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Particle Therapy: State-of-the-Art and Future Prospects
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Particle Therapy: State-of-the-Art and Future Prospects

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

Deadline for manuscript submissions: 31 July 2024 | Viewed by 22683

Special Issue Editors

Dr. Chia-Ho Hua

E-Mail Website
Guest Editor
Medical Physics Research, Department of Radiation Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas, Memphis, TN 38105, USA
Interests: proton therapy; pediatric cancers; medical imaging; normal tissue toxicity
Dr. Matthew J. Krasin

E-Mail Website
Guest Editor
Radiation Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas, Memphis, TN 38105, USA
Interests: proton therapy; pediatric cancers; medical imaging; normal tissue toxicity

Special Issue Information

Dear Colleagues,

Although particle therapy is, at present, perceived as a not sufficiently utilized in radiation-therapy facilities worldwide, we have witnessed its rapid development in recent decades, and it is believed that its impact will be more substantial when the technology and clinical practices are optimized. Exciting technical advances have been reported recently, including ultra-high dose rates, biological optimizations, proton arcs, multi-ion therapy, superconducting gantry, improvements in beam-delivery efficiency, uncertainty reduction, and MR-guided proton therapy. On the other hand, the medical community eagerly awaits the data that demonstrate the clinical benefits of using particle therapy. This Special Issue is devoted to the worldwide efforts in developing, improving, and using the most complex radiotherapy modality.

We invite submissions of articles that address the following topics:

  • Technical advances in proton and ion therapies;
  • Clinical evidence in particle therapy;
  • Clinical indications of particle therapy;
  • Controversies in particle therapy;
  • Novel applications of particle therapy to treat cancer and noncancerous tumors;
  • Predictive outcome modeling for patients receiving particle therapy;
  • Imaging for particle therapy—image guidance, uncertainty reduction, adaptive therapy, treatment effects.

Dr. Chia-Ho Hua
Dr. Matthew J. Krasin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

 

Keywords

  • particle therapy
  • proton therapy
  • ion therapy
  • carbon ion
  • radiotherapy
  • cancer treatment
  • late effects
  • medical imaging

Published Papers (16 papers)

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Research

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19 pages, 2943 KiB  
Article
Sacral-Nerve-Sparing Planning Strategy in Pelvic Sarcomas/Chordomas Treated with Carbon-Ion Radiotherapy
by Ankita Nachankar, Mansure Schafasand, Eugen Hug, Giovanna Martino, Joanna Góra, Antonio Carlino, Markus Stock and Piero Fossati
Cancers 2024, 16(7), 1284; https://doi.org/10.3390/cancers16071284 - 26 Mar 2024
Viewed by 551
Abstract
To minimize radiation-induced lumbosacral neuropathy (RILSN), we employed sacral-nerve-sparing optimized carbon-ion therapy strategy (SNSo-CIRT) in treating 35 patients with pelvic sarcomas/chordomas. Plans were optimized using Local Effect Model-I (LEM-I), prescribed DRBE|LEM-I|D50% (median dose to HD-PTV) = 73.6 (70.4–76.8) Gy (RBE)/16 fractions. Sacral [...] Read more.
To minimize radiation-induced lumbosacral neuropathy (RILSN), we employed sacral-nerve-sparing optimized carbon-ion therapy strategy (SNSo-CIRT) in treating 35 patients with pelvic sarcomas/chordomas. Plans were optimized using Local Effect Model-I (LEM-I), prescribed DRBE|LEM-I|D50% (median dose to HD-PTV) = 73.6 (70.4–76.8) Gy (RBE)/16 fractions. Sacral nerves were contoured between L5-S3 levels. DRBE|LEM-I to 5% of sacral nerves-to-spare (outside HD-CTV) (DRBE|LEM-I|D5%) were restricted to <69 Gy (RBE). The median follow-up was 25 months (range of 2–53). Three patients (9%) developed late RILSN (≥G3) after an average period of 8 months post-CIRT. The RILSN-free survival at 2 years was 91% (CI, 81–100). With SNSo-CIRT, DRBE|LEM-I|D5% for sacral nerves-to-spare = 66.9 ± 1.9 Gy (RBE), maintaining DRBE|LEM-I to 98% of HD-CTV (DRBE|LEM-I|D98%) = 70 ± 3.6 Gy (RBE). Two-year OS and LC were 100% and 93% (CI, 84–100), respectively. LETd and DRBE with modified-microdosimetric kinetic model (mMKM) were recomputed retrospectively. DRBE|LEM-I and DRBE|mMKM were similar, but DRBE-filtered-LETd was higher in sacral nerves-to-spare in patients with RILSN than those without. At DRBE|LEM-I cutoff = 64 Gy (RBE), 2-year RILSN-free survival was 100% in patients with <12% of sacral nerves-to-spare voxels receiving LETd > 55 keV/µm than 75% (CI, 54–100) in those with ≥12% of voxels (p < 0.05). DRBE-filtered-LETd holds promise for the SNSo-CIRT strategy but requires longer follow-up for validation. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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14 pages, 2054 KiB  
Article
Evaluating the Impact of Bowel Gas Variations for Wilms’ Tumor in Pediatric Proton Therapy
by Ozgur Ates, Fakhriddin Pirlepesov, Jinsoo Uh, Chia-ho Hua, Thomas E. Merchant, Andrew Boria, Andrew M. Davidoff, Dylan E. Graetz and Matthew J. Krasin
Cancers 2024, 16(3), 642; https://doi.org/10.3390/cancers16030642 - 2 Feb 2024
Viewed by 749
Abstract
(1) Background: Proton therapy, a precise form of radiation treatment, can be significantly affected by variations in bowel content. The purpose was to identify the most beneficial gantry angles that minimize deviations from the treatment plan quality, thus enhancing the safety and efficacy [...] Read more.
(1) Background: Proton therapy, a precise form of radiation treatment, can be significantly affected by variations in bowel content. The purpose was to identify the most beneficial gantry angles that minimize deviations from the treatment plan quality, thus enhancing the safety and efficacy of proton therapy for Wilms’ tumor patients. (2) Methods: Thirteen patients with Wilms’ tumor, enrolled in the SJWT21 clinical trial, underwent proton therapy. The variations in bowel gas were systematically monitored using daily Cone Beam Computed Tomography (CBCT) imaging. Air cavities identified in daily CBCT images were analyzed to construct daily verification plans and measure water equivalent path length (WEPL) changes. A worst-case scenario simulation was conducted to identify the safest beam angles. (3) Results: The study revealed a maximum decrease in target dose (ΔD100%) of 8.0%, which corresponded to a WEPL variation (ΔWEPL) of 11.3 mm. The average reduction in target dose, denoted as mean ΔD100%, was found to be 2.8%, with a standard deviation (SD) of 3.2%. The mean ΔWEPL was observed as 3.3 mm, with an SD of 2.7 mm. The worst-case scenario analysis suggested that gantry beam angles oriented toward the patient’s right and posterior aspects from 110° to 310° were associated with minimized WEPL discrepancies. (4) Conclusions: This study comprehensively evaluated the influence of bowel gas variability on treatment plan accuracy and proton range uncertainties in pediatric proton therapy for Wilms’ tumor. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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18 pages, 1400 KiB  
Article
Exploring Helium Ions’ Potential for Post-Mastectomy Left-Sided Breast Cancer Radiotherapy
by Santa Gabriella Bonaccorsi, Thomas Tessonnier, Line Hoeltgen, Eva Meixner, Semi Harrabi, Juliane Hörner-Rieber, Thomas Haberer, Amir Abdollahi, Jürgen Debus and Andrea Mairani
Cancers 2024, 16(2), 410; https://doi.org/10.3390/cancers16020410 - 18 Jan 2024
Cited by 3 | Viewed by 1327
Abstract
Proton therapy presents a promising modality for treating left-sided breast cancer due to its unique dose distribution. Helium ions provide increased conformality thanks to a reduced lateral scattering. Consequently, the potential clinical benefit of both techniques was explored. An explorative treatment planning study [...] Read more.
Proton therapy presents a promising modality for treating left-sided breast cancer due to its unique dose distribution. Helium ions provide increased conformality thanks to a reduced lateral scattering. Consequently, the potential clinical benefit of both techniques was explored. An explorative treatment planning study involving ten patients, previously treated with VMAT (Volumetric Modulated Arc Therapy) for 50 Gy in 25 fractions for locally advanced, node-positive breast cancer, was carried out using proton pencil beam therapy with a fixed relative biological effectiveness (RBE) of 1.1 and helium therapy with a variable RBE described by the mMKM (modified microdosimetric kinetic model). Results indicated that target coverage was improved with particle therapy for both the clinical target volume and especially the internal mammary lymph nodes compared to VMAT. Median dose value analysis revealed that proton and helium plans provided lower dose on the left anterior descending artery (LAD), heart, lungs and right breast than VMAT. Notably, helium therapy exhibited improved ipsilateral lung sparing over protons. Employing NTCP models as available in the literature, helium therapy showed a lower probability of grade ≤ 2 radiation pneumonitis (22% for photons, 5% for protons and 2% for helium ions), while both proton and helium ions reduce the probability of major coronary events with respect to VMAT. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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17 pages, 4403 KiB  
Article
Setup Uncertainty of Pediatric Brain Tumor Patients Receiving Proton Therapy: A Prospective Study
by Jared Becksfort, Jinsoo Uh, Andrew Saunders, Julia A. Byrd, Hannah M. Worrall, Matt Marker, Christian Melendez-Suchi, Yimei Li, Jenghwa Chang, Kavitha Raghavan, Thomas E. Merchant and Chia-ho Hua
Cancers 2023, 15(22), 5486; https://doi.org/10.3390/cancers15225486 - 20 Nov 2023
Viewed by 1045
Abstract
This study quantifies setup uncertainty in brain tumor patients who received image-guided proton therapy. Patients analyzed include 165 children, adolescents, and young adults (median age at radiotherapy: 9 years (range: 10 months to 24 years); 80 anesthetized and 85 awake) enrolled in a [...] Read more.
This study quantifies setup uncertainty in brain tumor patients who received image-guided proton therapy. Patients analyzed include 165 children, adolescents, and young adults (median age at radiotherapy: 9 years (range: 10 months to 24 years); 80 anesthetized and 85 awake) enrolled in a single-institution prospective study from 2020 to 2023. Cone-beam computed tomography (CBCT) was performed daily to calculate and correct manual setup errors, once per course after setup correction to measure residual errors, and weekly after treatments to assess intrafractional motion. Orthogonal radiographs were acquired consecutively with CBCT for paired comparisons of 40 patients. Translational and rotational errors were converted from 6 degrees of freedom to a scalar by a statistical approach that considers the distance from the target to the isocenter. The 95th percentile of setup uncertainty was reduced by daily CBCT from 10 mm (manual positioning) to 1–1.5 mm (after correction) and increased to 2 mm by the end of fractional treatment. A larger variation existed between the roll corrections reported by radiographs vs. CBCT than for pitch and yaw, while there was no statistically significant difference in translational variation. A quantile mixed regression model showed that the 95th percentile of intrafractional motion was 0.40 mm lower for anesthetized patients (p=0.0016). Considering additional uncertainty in radiation-imaging isocentricity, the commonly used total plan robustness of 3 mm against positional uncertainty would be appropriate for our study cohort. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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12 pages, 1586 KiB  
Article
Interplay Effect of Splenic Motion for Total Lymphoid Irradiation in Pediatric Proton Therapy
by Ozgur Ates, Jinsoo Uh, Fakhriddin Pirlepesov, Chia-ho Hua, Brandon Triplett, Amr Qudeimat, Akshay Sharma, Thomas E. Merchant and John T. Lucas, Jr.
Cancers 2023, 15(21), 5161; https://doi.org/10.3390/cancers15215161 - 26 Oct 2023
Viewed by 663
Abstract
(1) Background: The most significant cause of an unacceptable deviation from the planned dose during respiratory motion is the interplay effect. We examined the correlation between the magnitude of splenic motion and its impact on plan quality for total lymphoid irradiation (TLI); (2) [...] Read more.
(1) Background: The most significant cause of an unacceptable deviation from the planned dose during respiratory motion is the interplay effect. We examined the correlation between the magnitude of splenic motion and its impact on plan quality for total lymphoid irradiation (TLI); (2) Methods: Static and 4D CT images from ten patients were used for interplay effect simulations. Patients’ original plans were optimized based on the average CT extracted from the 4D CT and planned with two posterior beams using scenario-based optimization (±3 mm of setup and ±3% of range uncertainty) and gradient matching at the level of mid-spleen. Dynamically accumulated 4D doses (interplay effect dose) were calculated based on the time-dependent delivery sequence of radiation fluence across all phases of the 4D CT. Dose volume parameters for each simulated treatment delivery were evaluated for plan quality; (3) Results: Peak-to-peak splenic motion (≤12 mm) was measured from the 4D CT of ten patients. Interplay effect simulations revealed that the ITV coverage of the spleen remained within the protocol tolerance for splenic motion, ≤8 mm. The D100% coverage for ITV spleen decreased from 95.0% (nominal plan) to 89.3% with 10 mm and 87.2% with 12 mm of splenic motion; (4) Conclusions: 4D plan evaluation and robust optimization may overcome problems associated with respiratory motion in proton TLI treatments. Patient-specific respiratory motion evaluations are essential to confirming adequate dosimetric coverage when proton therapy is utilized. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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16 pages, 5696 KiB  
Article
The Applications and Pitfalls of Cone-Beam Computed Tomography-Based Synthetic Computed Tomography for Adaptive Evaluation in Pencil-Beam Scanning Proton Therapy
by Pingfang Tsai, Yu-Lun Tseng, Brian Shen, Christopher Ackerman, Huifang A. Zhai, Francis Yu, Charles B. Simone II, J. Isabelle Choi, Nancy Y. Lee, Rafi Kabarriti, Stanislav Lazarev, Casey L. Johnson, Jiayi Liu, Chin-Cheng Chen and Haibo Lin
Cancers 2023, 15(20), 5101; https://doi.org/10.3390/cancers15205101 - 22 Oct 2023
Cited by 1 | Viewed by 1035
Abstract
Purpose: The study evaluates the efficacy of cone-beam computed tomography (CBCT)-based synthetic CTs (sCT) as a potential alternative to verification CT (vCT) for enhanced treatment monitoring and early adaptation in proton therapy. Methods: Seven common treatment sites were studied. Two sets of sCT [...] Read more.
Purpose: The study evaluates the efficacy of cone-beam computed tomography (CBCT)-based synthetic CTs (sCT) as a potential alternative to verification CT (vCT) for enhanced treatment monitoring and early adaptation in proton therapy. Methods: Seven common treatment sites were studied. Two sets of sCT per case were generated: direct-deformed (DD) sCT and image-correction (IC) sCT. The image qualities and dosimetric impact of the sCT were compared to the same-day vCT. Results: The sCT agreed with vCT in regions of homogeneous tissues such as the brain and breast; however, notable discrepancies were observed in the thorax and abdomen. The sCT outliers existed for DD sCT when there was an anatomy change and for IC sCT in low-density regions. The target coverage exhibited less than a 5% variance in most DD and IC sCT cases when compared to vCT. The Dmax of serial organ-at-risk (OAR) in sCT plans shows greater deviation from vCT than small-volume dose metrics (D0.1cc). The parallel OAR volumetric and mean doses remained consistent, with average deviations below 1.5%. Conclusion: The use of sCT enables precise treatment and prompt early adaptation for proton therapy. The quality assurance of sCT is mandatory in the early stage of clinical implementation. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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14 pages, 4674 KiB  
Article
Pencil Beam Scanning Bragg Peak FLASH Technique for Ultra-High Dose Rate Intensity-Modulated Proton Therapy in Early-Stage Breast Cancer Treatment
by Grant Lattery, Tyler Kaulfers, Chingyun Cheng, Xingyi Zhao, Balaji Selvaraj, Haibo Lin, Charles B. Simone II, J. Isabelle Choi, Jenghwa Chang and Minglei Kang
Cancers 2023, 15(18), 4560; https://doi.org/10.3390/cancers15184560 - 14 Sep 2023
Cited by 2 | Viewed by 2430
Abstract
Bragg peak FLASH-RT can deliver highly conformal treatment and potentially offer improved normal tissue protection for radiotherapy patients. This study focused on developing ultra-high dose rate (≥40 Gy × RBE/s) intensity-modulated proton therapy (IMPT) for hypofractionated treatment of early-stage breast cancer. A novel [...] Read more.
Bragg peak FLASH-RT can deliver highly conformal treatment and potentially offer improved normal tissue protection for radiotherapy patients. This study focused on developing ultra-high dose rate (≥40 Gy × RBE/s) intensity-modulated proton therapy (IMPT) for hypofractionated treatment of early-stage breast cancer. A novel tracking technique was developed to enable pencil beaming scanning (PBS) of single-energy protons to adapt the Bragg peak (BP) to the target distally. Standard-of-care PBS treatment plans of consecutively treated early-stage breast cancer patients using multiple energy layers were reoptimized using this technique, and dose metrics were compared between single-energy layer BP FLASH and conventional IMPT plans. FLASH dose rate coverage by volume (V40Gy/s) was also evaluated for the FLASH sparing effect. Distal tracking can precisely stop BP at the target distal edge. All plans (n = 10) achieved conformal IMPT-like dose distributions under clinical machine parameters. No statistically significant differences were observed in any dose metrics for heart, ipsilateral lung, most ipsilateral breast, and CTV metrics (p > 0.05 for all). Conventional plans yielded slightly superior target and skin dose uniformities with 4.5% and 12.9% lower dose maxes, respectively. FLASH-RT plans reached 46.7% and 61.9% average-dose rate FLASH coverage for tissues receiving more than 1 and 5 Gy plan dose total under the 250 minimum MU condition. Bragg peak FLASH-RT techniques achieved comparable plan quality to conventional IMPT while reaching adequate dose rate ratios, demonstrating the feasibility of early-stage breast cancer clinical applications. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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10 pages, 1660 KiB  
Article
Monitoring of Interfractional Proton Range Verification and Dosimetric Impact Based on Daily CBCT for Pediatric Patients with Pelvic Tumors
by Ozgur Ates, Jinsoo Uh, Fakhriddin Pirlepesov, Chia-Ho Hua, Thomas E. Merchant and Matthew J. Krasin
Cancers 2023, 15(17), 4200; https://doi.org/10.3390/cancers15174200 - 22 Aug 2023
Viewed by 912
Abstract
(1) Background: Synthetic CT images of the pelvis were generated from daily CBCT images to monitor changes in water equivalent path length (WEPL) and determine the dosimetric impact of anatomy changes along the proton beam’s path; (2) Methods: Ten pediatric patients with pelvic [...] Read more.
(1) Background: Synthetic CT images of the pelvis were generated from daily CBCT images to monitor changes in water equivalent path length (WEPL) and determine the dosimetric impact of anatomy changes along the proton beam’s path; (2) Methods: Ten pediatric patients with pelvic tumors treated using proton therapy with daily CBCT were included. The original planning CT was deformed to the same-day CBCT to generate synthetic CT images for WEPL comparison and dosimetric evaluation; (3) Results: WEPL changes of 20 proton fields at the distal edge of the CTV ranged from 0.1 to 12 mm with a median of 2.5 mm, and 75th percentile of 5.1 mm for (the original CT—rescanned CT) and ranged from 0.3 to 10.1 mm with a median of 2.45 mm and 75th percentile of 4.8 mm for (the original CT—synthetic CT). The dosimetric impact was due to proton range pullback or overshoot, which led to reduced coverage in CTV Dmin averaging 12.1% and 11.3% in the rescanned and synthetic CT verification plans, respectively; (4) Conclusions: The study demonstrated that synthetic CT generated by deforming the original planning CT to daily CBCT can be used to quantify proton range changes and predict adverse dosimetric scenarios without the need for excessive rescanned CT scans during large interfractional variations in adaptive proton therapy of pediatric pelvic tumors. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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10 pages, 1204 KiB  
Article
Pediatric Experience and Outcomes from the First Single-Vault Compact Proton Therapy Center
by Stephanie M. Perkins, Sabrina Prime, Michael Watts, Jiayi Huang and Tianyu Zhao
Cancers 2023, 15(16), 4072; https://doi.org/10.3390/cancers15164072 - 12 Aug 2023
Viewed by 1126
Abstract
The first single-vault compact proton therapy center opened in 2013, utilizing a gantry-mounted synchrocylotron. The center was placed within a large academic radiation oncology department with a high priority for pediatric cancer care. Here we performed a retrospective study of pediatric (≤21 years) [...] Read more.
The first single-vault compact proton therapy center opened in 2013, utilizing a gantry-mounted synchrocylotron. The center was placed within a large academic radiation oncology department with a high priority for pediatric cancer care. Here we performed a retrospective study of pediatric (≤21 years) patients treated with proton therapy at our institution between 2013–2022. Patient, tumor, and treatment characteristics were obtained including race, socioeconomic status, insurance type, distance travelled, need for anesthesia, and outside referrals for proton therapy. In total, 250 pediatric patients were treated with proton therapy comprising 18% of our proton patient volume. Median follow-up was 3.1 years, 38.4% were female and 83% were white. The majority of cases were CNS (69.6%) and a large number of patients (80/250, 32%) required craniospinal irradiation. Anesthesia was required for 39.6% of patients. Average distance travelled for treatment was 111 miles and 23% of patients were referred from outside institutions for proton therapy. Insurance type was private/commercial for 61.2% followed by Medicaid for 32%. We found that 23% of patients lived in census tracts with >25% of people living below the national poverty line. Overall survival at 3 years was excellent at 83.7% with better outcomes for CNS patients compared to non-CNS patients. There were no cases of secondary malignancy at this early time point. As the world’s first compact proton therapy center, we found that proton therapy increased our pediatric volume and provided proton therapy to a diverse group of children in our region. These data highlight some of the expected patient and tumor characteristics and necessary resources for providing pediatric proton beam therapy. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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14 pages, 4685 KiB  
Article
CBCT-Based Dose Monitoring and Adaptive Planning Triggers in Head and Neck PBS Proton Therapy
by Keaton Reiners, Roi Dagan, Adam Holtzman, Curtis Bryant, Sebastian Andersson, Rasmus Nilsson, Liu Hong, Perry Johnson and Yawei Zhang
Cancers 2023, 15(15), 3881; https://doi.org/10.3390/cancers15153881 - 30 Jul 2023
Cited by 4 | Viewed by 1775
Abstract
Purpose: To investigate the feasibility of using cone-beam computed tomography (CBCT)-derived synthetic CTs to monitor the daily dose and trigger a plan review for adaptive proton therapy (APT) in head and neck cancer (HNC) patients. Methods: For 84 HNC patients treated with proton [...] Read more.
Purpose: To investigate the feasibility of using cone-beam computed tomography (CBCT)-derived synthetic CTs to monitor the daily dose and trigger a plan review for adaptive proton therapy (APT) in head and neck cancer (HNC) patients. Methods: For 84 HNC patients treated with proton pencil-beam scanning (PBS), same-day CBCT and verification CT (vfCT) pairs were retrospectively collected. The ground truth CT (gtCT) was created by deforming the vfCT to the same-day CBCT, and it was then used as a dosimetric baseline and for establishing plan review trigger recommendations. Two different synthetic CT algorithms were tested; the corrected CBCT (corrCBCT) was created using an iterative image correction method and the virtual CT (virtCT) was created by deforming the planning CT to the CBCT, followed by a low-density masking process. Clinical treatment plans were recalculated on the image sets for evaluation. Results: Plan review trigger criteria for adaptive therapy were established after closely reviewing the cohort data. Compared to the vfCT, the corrCBCT and virtCT reliably produced dosimetric data more similar to the gtCT. The average discrepancy in D99 for high-risk clinical target volumes (CTV) was 1.1%, 0.7%, and 0.4% and for standard-risk CTVs was 1.8%, 0.5%, and 0.5% for the vfCT, corrCBCT, and virtCT, respectively. Conclusion: Streamlined APT has been achieved with the proposed plan review criteria and CBCT-based synthetic CT workflow. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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11 pages, 1357 KiB  
Article
Carbon-Ion Radiotherapy Combined with Concurrent Chemotherapy for Locally Advanced Pancreatic Cancer: A Retrospective Case Series Analysis
by Masahiko Okamoto, Shintaro Shiba, Daijiro Kobayashi, Yuhei Miyasaka, Shohei Okazaki, Kei Shibuya and Tatsuya Ohno
Cancers 2023, 15(10), 2857; https://doi.org/10.3390/cancers15102857 - 22 May 2023
Cited by 1 | Viewed by 2167
Abstract
Systemic chemotherapy has significantly improved in recent years. In this study. the clinical impact of carbon-ion radiotherapy (CIRT) with concurrent chemotherapy for locally advanced unresectable pancreatic cancer (URPC) was evaluated. Methods: Patients with URPC who were treated with CIRT between January 2016 and [...] Read more.
Systemic chemotherapy has significantly improved in recent years. In this study. the clinical impact of carbon-ion radiotherapy (CIRT) with concurrent chemotherapy for locally advanced unresectable pancreatic cancer (URPC) was evaluated. Methods: Patients with URPC who were treated with CIRT between January 2016 and December 2020 were prospectively registered and analyzed. The major criteria for registration were (1) diagnosed as URPC on imaging; (2) pathologically diagnosed adenocarcinoma; (3) no distant metastasis; (4) Eastern Cooperative Oncology Group performance status of 0–2; (5) tumors without gastrointestinal tract invasion; and (6) available for concurrent chemotherapy. Patients who received neoadjuvant chemotherapy (NAC) for more than one year prior to CIRT were excluded. Results: Forty-four patients met the inclusion criteria, and thirty-seven received NAC before CIRT. The median follow-up period of living patients was 26.0 (6.0–68.6) months after CIRT. The estimated two-year overall survival, local control, and progression-free survival rates after CIRT were 56.6%, 76.1%, and 29.0%, respectively. The median survival time of all patients was 29.6 months after CIRT and 34.5 months after the initial NAC. Conclusion: CIRT showed survival benefits for URPC even in the multiagent chemotherapy era. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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17 pages, 3689 KiB  
Article
An Integrated Monte Carlo Model for Heterogeneous Glioblastoma Treated with Boron Neutron Capture Therapy
by Leyla Moghaddasi and Eva Bezak
Cancers 2023, 15(5), 1550; https://doi.org/10.3390/cancers15051550 - 1 Mar 2023
Cited by 2 | Viewed by 1557
Abstract
Background: Glioblastomas (GBMs) are notorious for their aggressive features, e.g., intrinsic radioresistance, extensive heterogeneity, hypoxia, and highly infiltrative behaviours. The prognosis has remained poor despite recent advances in systemic and modern X-ray radiotherapy. Boron neutron capture therapy (BNCT) represents an alternative radiotherapy technique [...] Read more.
Background: Glioblastomas (GBMs) are notorious for their aggressive features, e.g., intrinsic radioresistance, extensive heterogeneity, hypoxia, and highly infiltrative behaviours. The prognosis has remained poor despite recent advances in systemic and modern X-ray radiotherapy. Boron neutron capture therapy (BNCT) represents an alternative radiotherapy technique for GBM. Previously, a Geant4 BNCT modelling framework was developed for a simplified model of GBM. Purpose: The current work expands on the previous model by applying a more realistic in silico GBM model with heterogeneous radiosensitivity and anisotropic microscopic extensions (ME). Methods: Each cell within the GBM model was assigned an α/β value associated with different GBM cell lines and a 10B concentration. Dosimetry matrices corresponding to various MEs were calculated and combined to evaluate cell survival fractions (SF) using clinical target volume (CTV) margins of 2.0 & 2.5 cm. SFs for the BNCT simulation were compared with external X-ray radiotherapy (EBRT) SFs. Results: The SFs within the beam region decreased by more than two times compared to EBRT. It was demonstrated that BNCT results in markedly reduced SFs for both CTV margins compared to EBRT. However, the SF reduction as a result of the CTV margin extension using BNCT was significantly lower than using X-ray EBRT for one MEP distribution, while it remained similar for the other two MEP models. Conclusions: Although the efficiency of BNCT in terms of cell kill is superior to EBRT, the extension of the CTV margin by 0.5 cm may not increase the BNCT treatment outcome significantly. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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Review

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15 pages, 1108 KiB  
Review
The Role of Carbon Ion Therapy in the Changing Oncology Landscape—A Narrative Review of the Literature and the Decade of Carbon Ion Experience at the Italian National Center for Oncological Hadrontherapy
by Ester Orlandi, Amelia Barcellini, Barbara Vischioni, Maria Rosaria Fiore, Viviana Vitolo, Alberto Iannalfi, Maria Bonora, Agnieszka Chalaszczyk, Rossana Ingargiola, Giulia Riva, Sara Ronchi, Francesca Valvo, Piero Fossati, Mario Ciocca, Alfredo Mirandola, Silvia Molinelli, Andrea Pella, Guido Baroni, Marco Giuseppe Pullia, Angelica Facoetti, Roberto Orecchia, Lisa Licitra, Gianluca Vago and Sandro Rossiadd Show full author list remove Hide full author list
Cancers 2023, 15(20), 5068; https://doi.org/10.3390/cancers15205068 - 20 Oct 2023
Cited by 6 | Viewed by 1060
Abstract
Background: Currently, 13 Asian and European facilities deliver carbon ion radiotherapy (CIRT) for preclinical and clinical activity, and, to date, 55 clinical studies including CIRT for adult and paediatric solid neoplasms have been registered. The National Center for Oncological Hadrontherapy (CNAO) is the [...] Read more.
Background: Currently, 13 Asian and European facilities deliver carbon ion radiotherapy (CIRT) for preclinical and clinical activity, and, to date, 55 clinical studies including CIRT for adult and paediatric solid neoplasms have been registered. The National Center for Oncological Hadrontherapy (CNAO) is the only Italian facility able to accelerate both protons and carbon ions for oncological treatment and research. Methods: To summarise and critically evaluate state-of-the-art knowledge on the application of carbon ion radiotherapy in oncological settings, the authors conducted a literature search till December 2022 in the following electronic databases: PubMed, Web of Science, MEDLINE, Google Scholar, and Cochrane. The results of 68 studies are reported using a narrative approach, highlighting CNAO’s clinical activity over the last 10 years of CIRT. Results: The ballistic and radiobiological hallmarks of CIRT make it an effective option in several rare, radioresistant, and difficult-to-treat tumours. CNAO has made a significant contribution to the advancement of knowledge on CIRT delivery in selected tumour types. Conclusions: After an initial ramp-up period, CNAO has progressively honed its clinical, technical, and dosimetric skills. Growing engagement with national and international networks and research groups for complex cancers has led to increasingly targeted patient selection for CIRT and lowered barriers to facility access. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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12 pages, 1158 KiB  
Systematic Review
Carbon Ion Radiotherapy: An Evidence-Based Review and Summary Recommendations of Clinical Outcomes for Skull-Base Chordomas and Chondrosarcomas
by Adam L. Holtzman, Katharina Seidensaal, Alberto Iannalfi, Kyung Hwan Kim, Masashi Koto, Wan-Chin Yang, Cheng-Ying Shiau, Anita Mahajan, Safia K. Ahmed, Daniel M. Trifiletti, Jennifer L. Peterson, Daniel M. Koffler, Laura A. Vallow, Bradford S. Hoppe and Michael S. Rutenberg
Cancers 2023, 15(20), 5021; https://doi.org/10.3390/cancers15205021 - 17 Oct 2023
Cited by 2 | Viewed by 1116
Abstract
Skull-base chordoma and chondrosarcoma are rare radioresistant tumors treated with surgical resection and/or radiotherapy. Because of the established dosimetric and biological benefits of heavy particle therapy, we performed a systematic and evidence-based review of the clinical outcomes of patients with skull-base chordoma and [...] Read more.
Skull-base chordoma and chondrosarcoma are rare radioresistant tumors treated with surgical resection and/or radiotherapy. Because of the established dosimetric and biological benefits of heavy particle therapy, we performed a systematic and evidence-based review of the clinical outcomes of patients with skull-base chordoma and chondrosarcoma treated with carbon ion radiotherapy (CIRT). A literature review was performed using a MEDLINE search of all articles to date. We identified 227 studies as appropriate for review, and 24 were ultimately included. The published data illustrate that CIRT provides benchmark disease control outcomes for skull-base chordoma and chondrosarcoma, respectively, with acceptable toxicity. CIRT is an advanced treatment technique that may provide not only dosimetric benefits over conventional photon therapy but also biologic intensification to overcome mechanisms of radioresistance. Ongoing research is needed to define the magnitude of benefit, patient selection, and cost-effectiveness of CIRT compared to other forms of radiotherapy. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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32 pages, 845 KiB  
Systematic Review
A Systematic Review of LET-Guided Treatment Plan Optimisation in Proton Therapy: Identifying the Current State and Future Needs
by Melissa McIntyre, Puthenparampil Wilson, Peter Gorayski and Eva Bezak
Cancers 2023, 15(17), 4268; https://doi.org/10.3390/cancers15174268 - 25 Aug 2023
Cited by 2 | Viewed by 1260
Abstract
The well-known clinical benefits of proton therapy are achieved through higher target-conformality and normal tissue sparing than conventional radiotherapy. However, there is an increased sensitivity to uncertainties in patient motion/setup, proton range and radiobiological effect. Although recent efforts have mitigated some uncertainties, radiobiological [...] Read more.
The well-known clinical benefits of proton therapy are achieved through higher target-conformality and normal tissue sparing than conventional radiotherapy. However, there is an increased sensitivity to uncertainties in patient motion/setup, proton range and radiobiological effect. Although recent efforts have mitigated some uncertainties, radiobiological effect remains unresolved due to a lack of clinical data for relevant endpoints. Therefore, RBE optimisations may be currently unsuitable for clinical treatment planning. LET optimisation is a novel method that substitutes RBE with LET, shifting LET hotspots outside critical structures. This review outlines the current status of LET optimisation in proton therapy, highlighting knowledge gaps and possible future research. Following the PRISMA 2020 guidelines, a search of the MEDLINE® and Scopus databases was performed in July 2023, identifying 70 relevant articles. Generally, LET optimisation methods achieved their treatment objectives; however, clinical benefit is patient-dependent. Inconsistencies in the reported data suggest further testing is required to identify therapeutically favourable methods. We discuss the methods which are suitable for near-future clinical deployment, with fast computation times and compatibility with existing treatment protocols. Although there is some clinical evidence of a correlation between high LET and adverse effects, further developments are needed to inform future patient selection protocols for widespread application of LET optimisation in proton therapy. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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10 pages, 485 KiB  
Study Protocol
Pragmatic, Prospective Comparative Effectiveness Trial of Carbon Ion Therapy, Surgery, and Proton Therapy for the Management of Pelvic Sarcomas (Soft Tissue/Bone) Involving the Bone: The PROSPER Study Rationale and Design
by Bradford S. Hoppe, Ivy A. Petersen, Benjamin K. Wilke, Todd A. DeWees, Reiko Imai, Eugen B. Hug, Maria Rosaria Fiore, Jürgen Debus, Piero Fossati, Shigeru Yamada, Ester Orlandi, Qing Zhang, Cihang Bao, Katharina Seidensaal, Byron C. May, Anna C. Harrell, Matthew T. Houdek, Laura A. Vallow, Peter S. Rose, Michael G. Haddock, Jonathan B. Ashman, Krista A. Goulding, Steven Attia, Sunil Krishnan, Anita Mahajan, Robert L. Foote, Nadia N. Laack, Sameer R. Keole, Chris J. Beltran, Eric M. Welch, Mohammed Karim and Safia K. Ahmedadd Show full author list remove Hide full author list
Cancers 2023, 15(6), 1660; https://doi.org/10.3390/cancers15061660 - 8 Mar 2023
Cited by 5 | Viewed by 2084
Abstract
Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both [...] Read more.
Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic chordoma, chondrosarcoma, osteosarcoma, Ewing sarcoma with bone involvement, rhabdomyosarcoma (RMS) with bone involvement, or non-RMS soft tissue sarcoma with bone involvement. Treatment arms include (1) CIRT (n = 30) delivered in Europe and Asia, (2) surgical treatment with or without adjuvant radiotherapy (n = 30), and (3) proton therapy (n = 30). Arms two and three will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota. The primary end point is to compare the 1-year change in functional QOL between CIRT and surgical treatment. Additional comparisons among the three arms will be made between treatment sequelae, local control, and other QOL measures. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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