Challenges and opportunities in the development and clinical implementation of artificial intelligence based synthetic computed tomography for magnetic resonance only radiotherapy.

Synthetic computed tomography (sCT) generated from magnetic resonance imaging (MRI) can serve as a substitute for planning CT in radiation therapy (RT), thereby removing registration uncertainties associated with multi-modality imaging pairing, reducing costs and patient radiation exposure. CE/FDA-approved sCT solutions are nowadays available for pelvis, brain, and head and neck, while more complex deep learning (DL) algorithms are under investigation for other anatomic sites. The main challenge in achieving a widespread clinical implementation of sCT lies in the absence of consensus on sCT commissioning and quality assurance (QA), resulting in variation of sCT approaches across different hospitals. To address this issue, a group of experts gathered at the ESTRO Physics Workshop 2022 to discuss the integration of sCT solutions into clinics and report the process and its outcomes. This position paper focuses on aspects of sCT development and commissioning, outlining key elements crucial for the safe implementation of an MRI-only RT workflow.

Randomized self-controlled study comparing open-face vs. closed immobilization masks in fractionated cranial radiotherapy.

PURPOSE: To compare patient discomfort and immobilisation performance of open-face and closed immobilization masks in cranial radiotherapy. MATERIAL AND METHODS: This was a single-center randomized self-controlled clinical trial. At CT simulation, an open-face and closed mask was made for each patient and treatment plans with identical dose prescription were generated for each mask. Patients were randomised to start treatment with an open-face or closed mask. Masks were switched halfway through the treatment course; every patient was their own control. Patients self-reported discomfort, anxiety and pain using the visual analogue scale (VAS). Inter- and intrafraction set-up variability was measured with planar kV imaging and a surface guided radiotherapy (SGRT) system for the open-face masks. RESULTS: 30 patients with primary or metastatic brain tumors were randomized - 29 completed radiotherapy to a median total dose of 54 Gy (range 30-60 Gy). Mean discomfort VAS score was significantly lower with open-face masks (0.5, standard deviation 1.0) vs. closed masks (3.3, standard deviation 2.9), P < 0.0001. Anxiety and pain VAS scores were significantly lower with open-face masks (P < 0.0001). Closed masks caused more discomfort in infraorbital (P < 0.001) and maxillary (P = 0.02) areas. Two patients and 27 patients preferred closed or open-face masks, respectively. Interfraction longitudinal shifts and roll and yaw rotations were significantly smaller and lateral shifts were significantly larger with closed masks in combination with the laser system (P < 0.05) compared to open masks in combination with a SGRT system. Intrafraction variability did not differ between the masks. CONCLUSIONS: Open-face masks are associated with decreased patient discomfort without compromising patient positioning and immobilisation accuracy.

The Use of MR-Guided Radiation Therapy for Head and Neck Cancer and Recommended Reporting Guidance.

Although magnetic resonance imaging (MRI) has become standard diagnostic workup for head and neck malignancies and is currently recommended by most radiological societies for pharyngeal and oral carcinomas, its utilization in radiotherapy has been heterogeneous during the last decades. However, few would argue that implementing MRI for annotation of target volumes and organs at risk provides several advantages, so that implementation of the modality for this purpose is widely accepted. Today, the term MR-guidance has received a much broader meaning, including MRI for adaptive treatments, MR-gating and tracking during radiotherapy application, MR-features as biomarkers and finally MR-only workflows. First studies on treatment of head and neck cancer on commercially available dedicated hybrid-platforms (MR-linacs), with distinct common features but also differences amongst them, have also been recently reported, as well as "biological adaptation" based on evaluation of early treatment response via functional MRI-sequences such as diffusion weighted ones. Yet, all of these approaches towards head and neck treatment remain at their infancy, especially when compared to other radiotherapy indications. Moreover, the lack of standardization for reporting MR-guided radiotherapy is a major obstacle both to further progress in the field and to conduct and compare clinical trials. Goals of this article is to present and explain all different aspects of MR-guidance for radiotherapy of head and neck cancer, summarize evidence, as well as possible advantages and challenges of the method and finally provide a comprehensive reporting guidance for use in clinical routine and trials.

Dosimetric Analysis of Proximal Bronchial Tree Subsegments to Assess The Risk of Severe Toxicity After Stereotactic Body Radiation Therapy of Ultra-central Lung Tumors.

•Stereotactic body radiation therapy (SBRT) for ultra-central lung tumors is associated with high toxicity rates.•To evaluate differences in radiosensitivity within the proximal bronchial tree (PBT), the PBT was sub-segmented into seven anatomical sections.•A risk-adapted SBRT regimen of EQD2_10 = 54.4 Gy in 8 or 10 fractions results in excellent local control and low rates of severe toxicity.•Data from a recent meta-analysis, the NORDIC Hilus trial and dosimetric data from this study were combined to create a NTCP model.•A dose threshold of EQD2_3 = 100 Gy to the PBT or any of its subsegments is expected to result in low rates of severe bronchial toxicity.

Dosimetric analysis of 17 cardiac Sub-structures, Toxicity, and survival in ultra central lung tumor patients treated with SBRT.

•Data on cardiac toxicity after SBRT for ultra-central lung tumors remains limited.•We analyzed the dose to 18 cardiac sub-structures and cardiovascular toxicity.•A SBRT regimen of 45 Gy in 8-10 fractions yields good local control and low toxicity.•The highest cardiac doses were observed in the pulmonary artery and left atrium.•Higher doses to the base of the heart seem to be associated with non-cancer deaths.

Patient-specific quality assurance strategies for synthetic computed tomography in magnetic resonance-only radiotherapy of the abdomen.

Background and purpose: The superior tissue contrast of magnetic resonance (MR) compared to computed tomography (CT) led to an increasing interest towards MR-only radiotherapy. For the latter, the dose calculation should be performed on a synthetic CT (sCT). Patient-specific quality assurance (PSQA) methods have not been established yet and this study aimed to assess several software-based solutions. Materials and methods: A retrospective study was performed on 20 patients treated at an MR-Linac, which were selected to evenly cover four subcategories: (i) standard, (ii) air pockets, (iii) lung and (iv) implant cases. The neural network (NN) CycleGAN was adopted to generate a reference sCT, which was then compared to four PSQA methods: (A) water override of body, (B) five tissue classes with bulk densities, (C) sCT generated by a separate NN (pix2pix) and (D) deformed CT. Results: The evaluation of the dose endpoints demonstrated that while all methods A-D provided statistically equivalent results (p = 0.05) within the 2% level for the standard cases (i), only the methods C-D guaranteed the same result over the whole cohort. The bulk densities override was shown to be a valuable method in absence of lung tissue within the beam path. Conclusion: The observations of this study suggested that the use of an additional sCT generated by a separate NN was an appropriate tool to perform PSQA of a sCT in an MR-only workflow at an MR-Linac. The time and dose endpoints requirements were respected, namely within 10 min and 2%.

Enabling ultra-high dose rate electron beams at a clinical linear accelerator for isocentric treatments.

BACKGROUND AND PURPOSE: Radiotherapy delivery with ultra-high dose rates (UHDR) has consistently produced normal tissue sparing while maintaining efficacy for tumour control in preclinical studies, known as the FLASH effect. Modified clinical electron linacs have been used for pre-clinical studies at reduced source-surface distance (SSD) and novel intra-operative devices are becoming available. In this context, we modified a clinical linac to deliver 16 MeV UHDR electron beams with an isocentric setup. MATERIALS AND METHODS: The first Varian TrueBeam (SN 1001) was clinically operative between 2009-2022, it was then decommissioned and converted into a research platform. The 18 MeV electron beam was converted into the experimental 16 MeV UHDR. Modifications were performed by Varian and included a software patch, thinner scattering foil and beam tuning. The dose rate, beam characteristics and reproducibility were measured with electron applicators at SSD = 100 cm. RESULTS: The dose per pulse at isocenter was up to 1.28 Gy/pulse, corresponding to average and instantaneous dose rates up to 256 Gy/s and 3⋅105 Gy/s, respectively. Beam characteristics were equivalent between 16 MeV UHDR and conventional for field sizes up to 10x10cm2 and an overall beam reproducibility within ± 2.5% was measured. CONCLUSIONS: We report on the first technical conversion of a Varian TrueBeam to produce 16 MeV UHDR electron beams. This research platform will allow isocenter experiments and deliveries with conventional setups up to field sizes of 10x10 cm2 within a hospital environment, reducing the gap between preclinical and clinical electron FLASH investigations.

Effect of 0.35 T and 1.5 T magnetic fields on superficial dose in MR-guided radiotherapy of laryngeal cancer.

Background: Treatment of head and neck cancer on linear accelerators with on-board magnetic resonance imaging (MR-linac) might be beneficial to reduce side effects and increase accuracy. For many head and neck cancer patients, dose coverage of the often superficially located planning target volumes (PTVs) is required. This study examines the impact of the electron return effect (ERE) on the surface dose in MR-guided radiotherapy (MRgRT) compared to conventional radiotherapy. Materials and methods: For this bicentric dosimetric study, 14 cases of laryngeal carcinomas with PTVs reaching up to the skin surface were included. For each patient, five different plans were compared, two VMAT plans (with and without a 5 mm bolus) and three IMRT MRgRT plans (0.35 T, 1.5 T and 0 T, each without bolus). Dose distributions were also validated with film measurements. Results: A similar coverage on the most superficial 3-5 mm of the PTV was achieved in the VMAT plans with bolus and the MRgRT plans for both 0.35 T and 1.5 T. However, coverage on this region was usually not achieved for VMAT without bolus and the 0 T plans. The film measurements on phantoms confirmed the results with the relative error never exceeding the calculated differences between the plans. Conclusion: The present study could demonstrate that the ERE for both commercially available MR-linac variants provides sufficient coverage of the superficial tissue layers in MRgRT-plans for laryngeal carcinoma.

Reduction of patient specific quality assurance through plan complexity metrics for VMAT plans with an open-source TPS script.

PURPOSE: Volumetric modulated arc therapy (VMAT) is a widespread technique for the delivery of normo-fractionated radiation therapy (NFRT) and stereotactic body radiation therapy (SBRT). It is associated with a significant hardware burden requiring dose rate modulation, collimator movement and gantry rotation synchronisation. Patient specific quality assurance (PSQA) guarantees that the linacs can precisely and accurately deliver the planned dose. However, PSQA requires a significant time allocation and class solutions to reduce this while guaranteeing the deliverability of the plans should be investigated. METHODS: In this study, an in-house developed Eclipse Scripting API (ESAPI) script was used to extract five independent plan complexity metrics from N = 667 VMAT treatment fields. The correlation between metrics and portal dosimetry measurements was investigated with Pearson correlation, box plot analysis and receiver operating characteristic curves, which were used to defined the best performing metric and its threshold. RESULTS: The incidence of fields failing the clinical PSQA criteria of 3%/2mm (NFRT) and 3%/1.5mm (SBRT) was low (N = 1). The mean MLC opening was the metric with the highest correlation with the portal dosimetry data and among the best in discriminating the requirement of PSQA. The thresholds of 16.12 mm (NFRT) and 7.96 mm (SBRT) corresponded to true positive rates higher than 90%. CONCLUSIONS: This work presents a quantitative approach to reduce the time allocation for PSQA by identifying the most complex plans demanding a dedicated measurement. The proposed method requires PSQA for approximately 10% of the plans. The ESAPI script is distributed open-source to ease the investigation and implementation at other institutions.

Synthetic computed tomography for low-field magnetic resonance-guided radiotherapy in the abdomen.

Background and purpose: The requirement of computed tomography (CT) for radiotherapy planning may be bypassed by synthetic CT (sCT) generated from magnetic resonance (MR), which has recently led to the clinical introduction of MR-only radiotherapy for specific sites. Further developments are required for abdominal sCT, mostly due to the presence of mobile air pockets affecting the dose calculation. In this study we aimed to overcome this limitation for abdominal sCT at a low field (0.35 T) hybrid MR-Linac. Materials and methods: A retrospective analysis was conducted enrolling 168 patients corresponding to 215 MR-CT pairs. After the exclusion criteria, 152 volumetric images were used to train the cycle-consistent generative adversarial network (CycleGAN) and 34 to test the sCT. Image similarity metrics and dose recalculation analysis were performed. Results: The generated sCT faithfully reproduced the original CT and the location of the air pockets agreed with the MR scan. The dose calculation did not require manual bulk density overrides and the mean deviations of the dose-volume histogram dosimetric points were within 1 % of the CT, without any outlier above 2 %. The mean gamma passing rates were above 99 % for the 2 %/ 2 mm analysis and no cases below 95 % were observed. Conclusions: This study presented the implementation of CycleGAN to perform sCT generation in the abdominal region for a low field hybrid MR-Linac. The sCT was shown to correctly allocate the electron density for the mobile air pockets and the dosimetric analysis demonstrated the potential for future implementation of MR-only radiotherapy in the abdomen.

MR-Guided Adaptive Radiotherapy for Head and Neck Cancer: Prospective Evaluation of Migration and Anatomical Changes of the Major Salivary Glands.

The aim of this study was to quantify anatomical changes of parotids and submandibular glands and evaluate potential dosimetric advantages during weekly adaptive MR-guided radiotherapy (MRgRT) for the definitive treatment of head and neck cancer (HNC). The data and plans of 12 patients treated with bilateral intensity-modulated radiotherapy for HNC using MR-linac, with weekly offline adaptations, were prospectively evaluated. The positional and volumetric changes of the salivary glands were analyzed by manual segmentation in weekly MRI images and the dosimetric impact of these anatomical changes on the adapted treatment plans was assessed. The mean volume change in parotid and submandibular gland volume was -31.9% (p < 0.0001) and -29.7% (p < 0.0001) after five weeks, respectively. The volume change was significantly correlated with the cumulative dose for the respective gland at the time of volume measurement. Inter-parotid distance changed by -5.4% (6.5 mm) on average after five weeks (p = 0.0005). The distance became significantly smaller only in the left-right direction. The inter-submandibular gland distance changed by 0.7 mm (p = 0.38). This study demonstrated significant changes in salivary gland volumes and position following daily MR guidance and weekly plan adaptation. Ongoing clinical trials will provide data on the clinical impact of these changes and novel MR-based adaptation strategies.

Systematic Review on the Association of Radiomics with Tumor Biological Endpoints.

Radiomics supposes an alternative non-invasive tumor characterization tool, which has experienced increased interest with the advent of more powerful computers and more sophisticated machine learning algorithms. Nonetheless, the incorporation of radiomics in cancer clinical-decision support systems still necessitates a thorough analysis of its relationship with tumor biology. Herein, we present a systematic review focusing on the clinical evidence of radiomics as a surrogate method for tumor molecular profile characterization. An extensive literature review was conducted in PubMed, including papers on radiomics and a selected set of clinically relevant and commonly used tumor molecular markers. We summarized our findings based on different cancer entities, additionally evaluating the effect of different modalities for the prediction of biomarkers at each tumor site. Results suggest the existence of an association between the studied biomarkers and radiomics from different modalities and different tumor sites, even though a larger number of multi-center studies are required to further validate the reported outcomes.

Benefit of replanning in MR-guided online adaptive radiation therapy in the treatment of liver metastasis.

PURPOSE: To assess the effects of daily adaptive MR-guided replanning in stereotactic body radiation therapy (SBRT) of liver metastases based on a patient individual longitudinal dosimetric analysis. METHODS: Fifteen patients assigned to SBRT for oligometastatic liver metastases underwent daily MR-guided target localization and on-table treatment plan re-optimization. Gross tumor volume (GTV) and organs at risk (OARs) were adapted to the anatomy-of-the-day. A reoptimized plan (RP) and a rigidly shifted baseline plan (sBP) without re-optimization were generated for each fraction. After extraction of DVH parameters for GTV, planning target volume (PTV), and OARs (stomach, duodenum, bowel, liver, heart) plans were compared on a per-patient basis. RESULTS: Median pre-treatment GTV and PTV were 14.9 cc (interquartile range (IQR): 7.7-32.9) and 62.7 cc (IQR: 42.4-105.5) respectively. SBRT with RP improved PTV coverage (V100%) for 47/75 of the fractions and reduced doses to the most proximal OARs (D1cc, Dmean) in 33/75 fractions compared to sBP. RP significantly improved PTV coverage (V100%) for metastases within close proximity to an OAR by 4.0% (≤ 0.2 cm distance from the edge of the PTV to the edge of the OAR; n = 7; p = 0.01), but only by 0.2% for metastases farther away from OAR (> 2 cm distance; n = 7; p = 0.37). No acute grade 3 treatment-related toxicities were observed. CONCLUSIONS: MR-guided online replanning SBRT improved target coverage and OAR sparing for liver metastases with a distance from the edge of the PTV to the nearest luminal OAR < 2 cm. Only marginal improvements in target coverage were observed for target distant to critical OARs, indicating that these patients do not benefit from daily adaptive replanning.

In-field stereotactic body radiotherapy (SBRT) reirradiation for pulmonary malignancies as a multicentre analysis of the German Society of Radiation Oncology (DEGRO).

Data of thoracic in-field reirradiation with two courses of stereotactic body radiotherapy (SBRT) is scarce. Aim of this study is to investigate feasibility and safety of this approach. Patients with a second course of thoracic SBRT and planning target volume (PTV) overlap were analyzed in this retrospective, multicenter study. All plans and clinical data were centrally collected. 27 patients from 8 centers have been amenable for evaluation: 12 with non-small-cell lung cancer, 16 with metastases, treated from 2009 (oldest first course) to 2020 (latest second course). A median dose of 38.5 Gy to the 65%-isodose over a median of 5 fractions was prescribed in the first course and 40 Gy in 5 fractions for the second SBRT-course. Median PTV of the second SBRT was 29.5 cm3, median PTV overlap 22 cm3. With a median interval of 20.2 months between the two SBRT-courses, 1-year OS, and -LCR were 78.3% and 70.3% respectively. 3 patients developed grade 1 and one grade 2 pneumonitis. No grade > 2 toxicity was observed. Peripheral location and dose were the only factors correlating with tumor control. A second SBRT-course with PTV overlap appears safe and achieves reasonable local control.

PIBS: Proton and ion beam spectroscopy for in vivo measurements of oxygen, carbon, and calcium concentrations in the human body.

Proton and ion beam therapy has proven to benefit tumour control with lower side-effects, mostly in paediatrics. Here we demonstrate a feasible technique for proton and ion beam spectroscopy (PIBS) capable of determining the elemental compositions of the irradiated tissues during particle therapy. This follows the developments in prompt gamma imaging for online range verification and the inheritance from prompt gamma neutron activation analysis. Samples of water solutions were prepared to emulate varying oxygen and carbon concentrations. The irradiation of those samples and other tissue surrogate inserts by protons and ion beams under clinical conditions clearly showed a logarithmic relationship between the target elemental composition and the prompt gamma production. This finding is in line with the known logarithmic dependence of the pH with the proton molar concentration. Elemental concentration changes of 1% for calcium and 2% for oxygen in adipose, brain, breast, liver, muscle and bone-related tissue surrogates were clearly identified. Real-time in vivo measurements of oxygen, carbon and calcium concentrations will be evaluated in a pre-clinical and clinical environment. This technique should have an important impact in the assessment of tumour hypoxia over the course of several treatment fractions and the tracking of calcifications in brain metastases.

Prompt gamma spectroscopy for absolute range verification of 12C ions at synchrotron-based facilities.

The physical range uncertainty limits the exploitation of the full potential of charged particle therapy. In this work, we face this issue aiming to measure the absolute Bragg peak position in the target. We investigate p, 4He, 12C and 16O beams accelerated at the Heidelberg Ion-Beam Therapy Center. The residual range of the primary 12C ions is correlated to the energy spectrum of the prompt gamma radiation. The prompt gamma spectroscopy method was demonstrated for proton beams accelerated by cyclotrons and is developed here for the first time for heavier ions accelerated by a synchrotron. We develop a detector system that includes (i) a spectroscopic unit based on cerium(III) bromide and bismuth germanium oxide scintillating crystals, (ii) a beam trigger based on an array of scintillating fibers and (iii) a data acquisition system based on a FlashADC. We test the system in two different scenarios. In the first series of experiments, we detect and identify 19 independent spectral lines over a wide gamma energy spectrum in the presence of the four ion species for different targets, including a water target with a titanium insert. In the second series of experiments, we introduce a collimator aiming to relate the spectral information to the range of the primary particles. We perform extensive measurements for a 12C beam and demonstrate submillimetric precision for the measurement of its Bragg peak position in the experimental setup. The features of the energy and time spectra for gamma radiation induced by p, 4He and 16O are investigated upstream and downstream from the Bragg peak position. We conclude the analysis by extrapolating the required future developments, which would be needed to achieve range verification with a 2 mm accuracy during a single fraction delivery of [Formula: see text] physical dose.

Dosimetric and geometric end-to-end accuracy of a magnetic resonance guided linear accelerator.

The introduction of real-time imaging by magnetic resonance guided linear accelerators (MR-Linacs) enabled adaptive treatments and gating on the tumor position. Different end-to-end tests monitored the accuracy of our MR-Linac during the first year of clinical operation. We report on the stability of these tests covering a static, adaptive and gating workflow. Film measurements showed gamma passing rates of 96.4% ± 3.4% for the static tests (five measurements) and for the two adaptive tests 98.9% and 99.99%, respectively (criterion 2%/2mm). The gated point dose measurements in the breathing phantom were 2.7% lower than in the static phantom.

Results from the experimental evaluation of CeBr 3 scintillators for 4 He prompt gamma spectroscopy.

PURPOSE: The presence of range uncertainties hinders the exploitation of the full potential of charged particle therapy. Several range verification techniques have been proposed to mitigate this limitation. Prompt gamma spectroscopy (PGS) is among the most promising solutions for online and in vivo range verification. In this work, we present the experimental results of the detection of prompt gamma radiation, induced by 4 He beams at the Heidelberg Ion-Beam Therapy Center (HIT). The results were obtained, using a spectroscopic unit of which the design has been optimized using Monte Carlo simulations. METHODS: The spectroscopic unit is composed by a primary cerium bromide (CeBr 3 ) crystal surrounded by a secondary bismuth germanate (BGO) crystal for anticoincidence detection (AC). The digitalization of the signals is performed with an advanced FADC/FPGA system. The 4 He beams at clinical energies and intensities are delivered to multiple targets in the experimental cave at the HIT. We analyze the production of prompt gamma on oxygen and carbon targets, as well as high Z materials such as titanium and aluminum. The quantitative analysis includes a systematic comparison of the signal-to-noise ratio (SNR) improvement for the spectral lines when introducing the AC detection. Moreover, the SNR improvement could provide a reduction of the number of events required to draw robust conclusions. We perform a statistic analysis to determine the magnitude of such an effect. RESULTS: We present the energy spectra detected by the primary CeBr 3 and the secondary BGO. The combination of these two detectors leads to an average increase of the signal-to-noise ratio by a factor 2.1, which confirms the Monte Carlo predictions. The spectroscopic unit is capable of detecting efficiently the discrete gamma emission over the full energy spectrum. We identify and analyze 19 independent spectral lines in an energy range spacing from E γ = 0.718  MeV to E γ = 6.13  MeV. Moreover, when introducing the AC detection, the number of events required to determine robustly the intensity of the discrete lines decreases. Finally, the analysis of the low-energy reaction lines determines whether a thin metal insert is introduced in the beam direction. CONCLUSIONS: This work provides the experimental characterization of the spectroscopy unit in development for range verification through PGS at the HIT. Excellent performances have been demonstrated over the full prompt gamma energy spectrum with 4 He beams at clinical energies and intensities.

CeBr3 scintillators for 4 He prompt gamma spectroscopy: Results from a Monte Carlo optimization study.

PURPOSE: Range uncertainties limit the potential of charged particle therapy. In vivo and online range verification techniques could increase the confidence in the dose delivery distribution and lead to more conformal treatments. Prompt gamma imaging and prompt gamma spectroscopy (PGS) have been demonstrated for such a purpose. The successful application of these techniques requires the development of a dedicated detector system optimized to the radiation energy ranges and the intensity. In this work, we investigated a detector system based on CeBr3 crystals capable of performing spectroscopy of the prompt gamma radiation induced by 4 He beams. METHODS: We performed Monte Carlo simulations to optimize the detector system. The study was carried out both with the Geant4 toolkit and the FLUKA package. The simulated system consisted of a primary crystal for spectroscopy and secondary crystals for noise reduction in anticoincidence (AC). For comparison purposes, we considered a configuration without AC crystals. We first defined the dimensions of the primary cerium bromide (CeBr3 ) crystal and the secondary bismuth germanate (BGO) or CeBr3 crystals. We then evaluated their detection performance for monoenergetic gamma radiation up to 7 MeV in such way that the probability of the photo-peak detection was maximized in comparison to the number of escape peak and Compton events. We simulated realistic prompt gamma radiation spectra induced by 4 He beams on homogeneous targets (water, graphite, and aluminum) and on implants (water with an aluminum insert). Finally, we tested the performances of the optimized systems in the detection of the realistic gamma spectra. The quantitative analysis was accomplished by comparing the signal-to-noise ratio between the different configurations and the ability to resolve the discrete reactions. RESULTS: We present the optimized dimensions for the primary CeBr3 crystals with and without AC shielding. The specific values are given over a wide range of crystal volumes. The results show an optimal primary CeBr3 crystal with an approximately diameter to length ratio of 1 without AC shielding and 0.5 with AC shielding. The secondary BGO and CeBr3 should have a transverse dimension of 3 and 4.56 cm, respectively. The analysis of the prompt gamma spectra from 4 He beams highlighted the presence of specific discrete reactions not observed in 1 H studies, for example, 12 C transition 0+ (7.65 MeV) →2+ (4.44 MeV). This reaction is responsible for the generation of the 3.21 MeV prompt gamma peak. The optimized primary crystal provides a significant increase in the signal-to-noise ratio together with an improved resolution of the discrete gamma lines, especially in the high-energy region. The detection configuration with an optimized anticoincidence crystal improved the signal-to-noise ratio up to a factor of 3.5. CONCLUSIONS: This work provides the optimal geometry for primary and secondary crystals to be used in range verification through PGS. The simulations show that such a PGS system may allow for the simultaneous detection of the discrete lines from a thin metal implant within a water phantom.