Effects of model size and composition on quality of head-and-neck knowledge-based plans.

PURPOSE: Knowledge-based planning (KBP) aims to automate and standardize treatment planning. New KBP users are faced with many questions: How much does model size matter, and are multiple models needed to accommodate specific physician preferences? In this study, six head-and-neck KBP models were trained to address these questions. METHODS: The six models differed in training size and plan composition: The KBPFull (n = 203 plans), KBP101 (n = 101), KBP50 (n = 50), and KBP25 (n = 25) were trained with plans from two head-and-neck physicians. KBPA and KBPB each contained n = 101 plans from only one physician, respectively. An independent set of 39 patients treated to 6000-7000 cGy by a third physician was re-planned with all KBP models for validation. Standard head-and-neck dosimetric parameters were used to compare resulting plans. KBPFull plans were compared to the clinical plans to evaluate overall model quality. Additionally, clinical and KBPFull plans were presented to another physician for blind review. Dosimetric comparison of KBPFull against KBP101 , KBP50 , and KBP25 investigated the effect of model size. Finally, KBPA versus KBPB tested whether training KBP models on plans from one physician only influences the resulting output. Dosimetric differences were tested for significance using a paired t-test (p < 0.05). RESULTS: Compared to manual plans, KBPFull significantly increased PTV Low D95% and left parotid mean dose but decreased dose cochlea, constrictors, and larynx. The physician preferred the KBPFull plan over the manual plan in 20/39 cases. Dosimetric differences between KBPFull , KBP101 , KBP50 , and KBP25 plans did not exceed 187 cGy on aggregate, except for the cochlea. Further, average differences between KBPA and KBPB were below 110 cGy. CONCLUSIONS: Overall, all models were shown to produce high-quality plans. Differences between model outputs were small compared to the prescription. This indicates only small improvements when increasing model size and minimal influence of the physician when choosing treatment plans for training head-and-neck KBP models.

Toward automatic beam angle selection for pencil-beam scanning proton liver treatments: A deep learning-based approach.

BACKGROUND: Dose deposition characteristics of proton radiation can be advantageous over photons. Proton treatment planning, however, poses additional challenges for the planners. Proton therapy is usually delivered with only a small number of beam angles, and the quality of a proton treatment plan is largely determined by the beam angles employed. Finding the optimal beam angles for a proton treatment plan requires time and experience, motivating the investigation of automatic beam angle selection methods. PURPOSE: A deep learning-based approach to automatic beam angle selection is proposed for the proton pencil-beam scanning treatment planning of liver lesions. METHODS: We cast beam-angle selection as a multi-label classification problem. To account for angular boundary discontinuity, the underlying convolution neural network is trained with the proposed Circular Earth Mover's Distance-based regularization and multi-label circular-smooth label technique. Furthermore, an analytical algorithm emulating proton treatment planners' clinical practice is employed in post-processing to improve the output of the model. Forty-nine patients that received proton liver treatments between 2017 and 2020 were randomly divided into training (n = 31), validation (n = 7), and test sets (n = 11). AI-selected beam angles were compared with those angles selected by human planners, and the dosimetric outcome was investigated by creating plans using knowledge-based treatment planning. RESULTS: For 7 of the 11 cases in the test set, AI-selected beam angles agreed with those chosen by human planners to within 20° (median angle difference = 10°; mean = 18.6°). Moreover, out of the total 22 beam angles predicted by the model, 15 (68%) were within 10° of the human-selected angles. The high correlation in beam angles resulted in comparable dosimetric statistics between proton treatment plans generated using AI- and human-selected angles. For the cases with beam angle differences exceeding 20°, the dosimetric analysis showed similar plan quality although with different emphases on organ-at-risk sparing. CONCLUSIONS: This pilot study demonstrated the feasibility of a novel deep learning-based beam angle selection technique. Testing on liver cancer patients showed that the resulting plans were clinically viable with comparable dosimetric quality to those using human-selected beam angles. In tandem with auto-contouring and knowledge-based treatment planning tools, the proposed model could represent a pathway for nearly fully automated treatment planning in proton therapy.

Wide-Scale Clinical Implementation of Knowledge-Based Planning: An Investigation of Workforce Efficiency, Need for Post-automation Refinement, and Data-Driven Model Maintenance.

PURPOSE: Our purpose was to investigate the effect of automated knowledge-based planning (KBP) on real-world clinical workflow efficiency, assess whether manual refinement of KBP plans improves plan quality across multiple disease sites, and develop a data-driven method to periodically improve KBP automated planning routines. METHODS AND MATERIALS: Using clinical knowledge-based automated planning routines for prostate, prostatic fossa, head and neck, and hypofractionated lung disease sites in a commercial KBP solution, workflow efficiency was compared in terms of planning time in a pre-KBP (n = 145 plans) and post-KBP (n = 503) patient cohort. Post-KBP, planning was initialized with KBP (KBP-only) and subsequently manually refined (KBP +human). Differences in planning time were tested for significance using a 2-tailed Mann-Whitney U test (P < .05, null hypothesis: planning time unchanged). Post-refinement plan quality was assessed using site-specific dosimetric parameters of the original KBP-only plan versus KBP +human; 2-tailed paired t test quantified statistical significance (Bonferroni-corrected P < .05, null hypothesis: no dosimetric difference after refinement). If KBP +human significantly improved plans across the cohort, optimization objectives were changed to create an updated KBP routine (KBP'). Patients were replanned with KBP' and plan quality was compared with KBP +human as described previously. RESULTS: KBP significantly reduced planning time in all disease sites: prostate (median: 7.6 hrs â†’ 2.1 hrs; P < .001), prostatic fossa (11.1 hrs â†’ 3.7 hrs; P = .001), lung (9.9 hrs â†’ 2.0 hrs; P < .001), and head and neck (12.9 hrs â†’ 3.5 hrs; P <.001). In prostate, prostatic fossa, and lung disease sites, organ-at-risk dose changes in KBP +human versus KBP-only were minimal (<1% prescription dose). In head and neck, KBP +human did achieve clinically relevant dose reductions in some parameters. The head and neck routine was updated (KBP'HN) to incorporate dose improvements from manual refinement. The only significant dosimetric differences to KBP +human after replanning with KBP'HN were in favor of the new routine. CONCLUSIONS: KBP increased clinical efficiency by significantly reducing planning time. On average, human refinement offered minimal dose improvements over KBP-only plans. In the single disease site where KBP +human was superior to KBP-only, differences were eliminated by adjusting optimization parameters in a revised KBP routine.

Framework for Evaluation of Automated Knowledge-Based Planning Systems Using Multiple Publicly Available Prostate Routines.

PURPOSE: To establish a framework for the evaluation of knowledge-based planning routines that empowers new adopters to select systems that best match their clinical priorities. We demonstrate the power of this framework using 4 publicly available prostate routines. METHODS AND MATERIALS: Four publicly available prostate routines (CCMB, Miami, UCSD, WUSTL) were automatically applied across a 25-patient cohort using Eclipse scripting and a PTV prescription of V81 Gy = 95%. The institutions' routines differed in contouring guidelines for planning target volume (PTV) and organs at risk, beam arrangements, and optimization parameters. Model-estimated dose-volume histograms (DVHs) and deliverable postoptimization DVHs were extracted from plans to calculate average DVHs for each routine. Each routine's average calculated DVH was subtracted from the average DVH for all plans and from the model's average predicted DVH for comparison. DVH metrics for PTV (DMAX, D1%, D99%, DMIN), Rectum (DMAX, V70, V60, V40), Bladder (V75, V40), Femur (DMAX), and PenileBulb (DMEAN) were compared with the average using 2-sided paired t tests (Bonferroni-corrected P < .05). To control for contouring effects, the full analysis was conducted for 2 PTV margin schemas: 5 mm uniform and 3 mm or 7 mm posterior/else. RESULTS: Calculated plans generally aligned with their routine's DVH estimations, except CCMB organ-at-risk Dmaxes. Dosimetric parameter differences were not significant, with the exception of PTV DMAX (Miami = 111.1% [P < .001]), PTV D99% (Miami = 97.4% [P = .05]; UCSD = 97.4% [P = .03]; CCMB = 98.5% [P = .001]), Rectum V40 (Miami = 19.1% [P < .001]; UCSD = 22.7% [P = .003]; CCMB = 53.5% [P < .001]), and Femur DMAX (WUSTL = 48.6% [P = .001.]; CCMB = 37.9% [P < .001]). Overall, UCSD and Miami had lower rectum doses, and CCMB and WUSTL had higher PTV homogeneity. Conclusions were unchanged with different PTV margin schemas. CONCLUSIONS: Using publicly available knowledge-based planning routines spares clinicians substantial effort in developing new models. Our results allow clinicians to select the prostate routine that matches their clinical priorities, and our methodology sets the precedent for comparing routines for different treatment sites.

Noninferiority Study of Automated Knowledge-Based Planning Versus Human-Driven Optimization Across Multiple Disease Sites.

PURPOSE: To evaluate whether automated knowledge-based planning (KBP) (a) is noninferior to human-driven planning across multiple disease sites and (b) systematically affects dosimetric plan quality and variability. METHODS AND MATERIALS: Clinical KBP automated planning routines were developed for prostate, prostatic fossa, hypofractionated lung, and head and neck. Clinical implementation consisted of independent generation of human-generated and KBP plans (145 cases across all sites), followed by blinded plan selection. Reviewing physicians were prompted to select a single plan; when plan equivalence was volunteered, this scored as KBP selection. Plan selection analysis used a noninferiority framework testing the hypothesis that KBP is not worse than human-driven planning (threshold: lower 95% confidence interval [CI] > 0.45 = noninferiority; > 0.5 = superiority). Target and organ-at-risk metrics were compared by dose differencing: ΔDx = Dx, human-Dx, KBP (2-tailed paired t test, Bonferroni-corrected P < .05 significance threshold). To evaluate the aggregated effect of KBP on planning performance, we examined post-KBP dosimetric parameters against 183 plans generated just before KBP implementation (2-tailed unpaired t test, Bonferroni-corrected P < .05). RESULTS: Across all disease sites, the KBP success rate (physician preferred + equivalent) was noninferior compared with human-driven planning (83 of 145 = 57.2%; range, 49.2%-65.3%) but did not cross the threshold for superiority. The KBP success rate in respective disease sites was superior with head and neck ([22 + 2]/36 = 66.7%; 95% CI, 51%-82%) and noninferior for lung stereotactic body radiation therapy ([21 + 2]/36 = 63.9%; 95% CI, 48%-80%) but did not meet noninferiority criteria with prostate ([16 + 3]/41 = 46.3%; 95% CI, 31%-62%) or prostatic fossa ([17 + 0]/32 = 53.1%; 95% CI, 36%-70%). Prostate, prostatic fossa, and head and neck showed significant differences in KBP-selected plans versus human-selected plans, with KBP generally exhibiting greater organ-at-risk sparing and human plans exhibiting better target homogeneity. Analysis of plan quality pre- and post-KBP showed some reductions in organ doses and quality metric variability in prostate and head and neck. CONCLUSIONS: Fully automated KBP was noninferior to human-driven plan optimization across multiple disease sites. Dosimetric analysis of treatment plans before and after KBP implementation showed a systematic shift to higher plan quality and lower variability with the introduction of KBP.

Automated Closed- and Open-Loop Validation of Knowledge-Based Planning Routines Across Multiple Disease Sites.

PURPOSE: Knowledge-based planning (KBP) clinical implementation necessitates significant upfront effort, even within a single disease site. The purpose of this study was to demonstrate an efficient method for clinicians to assess the noninferiority of KBP across multiple disease sites and estimate any systematic dosimetric differences after implementation. We sought to establish these endpoints in a plurality of previously treated patients (validation set) with both closed-loop (training set overlapping validation set) and open-loop (independent training set) KBP routines. METHODS AND MATERIALS: We identified 53 prostate, 24 prostatic fossa, 54 hypofractionated lung, and 52 head and neck patients treated with volumetric modulated arc therapy in the year directly preceding our clinic's broad adoption of RapidPlan (Varian Medical Systems, Palo Alto, CA). Using the Varian Eclipse Scripting API, our program takes as input a list of patients, then performs semiautomated structure matching, fully automated RapidPlan-driven optimization, and plan comparison. All plans were normalized to the planning target volume (PTV) D95% = 100%. Dose metric differences (ΔDx = Dx,clinical - Dx,KBP) were computed for standard PTV and organ-at-risk (OAR) dose-volume histogram parameters across disease sites. A 2-tailed paired t test quantified statistical significance (P < .001). RESULTS: Statistically significant organ dose-volume histogram improvements were observed in the KBP cohort: the rectum, bladder, and penile bulb in prostate/prostatic fossa; and the larynx, esophagus, cricopharyngeus, parotid glands, and cochlea in head and neck. No OAR dose metric was statistically worse in any KBP sample. PTV ΔD1% increases in prostatic fossa were deemed acceptable given organ-sparing gains. PTV ΔD1% and internal target volume ΔD99% increase for the lung was by design owing to the prescription normalization variance in the pre-KBP lung sample. CONCLUSIONS: Our automated method showed multiple disease sites' KBP routines to be noninferior to manual planning, with statistically significant superiority in some aspects of OAR sparing. This method is applicable to any institution implementing either closed-loop or open-loop KBP autoplanning routines.

Geometric and dosimetric evaluation of atlas based auto-segmentation of cardiac structures in breast cancer patients.

BACKGROUND AND PURPOSE: Auto-segmentation represents an efficient tool to segment organs on CT imaging. Primarily used in clinical setting, auto-segmentation plays an increasing role in research, particularly when analyzing thousands of images in the "big data" era. In this study we evaluate the accuracy of cardiac dosimetric endpoints derived from atlas based auto-segmentation compared to gold standard manual segmentation. MATERIAL AND METHODS: Heart and cardiac substructures were manually delineated on 54 breast cancer patients. Twenty-seven patients were used to build the auto-segmentation atlas, the other 27 to validate performance. We evaluated accuracy of the auto-segmented contours with standard geometric indices and assessed dosimetric endpoints. RESULTS: Auto-segmented contours overlapped geometrically with manual contours of the heart and chambers with Dice-similarity coefficients of 0.93 ±â€¯0.02 (mean ±â€¯standard deviation) and 0.79 ±â€¯0.07 respectively. Similarly, there was a strong link between dosimetric parameters derived from auto-segmented and manual contours (R2 = 0.955-1.000). On the other hand, the left anterior descending artery had little geometric overlap (Dice-similarity coefficient 0.09 ±â€¯0.07), though acceptable representation of dosimetric parameters (R2 = 0.646-0.992). CONCLUSIONS: The atlas based auto-segmentation approach delineates heart structures with sufficient accuracy for research purposes. Our results indicate that quality of auto-segmented contours cannot be determined by geometric values only.

Immobilization for carbon ion beam ablation of cardiac structures in a porcine model.

INTRODUCTION: Whereas hadron therapy of static targets is clinically established, treatment of moving organs remains a challenge. One strategy is to minimize motion of surrounding tissue mechanically and to mitigate residual motion with an appropriate irradiation technique. In this technical note, we present and characterize such an immobilization technique for a novel noncancerous application: the irradiation of small targets in hearts with scanned carbon ion beams in a porcine model for elimination of arrhythmias. MATERIAL AND METHODS: A device for immobilization was custom-built. Both for the treatment planning 4D-CT scan and for irradiation, breath-hold at end-exhale was enforced using a remotely-controlled respirator. Target motion was thus reduced to heartbeat only. Positioning was verified by orthogonal X-rays followed by couch shift if necessary. Reproducibility of bony anatomy, diaphragm, and heart position after repositioning and between repeated breath-hold maneuvers was evaluated on X-rays and cardiac-gated 4D-CTs. Treatment was post hoc simulated on sequential 4D-CTs for a subset of animals, after immediate repositioning and after a delay of one week, similar to the delay between imaging and irradiation. RESULTS: Breath-hold without repositioning was highly reproducible with an RMS deviation of at most one millimeter. 4D-CTs showed larger deformations in soft tissue, but treatment simulation on sequential images resulted in full target coverage (V95 >95%). CONCLUSION: The method of immobilization permitted reproducible positioning of mobile, thoracic targets for range-sensitive particle therapy. The presented immobilization strategy could be a reasonable approach for future animal investigations with the ultimate goal of translation to therapy in men.

A descriptive and broadly applicable model of therapeutic and stray absorbed dose from 6 to 25 MV photon beams.

PURPOSE: To develop a simple model of therapeutic and stray absorbed dose for a variety of treatment machines and techniques without relying on proprietary machine-specific parameters. METHODS: Dosimetry measurements conducted in this study and from the literature were used to develop an analytical model of absorbed dose from a variety of treatment machines and techniques in the 6 to 25 MV interval. A modified one-dimensional gamma-index analysis was performed to evaluate dosimetric accuracy of the model on an independent dataset consisting of measured dose profiles from seven treatment units spanning four manufacturers. RESULTS: The average difference between the calculated and measured absorbed dose values was 9.9% for those datasets on which the model was trained. Additionally, these results indicate that the model can provide accurate calculations of both therapeutic and stray radiation dose from a wide variety of radiotherapy units and techniques. CONCLUSIONS: We have developed a simple analytical model of absorbed dose from external beam radiotherapy treatments in the 6 to 25 MV beam energy range. The model has been tested on measured data from multiple treatment machines and techniques, and is broadly applicable to contemporary external beam radiation therapy.

ECG-based 4D-dose reconstruction of cardiac arrhythmia ablation with carbon ion beams: application in a porcine model.

Noninvasive ablation of cardiac arrhythmia by scanned particle radiotherapy is highly promising, but especially challenging due to cardiac and respiratory motion. Irradiations for catheter-free ablation in intact pigs were carried out at the GSI Helmholtz Center in Darmstadt using scanned carbon ions. Here, we present real-time electrocardiogram (ECG) data to estimate time-resolved (4D) delivered dose. For 11 animals, surface ECGs and temporal structure of beam delivery were acquired during irradiation. R waves were automatically detected from surface ECGs. Pre-treatment ECG-triggered 4D-CT phases were synchronized to the R-R interval. 4D-dose calculation was performed using GSI's in-house 4D treatment planning system. Resulting dose distributions were assessed with respect to coverage (D95 and V95), heterogeneity (HI = D5-D95) and normal tissue exposure. Final results shown here were performed offline, but first calculations were started shortly after irradiation The D95 for TV and PTV was above 95% for 10 and 8 out of 11 animals, respectively. HI was reduced for PTV versus TV volumes, especially for some of the animals targeted at the atrioventricular junction, indicating residual interplay effects due to cardiac motion. Risk structure exposure was comparable to static and 4D treatment planning simulations. ECG-based 4D-dose reconstruction is technically feasible in a patient treatment-like setting. Further development of the presented approach, such as real-time dose calculation, may contribute to safe, successful treatments using scanned ion beams for cardiac arrhythmia ablation.

Helium ions for radiotherapy? Physical and biological verifications of a novel treatment modality.

PURPOSE: Modern facilities for actively scanned ion beam radiotherapy allow in principle the use of helium beams, which could present specific advantages, especially for pediatric tumors. In order to assess the potential use of these beams for radiotherapy, i.e., to create realistic treatment plans, the authors set up a dedicated (4)He beam model, providing base data for their treatment planning system TRiP98, and they have reported that in this work together with its physical and biological validations. METHODS: A semiempirical beam model for the physical depth dose deposition and the production of nuclear fragments was developed and introduced in TRiP98. For the biological effect calculations the last version of the local effect model was used. The model predictions were experimentally verified at the HIT facility. The primary beam attenuation and the characteristics of secondary charged particles at various depth in water were investigated using (4)He ion beams of 200 MeV/u. The nuclear charge of secondary fragments was identified using a ΔE/E telescope. 3D absorbed dose distributions were measured with pin point ionization chambers and the biological dosimetry experiments were realized irradiating a Chinese hamster ovary cells stack arranged in an extended target. RESULTS: The few experimental data available on basic physical processes are reproduced by their beam model. The experimental verification of absorbed dose distributions in extended target volumes yields an overall agreement, with a slight underestimation of the lateral spread. Cell survival along a 4 cm extended target is reproduced with remarkable accuracy. CONCLUSIONS: The authors presented a simple simulation model for therapeutical (4)He beams which they introduced in TRiP98, and which is validated experimentally by means of physical and biological dosimetries. Thus, it is now possible to perform detailed treatment planning studies with (4)He beams, either exclusively or in combination with other ion modalities.

Feasibility Study on Cardiac Arrhythmia Ablation Using High-Energy Heavy Ion Beams.

High-energy ion beams are successfully used in cancer therapy and precisely deliver high doses of ionizing radiation to small deep-seated target volumes. A similar noninvasive treatment modality for cardiac arrhythmias was tested here. This study used high-energy carbon ions for ablation of cardiac tissue in pigs. Doses of 25, 40, and 55 Gy were applied in forced-breath-hold to the atrioventricular junction, left atrial pulmonary vein junction, and freewall left ventricle of intact animals. Procedural success was tracked by (1.) in-beam positron-emission tomography (PET) imaging; (2.) intracardiac voltage mapping with visible lesion on ultrasound; (3.) lesion outcomes in pathohistolgy. High doses (40-55 Gy) caused slowing and interruption of cardiac impulse propagation. Target fibrosis was the main mediator of the ablation effect. In irradiated tissue, apoptosis was present after 3, but not 6 months. Our study shows feasibility to use high-energy ion beams for creation of cardiac lesions that chronically interrupt cardiac conduction.

Treatment of arrhythmias by external charged particle beams: a Langendorff feasibility study.

Hadron therapy has already proven to be successful in cancer therapy, and might be a noninvasive alternative for the ablation of cardiac arrhythmias in humans. We present a pilot experiment investigating acute effects of a 12C irradiation on the AV nodes of porcine hearts in a Langendorff setup. This setup was adapted to the requirements of charged particle therapy. Treatment plans were computed on calibrated CTs of the hearts. Irradiation was applied in units of 5 and 10 Gy over a period of about 3 h until a total dose of up to 160 Gy was reached. Repeated application of the same irradiation field helped to mitigate motion artifacts in the resulting dose distribution. After irradiation, PET scans were performed to verify accurate dose application. Acute AV blocks were identified. No other acute effects were observed. Hearts were kept in sinus rhythm for up to 6 h in the Langendorff setup. We demonstrated that 12C ions can be used to select a small target in the heart and, thereby, influence the electrical conduction system. Second, our pilot study seems to suggest that no adverse effects have to be expected immediately during heavy ion irradiation in performing subsequent experiments with doses of 30-60 Gy and intact pigs.

Atrioventricular node ablation in Langendorff-perfused porcine hearts using carbon ion particle therapy: methods and an in vivo feasibility investigation for catheter-free ablation of cardiac arrhythmias.

BACKGROUND: Particle therapy, with heavy ions such as carbon-12 ((12)C), delivered to arrhythmogenic locations of the heart could be a promising new means for catheter-free ablation. As a first investigation, we tested the feasibility of in vivo atrioventricular node ablation, in Langendorff-perfused porcine hearts, using a scanned 12C beam. METHODS AND RESULTS: Intact hearts were explanted from 4 (30-40 kg) pigs and were perfused in a Langendorff organ bath. Computed tomographic scans (1 mm voxel and slice spacing) were acquired and (12)C ion beam treatment planning (optimal accelerator energies, beam positions, and particle numbers) for atrioventricular node ablation was conducted. Orthogonal x-rays with matching of 4 implanted clips were used for positioning. Ten Gray treatment plans were repeatedly administered, using pencil beam scanning. After delivery, positron emission tomography-computed tomographic scans for detection of ß(+) ((11)C) activity were obtained. A (12)C beam with a full width at half maximum of 10 mm was delivered to the atrioventricular node. Delivery of 130 Gy caused disturbance of atrioventricular conduction with transition into complete heart block after 160 Gy. Positron emission computed tomography demonstrated dose delivery into the intended area. Application did not induce arrhythmias. Macroscopic inspection did not reveal damage to myocardium. Immunostaining revealed strong γH2AX signals in the target region, whereas no γH2AX signals were detected in the unirradiated control heart. CONCLUSIONS: This is the first report of the application of a (12)C beam for ablation of cardiac tissue to treat arrhythmias. Catheter-free ablation using 12C beams is feasible and merits exploration in intact animal studies as an energy source for arrhythmia elimination.

Out-of-field dose studies with an anthropomorphic phantom: comparison of X-rays and particle therapy treatments.

BACKGROUND AND PURPOSE: Characterization of the out-of-field dose profile following irradiation of the target with a 3D treatment plan delivered with modern techniques. METHODS: An anthropomorphic RANDO phantom was irradiated with a treatment plan designed for a simulated 5 × 2 × 5 cm(3) tumor volume located in the center of the head. The experiment was repeated with all most common radiation treatment types (photons, protons and carbon ions) and delivery techniques (Intensity Modulated Radiation Therapy, passive modulation and spot scanning). The measurements were performed with active diamond detector and passive thermoluminescence (TLD) detectors to investigate the out-of-field dose both inside and outside the phantom. RESULTS: The highest out-of-field dose values both on the surface and inside the phantom were measured during the treatment with 25 MV photons. In the proximity of the Planned Target Volume (PTV), the lowest lateral dose profile was observed for passively modulated protons mainly because of the presence of the collimator in combination with the chosen volume shape. In the far out-of-field region (above 100mm from the PTV), passively modulated ions were characterized by a less pronounced dose fall-off in comparison with scanned beams. Overall, the treatment with scanned carbon ions delivered the lowest dose outside the target volume. CONCLUSIONS: For the selected PTV, the use of the collimator in proton therapy drastically reduced the dose deposited by ions or photons nearby the tumor. Scanning modulation represents the optimal technique for achieving the highest dose reduction far-out-of-field.