Curative carbon ion radiotherapy in a head and neck mucosal melanoma series: Facing the future within multidisciplinarity.

PURPOSE: To evaluate efficacy and toxicity of carbon ion radiotherapy (CIRT) in locally advanced head and neck mucosal melanoma (HNMM) patients treated at our Institute. MATERIALS AND METHODS: Between June 2013 and June 2020, 40 HNMM patients were treated with CIRT. Prescription dose was 65.6-68.8 Gy relative biological effectiveness [RBE] in 16 fractions. Twelve (30%) patients received only biopsy, 28 (70%) surgical resection before CIRT. Immunotherapy was administered before and/or after CIRT in 45% of patients, mainly for distant progression (89%). RESULTS: Median follow-up was 18 months. 2-year Local Relapse Free Survival (LRFS), Overall Survival (OS), Progression Free Survival (PFS) and Distant Metastasis Free Survival (DMFS) were 84.5%, 58.6%, 33.2% and 37.3%, respectively. At univariate analysis, LRFS was significantly better for non-recurrent status, < 2 surgeries before CIRT and treatment started < 9 months from the initial diagnosis, with no significant differences for operated versus unresected patients. After relapse, immunotherapy provided longer median OS (17 months vs 3.6, p-value<0.001). Late toxicity ≥ G3 (graded with CTCAE 5.0 scale) was reported in 10% of patients. CONCLUSION: CIRT in advanced HNMM patients is safe and locally effective. Prospective trials are warranted to assess the role of targeted/immune- systemic therapy to improve OS.

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.

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.

Role of diffusion-weighted MRI in recurrent rectal cancer treated with carbon ion radiotherapy.

Aim: To evaluate the association between pretreatment diffusion-weighted MRI (DW-MRI) and 12-month radiological response in locally recurrent rectal cancer treated with carbon ion radiotherapy. Methods: Histogram analysis was performed on pretreatment DW-MRI for patients re-irradiated with carbon ion radiotherapy for local recurrence of rectal cancer. Results: A total of 17 patients were enrolled in the study. Pretreatment DW-MRI b-value of 1000 s/mm2 (b1000) and apparent diffusion coefficient (ADC) lesion median values for 1-year nonresponders (six patients) and responders (11 patients) demonstrated a median (interquartile of median values) of 62.5 (23.9) and 34.0 (13.0) and 953.0 (277.0) and 942.5 (339.0) µm2/s, respectively. All b1000 histogram features (h-features) and ADC h-kurtosis showed statistically significant differences, whereas only b1000 h-median, b1000 h-interquartile range and ADC h-kurtosis demonstrated remarkable diagnostic accuracy. Conclusion: DW-MRI showed promising results in predicting carbon ion radiotherapy outcome in local recurrence of rectal cancer, particularly with regard to b1000 h-median, b1000 h-interquartile range and ADC h-kurtosis.

Carbon ion radiotherapy is a form of advanced radiotherapy that is especially suitable for radioresistant and/or difficult-to-irradiate tumors. In case of recurrence of rectal cancer after pelvic photon beam radiotherapy, carbon ion radiotherapy may be an option. In this study, the authors looked at the potential role of specific MRI sequences performed before treatment to predict response to carbon ion radiotherapy. If confirmed in a larger prospective cohort, the findings of this study may drive clinical decisions toward a more tumor- and patient-tailored therapeutic approach.

Dosimetric and Clinical Risk Factors for the Development of Maxillary Osteoradionecrosis in Adenoid Cystic Carcinoma (ACC) Patients Treated With Carbon Ion Radiotherapy.

Background: The present study aims to evaluate dosimetric and clinical risk factors for the development of maxillary osteoradionecrosis (ORN) in head and neck adenoid cystic carcinoma (ACC) patients treated with carbon ion radiotherapy (CIRT). Methods: Clinical data and treatment plans of ACC patients, consecutively treated from January 2013 to September 2016 within the phase II clinical trial CNAO S9/2012/C, were retrospectively reviewed. ORN and other treatment-related toxicity were graded according to the Common Terminology Criteria for Adverse Events (CTACE), version 4.0. The maxillary bone was contoured on the planning CT, and only patients receiving more than 10% of the prescription dose at their maxilla were considered for the analysis (67 patients). The volumes of maxilla receiving doses from 10 Gy (RBE) to 60 Gy (RBE) (VD), with an increment of 10 Gy (RBE), and additional clinical factors were correlated to the incidence of ORN with univariate analysis (Chi-square test). The logistic regression model was subsequently applied for multivariate analysis. Treatment plans calculated with a local effect model (LEM)-based optimization were recalculated with the modified microdosimetric kinetic model (MKM), and compared with literature data from the Japanese experience. Results: The median time interval from the start of CIRT to ORN appearance was 24 months (range, 8-54 months). Maxillary ORN was observed in 11 patients (16.4%). Grade 1 ORN was observed in 2 patients (18.1%), G2 in 4 (36.3%), G3 in 4 (36.3%) and G4 in 1 (9.3%). From univariate analysis, the site of the tumor, the presence of teeth within the PTV and acute mucositis correlated with the development of maxillary ORN. VD were significantly higher for all the dose levels tested in patients with maxillary ORN than patients without necrosis, according to both radiobiological models. The multivariate analysis showed that V60 significantly correlated with ORN risk. Conclusion: The volume of maxilla irradiated with high dose values was relevant for ORN development in our cohort of ACC patients. These results are in line with previously published data obtained with a different radiobiological model. Our findings might be helpful to prevent the risk of ORN in patients receiving CIRT.

Time-resolved MRI for off-line treatment robustness evaluation in carbon-ion radiotherapy of pancreatic cancer.

PURPOSE: In this study, we investigate the use of magnetic resonance imaging (MRI) for the clinical evaluation of gating treatment robustness in carbon-ion radiotherapy (CIRT) of pancreatic cancer. Indeed, MRI allows radiation-free repeated scans and fast dynamic sequences for time-resolved (TR) imaging (cine-MRI), providing information on inter- and intra-fraction cycle-to-cycle variations of respiratory motion. MRI can therefore support treatment planning and verification, overcoming the limitations of the current clinical standard, that is, four-dimensional computed tomography (4DCT), which describes an "average" breathing cycle neglecting breathing motion variability. METHODS: We integrated a technique to generate a virtual CT (vCT) from 3D MRI with a method for 3D reconstruction from 2D cine-MRI, to produce TR vCTs for dose recalculations. For eight patients, the method allowed evaluating inter-fraction variations at end-exhale and intra-fraction cycle-to-cycle variability within the gating window in terms of tumor displacement and dose to the target and organs at risk. RESULTS: The median inter-fraction tumor motion was in the range 3.33-12.16 mm, but the target coverage was robust (-0.4% median D95% variation). Concerning cycle-to-cycle variations, the gating technique was effective in limiting tumor displacement (1.35 mm median gating motion) and corresponding dose variations (-3.9% median D95% variation). The larger exposure of organs at risk (duodenum and stomach) was caused by inter-fraction motion, whereas intra-fraction cycle-to-cycle dose variations were limited. CONCLUSIONS: This study proposed a method for the generation of TR vCTs from MRI, which enabled an off-line evaluation of gating treatment robustness and suggested its feasibility to support treatment planning of pancreatic tumors in CIRT.

How LEM-based RBE and dose-averaged LET affected clinical outcomes of sacral chordoma patients treated with carbon ion radiotherapy.

PURPOSE/OBJECTIVE: To understand the role of relative biological effectiveness (RBE) and dose-averaged linear energy transfer (LETd) distributions in the treatment of sacral chordoma (SC) patients with carbon ion radiotherapy (CIRT). MATERIAL/METHODS: Clinical plans of 50 SC patients consecutively treated before August 2018 with a local effect model-based optimization were recalculated with the modified microdosimetric kinetic RBE model (mMKM). Twenty-six patients were classified as progressive disease and the relapse volume was contoured on the corresponding follow-up diagnostic sequence. The remaining 24 patients populated the control group. Target prescription dose (DRBE|50%), near-to-minimum- (DRBE|95%) and near-to-maximum- (DRBE|2%) doses were compared between the two cohorts in both RBE systems. LETd distribution was evaluated for in-field relapsed cases with respect to the control group. RESULTS: Target DMKM|50% and DMKM|95% were respectively 10% and 18% lower than what we aimed at. Dosimetric evaluators showed no significant difference, in neither of the RBE frameworks, between relapsed and control sets. Half of the relapse volumes were located in a well-covered high dose region. On average, over these cases, median target LETd was significantly lower than the control cohort mean value (27 vs 30 keV/µm). Most notably, the volume receiving dose from high-LET particles (>50 keV/µm) lay substantially below recently reported data in the literature. CONCLUSION: A combined multi model RBE- and LET-based optimization could play a key role in the enhancement of the therapeutic ratio of CIRT for large radioresistant tumors such as sacral chordomas.

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.

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.

Is a tailored strategy using proton beam radiotherapy for reirradiation advantageous for elderly women? A case report.

BACKGROUND: The management of primary or recurrent vaginal tumours in an aging population is challenging for gynecologic and radiation oncologists. In patients unsuited for surgery and already irradiated on the pelvis, proton beam radiotherapy may be worthwhile due to its ballistic advantages. CASE REPORT: We report the case of an 80-year-old woman with a squamous cell carcinoma of the vagina after a history of pelvic radiation and vaginal brachytherapy delivered for a previous endometrial adenocarcinoma. She received proton beam radiotherapy with a complete response after 12 months and mild toxicity. CONCLUSIONS: The complexity of reirradiation management in the frail and elderly population requires attention. Efforts should be focused on maintaining autonomy and quality of life in order to improve adherence and clinical compliance to the treatment. In the era of the tailored approach, hadrontherapy can play an important role to minimize toxicity, obtain good local control, and reduce the overall treatment time.

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.

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.

Multi-parametric qualitative and quantitative MRI assessment as predictor of histological grading in previously treated meningiomas.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Adenoid Cystic Carcinoma of Bartholin's Gland: What Is the Best Approach?

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.

The multiplanar analysis of the retromandibular vein in surgical planning for parotid gland tumors.

OBJECTIVE: To analyze the effectiveness of the multiplanar analysis of the retromandibular vein in establishing the position of the parotid gland tumor and its relationship with the facial nerve, together with the most common radiological criteria (facial nerve line, Utrecht line, retromandibular vein and parapharyngeal space variations) using the magnetic resonance imaging. STUDY DESIGN: Retrospective study SETTING: Tertiary Academic Hospital SUBJECTS AND METHODS: 128 preoperative magnetic resonances were analyzed to study preoperative tumor location (medial or lateral to the expected course of the facial nerve) based on comparison between the radiological criteria and the surgical findings. RESULTS: FN line had the lowest accuracy at 77%, whereas the retromandibular vein achieved 85% accuracy and the UT line achieved accuracy of 93%. The retromandibular vein could not be identified in 11 cases (9%). The multiplanar evaluation of the retromandibular vein allowed us to identify it on almost all MR images (99% of cases) and reach 87% of accuracy. The parapharyngeal space evaluation achieved 92% of accuracy. In the subgroup of 66 cases where the neoplasms were strictly related to the main trunk, where the surgery entailed manipulation if situated laterally to the tumor, the multiplanar evaluation of the retromandibular vein reached 98% of accuracy and UT line achieved 94%. CONCLUSIONS: The multiplanar modality, combined with the evaluation of the parapharyngeal space, is effective in helping the surgeon to achieve accurate planning: it enables the tumor to be located and the facial nerve course predicted with a good precision.