Special Issue "Proton and Carbon Ion Therapy"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 January 2018)

Special Issue Editor

Guest Editor
Dr. Yoshio Hishikawa

Department of Radiology, Medipolis Proton Therapy and Research Center, Ibusuki, Japan
Website | E-Mail
Phone: 81-993-23-6600
Interests: proton therapy; carbon-ion therapy; breast cancer; pancreatic cancer

Special Issue Information

Dear Colleagues,

Proton therapy was introduced in the 1940s and carbon-ion therapy was started in the 1990s. Recently the particle therapy of protons and carbon ions has spread to many countries around the world. Compared to conventional radiation treatment with X-rays, there are clinical reports that particle therapy is more effective against: 1) malignant tumors with less X-ray sensitivity; 2) tumors close to vital organs; and 3) large tumors.

In the upcoming Special Issue, we would like to discuss how particle therapy is employed for cancers that are difficult to treat with X-ray therapy, as well as possible future uses of this therapy and its current state of progress. It would also be beneficial to look into the efficacy of combining particle therapy with chemotherapy.

If we are able to clarify the strong points of ion beam radiotherapy in this special edition, we can expect progress on differentiating the uses of proton therapy and carbon-ion therapy from X-ray radiotherapy.

We also welcome advice from facilities that have experience with proton therapy and/or carbon-ion therapy to those medical institutions that are considering introducing it.

Dr. Yoshio Hishikawa
Guest Editor

Manuscript Submission Information

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Published Papers (12 papers)

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Research

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Open AccessArticle FRoG—A New Calculation Engine for Clinical Investigations with Proton and Carbon Ion Beams at CNAO
Cancers 2018, 10(11), 395; https://doi.org/10.3390/cancers10110395
Received: 28 August 2018 / Revised: 15 October 2018 / Accepted: 16 October 2018 / Published: 23 October 2018
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Abstract
A fast and accurate dose calculation engine for hadrontherapy is critical for both routine clinical and advanced research applications. FRoG is a graphics processing unit (GPU)-based forward calculation tool developed at CNAO (Centro Nazionale di Adroterapia Oncologica) and at HIT (Heidelberg Ion Beam [...] Read more.
A fast and accurate dose calculation engine for hadrontherapy is critical for both routine clinical and advanced research applications. FRoG is a graphics processing unit (GPU)-based forward calculation tool developed at CNAO (Centro Nazionale di Adroterapia Oncologica) and at HIT (Heidelberg Ion Beam Therapy Center) for fast and accurate calculation of both physical and biological dose. FRoG calculation engine adopts a triple Gaussian parameterization for the description of the lateral dose distribution. FRoG provides dose, dose-averaged linear energy transfer, and biological dose-maps, -profiles, and -volume-histograms. For the benchmark of the FRoG calculation engine, using the clinical settings available at CNAO, spread-out Bragg peaks (SOBPs) and patient cases for both proton and carbon ion beams have been calculated and compared against FLUKA Monte Carlo (MC) predictions. In addition, FRoG patient-specific quality assurance (QA) has been performed for twenty-five proton and carbon ion fields. As a result, for protons, biological dose values, using a relative biological effectiveness (RBE) of 1.1, agree on average with MC within ~1% for both SOBPs and patient plans. For carbon ions, RBE-weighted dose (DRBE) agreement against FLUKA is within ~2.5% for the studied SOBPs and patient plans. Both MKM (Microdosimetric Kinetic Model) and LEM (Local Effect Model) DRBE are implemented and tested in FRoG to support the NIRS (National Institute of Radiological Sciences)-based to LEM-based biological dose conversion. FRoG matched the measured QA dosimetric data within ~2.0% for both particle species. The typical calculation times for patients ranged from roughly 1 to 4 min for proton beams and 3 to 6 min for carbon ions on a NVIDIA® GeForce® GTX 1080 Ti. This works demonstrates FRoG’s potential to bolster clinical activity with proton and carbon ion beams at CNAO. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
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Open AccessArticle Proton Beam Therapy in Combination with Intra-Arterial Infusion Chemotherapy for T4 Squamous Cell Carcinoma of the Maxillary Gingiva
Cancers 2018, 10(9), 333; https://doi.org/10.3390/cancers10090333
Received: 26 August 2018 / Revised: 12 September 2018 / Accepted: 13 September 2018 / Published: 15 September 2018
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Abstract
This study aimed to evaluate the therapeutic effect and toxicity of proton beam therapy in combination with intra-arterial infusion chemotherapy in patients with squamous cell carcinoma of the maxillary gingiva. Between December 2010 and March 2016, 30 patients with T4 squamous cell carcinoma [...] Read more.
This study aimed to evaluate the therapeutic effect and toxicity of proton beam therapy in combination with intra-arterial infusion chemotherapy in patients with squamous cell carcinoma of the maxillary gingiva. Between December 2010 and March 2016, 30 patients with T4 squamous cell carcinoma of the maxillary gingiva were treated with radiotherapy and retrograde intra-arterial infusion chemotherapy using cisplatin (20–40 mg/m2, 4–6 times). Radiotherapy was basically administered using boost proton beam therapy for primary tumor and neck lymph node tumors, following 36–40 Gy photon radiation therapy delivered to the prophylactic area, to a total dose of 70.4–74.8 Gy. The median follow-up was 33 months. The 3-year local control and overall survival rates were 69% and 59%, respectively. Major grade 3 or higher acute toxicities included mucositis, neutropenia, and dermatitis in 12 (40%), 5 (17%), and 3 (10%) patients, respectively. No grade 3 or higher late toxicities were observed. These results suggested that proton beam therapy in combination with intra-arterial infusion chemotherapy was not inferior to other treatment protocols and should be considered as a safe and effective option in patients with T4 squamous cell carcinoma of the maxillary gingiva. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
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Open AccessArticle Electron Nuclear Dynamics Simulations of Proton Cancer Therapy Reactions: Water Radiolysis and Proton- and Electron-Induced DNA Damage in Computational Prototypes
Cancers 2018, 10(5), 136; https://doi.org/10.3390/cancers10050136
Received: 14 February 2018 / Revised: 22 April 2018 / Accepted: 28 April 2018 / Published: 6 May 2018
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Abstract
Proton cancer therapy (PCT) utilizes high-energy proton projectiles to obliterate cancerous tumors with low damage to healthy tissues and without the side effects of X-ray therapy. The healing action of the protons results from their damage on cancerous cell DNA. Despite established clinical [...] Read more.
Proton cancer therapy (PCT) utilizes high-energy proton projectiles to obliterate cancerous tumors with low damage to healthy tissues and without the side effects of X-ray therapy. The healing action of the protons results from their damage on cancerous cell DNA. Despite established clinical use, the chemical mechanisms of PCT reactions at the molecular level remain elusive. This situation prevents a rational design of PCT that can maximize its therapeutic power and minimize its side effects. The incomplete characterization of PCT reactions is partially due to the health risks associated with experimental/clinical techniques applied to human subjects. To overcome this situation, we are conducting time-dependent and non-adiabatic computer simulations of PCT reactions with the electron nuclear dynamics (END) method. Herein, we present a review of our previous and new END research on three fundamental types of PCT reactions: water radiolysis reactions, proton-induced DNA damage and electron-induced DNA damage. These studies are performed on the computational prototypes: proton + H2O clusters, proton + DNA/RNA bases and + cytosine nucleotide, and electron + cytosine nucleotide + H2O. These simulations provide chemical mechanisms and dynamical properties of the selected PCT reactions in comparison with available experimental and alternative computational results. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
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Open AccessArticle Proton Beam Therapy Alone for Intermediate- or High-Risk Prostate Cancer: An Institutional Prospective Cohort Study
Cancers 2018, 10(4), 116; https://doi.org/10.3390/cancers10040116
Received: 30 January 2018 / Revised: 5 April 2018 / Accepted: 6 April 2018 / Published: 10 April 2018
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Abstract
The role of proton beam therapy (PBT) as monotherapy for localized prostate cancer (PCa) remains unclear. The purpose of this study was to evaluate the efficacy and adverse events of PBT alone for these patients. Between January 2011 and July 2014, 218 patients [...] Read more.
The role of proton beam therapy (PBT) as monotherapy for localized prostate cancer (PCa) remains unclear. The purpose of this study was to evaluate the efficacy and adverse events of PBT alone for these patients. Between January 2011 and July 2014, 218 patients with intermediate- and high-risk PCa who declined androgen deprivation therapy (ADT) were enrolled to the study and were treated with PBT following one of the following protocols: 74 Gray (GyE) with 37 fractions (fr) (74 GyE/37 fr), 78 GyE/39 fr, and 70 GyE/28 fr. The 5-year progression-free survival rate in the intermediate- and high-risk groups was 97% and 83%, respectively (p = 0.002). The rate of grade 2 or higher late gastrointestinal toxicity was 3.9%, and a significant increased incidence was noted in those who received the 78 GyE/39 fr protocol (p < 0.05). Grade 2 or higher acute and late genitourinary toxicities were observed in 23.5% and 3.4% of patients, respectively. Our results indicated that PBT monotherapy can be a beneficial treatment for localized PCa. Furthermore, it can preserve the quality of life of these patients. We believe that this study provides crucial hypotheses for further study and for establishing new treatment strategies. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
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Open AccessArticle Proton Partial Breast Irradiation: Detailed Description of Acute Clinico-Radiologic Effects
Cancers 2018, 10(4), 111; https://doi.org/10.3390/cancers10040111
Received: 12 February 2018 / Revised: 26 March 2018 / Accepted: 4 April 2018 / Published: 7 April 2018
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Abstract
Introduction: Accelerated partial breast irradiation (APBI) with protons results in a very different acute effect profile than standard whole breast irradiation. We reviewed our initial experience with proton APBI and felt that a detailed description of these effects were needed to permit a [...] Read more.
Introduction: Accelerated partial breast irradiation (APBI) with protons results in a very different acute effect profile than standard whole breast irradiation. We reviewed our initial experience with proton APBI and felt that a detailed description of these effects were needed to permit a common tool to compare experience with this developing technology. Methods: Sixty sequential patients treated with proton APBI on a prospective protocol were evaluated and 43 patients with a minimum six-month follow-up underwent detailed photographic and radiologic analysis. The tumorectomy cavity plus an additional 1.5 cm clinical target volume (CTV) was treated with two or three passively-scattered proton beams to a dose of 34 Gy in 10 fractions in one week. Photographs were taken at the end of radiation, at two weeks, six weeks, and every six months thereafter. Mammography was obtained at six months after radiation and annually thereafter. All visual changes were categorized using the smallest meaningful gradations in findings and are demonstrated herein. All treatment-related mammographic findings are reported. Findings: Visual and mammographic findings showed a clear time-dependent relationship and significant variation between individuals. Peak skin reaction occurred at two to six weeks after completion of therapy. At two weeks most patients had either no visible effects and patchy erythema involving <50% of the treated skin (60%). At six weeks most patients had either patchy erythema involving <50% of the overlying skin (33%) or patchy erythema involving >50% of the treated skin (28%). Only one patient developed any moist desquamation. At six months most patients had no visible skin changes (57%) or a small, circular area of mild hyperpigmentation (33%). Mammographic changes seen at six months were regional skin thickening (40%), residual seroma (14%), localized retraction (26%), and fat necrosis (2%). A subcategorized variant on the CTCAE 4.0 was developed to foster granular recording of these findings. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
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Open AccessFeature PaperArticle Study of the Influence of NanOx Parameters
Received: 9 February 2018 / Revised: 7 March 2018 / Accepted: 16 March 2018 / Published: 21 March 2018
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Abstract
NanOx is a new biophysical model that aims at predicting the biological effect of ions in the context of hadron therapy. It integrates the fully-stochastic nature of ionizing radiation both at micrometric and nanometric scales and also takes into account the production and [...] Read more.
NanOx is a new biophysical model that aims at predicting the biological effect of ions in the context of hadron therapy. It integrates the fully-stochastic nature of ionizing radiation both at micrometric and nanometric scales and also takes into account the production and diffusion of reactive chemical species. In order to further characterize the new framework, we discuss the meaning and relevance of most of the NanOx parameters by evaluating their influence on the linear-quadratic coefficient α and on the dose deposited to achieve 10% or 1% of cell survival, D 10 % or D 1 % , as a function of LET. We perform a theoretical study in which variations in the input parameters are propagated into the model predictions for HSG, V79 and CHO-K1 cells irradiated by monoenergetic protons and carbon ions. We conclude that, in the current version of NanOx, the modeling of a specific cell line relies on five parameters, which have to be adjusted to several experimental measurements: the average cellular nuclear radius, the linear-quadratic coefficients describing photon irradiations and the α values associated with two carbon ions of intermediate and high-LET values. This may have interesting implications toward a clinical application of the new biophysical model. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
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Open AccessArticle Proton Beam Therapy without Fiducial Markers Using Four-Dimensional CT Planning for Large Hepatocellular Carcinomas
Received: 30 January 2018 / Revised: 7 March 2018 / Accepted: 12 March 2018 / Published: 14 March 2018
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Abstract
We evaluated the effectiveness and toxicity of proton beam therapy (PBT) for hepatocellular carcinomas (HCC) >5 cm without fiducial markers using four-dimensional CT (4D-CT) planning. The subjects were 29 patients treated at our hospital between March 2011 and March 2015. The median total [...] Read more.
We evaluated the effectiveness and toxicity of proton beam therapy (PBT) for hepatocellular carcinomas (HCC) >5 cm without fiducial markers using four-dimensional CT (4D-CT) planning. The subjects were 29 patients treated at our hospital between March 2011 and March 2015. The median total dose was 76 Cobalt Gray Equivalents (CGE) in 20 fractions (range; 66–80.5 CGE in 10–32 fractions). Therapy was delivered with end-expiratory phase gating. An internal target volume (ITV) margin was added through the analysis of respiratory movement with 4D-CT. Patient age ranged from 38 to 87 years (median, 71 years). Twenty-four patients were Child–Pugh class A and five patients were class B. Tumor size ranged from 5.0 to 13.9 cm (median, 6.9 cm). The follow-up period ranged from 2 to 72 months (median; 27 months). All patients completed PBT according to the treatment protocol without grade 4 (CTCAE v4.03 (draft v5.0)) or higher adverse effects. The two-year local tumor control (LTC), progression-free survival (PFS), and overall survival (OS) rates were 95%, 22%, and 61%, respectively. The LTC was not inferior to that of previous reports using fiducial markers. Respiratory-gated PBT with 4D-CT planning without fiducial markers is a less invasive and equally effective treatment for large HCCs as PBT with fiducial markers. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
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Open AccessFeature PaperArticle Respiratory-Gated Proton Beam Therapy for Hepatocellular Carcinoma Adjacent to the Gastrointestinal Tract without Fiducial Markers
Received: 29 January 2018 / Revised: 16 February 2018 / Accepted: 19 February 2018 / Published: 21 February 2018
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Abstract
The efficacy of proton beam therapy (PBT) for hepatocellular carcinoma (HCC) has been reported, but insertion of fiducial markers in the liver is usually required. We evaluated the efficacy and toxicity of respiratory-gated PBT without fiducial markers for HCC located within 2 cm [...] Read more.
The efficacy of proton beam therapy (PBT) for hepatocellular carcinoma (HCC) has been reported, but insertion of fiducial markers in the liver is usually required. We evaluated the efficacy and toxicity of respiratory-gated PBT without fiducial markers for HCC located within 2 cm of the gastrointestinal tract. From March 2011 to December 2015 at our institution, 40 patients were evaluated (median age, 72 years; range, 38–87 years). All patients underwent PBT at a dose of 60 to 80 cobalt gray equivalents (CGE) in 20 to 38 fractions. The median follow-up period was 19.9 months (range, 1.2–72.3 months). The median tumor size was 36.5 mm (range, 11–124 mm). Kaplan–Meier estimates of the 2-year overall survival, progression-free survival, and local tumor control rates were 76%, 60%, and 94%, respectively. One patient (2.5%) developed a grade 3 gastric ulcer and one (2.5%) developed grade 3 ascites retention; none of the remaining patients developed grade >3 toxicities (National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.0.). This study indicates that PBT without fiducial markers achieves good local control without severe treatment-related toxicity of the gastrointestinal tract for HCC located within 2 cm of the gastrointestinal tract. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
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Open AccessFeature PaperArticle Towards a Clinical Decision Support System for External Beam Radiation Oncology Prostate Cancer Patients: Proton vs. Photon Radiotherapy? A Radiobiological Study of Robustness and Stability
Received: 27 November 2017 / Revised: 19 January 2018 / Accepted: 14 February 2018 / Published: 18 February 2018
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Abstract
We present a methodology which can be utilized to select proton or photon radiotherapy in prostate cancer patients. Four state-of-the-art competing treatment modalities were compared (by way of an in silico trial) for a cohort of 25 prostate cancer patients, with and without [...] Read more.
We present a methodology which can be utilized to select proton or photon radiotherapy in prostate cancer patients. Four state-of-the-art competing treatment modalities were compared (by way of an in silico trial) for a cohort of 25 prostate cancer patients, with and without correction strategies for prostate displacements. Metrics measured from clinical image guidance systems were used. Three correction strategies were investigated; no-correction, extended-no-action-limit, and online-correction. Clinical efficacy was estimated via radiobiological models incorporating robustness (how probable a given treatment plan was delivered) and stability (the consistency between the probable best and worst delivered treatments at the 95% confidence limit). The results obtained at the cohort level enabled the determination of a threshold for likely clinical benefit at the individual level. Depending on the imaging system and correction strategy; 24%, 32% and 44% of patients were identified as suitable candidates for proton therapy. For the constraints of this study: Intensity-modulated proton therapy with online-correction was on average the most effective modality. Irrespective of the imaging system, each treatment modality is similar in terms of robustness, with and without the correction strategies. Conversely, there is substantial variation in stability between the treatment modalities, which is greatly reduced by correction strategies. This study provides a ‘proof-of-concept’ methodology to enable the prospective identification of individual patients that will most likely (above a certain threshold) benefit from proton therapy. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
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Open AccessFeature PaperArticle Synchrotron-Based Pencil Beam Scanning Nozzle with an Integrated Mini-Ridge Filter: A Dosimetric Study to Optimize Treatment Delivery
Cancers 2017, 9(12), 170; https://doi.org/10.3390/cancers9120170
Received: 10 October 2017 / Revised: 5 December 2017 / Accepted: 11 December 2017 / Published: 13 December 2017
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Abstract
A mini-ridge filter is often used to widen the Bragg peak in the longitudinal direction at low energies but not high energies. To facilitate the clinical use of a mini-ridge filter, we performed a planning study for the feasibility of a mini-ridge filter [...] Read more.
A mini-ridge filter is often used to widen the Bragg peak in the longitudinal direction at low energies but not high energies. To facilitate the clinical use of a mini-ridge filter, we performed a planning study for the feasibility of a mini-ridge filter as an integral part of the synchrotron nozzle (IMRF). Dose models with and without IMRF were commissioned in a commercial Treatment planning system (TPS). Dosimetric characteristics in a homogenous water phantom were compared between plans with and without IMRF for a fixed spread-out Bragg peak width of 4 cm with distal ranges varying from 8 to 30 g/cm2. Six clinical cases were then used to compare the plan quality between plans. The delivery efficiency was also compared between plans in both the phantom and the clinical cases. The Bragg peak width was increased by 0.18 cm at the lowest energy and by only about 0.04 cm at the highest energy. The IMRF increased the spot size (σ) by up to 0.1 cm at the lowest energy and by only 0.02 cm at the highest energy. For the phantom, the IMRF negligibly affected dose at high energies but increased the lateral penumbra by up to 0.12 cm and the distal penumbra by up to 0.06 cm at low energies. For the clinical cases, the IMRF slightly increased dose to the organs at risk. However, the beam delivery time was reduced from 18.5% to 47.1% for the lung, brain, scalp, and head and neck cases, and dose uniformities of target were improved up to 2.9% for these cases owing to the reduced minimum monitor unit effect. In conclusion, integrating a mini-ridge filter into a synchrotron nozzle is feasible for improving treatment efficiency without significantly sacrificing the plan quality. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
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Review

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Open AccessFeature PaperReview Evolution of Carbon Ion Radiotherapy at the National Institute of Radiological Sciences in Japan
Received: 4 February 2018 / Revised: 2 March 2018 / Accepted: 2 March 2018 / Published: 6 March 2018
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Abstract
Charged particles can achieve better dose distribution and higher biological effectiveness compared to photon radiotherapy. Carbon ions are considered an optimal candidate for cancer treatment using particles. The National Institute of Radiological Sciences (NIRS) in Chiba, Japan was the first radiotherapy hospital dedicated [...] Read more.
Charged particles can achieve better dose distribution and higher biological effectiveness compared to photon radiotherapy. Carbon ions are considered an optimal candidate for cancer treatment using particles. The National Institute of Radiological Sciences (NIRS) in Chiba, Japan was the first radiotherapy hospital dedicated for carbon ion treatments in the world. Since its establishment in 1994, the NIRS has pioneered this therapy with more than 69 clinical trials so far, and hundreds of ancillary projects in physics and radiobiology. In this review, we will discuss the evolution of carbon ion radiotherapy at the NIRS and some of the current and future projects in the field. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
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Other

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Open AccessTechnical Note Clinical Implementation of Robust Optimization for Craniospinal Irradiation
Received: 25 October 2017 / Revised: 15 December 2017 / Accepted: 26 December 2017 / Published: 3 January 2018
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Abstract
With robust optimization for spot scanning proton therapy now commercially available, the ability exists to account for setup, range, and interfield uncertainties during optimization. Robust optimization is particularly beneficial for craniospinal irradiation (CSI) where the large target volume lends itself to larger setup [...] Read more.
With robust optimization for spot scanning proton therapy now commercially available, the ability exists to account for setup, range, and interfield uncertainties during optimization. Robust optimization is particularly beneficial for craniospinal irradiation (CSI) where the large target volume lends itself to larger setup uncertainties and the need for robust match lines can all be handled with the uncertainty parameters found inside the optimizer. Suggested robust optimization settings, parameters, and image guidance for CSI patients using proton therapy spot scanning are provided. Useful structures are defined and described. Suggestions are given for perturbations to be entered into the optimizer in order to achieve a plan that provides robust target volume coverage and critical structure sparing as well as a robust match line. Interfield offset effects, a concern when using multifield optimization, can also be addressed within the robust optimizer. A robust optimizer can successfully be employed to produce robust match lines, target volume coverage, and critical structure sparing under specified uncertainties. The robust optimizer can also be used to reduce effects arising from interfield uncertainties. Using robust optimization, a plan robust against setup, range, and interfield uncertainties for craniospinal treatments can be created. Utilizing robust optimization allows one to ensure critical structures are spared and target volumes are covered under the desired uncertainty parameters. Full article
(This article belongs to the Special Issue Proton and Carbon Ion Therapy)
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