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Purpose: The development of online-adaptive proton therapy (PT) is essential to overcome limitations encountered by day-to-day variations of the patient's anatomy. Range verification could play an essential role in an online feedback loop for the detection of treatment deviations such as anatomical changes. Here, we present the results of the first systematic patient study regarding the detectability of anatomical changes by a prompt-gamma imaging (PGI) slit-camera system., Methods and Materials: For 15 patients with prostate cancer, PGI measurements were performed during 105 fractions (201 fields) with in-room control computed tomography (CT)acquisitions. Field-wise doses on control CT scans were manually classified as whether showing relevant or non-relevant anatomical changes. This manual classification of the treatment fields was then used to establish an automatic field-wise ground truth based on spot-wise dosimetric range shifts, which were retrieved from integrated depth-dose (IDD) profiles. To determine the detection capability of anatomical changes with PGI, spot-wise PGI-based range shifts were initially compared with corresponding dosimetric IDD range shifts. As final endpoint, the agreement of a developed field-wise PGI classification model with the field-wise ground truth was determined. Therefore, the PGI model was optimized and tested for a subcohort of 131 and 70 treatment fields, respectively., Results: The correlation between PGI and IDD range shifts was high, ρ pearson  = 0.67 (p < 0.01). Field-wise binary PGI classification resulted in an area under the curve of 0.72 and 0.80 for training and test cohorts, respectively. The model detected relevant anatomical changes in the independent test cohort, with a sensitivity and specificity of 74% and 79%, respectively., Conclusions: For the first time, evidence of the detection capability of anatomical changes in prostate-cancer PT from clinically acquired PGI data is shown. This emphasizes the benefit of PGI-based range verification and demonstrates its potential for online-adaptive PT., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Uncertainty in computed tomography (CT)-based range prediction substantially impairs the accuracy of proton therapy. Direct determination of the stopping-power ratio (SPR) from dual-energy CT (DECT) has been proposed (DirectSPR), and initial validation studies in phantoms and biological tissues have proven a high accuracy. However, a thorough validation of range prediction in patients has not yet been achieved by any means. Here, we present the first systematic validation of CT-based proton range prediction in patients using prompt gamma imaging (PGI)., Methods and Materials: A PGI slit camera system with improved positioning accuracy, using a floor-based docking station, was used. Its overall uncertainty for range prediction validation was determined experimentally with both x-ray and beam measurements. The accuracy of range prediction in patients was determined from clinical PGI measurements during hypofractionated treatment of 5 patients with prostate cancer - in total 30 fractions with in-room control-CTs. For each pencil-beam-scanning spot, the range shift was obtained by comparing the PGI measurement to a control-CT-based PGI simulation. Three different SPR prediction approaches were applied in simulations: a standard CT-number-to-SPR conversion (Hounsfield look-up table [HLUT]), an adapted HLUT (DECT optimized), and DirectSPR. The spot-wise weighted mean range shift from all spots served as a measure for the accuracy of the respective range prediction approach., Results: A mean range prediction accuracy of 0.0% ± 0.5%, 0.3% ± 0.4%, and 1.8% ± 0.4% was obtained for DirectSPR, adapted HLUT, and standard HLUT, respectively. The overall validation uncertainty of the second-generation PGI slit camera is about 1 mm (2σ) for all approaches, which is smaller than the range prediction uncertainty for deep-seated tumors., Conclusions: For the first time, range prediction accuracy was assessed in clinical routine using PGI range verification in prostate cancer treatments. Both DECT-derived range prediction approaches agree well with the measured proton range from PGI verification, whereas the standard HLUT approach differs relevantly. These results endorse the recent reduction of clinical safety margins in DirectSPR-based treatment planning in our institution., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Proton radiotherapy (PT) requires accurate target alignment before each treatment fraction, ideally utilizing 3D in-room X-ray computed tomography (CT) imaging. Typically, the optimal patient position is determined based on anatomical landmarks or implanted markers. In the presence of non-rigid anatomical changes, however, the planning scenario cannot be exactly reproduced and positioning should rather aim at finding the optimal position in terms of the actually applied dose. In this work, dose-guided patient alignment, implemented as multicriterial optimization (MCO) problem, was investigated in the scope of intensity-modulated and double-scattered PT (IMPT and DSPT) for the first time. A method for automatically determining the optimal patient position with respect to pre-defined clinical goals was implemented. Linear dose interpolation was used to access a continuous space of potential patient shifts. Fourteen head and neck (H&N) and eight prostate cancer patients with up to five repeated CTs were included. Dose interpolation accuracy was evaluated and the potential dosimetric advantages of dose-guided over bony-anatomy-based patient alignment investigated by comparison of clinically relevant target and organ-at-risk (OAR) dose-volume histogram (DVH) parameters. Dose interpolation was found sufficiently accurate with average pass-rates of 90% and 99% for an exemplary H&N and prostate patient, respectively, using a 2% dose-difference criterion. Compared to bony-anatomy-based alignment, the main impact of automated MCO-based dose-guided positioning was a reduced dose to the serial OARs (spinal cord and brain stem) for the H&N cohort. For the prostate cohort, under-dosage of the target structures could be efficiently diminished. Limitations of dose-guided positioning were mainly found in reducing target over-dosage due to weight loss for H&N patients, which might require adaptation of the treatment plan. Since labor-intense online quality-assurance is not required for dose-guided patient positioning, it might, nevertheless, be considered an interesting alternative to full online re-planning for initially mitigating the effects of anatomical changes., (Copyright © 2018. Published by Elsevier GmbH.)

Purpose: To compare early and late toxicities, dosimetric parameters and quality of life (QoL) between conventionally fractionated proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT) in prostate cancer (PCA) patients. Methods: Eighty-eight patients with localized PCA treated between 2013 and 2017 with either definitive PBT (31) or IMRT (57) were matched using propensity score matching on PCA risk group, transurethral resection of the prostate, prostate volume, diabetes mellitus and administration of anticoagulants resulting in 29 matched pairs. Early and late genitourinary (GU) and gastrointestinal (GI) toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) and QoL based on EORTC-QLQ-C30/PR25 questionnaires were collected prospectively until 12 months after radiotherapy (RT). Associations between toxicities and dose-volume parameters in corresponding organs at risk (OARs) were modeled by logistic regression. Results: There were no significant differences in GI and GU toxicities between both treatment groups except for late urinary urgency, which was significantly lower after PBT (IMRT: 25.0%, PBT: 0%, p  = .047). Late GU toxicities and obstruction grade ≥2 were significantly associated with the relative volume of the anterior bladder wall receiving 70 Gy and the entire bladder receiving 60 Gy, respectively. The majority of patients in both groups reported high functioning and low symptom scores for the QoL questionnaires before and after RT. No or little changes were observed for most items between baseline and 3 or 12 months after RT, respectively. Global health status increased more at 12 months after IMRT ( p  = .040) compared to PBT, while the change of constipation was significantly better at 3 months after PBT compared to IMRT ( p  = .034). Conclusions: Overall, IMRT and PBT were well tolerated. Despite the superiority of PBT in early constipation and IMRT in late global health status compared to baseline, overall QoL and the risks of early and late GU and GI toxicities were similar for conventionally fractionated IMRT and PBT.

Hypofractionated radiotherapy is becoming popular for the treatment of localized prostate cancer, even though the rectum remains a dose-limiting organ at risk. The value of the use of an implantable retroprostatic spacer (RPS) for the reduction of rectal toxicity has not been studied for moderately hypofractionated proton beam therapy (PBT). This study therefore aimed to assess the gastrointestinal (GI) and genitourinary (GU) toxicities in patients with localized prostate cancer treated with moderately hypofractionated PBT with or without an implantable RPS. It is hypothesized that grade > 1 GI toxicity can be reduced by the RPS. In this single-institution analysis of prospectively collected data, patients with localized prostate cancer were recruited between October 2018 and February 2023. Men were treated with PBT up to 57-62 Gy (RBE) in 20 fractions with [PBT with RPS] or without a RPS [PBT without RPS]. Patients were initially assigned to receive PBT with RPS, but the onset of the COVID-19 pandemic led to a reprioritization of healthcare resources and patients were subsequently treated without RPS. Outcomes in this interim analysis include comparison of early (at 3 months) and late toxicity (at 1 year) per CTCAE v4.0 as well as of rectal dose-volume histograms between the two groups. In total, 58 men, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 were treated. Of these, 30 received PBT with RPS and 28 PBT without RPS. Baseline characteristics were well balanced in both groups. Baseline GI and GU symptoms as well as acute toxicity were not significantly different between both groups (Table 1). There was a statistical trend of a higher late grade > 1 GI toxicity in men without RPS (11%) (p = 0.07). Rectal dose parameters, i.e. volume receiving 40 or 57 Gy (V40Gy, V57Gy), and the maximum dose to the rectum (rectal Dmax) were all statistically significantly lower in patients treated with PBT and RPS (p<0.001). Rectal dose parameters were significantly reduced with the use of a RPS, possibly resulting in lower grade > 1 GI toxicity. Enrollment still continues and further assessment in a larger population is required. Table 1. Summary of genitourinary and gastrointestinal toxicity Abbreviations: CTCAE = Common Terminology Criteria of Adverse Events; GI = gastrointestinal; GU = genitourinary; Mon = months; Yr = year; PBT = proton beam therapy; RPS = retroprostatic spacer [ABSTRACT FROM AUTHOR]