II, 8 WHO III) and studied with MRI including T2 TSE, FLAIR, Gradient Echo, DWI, and pre- and post-contrast T1 sequences. Lesion masks were segmented on post-contrast T1 sequences and rigidly registered to ADC maps to extract quantitative parameters from conventional DWI and intravoxel incoherent motion model assessing tumor perfusion. Two expert neuroradiologists assessed morphological features of meningiomas with semi-quantitative scores.Univariate analysis showed different distributions (p 0.05) of quantitative diffusion parameters (Wilcoxon rank-sum test) and morphological features (Pearson's chi-square; Fisher's exact test) among meningiomas grouped in low-grade (WHO I) and higher grade forms (WHO II/III); the only exception consisted of the tumor-brain interface. A multivariate logistic regression, combining all parameters showing statistical significance in the univariate analysis, allowed discrimination between the groups of meningiomas with high sensitivity (0.968) and specificity (0.925). Heterogeneous contrast enhancement and low ADC were the best independent predictors of atypia and anaplasia.Our multi-parametric MRI assessment showed high sensitivity and specificity in predicting histological grading of meningiomas. Such an assessment may be clinically useful in characterizing lesions without histological diagnosis. Key points • When surgery and biopsy are not feasible, parameters obtained from both conventional and diffusion-weighted MRI can predict atypia and anaplasia in meningiomas with high sensitivity and specificity. • Low ADC values and heterogeneous contrast enhancement are the best predictors of higher grade meningioma.

BACKGROUND AND PURPOSE To compare RECIST 1.1 with volume modifications in patients with sacral chordoma not suitable for surgery treated with carbon ions radiotherapy (CIRT) alone. To evaluate patients pain before and after CIRT. To detect if baseline Apparent Diffusion Coefficient values (ADC) from Diffusion Weighted sequences could predict response to treatment. MATERIAL AND METHODS Patients included had one cycle of CIRT and underwent MRI before and after treatment. For each MRI, lesion maximum diameter and volume were obtained, and ADC values were analyzed within the whole lesion volume. Patients pain was evaluated with Numerical Rating Scale (NRS), considering the upper tumor level at baseline MRIs. RESULTS 39 patients were studied (mean follow-up 18 months). Considering RECIST 1.1 there was not a significant reduction in tumor diameters (p = 0.19), instead there was a significant reduction in tumor volume (p

Introduction: Several efforts are being implemented at the European level to measure provision of up-to-date radiation treatments across the continent. Methods: A snapshot survey involving all radiation oncology centers within Lombardy, Italy, was performed in 2012 and repeated in 2014 and 2016, in cooperation with regional governmental officers. Centers were asked to provide detailed information concerning all individual patients being treated on the index day, and to report data on available local resources. Results: We observed an increase in the number of centers and of megavoltage units (MVU) (from 76 to 87, i.e., 8.7 MVU per million inhabitants in 2016). Mean number of MVU per center was 2.5. Average age of MVU increased from 5.3 to 7.5 years and patients on the waiting list also increased. Conformal 3D radiotherapy (RT) treatments decreased from 56% to 42% and were progressively replaced by intensity-modulated RT treatments (from 39% to 49%). Waiting times were overall satisfactory. Radiation oncologists treated on average 152 and radiation therapists 100 RT courses per year. Average reimbursement per course was €4,879 (range €2,476–€8,014). Conclusions: The methodology of snapshot survey proved feasible and provided valuable information about radiation oncology provision and accessibility in Lombardy.

In inoperable patients, the management of angiosarcoma of the scalp is challenging. Due to intrinsic, dosimetric and radiobiological properties, proton beam radiotherapy may be an effective and safe option to offer to these difficult-to-cure patients. Here, we report a case of angiosarcoma of the scalp treated successfully with proton beam radiotherapy. Angiosarcoma is a rare malignancy concerning around 2% of soft-tissue sarcomas and 5% of cutaneous soft-tissue sarcomas. Cutaneous angiosarcomas can occur in any part of the body, but the head and neck region is a common primary site and the scalp is a frequent site in elderly patients.

Background: The standard approach for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME). After nCRT 20% of patients achieve a clinical complete response (pCR) and could be treated with a non-operative management (NOM). Methods: The panel of the Italian Association of Medical Oncology (AIOM) Guidelines on rectal cancer applied the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach addressing the following question: Should NOM vs. TME be used for patients with rectal cancer with clinical complete response after nCRT? Five outcomes were identified: disease-free survival (DFS), mortality, local recurrence, colostomy rate, and functional outcomes. Results: Nine studies were included in the analysis. A higher risk of disease recurrence was observed in the NOM group compared to the TME group (RR = 1.69, 95% CI 1.08, 2.64) on the other hand, we observed a slightly positive but not significant effect on mortality of NOM (RR = 0.82, 95% CI 0.46, 1.45). Patients in the NOM group were more likely to experience local recurrence (RR = 5.37, 95% CI 2.56, 11.27) and patients in the TME group were more likely to have a permanent colostomy (RR = 0.15, 95% CI 0.08, 0.29). Only one study evaluated functional outcomes. The overall certainty of evidence was rated as very low. Conclusions: NOM was found to correlate with a higher risk of local recurrence which did not translate in worse OS and a lower colostomy rate. Due to the paucity of evidences, no recommendations are possible. NOM remains an experimental treatment; thus, patients managed with NOM should be enrolled in clinical trials with a dedicated follow-up schedule.

Purpose To generate virtual 4DCT from 4DMRI with field of view (FOV) extended to the entire involved patient anatomy, in order to evaluate its use in carbon ion radiation therapy (CIRT) of the abdominal site in a clinical scenario. Materials and methods The virtual 4DCT was generated by deforming a reference CT in order to (1) match the anatomy depicted in the 4DMRI within its FOV, by calculating deformation fields with deformable image registration to describe inter-fractional and breathing motion, and (2) obtain physically plausible deformation outside of the 4DMRI FOV, by propagating and modulating the previously obtained deformation fields. The implemented method was validated on a digital anthropomorphic phantom, for which a ground truth (GT) 4DCT was available. A CIRT treatment plan was optimized at the end-exhale reference CT and the RBE-weighted dose distribution was recalculated on both the virtual and GT 4DCTs. The method estimation error was quantified by comparing the virtual and GT 4DCTs and the corresponding recomputed doses. The method was then evaluated on 8 patients with pancreas or liver tumors treated with CIRT using respiratory gating at end-exhale. The clinical treatment plans adopted at the National Center for Oncological Hadrontherapy (CNAO, Pavia, Italy) were considered and the dose distribution was recomputed on all respiratory phases of the planning and virtual 4DCTs. By comparing the two datasets and the corresponding dose distributions, the geometrical and dosimetric impact of organ motion was assessed. Results For the phantom, the error outside of the 4DMRI FOV was up to 4.5 mm, but it remained sub-millimetric in correspondence to the target within the 4DMRI FOV. Although the impact of motion on the target D95% resulted in variations ranging from 22% to 90% between the planned dose and the doses recomputed on the GT 4DCT phases, the corresponding estimation error was ≤2.2%. In the patient cases, the variation of the baseline tumor position between the planning and the virtual end-exhale CTs presented a median (interquartile range) value of 6.0 (4.9) mm. For baseline variations larger than 5 mm, the tumor D95% variation between the plan and the dose recomputed on the end-exhale virtual CT resulted larger than 10%. Median variations higher than 10% in the target D95% and gastro-intestinal OARs D2% were quantified at the end-inhale, whereas close to the end-exhale phase, limited variations of relevant dose metrics were found for both tumor and OARs. Conclusions The negligible impact of the geometrical inaccuracy in the estimated anatomy outside of the 4DMRI FOV on the overall dosimetric accuracy suggests the feasibility of virtual 4DCT with extended FOV in CIRT of the abdominal site. In the analyzed patient group, inter-fractional variations such as baseline variation and breathing variability were quantified, demonstrating the method capability to support treatment planning in gated CIRT of the abdominal site.

Purpose To evaluate if baseline ADC from DWI sequences could predict response to treatment in patients with sacral chordoma not suitable for surgery treated with carbon ion radiotherapy (CIRT) alone compared with volume changes. Methods Fifty-nine patients with sacral chordoma not suitable for surgery underwent one cycle of CIRT alone and a minimum of 12-months follow-up. All patients underwent MRI before treatment (baseline), every three months in the first two years after treatment, and every six months afterwards. For each MRI, lesion volume was obtained and median, kurtosis, and skewness ADC were analyzed within the whole lesion volume. Volume changes between baseline and the last available follow-up were used to divide patients with partial response, progression of disease and stable disease (PR, PD, and SD). Results Ten patients were excluded since DWI sequences from baseline MRI were not available. ADC maps obtained from baseline DWI examinations of 50 lesions in the remaining 49 patients were considered. Seven lesions were categorized as PD, 30 PR, and 13 SD. PD showed significantly higher median ADC values at baseline (p = 0.003) compared with both PR and SD (1665vs1253vs1263 *10−6 mm²/s), and more negative skewness values (-0.26vs0.26vs0.08), although not significantly different (p = 0.16). Conclusions Preliminary results suggest that baseline ADC could predict response to treatment with CIRT, particularly to detect potential non-responder patients.

Purpose In image-guided particle radiotherapy of abdominal lesions, respiratory motion hinders treatment accuracy. In this study, 2D cineMRI data were used to quantify the tumor (GTV) motion and to evaluate the clinical approach based on deriving an internal target volume (ITV) from a planning 4DCT for gating treatments. Methods Seven patients with abdominal lesions were treated with carbon-ion therapy at the National Centre of Oncological Hadron-therapy (Italy). The MR scan was performed on the same day of the 4DCT acquisition. For four patients, an additional MR was acquired approximately after 1 week. The cineMRI combined with deformable image registration algorithm was used to quantify tumor motion. Afterwards, two ITVs were defined considering (1) all phases (ITVFB) and (2) only phases within the gating window (ITVG), and then compared with the clinical (4DCT-derived) ITVs (ITVCG and ITVCFB). Results Tumor residual motion estimated by cineMRI data in the two MRI sessions resulted not significantly different from 4DCT, although cineMRI accounted for cycle-to-cycle variations. The ITV normalized for the GTV median values were higher for ITVFB with respect to ITVG, ITVCFB and ITVCG. The Hausdorff distances with respect to the GTV were up to 10.55 mm, 3.13 mm, 5.56 mm and 2.51 mm, for ITVFB, ITVG, ITVCFB and ITVCG, respectively. According to both metrics, ITVCG and ITVG were not found significantly different. Conclusions CineMRI acquisitions allowed to quantify organ motion without delivering additional dose to the patient and to verify treatment margins in gated carbon-ion therapy of abdominal lesions.

To devise a novel Spatial Normalization framework for Voxel-based analysis (VBA) in brain radiotherapy. VBAs rely on accurate spatial normalization of different patients' planning CTs on a common coordinate system (CCS). The cerebral anatomy, well characterized by MRI, shows instead poor contrast in CT, resulting in potential inaccuracies in VBAs based on CT alone.We analyzed 50 meningioma patients treated with proton-therapy, undergoing planning CT and T1-weighted (T1w) MRI. The spatial normalization pipeline based on MR and CT images consisted in: intra-patient registration of CT to T1w, inter-patient registration of T1w to MNI space chosen as CCS, doses propagation to MNI. The registration quality was compared with that obtained by Statistical Parametric Mapping software (SPM), used as benchmark. To evaluate the accuracy of dose normalization, the dose organ overlap (DOO) score was computed on gray matter, white matter and cerebrospinal fluid before and after normalization. In addition, the trends in the DOOs distribution were investigated by means of cluster analysis.The registration quality was higher for the proposed method compared to SPM (p 0.001). The DOO scores showed a significant improvement after normalization (p 0.001). The cluster analysis highlighted 2 clusters, with one of them including the majority of data and exhibiting acceptable DOOs.Our study presents a robust tool for spatial normalization, specifically tailored for brain dose VBAs. Furthermore, the cluster analysis provides a formal criterion for patient exclusion in case of non-acceptable normalization results. The implemented framework lays the groundwork for future reliable VBAs in brain irradiation studies.

Hypofractionated radiotherapy (HRT) would be more convenient for men with low-risk prostate cancer and cost less than conventional radiotherapy (CRT) as long as HRT is noninferior to CRT in terms of survival and quality of life (QOL) is not found to be worse.To assess differences in QOL between men with low-risk prostate cancer who are treated with HRT vs CRT.In this phase 3 randomized clinical trial, men with low-risk prostate cancer were enrolled from sites within the National Cancer Institute's National Clinical Trials Network in the United States, Canada, and Switzerland.Random assignment to CRT (73.8 Gy in 41 fractions over 8.2 weeks) or to HRT (70 Gy in 28 fractions over 5.6 weeks).Quality of life was assessed using the Expanded Prostate Index Composite questionnaire measuring bowel, urinary, sexual, and hormonal domains; the 25-item Hopkins Symptom Checklist measuring anxiety and depression; and the EuroQol-5 Dimension questionnaire measuring global QOL. All data were collected at baseline and 6, 12, 24, and 60 months. Change scores were compared between treatment arms using the Wilcoxon signed rank test. A significance level of .0125 to adjust for multiple comparisons was used for an overall 2-sided type 1 error of .05. Clinical significance was determined for the Expanded Prostate Index Composite change scores by an effect size of 0.5.Of 1092 patients analyzable for the primary end point, 962 (mean [SD] age, 66.6 [7.4] years) consented to the QOL component. No statistically significant differences with regard to baseline characteristics nor any of the QOL baseline domains were measured between arms. There were no differences in change score between arms with respect to any of the Expanded Prostate Index Composite questionnaire domain scores except at 12 months when the HRT arm had a larger decline than the CRT arm in the bowel domain (mean score, -7.5 vs -3.7, respectively; P.001), but it did not reach clinical significance (effect size = 0.29). There were no differences between arms at any time point for the Hopkins Symptom Checklist nor EuroQol-5 Dimension questionnaire.Treatment with HRT is noninferior to CRT in men with low-risk prostate cancer in terms of disease-free survival and, as shown in the present study, in prostate cancer-specific (eg, bowel, bladder, sexual) and general QOL, as well as in anxiety and depression. This study provides evidence to affirm that HRT is a practice standard for men with low-risk prostate cancer.ClinicalTrials.gov identifier: NCT00331773.

The clinical application of different relative biological effectiveness (RBE) models for carbon ion RBE-weighted dose calculation hinders a global consensus in defining normal tissue constraints. This work aims to update the local effect model (LEM)-based constraints for the rectum using microdosimetric kinetic model (mMKM)-defined values, relying on RBE translation and the analysis of long-term clinical outcomes. LEM-optimized plans of treated patients, having suffered from prostate adenocarcinoma (n = 22) and sacral chordoma (n = 41), were recalculated with the mMKM using an in-house developed tool. The relation between rectum dose-volume points in the two RBE systems (DLEM|v and DMKM|v) was fitted to translate new LEM-based constraints. Normal tissue complication probability (NTCP) values, predicting late rectal toxicity, were obtained by applying published parameters. No late rectal toxicity events were reported within the patient cohort. The rectal toxicity outcome was confirmed using dosimetric analysis: DMKMVHs lay largely below original constraints, the translated DLEM|v values were 4.5%, 8.3%, 18.5%, and 35.4% higher than the nominal DMKM|v of the rectum volume, v&mdash, 1%, 5%, 10% and 20%. The average NTCP value ranged from 5% for the prostate adenocarcinoma, to 0% for the sacral chordoma group. The redefined constraints, to be confirmed prospectively with clinical data, are DLEM|5cc &le, 61 Gy(RBE) and DLEM|1cc &le, 66 Gy(RBE).

Objective: Accurate patient positioning is crucial in particle therapy due to the geometrical selectivity of particles. We report and discuss the National Center for Oncological Hadrontherapy (CNAO) experience in positioning accuracy and stability achieved with solid thermoplastic masks fixed on index base plates and assessed by daily orthogonal X-ray imaging. Methods: Positioning data were retrospectively collected (between 2012 and 2018) and grouped according to the treated anatomical site. 19696 fractions of 1325 patients were evaluated. The study was designed to assess: (i) the number of fractions in which a single correction vector was applied(SCV); (ii) the number of fractions in which further setup verification was performed (SV); (iii) the number of fractions in which SV lead to an additional correction within (MCV5min) 5 minutes from the first setup correction; (iv) the systematic (Σ) and random (σ) error components of the correction vectors applied. Results: A SCV was applied in 71.5% of fractions, otherwise SV was required. In 30.6% of fractions with SV, patient position was not further revised. In the remaining fractions, MCV5min were applied mainly in extracranial and cranial sites respectively. Interfraction Σ was ≤ 1.7 mm/0.7° and σ was ≤ 1.2 mm/0.6° in cranial sites while in extracranial sites Σ was ≤ 5.5 mm/0.9° and σ was ≤4.4 mm/0.9°. Setup residuals were submillimetric in all sites. In cranial patients, maximum intrafractional Σ was 0.8 mm/0.4°. Conclusion: This report extensively quantifies inter- and intrafraction setup accuracy on an institutional basis and confirms the need of image guidance to fully benefit from the geometrical selectivity of particles. Advances in knowledge: The reported analysis provides a board institutional data set on the evaluation of patient immobilization and bony anatomy alignment for several particle therapy clinical indications.