Knowledge-based DVH estimation and optimization for breast VMAT plans with and without avoidance sectors.

BACKGROUND: To analyze RapidPlan knowledge-based models for DVH estimation of organs at risk from breast cancer VMAT plans presenting arc sectors en-face to the breast with zero dose rate, feature imposed during the optimization phase (avoidance sectors AS). METHODS: CT datasets of twenty left breast patients in deep-inspiration breath-hold were selected. Two VMAT plans, PartArc and AvoidArc, were manually generated with double arcs from ~ 300 to ~ 160°, with the second having an AS en-face to the breast to avoid contralateral breast and lung direct irradiation. Two RapidPlan models were generated from the two plan sets. The two models were evaluated in a closed loop to assess the model performance on plans where the AS were selected or not in the optimization. RESULTS: The PartArc plans model estimated DVHs comparable with the original plans. The AvoidArc plans model estimated a DVH pattern with two steps for the contralateral structures when the plan does not contain the AS selected in the optimization phase. This feature produced mean doses of the contralateral breast, averaged over all patients, of 0.4 ± 0.1 Gy, 0.6 ± 0.2 Gy, and 1.1 ± 0.2 Gy for the AvoidArc plan, AvoidArc model estimation, RapidPlan generated plan, respectively. The same figures for the contralateral lung were 0.3 ± 0.1 Gy, 1.6 ± 0.6 Gy, and 1.2 ± 0.5 Gy. The reason was found in the possible incorrect information extracted from the model training plans due to the lack of knowledge about the AS. Conversely, in the case of plans with AS set in the optimization generated with the same AvoidArc model, the estimated and resulting DVHs were comparable. Whenever the AvoidArc model was used to generate DVH estimation for a plan with AS, while the optimization was made on the plan without the AS, the optimizer evidentiated the limitation of a minimum dose rate of 0.2 MU/°, resulting in an increased dose to the contralateral structures respect to the estimation. CONCLUSIONS: The RapidPlan models for breast planning with VMAT can properly estimate organ at risk DVH. Attention has to be paid to the plan selection and usage for model training in the presence of avoidance sectors.

Training and validation of a knowledge-based dose-volume histogram predictive model in the optimisation of intensity-modulated proton and volumetric modulated arc photon plans for pleural mesothelioma patients.

BACKGROUND: To investigate the performance of a narrow-scope knowledge-based RapidPlan (RP) model for optimisation of intensity-modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) plans applied to patients with pleural mesothelioma. Second, estimate the potential benefit of IMPT versus VMAT for this class of patients. METHODS: A cohort of 82 patients was retrospectively selected; 60 were used to "train" a dose-volume histogram predictive model; the remaining 22 provided independent validation. The performance of the RP models was benchmarked, comparing predicted versus achieved mean and near-to-maximum dose for all organs at risk (OARs) in the training set and by quantitative assessment of some dose-volume metrics in the comparison of the validation RP-based data versus the manually optimised training datasets. Treatment plans were designed for a prescription dose of 44 Gy in 22 fractions (proton doses account for a fixed relative biological effectiveness RBE = 1.1). RESULTS: Training and validation RP-based plans resulted dosimetrically similar for both VMAT and IMPT groups, and the clinical planning aims were met for all structures. The IMPT plans outperformed the VMAT ones for all OARs for the contra-lateral and the mean and low dose regions for the ipsilateral OARs. Concerning the prediction performance of the RP models, the linear regression for the near-to-maximum dose resulted in Dachieved = 1.03Dpredicted + 0.58 and Dachieved = 1.02Dpredicted + 1.46 for VMAT and IMPT, respectively. For the mean dose it resulted: Dachieved = 0.99Dpredicted + 0.34 and Dachieved = 1.05Dpredicted + 0.27 respectively. In both cases, the linear correlation between prediction and achievement is granted with an angular coefficient deviating from unity for less than 5%. Concerning the dosimetric comparison between manual plans in the training cohort and RP-based plans in the validation cohort, no clinical differences were observed for the target volumes in both the VMAT and IMPT groups. Similar consistency was observed for the dose-volume metrics analysed for the OAR. This proves the possibility of achieving the same quality of plans with manual procedures (the training set) or with automated RP-based methods (the validation set). CONCLUSION: Two models were trained and validated for VMAT and IMPT plans for pleural mesothelioma. The RP model performance resulted satisfactory as measured by the agreement between predicted and achieved (after full optimisation) dose-volume metrics. The IMPT plans outperformed the VMAT plans for all the OARs (with different intensities for contra- or ipsilateral structures). RP-based planning enabled the automation of part of the optimisation and the harmonisation of the dose-volume results between training and validation. The IMPT data showed a systematic significant dosimetric advantage over VMAT. In general, using an RP-based approach can simplify the optimisation workflow in these complex treatment indications without impacting the quality of plans.

Radiomics-based prognosis classification for high-risk prostate cancer treated with radiotherapy.

OBJECTIVE: The present study aimed to investigate if CT-based radiomics features could correlate to the risk of metastatic progression in high-risk prostate cancer patients treated with radical RT and long-term androgen deprivation therapy (ADT). MATERIALS AND METHODS: A total of 157 patients were investigated and radiomics features extracted from the contrast-free treatment planning CT series. Three volumes were segmented: the prostate gland only (CTV_p), the prostate gland with seminal vesicles (CTV_psv), and the seminal vesicles only (CTV_sv). The patients were split into two subgroups of 100 and 57 patients for training and validation. Five clinical and 62 radiomics features were included in the analysis. Considering metastases-free survival (MFS) as an endpoint, the predictive model was used to identify the subgroups with favorable or unfavorable prognoses (separated by a threshold selected according to the Youden method). Pure clinical, pure radiomic, and combined predictive models were investigated. RESULTS: With a median follow-up of 30.7 months, the MFS at 1 and 3 years was 97.2% ± 1.5 and 92.1% ± 2.0, respectively. Univariate analysis identified seven potential predictors for MFS in the CTV_p group, 11 in the CTV_psv group, and 9 in the CTV_sv group. After elastic net reduction, these were 4 predictors for MFS in the CTV_p group (positive lymph nodes, Gleason score, H_Skewness, and NGLDM_Contrast), 5 in the CTV_psv group (positive lymph nodes, Gleason score, H_Skewnesss, Shape_Surface, and NGLDM_Contrast), and 6 in the CTV_sv group (positive lymph nodes, Gleason score, H_Kurtosis, GLCM_Correlation, GLRLM_LRHGE, and GLZLM_SZLGE). The patients' group of the training and validation cohorts were stratified into favorable and unfavorable prognosis subgroups. For the combined model, for CTV_p, the mean MFS was 134 ± 14.5 vs. 96.9 ± 22.2 months for the favorable and unfavorable subgroups, respectively, and 136.5 ± 14.6 vs. 70.5 ± 4.3 months for CTV_psv and 150.0 ± 4.2 vs. 91.1 ± 8.6 months for CTV_sv, respectively. CONCLUSION: Radiomic features were able to predict the risk of metastatic progression in high-risk prostate cancer. Combining the radiomic features and clinical characteristics can classify high-risk patients into favorable and unfavorable prognostic groups.

Volumetric modulated arc therapy versus intensity-modulated proton therapy in the irradiation of infra diaphragmatic Hodgkin Lymphoma in female patients.

PURPOSE: To investigate the role of infra diaphragmatic intensity-modulated proton therapy (IMPT) compared to volumetric modulated arc therapy (VMAT) for female Hodgkin Lymphoma (HL) patients and to estimate the risk of secondary cancer and ovarian failure. METHODS: A comparative treatment planning study was performed on 14 patients, and the results were compared according to conventional dose-volume metrics. In addition, estimates of the excess absolute risk (EAR) of secondary cancer induction were determined for the bowel, the bladder and the rectum. For the ovaries, the risk of ovarian failure was estimated. RESULTS: The dosimetric findings demonstrate the equivalence between VMAT and IMPT in terms of target coverage. A statistically significant reduction of the mean and near-to-maximum doses was proven for the organs at risk. The EAR ratio estimated for IMPT to VMAT was 0.51 ± 0.32, 0.32 ± 0.35 and 0.05 ± 0.11 for the bowel, bladder and rectum, respectively. Concerning the risk of ovarian failure for the chronologic age ranging from 18 to 46 years, the expected net loss in fertility years ranged from 4.8 to 3.0 years for protons and 12.0 to 5.7 years for photons. CONCLUSION: This in-silico study confirmed the beneficial role of IMPT from a dosimetric point of view. Mathematical models suggested that the use of protons might be further advantageous due to the expected reduction of the risk of secondary cancer induction and its milder impact on the reduction of fertility.

A novel external beam radiotherapy method for cervical cancer patients using virtual straight or bending boost areas; an in-silico feasibility study.

AIM: To investigate the potential role of a novel spatially fractionated radiation therapy (SFRT) method where heterogeneous dose patterns are created in target areas with virtual rods, straight or curving, of variable position, diameter, separation and alignment personalised to a patient's anatomy. The images chosen for this study were CT scans acquired for the external beam part of radiotherapy. METHODS: Ten patients with locally advanced cervical cancer were retrospectively investigated with SFRT. The dose prescription was 30 Gy in 5 fractions to 90% target volume coverage. Peak-and-valley (SFRT_1) and peak-only (SFRT_2) strategies were applied to generate the heterogeneous dose distributions. The planning objectives for the target (CTV) were D90% ≥ 30 Gy, V45Gy ≥ 50-55% and V60Gy ≥ 30%. The planning objectives for the organs at risk (OAR) were: D2cm3 ≤ 23.75 Gy, 17.0 Gy, 19.5 Gy, 17.0 Gy for the bladder, rectum, sigmoid and bowel, respectively. The plan comparison was performed employing the quantitative analysis of the dose-volume histograms. RESULTS: The D2cm3 was 22.4 ± 2.0 (22.6 ± 2.1) and 13.9 ± 2.9 (13.2 ± 3.0) for the bladder and the rectum for SFRT_1 (SFRT_2). The results for the sigmoid and the bowel were 2.6 ± 3.1 (2.8 ± 3.0) and 9.1 ± 5.9 (9.7 ± 7.3), respectively. The hotspots in the target volume were V45Gy = 43.1 ± 7.5% (56.6 ± 5.6%) and V60Gy = 15.4 ± 5.6% (26.8 ± 6.6%) for SFRT_1 (SFRT_2). To account for potential uncertainties in the positioning, the dose prescription could be escalated to D90% = 33-35 Gy to the CTV without compromising any constraints to the OARs CONCLUSION: In this dosimetric study, the proposed novel planning technique for boosting the cervix uteri was associated with high-quality plans, respecting constraints for the organs at risk and approaching the level of dose heterogeneity achieved with routine brachytherapy. Based on a sample of 10 patients, the results are promising and might lead to a phase I clinical trial.

Dosimetric impact of volumetric modulated arc therapy for nasopharyngeal cancer treatment.

BACKGROUND: The purpose of the study was to evaluate the toxicity and outcome of nasopharyngeal carcinoma patients treated using 3-dimensional conformal radiotherapy (3DCRT) or volumetric modulated arc therapy (VMAT) technique. MATERIALS AND METHODS: 68 patients treated between 2006 and 2018 were retrospectively analysed. Since 2009 patients received 3DCRT with 50/70 Gy to the elective/boost volumes in 35 fractions; from then, VMAT with simultaneous integrated boost (SIB) with 54.45/69.96 Gy in 33, or 54/66 Gy in 30 fractions. Induction chemotherapy was administered in 74% of the patients, concomitant cisplatinum in 87%. Acute and late toxicity data, progression-free survival PSF and overall survival OS, and toxicity correlations with dose metrics were reported. RESULTS: With a median follow-up of 64 months, complete remission at the last evaluation was in 68% of the patients, while 28% and 9% had locoregional relapse and distant disease, respectively. The 5- and 10-year progression free survival (PFS) rates were 62.7 ± 6.5% and 53.2 ± 8.7%, respectively. The 5- and 10-year OS rates were 78.9 ± 5.5% and 61.4 ± 9.2%, respectively. At the multivariate Cox analysis TNM stage (p = 0.02) and concomitant chemotherapy (p = 0.01) resulted significant for PFS, concomitant chemotherapy (p = 0.04) for OS.Improvements in acute toxicity were presented for VMAT patients due to its ability to spare OARs. Odds ratio (OR) for acute salivary toxicity, between VMAT and 3DCRT, was 4.67 (p = 0.02). Dosimetrically, salivary toxicity correlated with mean parotid dose (p = 0.05), dysphagia with laryngeal (p = 0.04) and mean oral cavity (p = 0.06) doses, when dose-volume histograms (DVHs) are corrected for fractionation. CONCLUSION: This study is a proof of a significant benefit of the VMAT technique compared with 3DCRT in terms of side effects in nasopharynx patients, and adds dosimetric correlations.

The role of a knowledge based dose-volume histogram predictive model in the optimisation of intensity-modulated proton plans for hepatocellular carcinoma patients : Training and validation of a novel commercial system.

PURPOSE: To investigate the performance of a knowledge-based RapidPlan, for optimisation of intensity-modulated proton therapy (IMPT) plans applied to hepatocellular cancer (HCC) patients. METHODS: A cohort of 65 patients was retrospectively selected: 50 were used to "train" the model, while the remaining 15 provided independent validation. The performance of the RapidPlan model was benchmarked against manual optimisation and was also compared to volumetric modulated arc therapy (RapidArc) photon plans. A subanalysis appraised the performance of the RapidPlan model applied to patients with lesions ≤300 cm3 or larger. Quantitative assessment was based on several metrics derived from the constraints of the NRG-GI003 clinical trial. RESULTS: There was an equivalence between manual plans and RapidPlan-optimised IMPT plans, which outperformed the RapidArc plans. The planning dose-volume objectives were met on average for all structures except for D0.5 cm3 ≤30 Gy in the bowels. Limiting the results to the class-solution proton plans (all values in Gy), the data for manual plans vs RapidPlan-based IMPT plans, respectively, showed the following: D99% to the target of 47.5 ± 1.4 vs 47.2 ± 1.2; for organs at risk, the mean dose to the healthy liver was 6.7 ± 3.6 vs 6.7 ± 3.7; the mean dose to the kidneys was 0.2 ± 0.5 vs 0.1 ± 0.2; D0.5 cm3 for the bowels was 33.4 ± 16.4 vs 30.2 ± 16.0; for the stomach was 17.9 ± 19.9 vs 14.9 ± 18.8; for the oesophagus was 17.9 ± 15.1 vs 14.9 ± 13.9; for the spinal cord was 0.5 ± 1.6 vs 0.2 ± 0.7. The model performed similarly for cases with small or large lesions. CONCLUSION: A knowledge-based RapidPlan model was trained and validated for IMPT. The results demonstrate that RapidPlan can be trained adequately for IMPT in HCC. The quality of the RapidPlan-based plans is at least equivalent compared to what is achievable with manual planning. RapidPlan also confirmed the potential to optimise the quality of the proton therapy results, thus reducing the impact of operator planning skills on patient results.

Knowledge-based intensity-modulated proton planning for gastroesophageal carcinoma.

PURPOSE: To investigate the performance of a narrow-scope knowledge-based RapidPlan (RP) model, for optimisation of intensity-modulated proton therapy (IMPT) plans applied to patients with locally advanced carcinoma in the gastroesophageal junction. METHODS: A cohort of 60 patients was retrospectively selected; 45 were used to 'train' a dose-volume histogram predictive model; the remaining 15 provided independent validation. The performance of the RP model was benchmarked against manual optimisation. Quantitative assessment was based on several dose-volume metrics. RESULTS: Manual and RP-optimised IMPT plans resulted dosimetrically similar, and the planning dose-volume objectives were met for all structures. Concerning the validation set, the comparison of the manual vs RP-based plans, respectively, showed for the target (PTV): the homogeneity index was 6.3 ± 2.2 vs 5.9 ± 1.2, and V98% was 89.3 ± 2.9 vs 91.4 ± 2.2% (this was 97.2 ± 1.9 vs 98.8 ± 1.1 for the CTV). Regarding the organs at risk, no significant differences were reported for the combined lungs, the whole heart, the left anterior descending artery, the kidneys, the spleen and the spinal canal. The D0.1 cm3 for the left ventricle resulted in 40.3 ± 3.4 vs 39.7 ± 4.3 Gy(RBE). The mean dose to the liver was 3.4 ± 1.3 vs 3.6 ± 1.5 Gy(RBE). CONCLUSION: A narrow-scope knowledge-based RP model was trained and validated for IMPT delivery in locally advanced cancer of the gastroesophageal junction. The results demonstrate that RP can create models for effective IMPT. Furthermore, the equivalence between manual interactive and unattended RP-based optimisation could be displayed. The data also showed a high correlation between predicted and achieved doses in support of the valuable predictive power of the RP method.

The Potential Role of Intensity-Modulated Proton Therapy in Hepatic Carcinoma in Mitigating the Risk of Dose De-Escalation.

PURPOSE: To investigate the role of intensity-modulated proton therapy (IMPT) for hepatocellular carcinoma (HCC) patients to be treated with stereotactic body radiation therapy (SBRT) in a risk-adapted dose prescription regimen. METHODS: A cohort of 30 patients was retrospectively selected as "at-risk" of dose de-escalation due to the proximity of the target volumes to dose-limiting healthy structures. IMPT plans were compared to volumetric modulated arc therapy (VMAT) RapidArc (RA) plans. The maximum dose prescription foreseen was 75 Gy in 3 fractions. The dosimetric analysis was performed on several quantitative metrics on the target volumes and organs at risk to identify the relative improvement of IMPT over VMAT and to determine if IMPT could mitigate the need of dose reduction and quantify the consequent potential patient accrual rate for protons. RESULTS: IMPT and VMAT plans resulted in equivalent target dose distributions: both could ensure the required coverage for CTV and PTV. Systematic and significant improvements were observed with IMPT for all organs at risk and metrics. An average gain of 9.0 ± 11.6, 8.5 ± 7.7, 5.9 ± 7.1, 4.2 ± 6.4, 8.9 ± 7.1, 6.7 ± 7.5 Gy was found in the near-to-maximum doses for the ribs, chest wall, heart, duodenum, stomach and bowel bag respectively. Twenty patients violated one or more binding constraints with RA, while only 2 with IMPT. For all these patients, some dose de-intensification would have been required to respect the constraints. For photons, the maximum allowed dose ranged from 15.0 to 20.63 Gy per fraction while for the 2 proton cases it would have been 18.75 or 20.63 Gy. CONCLUSION: The results of this in-silico planning study suggests that IMPT might result in advantages compared to photon-based VMAT for HCC patients to be treated with ablative SBRT. In particular, the dosimetric characteristics of protons may avoid the need for dose de-escalation in a risk-adapted prescription regimen for those patients with lesions located in proximity of dose-limiting healthy structures. Depending on the selection thresholds, the number of patients eligible for treatment at the full dose can be significantly increased with protons.

Hypofractionated Whole Breast Irradiation and Simultaneous Integrated Boost in Large-breasted Patients: Long-term Toxicity and Cosmesis.

INTRODUCTION: The purpose of this study was to evaluate the impact of breast size on long-term toxicity and cosmesis in patients with breast cancer treated with hypofractionated simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT). PATIENTS AND METHODS: Patients with early stage breast cancer were treated with 3-week hypofractionated SIB-VMAT to the whole breast (40.5 Gy) and tumor bed (48 Gy). Two cohorts were identified: small/medium- (< 1000 cm3) and large- (> 1000 cm3) breasted patients. Acute and late (at 2 and 5 years) skin toxicity and cosmetic data were analyzed. Univariate and multivariate analysis evaluated associations between toxicity and dosimetric/anatomical variables. RESULTS: From August 2010 to March 2017, a total of 1160 patients were treated; 831 had at least 2 years of follow-up and were analyzed. Treated skin area (TSA) receiving at least 20 Gy > 400 cm2 and V105% of Boost > 5 cm3 were significant predictors for acute skin toxicity. Multivariate analysis at 2 years was significant for boost volume > 70 cm3, TSA > 400 cm2, and breast size > 1500 cm3. At 5 year analysis (352 patients), none of the analyzed variables was significant. For cosmetic outcome, only the breast size (> 1000 cm3) and the boost size > 70 cm3 at 2 and 5 years, respectively, confirmed significance. CONCLUSIONS: The TSA > 400 cm2 resulted as a significant predictor of both acute and late skin toxicity at 2 years; however, at 5 years, no breast size or dosimetric parameter suggested indications for increased toxicity. A worse cosmetic outcome was recorded at the 2-year follow up for large breasts, but was not confirmed at the 5-year follow-up. These long-term data suggest that hypofractionated SIB-VMAT is a viable modality also in large-breasted patients.

Volumetric modulated arc therapy versus intensity-modulated proton therapy in the postoperative irradiation of thymoma.

BACKGROUND: To investigate the role of intensity-modulated proton therapy (IMPT) compared to volumetric modulated arc therapy (VMAT) for the radiation treatment of thymoma cancer. METHODS: Twenty patients were retrospectively planned for IMPT [with (IMPT_R1 or IMPT_R2 according to the approach adopted) and without robust optimization] and VMAT. The results were compared according to dose-volume metrics on the clinical and planning target volumes (CTV and PTV) and the main organs at risk (heart, breasts, lungs, spinal cord and oesophagus). Estimates of the excess absolute risk (EAR) of secondary cancer induction were determined for the oesophagus, the breasts and the composite lungs. For the heart, the relative risk (RR) of chronic heart failure (CHF) was assessed. RESULTS: IMPT and VMAT plans resulted equivalent in terms of target coverage for both the CTV and the PTV. The CTV homogeneity index resulted in 0.03 ± 0.01 and 0.04 ± 0.01 for VMAT and all IMPT plans, respectively. The conformality index resulted in 1.1 ± 0.1 and 1.2 ± 0.1 for VMAT and all IMPT plans. The mean dose to the breasts resulted in 10.5 ± 5.0, 4.5 ± 3.4, 4.7 ± 3.5 and 4.6 ± 3.4 Gy for VMAT, IMPT, IMPT_R1 and IMPT_R2. For the lungs, the mean dose was 9.6 ± 2.3, 3.5 ± 1.5, 3.6 ± 1.6 and 3.8 ± 1.4 Gy; for the heart: 8.7 ± 4.4, 4.3 ± 1.9, 4.5 ± 2.0 and 4.4 ± 2.4 Gy and for the oesophagus 8.2 ± 3.5, 2.2 ± 3.4, 2.4 ± 3.6 and 2.5 ± 3.5 Gy. The RR for CHF was 1.6 ± 0.3 for VMAT and 1.3 ± 0.2 for IMPT (R1 or R2). The EAR was 3.6 ± 0.v vs 1.0 ± 0.6 or 1.2 ± 0.6 (excess cases/10,000 patients year) for the oesophagus; 17.4 ± 6.5 vs 5.7 ± 3.2 or 6.1 ± 3.8 for the breasts and 24.8 ± 4.3 vs 8.1 ± 2.7 or 8.7 ± 2.3 for the composite lungs for VMAT and IMPT_R, respectively. CONCLUSION: The data from this in-silico study suggest that intensity-modulated proton therapy could be significantly advantageous in the treatment of thymoma patients with particular emphasis to a substantial reduction of the risk of cardiac failure and secondary cancer induction. Robust planning is a technical pre-requisite for the safety of the delivery.

Volumetric modulated arc therapy versus intensity-modulated proton therapy in neoadjuvant irradiation of locally advanced oesophageal cancer.

BACKGROUND: To investigate the role of intensity-modulated proton therapy (IMPT) compared to volumetric modulated arc therapy (VMAT), realised with RapidArc and RapidPlan methods (RA_RP) for neoadjuvant radiotherapy in locally advanced oesophagal cancer. METHODS: Twenty patients were retrospectively planned for IMPT (with two fields, (IMPT_2F) or with three fields (IMPT_3F)) and RA_RP and the results were compared according to dose-volume metrics. Estimates of the excess absolute risk (EAR) of secondary cancer induction were determined for the lungs. For the cardiac structures, the relative risk (RR) of coronary artery disease (CAD) and chronic heart failure (CHF) were estimated. RESULTS: Both the RA_RP and IMPT approached allowed to achieve the required coverage for the gross tumour volume, (GTV) and the clinical and the planning target volumes, CTV and PTV (V98% > 98 for CTV and GTV and V95% > 95 for the PTV)). The conformity index resulted in 0.88 ± 0.01, 0.89 ± 0.02 and 0.89 ± 0.02 for RA_RP, IMPT_2F and IMPT_3F respectively. With the same order, the homogeneity index for the PTV resulted in 5.6 ± 0.6%, 4.4 ± 0.9% and 4.5 ± 0.8%. Concerning the organs at risk, the IMPT plans showed a systematic and statistically significant incremental sparing when compared to RA_RP, especially for the heart. The mean dose to the combined lungs was 8.6 ± 2.9 Gy for RA_RP, 3.2 ± 1.5 Gy and 2.9 ± 1.2 Gy for IMPT_2F and IMPT_3F. The mean dose to the whole heart resulted to 9.9 ± 1.9 Gy for RA_RP compared to 3.7 ± 1.3 Gy or 4.0 ± 1.4 Gy for IMPT_2F or IMPT_3F; the mean dose to the left ventricle resulted to 6.5 ± 1.6 Gy, 1.9 ± 1.5 Gy, 1.9 ± 1.6 Gy respectively. Similar sparing effects were observed for the liver, the kidneys, the stomach, the spleen and the bowels. The EAR per 10,000 patients-years of secondary cancer induction resulted in 19.2 ± 5.7 for RA_RP and 6.1 ± 2.7 for IMPT_2F or 5.7 ± 2.4 for IMPT_3F. The RR for the left ventricle resulted in 1.5 ± 0.1 for RA_RP and 1.1 ± 0.1 for both IMPT sets. For the coronaries, the RR resulted in 1.6 ± 0.4 for RA_RP and 1.2 ± 0.3 for protons. CONCLUSION: With regard to cancer of the oesophagogastric junction type I and II, the use of intensity-modulated proton therapy seems to have a clear advantage over VMAT. In particular, the reduction of the heart and abdominal structures dose could result in an optimised side effect profile. Furthermore, reduced risk of secondary neoplasia in the lung can be expected in long-term survivors and would be a great gain for cured patients.

Intensity modulated proton therapy compared to volumetric modulated arc therapy in the irradiation of young female patients with hodgkin's lymphoma. Assessment of risk of toxicity and secondary cancer induction.

BACKGROUND: To investigate the role of intensity modulated proton therapy (IMPT) compared to volumetric modulated arc therapy (VMAT) for advanced supradiaphragmatic Hodgkin's lymphoma (HL) in young female patients by assessing dosimetric features and modelling the risk of treatment related complications and radiation-induced secondary malignancies. METHODS: A group of 20 cases (planned according to the involved-site approach) were retrospectively investigated in a comparative planning study. Intensity modulated proton plans (IMPT) were compared to VMAT RapidArc plans (RA). Estimates of toxicity were derived from normal tissue complication probability (NTCP) calculations with either the Lyman or the Poisson models for a number of endpoints. Estimates of the risk of secondary cancer induction were determined for lungs, breasts, esophagus and thyroid. A simple model-based selection strategy was considered as a feasibility proof for the individualized selection of patients suitable for proton therapy. RESULTS: IMPT and VMAT plans resulted equivalent in terms of target dose distributions, both were capable to ensure high coverage and homogeneity. In terms of conformality, IMPT resulted ~ 10% better than RA plans. Concerning organs at risk, IMPT data presented a systematic improvement (highly significant) over RA for all organs, particularly in the dose range up to 20Gy. This lead to a composite average reduction of NTCP of 2.90 ± 2.24 and a reduction of 0.26 ± 0.22 in the relative risk of cardiac failures. The excess absolute risk per 10,000 patients-years of secondary cancer induction was reduced, with IMPT, of 9.1 ± 3.2, 7.2 ± 3.7 for breast and lung compared to RA. The gain in EAR for thyroid and esophagus was lower than 1. Depending on the arbitrary thresholds applied, the selection rate for proton treatment would have ranged from 5 to 75%. CONCLUSION: In relation to young female patients with advanced supradiaphragmatic HL, IMPT can in general offer improved dose-volume sparing of organs at risk leading to an anticipated lower risk of early or late treatment related toxicities. This would reflect also in significantly lower risk of secondary malignancies induction compared to advanced photon based techniques. Depending on the selection thresholds and with all the limits of a non-validated and very basic model, it can be anticipated that a significant fraction of patients might be suitable for proton treatments if all the risk factors would be accounted for.

A radiomic approach to predicting nodal relapse and disease-specific survival in patients treated with stereotactic body radiation therapy for early-stage non-small cell lung cancer.

PURPOSE: To describe the possibility of building a classifier for patients at risk of lymph node relapse and a predictive model for disease-specific survival in patients with early stage non-small cell lung cancer. METHODS: A cohort of 102 patients who received stereotactic body radiation treatment was retrospectively investigated. A set of 45 textural features was computed for the tumor volumes on the treatment planning CT images. Patients were split into two independent cohorts (70 patients, 68.9%, for training; and 32 patients, 31.4%, for validation). Three different models were built in the study. A stepwise backward linear discriminant analysis was applied to identify patients at risk of lymph node progression. The performance of the model was assessed by means of standard metrics derived from the confusion matrix. Furthermore, all textural features were correlated to survival data to build two separate predictive models for progression-free survival (PFS) and disease-specific survival (DS-OS). These models were built from the features/predictors found significant in univariate analysis and elastic net regularization by means of a multivarate Cox regression with backward selection. Low- and high-risk groups were identified by maximizing the separation by means of the Youden method. RESULTS: In the total cohort (77, 75.5%, males; and 25, 24.5%, females; median age 76.6 years), 15 patients presented nodal progression at the time of analysis; 19 patients (18.6%) died because of disease-specific causes, 25 (24.5%) died from other reasons, 28 (27.5%) were alive without disease, and 30 (29.4%) with either local or distant progression. The specificity, sensitivity, and accuracy of the classifier resulted 83.1 ± 24.5, 87.4 ± 1.2, and 85.4 ± 12.5 in the validation group (coherent with the findings in the training). The area under the curve for the classifier resulted in 0.84 ± 0.04 and 0.73 ± 0.05 for training and validation, respectively. The mean time for DS-OS and PFS for the low- and high-risk subgroups of patients (in the validation groups) were 88.2 month ± 9.0 month vs. 84.1 month ± 7.8 month (low risk) and 52.7 month ± 5.9 month vs. 44.6 month ± 9.2 month (high risk), respectively. CONCLUSION: Radiomics analysis based on planning CT images allowed a classifier and predictive models capable of identifying patients at risk of nodal relapse and high-risk of bad prognosis to be built. The radiomics signatures identified were mostly related to tumor heterogeneity.

Impact of hypofractionated schemes in radiotherapy for locally advanced head and neck cancer patients.

OBJECTIVE: To analyze two cohorts of locally advanced head and neck cancer (LAHNC) patients treated with two schedules of hypofractionated radiotherapy and 5 versus 3 mm clinical target volume-planning target volume (CTV-PTV) margins. METHODS: 145 patients were included. The patient cohort was divided into two groups. Group A included 97 patients treated with 69.96/54.45 grays (Gy) to the high-risk and low-risk volumes, respectively, in 33 fractions, with 5 mm margins. Group B included 48 patients treated with 66/54 Gy in 30 fractions using 3 mm margins. Toxicity was recorded according to the Common Toxicity Criteria version 3. Patient outcomes for locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) were determined. RESULTS: Median follow-up was 26 months. In terms of toxicity, acute dysphagia worsened significantly (P = 0.003) in group B, whereas acute salivary toxicity tended to significance (P = 0.071). No significant late toxicity differences were recorded. Rates of LRC at 1 and 2 years were 90.1% ± 2.6% and 84.2% ± 3.4%, respectively, with superiority for group A (P = 0.045). The statistical significance remained for the low-dose level (P = 0.007) but not for high dose (P = 0.110). Rates of DFS at 1 and 2 years were 84.9% ± 3.1% and 76.5% ± 3.9%, respectively, whereas rates of OS were 95.9% ± 1.8% and 91.6% ± 2.7%, respectively. No differences were observed between the two groups in terms of DFS (P = 0.270) and OS (P = 0.152). CONCLUSION: The use of reduced CTV to PTV margins and dose reduction with hypofractionation schedule can improve the pattern of toxicity in LAHNC patients. This approach resulted in an increased rate of locoregional progression, particularly in low-risk regions. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:E163-E170, 2020.

MLC parameters from static fields to VMAT plans: an evaluation in a RT-dedicated MC environment (PRIMO).

BACKGROUND: PRIMO is a graphical environment based on PENELOPE Monte Carlo (MC) simulation of radiotherapy beams able to compute dose distribution in patients, from plans with different techniques. The dosimetric characteristics of an HD-120 MLC (Varian), simulated using PRIMO, were here compared with measurements, and also with Acuros calculations (in the Eclipse treatment planning system, Varian). MATERIALS AND METHODS: A 10 MV FFF beam from a Varian EDGE linac equipped with the HD-120 MLC was used for this work. Initially, the linac head was simulated inside PRIMO, and validated against measurements in a water phantom. Then, a series of different MLC patterns were established to assess the MLC dosimetric characteristics. Those tests included: i) static fields: output factors from MLC shaped fields (2 × 2 to 10 × 10 cm2), alternate open and closed leaf pattern, MLC transmitted dose; ii) dynamic fields: dosimetric leaf gap (DLG) evaluated with sweeping gaps, tongue and groove (TG) effect assessed with profiles across alternate open and closed leaves moving across the field. The doses in the different tests were simulated in PRIMO and then compared with EBT3 film measurements in solid water phantom, as well as with Acuros calculations. Finally, MC in PRIMO and Acuros were compared in some clinical cases, summarizing the clinical complexity in view of a possible use of PRIMO as an independent dose calculation check. RESULTS: Static output factor MLC tests showed an agreement between MC calculated and measured OF of 0.5%. The dynamic tests presented DLG values of 0.033 ± 0.003 cm and 0.032 ± 0.006 cm for MC and measurements, respectively. Regarding the TG tests, a general agreement between the dose distributions of 1-2% was achieved, except for the extreme patterns (very small gaps/field sizes and high TG effect) were the agreement was about 4-5%. The analysis of the clinical cases, the Gamma agreement between MC in PRIMO and Acuros dose calculation in Eclipse was of 99.5 ± 0.2% for 3%/2 mm criteria of dose difference/distance to agreement. CONCLUSIONS: MC simulations in the PRIMO environment were in agreement with measurements for the HD-120 MLC in a 10 MV FFF beam from a Varian EDGE linac. This result allowed to consistently compare clinical cases, showing the possible use of PRIMO as an independent dose calculation check tool.

Adjuvant volumetric modulated arc therapy compared to 3D conformal radiation therapy for newly diagnosed soft tissue sarcoma of the extremities: outcome and toxicity evaluation.

OBJECTIVE: To assess the impact of adjuvant volumetric modulated arc therapy (VMAT) compared with three-dimensional conformal radiation therapy (3DCRT) in terms of toxicity and local control (LC) in patients with soft tissue sarcoma of the extremities. METHODS: From 2004 to 2016, 109 patients were treated, initially using 3DCRT and subsequently with VMAT. Clinical outcome was evaluated by contrast-enhanced MRI, thoracic and abdominal CT 3 months after treatments and then every 6 months. Toxicity was evaluated with Common Terminology Criteria for Adverse Events scale v. 4.3. RESULTS: Patients presented Stage III soft tissue sarcoma disease (77%), localized tumor (95%) at the lower extremity (87%), adipocytic histotype (46%). Surgical resection was performed in all patients, followed by adjuvant 3DCRT in 38, and VMAT in 71. The median total dose was 66 Gy/33 fractions (range 60-70 Gy;25-35 fractions). More successful bone sparing was recorded using VMAT (p < 0.001). Median follow-up was 61 months, 93 and 58 months for 3DCRT and VMAT group, respectively. The 2- and 5 year LC were 95.3±2.1%, and 87.4±3.4% for the whole cohort, 92.0±4.5%, 82.9±6.4% for 3DCRT, 97.1±2.0%, 89.6±4.1% for VMAT (p = 0.150). On univariate and multivariate analysis the factors recorded as conditioning LC were the status of the surgical resection margins (p = 0.028) and the total dose delivered (p = 0.013). CONCLUSION: The availability of modern radiotherapy technique permit a better conformity on the target with maximum sparing of normal tissue and acceptable side-effects. VMAT is a safe and feasible treatment with limited rate of toxicity, compared to 3DCRT. Results on LC of VMAT are encouraging. ADVANCES IN KNOWLEDGE: Soft tissue sarcoma of the extremities can benefit from the use of VMAT, with a reduction of the high dose to bones to avoid radiation osteonecrosis. An adequate total dose of at least 66 Gy and a radical surgical margin allow a good local control.

Predicting survival and local control after radiochemotherapy in locally advanced head and neck cancer by means of computed tomography based radiomics.

PURPOSE: To appraise the ability of a radiomics signature to predict clinical outcome after definitive radiochemotherapy (RCT) of stage III-IV head and neck cancer. METHODS: A cohort of 110 patients was included in a retrospective analysis. Radiomics texture features were extracted from the gross tumor volumes contoured on planning computed tomography (CT) images. The cohort of patients was randomly divided into a training (70 patients) and a validation (40 patients) cohorts. Textural features were correlated to survival and control data to build predictive models. All the significant predictors of the univariate analysis were included in a multivariate model. The quality of the models was appraised by means of the concordance index (CI). RESULTS: A signature with 3 features was identified as predictive of overall survival (OS) with CI = 0.88 and 0.90 for the training and validation cohorts, respectively. A signature with 2 features was identified for progression-free survival (PFS; CI = 0.72 and 0.80); 2 features also characterized the signature for local control (LC; CI = 0.72 and 0.82). In all cases, the stratification in high- and low-risk groups for the training and validation cohorts led to significant differences in the actuarial curves. In the validation cohort the mean OS times (in months) were 78.9 ± 2.1 vs 67.4 ± 6.0 in the low- and high-risk groups, respectively, the PFS was 73.1 ± 3.7 and 50.7 ± 7.2, while the LC was 78.7 ± 2.1 and 63.9 ± 6.5. CONCLUSION: CT-based radiomic signatures that correlate with survival and control after RCT were identified and allow low- and high-risk groups of patients to be identified.

Postmastectomy radiation therapy using VMAT technique for breast cancer patients with expander reconstruction.

Postmastectomy radiotherapy (PMRT) following immediate breast reconstruction is increasingly adopted in the management of breast cancer patients. We retrospectively evaluate the complication rates of PMRT using VMAT technique to immediate tissue expander-based reconstructions and the possible impact of tissue expander volume on radiotherapy planning. We reviewed the data of patients who underwent immediate expander breast reconstruction and received PMRT with VMAT (50 Gy in 25 fractions) on the reconstructed breast and axillary levels III-IV. Neoadjuvant or adjuvant systemic therapy was administered in most of the patients. Autologous fat grafting was routinely performed at the time of second-stage reconstruction. Between 2015 and 2017, PMRT was delivered to 46 consecutive patients (median age 50 years) with expander reconstruction. Median follow-up was 27 months (range 10-41). Two patients (4.3%) had a reconstruction failure, as expander rupture and infection, following the first- and the second-stage reconstruction, respectively. In most cases expanders were completely inflated before PMRT (65.2%). Median expander volume before PMRT was 425 cm3 (range 150-700 cm3). The amount of expander inflation did not significantly affect dosimetry, except for skin dose, with a surface receiving more than 30 Gy of 36.6 ± 0.9 cm2 and 47.0 ± 2.5 cm2 for a volume expander below or above the median, respectively. However, this variable was not predictor for complications. Disease progression was recorded in 15.2% of patients. PMRT using VMAT technique for breast cancer patients with expander reconstruction is associated with a very low complication rate. The expander volume before PMRT does not significantly compromise radiotherapy dose distribution.

Computed tomography based radiomic signature as predictive of survival and local control after stereotactic body radiation therapy in pancreatic carcinoma.

PURPOSE: To appraise the ability of a radiomics signature to predict clinical outcome after stereotactic body radiation therapy (SBRT) for pancreas carcinoma. METHODS: A cohort of 100 patients was included in this retrospective, single institution analysis. Radiomics texture features were extracted from computed tomography (CT) images obtained for the clinical target volume. The cohort of patients was randomly divided into two separate groups for the training (60 patients) and validation (40 patients). Cox regression models were built to predict overall survival and local control. The significant predictors at univariate analysis were included in a multivariate model. The quality of the models was appraised by means of area under the curve and concordance index. RESULTS: A clinical-radiomic signature associated with Overall Survival (OS) was found significant in both training and validation sets (p = 0.01 and 0.05 and concordance index 0.73 and 0.75 respectively). Similarly, a signature was found for Local Control (LC) with p = 0.007 and 0.004 and concordance index 0.69 and 0.75. In the low risk group, the median OS and LC in the validation group were 14.4 and 28.6 months while in the high-risk group were 9.0 and 17.5 months respectively. CONCLUSION: A CT based radiomic signature was identified which correlate with OS and LC after SBRT and allowed to identify low and high-risk groups of patients.