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Proton Therapy of Cancer Treatment

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 15 March 2027 | Viewed by 8268

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Special Issue Editors

Dr. Minglei Kang

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Guest Editor

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Interests: proton therapy; FLASH radiotherapy; motion management; optimization algorithm; adaptive radiation therapy; Monte Carlo simulation

Dr. Benjamin Durkee

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Co-Guest Editor

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Interests: radiation therapy; head and neck cancers; proton therapy; stereotactic body radiotherapy; stereotactic radiosurgery

Dr. Kuo Men

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Co-Guest Editor

Department of Radiation Oncology, National Cancer Center of China, Beijing, China
Interests: radiation therapy; machine learning; auto-segmentation; proton therapy; stereotactic body radiotherapy; adaptive radiation therapy

Special Issue Information

Dear Colleagues,

Proton therapy is rapidly evolving into one of the most promising modalities in radiation oncology. Its precision and ability to spare healthy tissues—especially when using pencil beam scanning—make it particularly advantageous for treating pediatric and hard-to-reach tumors. Technological innovations are expanding the limits of what is possible, bringing in a new era of enhanced capabilities, more affordable solutions, and groundbreaking treatment approaches.

Among the most exciting frontiers is FLASH radiotherapy (FLASH-RT), which delivers ultra-high dose rates and has shown remarkable potential in preclinical studies for reducing normal tissue toxicity without compromising tumor control. Proton systems, especially those based on cyclotrons with high beam current output, are uniquely positioned to deliver FLASH-RT effectively. Innovations such as single-energy layer delivery are further enabling ultra-high dose rates while simplifying hardware and maintaining high-quality dosimetry.

Beyond FLASH, a wave of cutting-edge developments—including proton arc therapy, upright positioning, MRI-guided proton therapy, compact single-room systems, and spatially fractionated proton RT—are reshaping how we approach complex and radioresistant cancers.

This Special Issue invites contributions from researchers, clinicians, and industry experts to highlight the latest breakthroughs in proton therapy. Join us in accelerating the clinical translation and shaping the future of precision cancer care worldwide.

Dr. Minglei Kang
Dr. Benjamin Durkee
Dr. Kuo Men
Guest Editors

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Keywords

proton therapy
FLASH radiotherapy
upright
pediatric cancer
head and neck cancer
affordable proton solutions
adaptive radiation therapy
treatment planning optimization
proton system commissioning

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Published Papers (5 papers)

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Research

24 pages, 8087 KB

Open AccessArticle

Evaluation of a Dynamic Collimation System to Improve IMPT Dose Distributions and Maintain Treatment Efficiency

by Nhan (Justin) Vu, Albert Du, Daniel E. Hyer, Alonso N. Gutierrez, Andrew Wroe, Ryan T. Flynn, Kaustubh Patwardhan, Eduardo Pons, Kevin Erhart, Karsten Wake, Wesley S. Culberson, Patrick M. Hill and Blake R. Smith

Cancers 2026, 18(10), 1573; https://doi.org/10.3390/cancers18101573 - 12 May 2026

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Abstract

Background and objectives: Previous dynamic collimator system (DCS) developments included: (1) hardware construction and commissioning, (2) an accurate dose calculation algorithm, (3) a quality assurance approach, and (4) development of optimization tools for treatment planning. Clinical DCS implementation necessitates efficient treatment plan delivery and fully integrated tools. In this work, a novel algorithm for minimizing treatment time was developed with the goal of reducing the DCS time increase, relative to conventional pencil beam scanning, to one minute or less per beam. In this extensive end-to-end evaluation, treatment plans generated with a modified U.S. Food and Drug Administration (FDA)-cleared treatment planning system were delivered on an Ion Beam Applications (IBA) Proteus Plus proton therapy system, with and without a DCS, to evaluate delivery times and dosimetric accuracy for a relatively large patient dataset, providing evidence of the clinical potential of the approach. Methods: Ten previously treated brain patients were replanned, consisting of both deep-seated central and superficial targets, the latter of which required an external 4 cm polyethylene range shifter. DCS treatments were optimized using a maximum conformity planning technique exploiting per-spot collimator capabilities. An optimization algorithm was incorporated to minimize treatment delivery time by determining the optimal sequencing of spot positions and collimator settings. Plan quality was quantified using conformity and dose-volume histogram (DVH)-based metrics while delivery accuracy was validated through measurements using both patient-specific quality assurance (PSQA) and log file analysis at the Miami Cancer Institute (MCI). Results: The DCS reduced the dose gradient index on average by 26.4% (17.7–37.1%) and the mean dose to the adjacent healthy tissue (within 10 mm of the target) by 19.3% (16.3–26.2%). The average reduction to the mean and maximum dose to the involved optic nerves was 50% (25.7–80.7%) and 18.7%, respectively, and the mean and D_2cc dose to the involved brainstem was reduced by 63.9% (31.5–96.4%) and 60.4% (10.8–99.8%), respectively. PSQA pass rates among DCS-collimated and baseline uncollimated treatments were 99.7% and 99.2%, respectively. DCS treatment fields were delivered within an average of 49 s (32–61 s) from their uncollimated intensity modulated proton therapy (IMPT) counterparts. Average spot position errors were −0.05 ± 0.2 mm and 0.04 ± 0.2 mm for the x- and y-position, respectively. The maximum error in magnitude for collimator positioning was 0.2 mm or less. Conclusions: DCS collimated IMPT treatments can provide significant dosimetric improvements over uncollimated treatments. These highly collimated treatments can be delivered with sufficient accuracy for clinical use while incurring an additional time penalty of around one minute or less per field compared to uncollimated treatments. Full article

(This article belongs to the Special Issue Proton Therapy of Cancer Treatment)

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17 pages, 591 KB

Open AccessArticle

Acute Toxicities During Proton Therapy with or Without Simultaneous Chemotherapy in Pediatric CNS Tumors: A Retrospective Cohort Study

by Eicke Schuermann, Sarah Peters, Jonas E. Adolph, Julien Merta, Stefan Rutkowski, Michael C. Frühwald, Philipp Dammann, Hermann L. Müller, Christof M. Kramm, Gudrun Fleischhack, Beate Timmermann and Stephan Tippelt

Cancers 2026, 18(5), 859; https://doi.org/10.3390/cancers18050859 - 7 Mar 2026

Viewed by 630

Abstract

Background: Proton beam therapy (PBT) is a valuable alternative to photon radiotherapy of CNS tumors in children and adolescents. While most recent studies deal with the outcome or long-term side effects of PBT, the aim of this study was to investigate the feasibility of PBT with a particular focus on the acute toxicity of a simultaneous radiochemotherapy (sPBCT). Patients and methods: We enrolled 199 children [median age 7.4 years (range, 0.9–17.9)], who received altogether 200 courses of PBT/sPBCT at initial diagnosis (n = 121) or at relapse (n = 79) with sPBCT in 52 (26%) courses. Data collection to PBT/sPBCT was based on the medical records and the KiProReg (Registry study of Standard Proton Therapy in Children at West German Proton Therapy Center) with a primarily descriptive-statistical and logistic regression analysis. Results: During PBT/sPBCT a total of n = 704 adverse events (AEs, mean 3.4 per course) were observed. Eighty-seven of them were graded as high-grade adverse events (HGAEs, Common Terminology Criteria for Adverse Eventº ≥3 (CTCAE)) which occurred in 67 (33.5%) PBT/sPBCT courses. HGAEs were in particular hematotoxicity (n = 43; 64.1%) and infections (n = 18; 26.8%). A significantly higher rate of HGAEs was documented in patients treated with sPBCT (n = 33/52; 63.5%) compared to those with PBT only (n = 34/148; 23.0%) (p = 0.001). In children with sPBCT, 15 (28.8%) patients could not receive the recommended dose or schedule of the planned chemotherapy (CTx) due to HGAEs, with the rate of planned CTx courses performed being significantly lower in patients receiving intensive intravenous CTx (p < 0.001). Interruptions of PBT and of simultaneous CTx were both significantly associated with the occurrence of infections [Odds ratios 3.002 (95% CI 1.005–8.971, p = 0.049) and 3.905 (95% CI 1.005–15.174, p = 0.049)]. Total discontinuation of treatment did not occur. Conclusions: Concurrent CTx during proton therapy is associated with a significant increased risk for HGAE occurrence and therapy interruptions requiring individual dose and schedule adjustments dependent on CTx intensity, very experienced interdisciplinary teams as well as intensive care and in-/out-patient oncology facilities on site. Full article

(This article belongs to the Special Issue Proton Therapy of Cancer Treatment)

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19 pages, 1669 KB

Open AccessArticle

Proton Beam Therapy Provides Longer Survival and Preserves Muscle Mass in Hepatocellular Carcinoma Compared to TACE+RFA

by Takuto Nosaka, Ryotaro Sugata, Yosuke Murata, Yu Akazawa, Tomoko Tanaka, Kazuto Takahashi, Tatsushi Naito, Masahiro Ohtani, Kenji Takata, Tetsuya Tsujikawa, Yoshitaka Sato, Yoshikazu Maeda, Hiroyasu Tamamura and Yasunari Nakamoto

Cancers 2025, 17(17), 2849; https://doi.org/10.3390/cancers17172849 - 30 Aug 2025

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Abstract

Background: Proton beam therapy (PBT) provides excellent tumor control with minimal hepatic toxicity in patients with unresectable hepatocellular carcinoma (HCC), by minimizing radiation exposure to non-cancerous liver tissue. Progressive skeletal muscle loss, often seen in cirrhosis and HCC, can negatively impact treatment outcomes and survival. This study compared the efficacy and safety of PBT with transarterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) in patients with unresectable HCC. Methods: A total of 91 patients (PBT/TACE+RFA, n = 41/50) ineligible for surgery or RFA alone were retrospectively analyzed, with propensity score matching applied to adjust for differences in baseline characteristics, resulting in matched groups of 33 patients each. The cross-sectional area of the psoas muscle at the third lumbar vertebra was assessed using computed tomography. Results: PBT resulted in longer overall survival (OS) and fewer hepatic and systemic adverse events compared to TACE+RFA, with no grade 3 or higher toxicities observed in the PBT group. Importantly, psoas muscle size remained stable after PBT, even in patients with tumors ≥ 3 cm, whereas TACE+RFA led to significant muscle loss regardless of tumor size, which was associated with poorer prognosis. These findings suggest that, for patients with unresectable HCC not adequately controlled by RFA alone, PBT may improve OS and help preserve muscle mass, while offering lower toxicity and more favorable clinical outcomes than TACE+RFA. Conclusions: Overall, PBT may represent an effective strategy for managing unresectable HCC. Full article

(This article belongs to the Special Issue Proton Therapy of Cancer Treatment)

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13 pages, 1609 KB

Open AccessArticle

A Decision-Making Method for Photon/Proton Selection for Nasopharyngeal Cancer Based on Dose Prediction and NTCP

by Guiyuan Li, Xinyuan Chen, Jialin Ding, Linyi Shen, Mengyang Li, Junlin Yi and Jianrong Dai

Cancers 2025, 17(16), 2620; https://doi.org/10.3390/cancers17162620 - 11 Aug 2025

Cited by 2 | Viewed by 1585

Abstract

Introduction: Decision-making regarding radiotherapy techniques for patients with nasopharyngeal cancer requires a comparison of photon and proton plans generated using planning software, which requires time and expertise. We developed a fully automated decision tool to select patients for proton therapy that predicts proton therapy (XT) and photon therapy (PT) dose distributions using only patient CT image data, predicts xerostomia and dysphagia probability using predicted critical organ mean doses, and makes decisions based on the Netherlands’ National Indication Protocol Proton therapy (NIPP) to select patients likely to benefit from proton therapy. Methods: This study used 48 nasopharyngeal patients treated at the Cancer Hospital of the Chinese Academy of Medical Sciences. We manually generated a photon plan and a proton plan for each patient. Based on this dose distribution, photon and proton dose prediction models were trained using deep learning (DL) models. We used the NIPP model to measure xerostomia levels 2 and 3, dysphagia levels 2 and 3, and decisions were made according to the thresholds given by this protocol. Results: The predicted doses for both photon and proton groups were comparable to those for manual plan (MP). The Mean Absolute Error (MAE) for each organ at risk in the photon and proton plans did not exceed 5% and showed a good performance of the dose prediction model. For proton, the normal tissue complication probability (NTCP) of xerostomia and dysphagia performed well, p > 0.05. There was no statistically significant difference. For photon, the NTCP of dysphagia performed well, p > 0.05. For xerostomia p < 0.05 but the absolute deviation was 0.85% and 0.75%, which would not have a great impact on the prediction result. Among the 48 patients’ decisions, 3 were wrong, and the correct rate was 93.8%. The area under curve (AUC) of operating characteristic curve (ROC) was 0.86, showing the good performance of the decision-making tool in this study. Conclusions: The decision tool based on DL and NTCP models can accurately select nasopharyngeal cancer patients who will benefit from proton therapy. The time spent generating comparison plans is reduced and the diagnostic efficiency of doctors is improved, and the tool can be shared with centers that do not have proton expertise. Trial registration: This study was a retrospective study, so it was exempt from registration. Full article

(This article belongs to the Special Issue Proton Therapy of Cancer Treatment)

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14 pages, 1413 KB

Open AccessArticle

NRG Oncology Liver Proton SBRT and Hypofractionated Radiation Therapy: Current Treatment Technical Assessment and Practice Patterns

by Minglei Kang, Paige A. Taylor, Jiajian Shen, Jun Zhou, Jatinder Saini, Theodore S. Hong, Kristin Higgins, Wei Liu, Ying Xiao, Charles B. Simone II and Liyong Lin

Cancers 2025, 17(14), 2369; https://doi.org/10.3390/cancers17142369 - 17 Jul 2025

Cited by 2 | Viewed by 2363

Abstract

Background/Objectives: Proton therapy delivers highly conformal doses to the target area without producing an exit dose, minimizing cumulative doses to healthy liver tissue. This study aims to evaluate current practices, challenges, and variations in the implementation of proton stereotactic body radiation therapy (SBRT) and hypofractionated therapy for liver malignancies, with the goal of providing a technical assessment to promote broader adoption and support future clinical trials. Methods and Materials: An extensive survey was conducted by NRG Oncology across North American proton treatment centers to assess the current practices of proton liver SBRT and hypofractionated therapy. The survey focused on key aspects, including patient selection, prescription and normal tissue constraints, simulation and motion management, treatment planning, quality assurance (QA), treatment delivery, and the use of image-guided radiation therapy (IGRT). Results: This survey captures the current practice patterns and status of proton SBRT and hypofractionated therapy in liver cancer treatment. Proton therapy is increasingly preferred for treating inoperable liver malignancies due to its ability to minimize healthy tissue exposure. However, the precision required for proton therapy presents challenges, particularly in managing uncertainties and target motion during high-dose fractions and short treatment courses. Survey findings revealed significant variability in clinical practices across centers, highlighting differences in motion management, dose fractionation schedules, and QA protocols. Conclusion: Proton SBRT and hypofractionated therapy offer significant potential for treating liver malignancies. A comprehensive approach involving precise patient selection, treatment planning, and QA is essential for ensuring safety and effectiveness. This survey provides valuable insights into current practices and challenges, offering a foundation for technical recommendations to optimize the use of proton therapy and guide future clinical trials. Full article

(This article belongs to the Special Issue Proton Therapy of Cancer Treatment)

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