Physical and Biological Characteristics of Particle Therapy for Oncologists.

Particle therapy is a promising and evolving modality of radiotherapy that can be used to treat tumors that are radioresistant to conventional photon beam radiotherapy. It has unique biological and physical advantages compared with conventional radiotherapy. The characteristic feature of particle therapy is the "Bragg peak," a steep and localized peak of dose, that enables precise delivery of the radiation dose to the tumor while effectively sparing normal organs. Especially, the charged particles (e.g., proton, helium, carbon) cause a high rate of energy loss along the track, thereby leading to high biological effectiveness, which makes particle therapy attractive. Using this property, the particle beam induces more severe DNA double-strand breaks than the photon beam, which is less influenced by the oxygen level. This review describes the general biological and physical aspects of particle therapy for oncologists, including non-radiation oncologists and beginners in the field.

Technological Advances in Charged-Particle Therapy.

Charted-particle therapy (CPT) benefits cancer patients by localizing doses in the tumor volume while minimizing the doses delivered to normal tissue through its unique physical and biological characteristics. The world's first CPT applied on humans was proton beam therapy (PBT), which was performed in the mid-1950s. Among heavy ions, carbon ions showed the most favorable biological characteristics for the treatment of cancer patients. Carbon ions show coincidence between the Bragg peak and maximum value of relative biological effectiveness. In addition, they show low oxygen enhancement ratios. Therefore, carbon-ion radiotherapy (CIRT) has become mainstream in the treatment of cancer patients using heavy ions. CIRT was first performed in 1977 at the Lawrence Berkeley Laboratory. The CPT technology has advanced in the intervening decades, enabling the use of rotating gantry, beam delivery with fast pencil-beam scanning, image-guided particle therapy, and intensity-modulated particle therapy. As a result, as of 2019, a total of 222,425 and 34,138 patients with cancer had been treated globally with PBT and CIRT, respectively. For more effective and efficient CPT, many groups are currently conducting further studies worldwide. This review summarizes recent technological advances that facilitate clinical use of CPT.

The influence of beam delivery uncertainty on dose uniformity and penumbra for pencil beam scanning in carbon-ion radiotherapy.

The dose uniformity and penumbra in the treatment field are important factors in radiotherapy, which affects the outcomes of radiotherapy. In this study, the integrated depth-dose-distributions (IDDDs) of 190 MeV/u and 260 MeV/u carbon beams in the active spot-scanning delivery system were measured and calculated by FLUKA Monte Carlo simulation based on the Heavy Ion Medical Machine (HIMM). Considering the dose distributions caused by secondary particles and scattering, we also used different types of pencil beam (PB) models to fit and compare the spatial distributions of PB. We superposed a bunch of PB to form a 20×20 cm2 treatment field with the double Gaussian and double Gaussian logistic beam models and calculated the influence of beam delivery error on the field flatness and penumbra, respectively. The simulated IDDDs showed good agreement with the measured values. The triple Gaussian and double Gaussian logistic beam models have good fitness to the simulated dose distributions. There are different influences on dose uniformity and penumbra resulting from beam uncertainties. These results would be helpful for understanding carbon ion therapy, and physical therapists are more familiar with beam characteristics for active scanning therapy, which provides a reference for commissioning and optimization of treatment plans in radiotherapy.

Intense carbon beams production with an all permanent magnet electron cyclotron resonance ion source for heavy ion medical machine.

LAPECR3 (Lanzhou All Permanent magnet Electron cyclotron Resonance ion source No. 3) had been developed as an ion injector of Heavy Ion Medical Machine (HIMM) accelerator facility since 2009. The first HIMM accelerator facility was built in Wuwei city in 2015, and the LAPCER3 ion source has delivered C5+ ion beam to HIMM for more than 1000 days in the past four years. In order to improve the performance of the LAPECR3 ion source for intense carbon beams production, continuous research and development work has been made. The recently developed LAPECR3 ion source together with the new low-energy beam transportation can provide better performance in terms of both beam intensity and quality. This paper will generally review the LAPECR3 ion source operation status for HIMM, and the recent improvement will be presented, especially the stable beams production of C4+ and C5+.

Experimental exploration of a mixed helium/carbon beam for online treatment monitoring in carbon ion beam therapy.

Recently, it has been proposed that a mixed helium/carbon beam could be used for online monitoring in carbon ion beam therapy. Fully stripped, the two ion species exhibit approximately the same mass/charge ratio and hence could potentially be accelerated simultaneously in a synchrotron to the same energy per nucleon. At the same energy per nucleon, helium ions have about three times the range of carbon ions, which could allow for simultaneous use of the carbon ion beam for treatment and the helium ion beam for imaging. In this work, measurements and simulations of PMMA phantoms as well as anthropomorphic phantoms irradiated sequentially with a helium ion and a carbon ion beam at equal energy per nucleon are presented. The range of the primary helium ion beam and the fragment tail of the carbon ion beam exiting the phantoms were detected using a novel range telescope made of thin plastic scintillator sheets read out by a flat-panel CMOS sensor. A 10:1 carbon to helium mixing ratio is used, generating a helium signal well above the carbon fragment background while adding little to the dose delivered to the patient. The range modulation of a narrow air gap of 1 mm thickness in the PMMA phantom that affects less than a quarter of the particles in a pencil beam were detected, demonstrating the achievable relative sensitivity of the presented method. Using two anthropomorphic pelvis phantoms it is shown that small rotations of the phantom as well as simulated bowel gas movements cause detectable changes in the helium/carbon beam exiting the phantom. The future prospects and limitations of the helium/carbon mixing as well as its technical feasibility are discussed.

Estimations of relative biological effectiveness of secondary fragments in carbon ion irradiation of water using CR-39 plastic detector and microdosimetric kinetic model.

PURPOSE: To estimate relative biological effectiveness (RBE) ascribed to secondary fragments in a lateral distribution of carbon ion irradiation. The RBE was estimated with the microdosimetric kinetic (MK) model and measured linear energy transfer (LET) obtained with CR-39 plastic detectors. METHODS: A water phantom was irradiated by a 12 C pencil beam with energy of 380 MeV/u at the Gunma University Heavy Ion Medical Center (GHMC), and CR-39 detectors were exposed to secondary fragments. Because CR-39 was insensitive to low LET, we conducted Monte Carlo simulations with Geant4 to calculate low LET particles. The spectra of low LET particles were combined with experimental spectra to calculate RBE. To estimate accuracy of RBE, we calculated RBE by changing yield of low LET particles by ± 10% and ± 40%. RESULTS: At a small angle, maximum RBE by secondary fragments was 1.3 for 10% survival fractions. RBE values of fragments gradually decreased as the angle became larger. The shape of the LET spectra in the simulation reproduced the experimental spectra, but there was a discrepancy between the simulation and experiment for the relative yield of fragments. When the yield of low LET particles was changed by ± 40%, the change in RBE was smaller than 10%. CONCLUSIONS: An RBE of 1.3 was expected for secondary fragments emitted at a small angle. Although, we observed a discrepancy in the relative yield of secondary fragments between simulation and experiment, precision of RBE was not so sensitive to the yield of low LET particles.

Dosimetric validation of Monte Carlo and analytical dose engines with raster-scanning 1H, 4He, 12C, and 16O ion-beams using an anthropomorphic phantom.

With high-precision radiotherapy on the rise towards mainstream healthcare, comprehensive validation procedures are essential, especially as more sophisticated technologies emerge. In preparation for the upcoming translation of novel ions, case-/disease-specific ion-beam selection and advanced multi-particle treatment modalities at the Heidelberg Ion-beam Therapy Center (HIT), we quantify the accuracy limits in particle therapy treatment planning under complex heterogeneous conditions for the four ions (1H, 4He, 12C, 16O) using a Monte Carlo Treatment Planning platform (MCTP), an independent GPU-accelerated analytical dose engine developed in-house (FRoG) and the clinical treatment planning system (Syngo RT Planning). Attaching an anthropomorphic half-head Alderson RANDO phantom to entrance window of a dosimetric verification water tank, a cubic target spread-out Bragg peak (SOBP) was optimized using the MCTP to best resolve effects of anatomic heterogeneities on dose homogeneity. Subsequent forward calculations were executed in FRoG and Syngo. Absolute and relative dosimetry was performed in the experimental beam room using 1D and 2D array ionization chamber detectors. Mean absolute percent deviation in dose (|%Δ|) between predictions and PinPoint ionization chamber measurements were within ∼2% for all investigated ions for both MCTP and FRoG. For protons and carbon ions, |%Δ| values were ∼4% for Syngo. For the four ions, 3D-γ analysis (3%/3mm criteria) of FLUKA and FRoG presented mean passing rates of 97.0(±2.4)% and 93.6(±4.2)%. FRoG demonstrated satisfactory agreement with gold standard Monte Carlo simulation and measurement, superior to the commercial system. Our pre-clinical trial landmarks the first measurements taken in anthropomorphic settings for helium, carbon and oxygen ion-beam therapy.

Review and performance of the Dose Profiler, a particle therapy treatments online monitor.

Particle therapy (PT) can exploit heavy ions (such as He, C or O) to enhance the treatment efficacy, profiting from the increased Relative Biological Effectiveness and Oxygen Enhancement Ratio of these projectiles with respect to proton beams. To maximise the gain in tumor control probability a precise online monitoring of the dose release is needed, avoiding unnecessary large safety margins surroundings the tumor volume accounting for possible patient mispositioning or morphological changes with respect to the initial CT scan. The Dose Profiler (DP) detector, presented in this manuscript, is a scintillating fibres tracker of charged secondary particles (mainly protons) that will be operating during the treatment, allowing for an online range monitoring. Such monitoring technique is particularly promising in the context of heavy ions PT, in which the precision achievable by other techniques based on secondary photons detection is limited by the environmental background during the beam delivery. Developed and built at the SBAI department of "La Sapienza", within the INSIDE collaboration and as part of a Centro Fermi flagship project, the DP is a tracker detector specifically designed and planned for clinical applications inside a PT treatment room. The DP operation in clinical like conditions has been tested with the proton and carbon ions beams of Trento proton-therapy center and of the CNAO facility. In this contribution the detector performances are presented, in the context of the carbon ions monitoring clinical trial that is about to start at the CNAO centre.

First prospective feasibility study of carbon-ion radiotherapy using compact superconducting rotating gantry.

OBJECTIVE: We had developed compact rotating gantry for carbon ion using superconducting magnets in 2015 which became clinically operational in 2017. The objective of this study was to assess the clinical feasibility and safety of using compact rotating gantry with three-dimensional active scanning in delivery of carbon-ion radiotherapy (C-ion RT) for relatively stationary tumours. METHODS: A prospective feasibility study was conducted with 10 patients who had been treated with C-ion RT using compact rotating gantry between April 2017 and April 2018 at Hospital of the National Institute of Radiological Sciences (NIRS) for head and neck and prostate cancers. The primary end point was evaluation of acute toxicities within 3 months of starting C-ion RT. RESULTS: Out of 10 cases 8 were of head and neck cancers and 2 were of prostate cancers. All of those eight head and neck cases were of locally advanced stages. Both of the prostate cancer patients belong to intermediate risk categories. None of the patients developed even Grade 2 or more severe skin reactions. Six out of eight cases with head and neck cancers experienced Grade 2 mucosal reactions; however, nobody developed Grade 3 or more severe mucosal reactions. There was no gastrointestinal reaction observed in prostate cancer patients. One patient developed Grade 2 genitourinary reaction. CONCLUSION: C-ion RT using compact rotating gantry and three-dimensional active scanning is a safe and feasible treatment for relatively less mobile tumours. ADVANCES IN KNOWLEDGE: This study will be the first step to establish the use of superconducting rotating gantry in C-ionRT in clinical setting paving the way for treating large number of patients and make it a standard of practice in the future.

Characterization of prompt gamma ray emission for in vivo range verification in particle therapy: A simulation study.

In this paper we investigate the emission and detection characteristics of prompt gamma (PG) rays for in vivo range verification during hadron therapy, using Geant4 simulations. Proton, 4He and 12C beams of varying energy are incident on water phantoms. The PG production yield, energy spectral characteristics and spatial correlation with the Bragg Peak (BP) have been quantified. Further, the angular distributions for PG detection with respect to a point-of-reference on the phantom surface have been explored. The temporal properties of PG emission and time-of-flight (TOF) of PG detection have also been investigated in correlation with the changing particle beam range. Our results show that the primary PG rays from nuclear interactions of the primary beam exhibit the closest correlation to the beam range but its signal is significantly masked by the concurrent secondary PG rays, particularly for heavier ions such as carbon ion beams. The PG TOF spectroscopy encodes the essential information of the beam range but requires high time resolution measurements to retrieve it. A hybrid PG detection system to utilize the energy, timing and spatial characteristics of PG rays is desirable for BP tracking in real-time.

Development of a Vaginal Immobilization Device: A Treatment-planning Study of Carbon-ion Radiotherapy and Intensity-modulated Radiation Therapy for Uterine Cervical Cancer.

AIM: We developed a vaginal immobilization device for external radiotherapy in gynaecological malignancies and evaluated its bowel dose-reduction effect during carbon-ion radiotherapy (CIRT) and intensity-modulated radiation therapy (IMRT) in patients with cervical cancer. PATIENTS AND METHODS: Computed tomographic images obtained with and without the device in seven patients with cervical cancer were assessed. Treatment plans for CIRT and IMRT were generated, and dose-volume parameters (V20, V25, V35, and D2cc) of the rectum, sigmoidal colon, and bladder were evaluated. RESULTS: The mean±standard deviation of the rectal volume in CIRT for V35 with and without the device were 2.1±2.1 and 13.6±4.4 ml, respectively, and those in IMRT were 2.0±2.2 and 13.7±3.8 ml, respectively; these values were significantly lower in CIRT and IMRT using this device. CONCLUSION: Using our novel vaginal immobilization device, high rectal doses were largely reduced in CIRT and IMRT.

Beam direction arrangement using a superconducting rotating gantry in carbon ion treatment for pancreatic cancer.

OBJECTIVES: Carbon ion radiotherapy provides a concentrated dose distribution to the target and has several advantages over photon radiotherapy. This study aimed to evaluate the optimal beam direction in carbon ion pencil beam scanning and compare dose distributions between the rotating gantry system (RGS) and fixed-beam port system (FBPS). METHODS: Patients with locally advanced pancreatic cancer were randomly selected. First, dose-volume parameters of 7-beam directions in the prone position were evaluated. Second, a composite plan developed using 4-beam directions in RGS was compared with that developed using FBPS, with a total prescribed dose of 55.2 Gy (relative biological effectiveness, RBE) in 12 fractions. RESULTS: Target coverages in the composite plan did not widely differ. For the first and second segments of the duodenum, the mean dose of D2cc was not significantly changed (23.80 ± 11.90 Gy [RBE] and 25.63 ± 10.41 Gy [RBE] for RGS and FBPS, respectively). However, the dose-volume histogram curve in RGS showed a prominent dose reduction in the low-dose region. No significant differences were observed in the stomach, third and fourth segments of the duodenum, and spinal cord. The mean dose of the total kidney was similar between RGS and FBPS. CONCLUSIONS: Compared with that of FBPS, the 4-beam arrangement in the prone position using RGS provides comparable or superior dose distribution in the surrounding normal organ while achieving the same target coverage. In addition, RGS allows for single-patient positioning. ADVANCES IN KNOWLEDGE: RGS is beneficial in delivering radiotherapy doses to the duodenum and allows for single-patient positioning and a simple planning process.

Evaluation of patient positional reproducibility on the treatment couch and its impact on dose distribution using rotating gantry system in scanned carbon-ion beam therapy.

PURPOSE: The daily variations in patient setup may cause beam range uncertainties. We evaluated the reproducibility of relative position between the patient and the treatment couch throughout the treatment course and assessed its effects on dose distributions when a beam passes through treatment couch using rotating gantry system. METHODS: We enrolled 1023 patients (=13072 fractions) treated by carbon-ion pencil beam scanning therapy. Seven treatment sites including prostate, head and neck, bone and soft tissue, rectum, liver, lung, and pancreas were investigated. Inter-fractional changes in couch position relative to the patient were defined as translational errors. Changes in couch rotation were defined as rotational errors. Treatment planning was performed for 4 patients in each of the treatment sites. Dose distributions were then re-calculated after the couch was shifted according to average, 95th percentile, and maximum values of translational error. RESULTS: Large positional errors (>1.5 cm) were observed in 5% of treatment fractions. Positional errors were largest in prostate and pancreas patients, while smallest in head and neck and lung patients. There were no or only small changes in PTV-D95 and CTV-D95 values for almost all treatment sites. Clinically significant changes were observed in the duodenum (difference in D2cc values ranged from -55% to 28% with maximum couch shift) in pancreas treatment. CONCLUSIONS: Although underdosage to the PTV or CTV was limited, significant overdoses to organs at risk were found. The improvement of immobilization technique and appropriate selection of gantry angles could reduce the uncertainties due to changes in patient position.

Commissioning of a respiratory gating system involving a pressure sensor in carbon-ion scanning radiotherapy.

This study reports the commissioning methodology and results of a respiratory gating system [AZ - 733 V/733 VI (Anzai Medical Co., Japan)] using a pressure sensor in carbon-ion scanning radiotherapy. Commissioning includes choosing a location and method for pressure sensor installation, delay time measurement of the system, and the final flow test. Additionally, we proposed a methodology for the determination of a threshold level of generating an on/off gate for the beam to the respiratory waveform, which is important for clinical application. Regarding the location and method for installation of the pressure sensor, the actual person's abdomen, back of the body position, and supine/prone positioning were checked. By comparing the motion between the pressure sensor output and the reference LED sensor motion, the chest rear surface was shown to be unsuitable for the sensor installation, due to noise in the signal caused by the cardiac beat. Regarding delay time measurement of the system, measurements were performed for the following four steps: (a). Actual motion to wave signal generation; (b). Wave signal to gate signal generation; (c). Gate signal to beam on/off signal generation; (d). Beam on/off signal to the beam irradiation. The total delay time measured was 46 ms (beam on)/33 ms (beam off); these were within the prescribed tolerance time (<100 ms). Regarding the final flow test, an end-to-end test was performed with a patient verification system using an actual carbon-ion beam; the respiratory gating irradiation was successfully performed, in accordance with the intended timing. Finally, regarding the method for determining the threshold level of the gate generation of the respiration waveform, the target motion obtained from 4D-CT was assumed to be correlated with the waveform obtained from the pressure sensor; it was used to determine the threshold value in amplitude direction.

OPTIMIZATION OF AN ADDITIONAL COLLIMATOR IN A BEAM DELIVERY SYSTEM FOR REDUCTION OF THE SECONDARY NEUTRON EXPOSURE IN PASSIVE CARBON-ION THERAPY.

The aim of this work is to optimize an additional collimator in a beam delivery system to reduce neutron exposure to patients in passive carbon-ion therapy. All studies were performed by Monte Carlo simulation assuming the beam delivery system at Heavy-Ion Medical Accelerator in Chiba. We calculated the neutron ambient dose equivalent at patient positions with an additional collimator, and optimized the position, aperture size and material of the collimator to reduce the neutron ambient dose equivalent. The collimator located 125 and 470 cm upstream from the isocenter could reduce the dose equivalent near the isocenter by 35%, while the collimator located 813 cm upstream from the isocenter was ineffective. As for the material of the collimator, iron and nickel could conduct reduction slightly better than aluminum and polymethyl methacrylate. The additional collimator is an effective method for the reduction of the neutron ambient dose equivalent near the isocenter.

Determination of k Q factors for cylindrical and plane-parallel ionization chambers in a scanned carbon ion beam by means of cross calibration.

The accuracy in the dosimetry of therapeutically used carbon ion beams is predominantly affected by the large uncertainty of the so-called k Q factor of the ionization chamber used for the measurements. Due to a lack of experimental data, the k Q factor of ionization chambers in carbon ion beams is still derived by calculation, and, for instance, a standard uncertainty of about 3% is given for k Q factors tabulated in the TRS-398 dosimetric protocol. Recently, k Q factors for two Farmer-type ionization chambers have been determined experimentally in the entrance channel of 429 MeV/u carbon ions, achieving about a threefold reduction of the uncertainty. To further improve the data basis on experimental k Q factors with low uncertainties, k Q factors for the same irradiation condition have now been determined for eight different cylindrical ionization chambers (NE2571, FC65-P, FC23-C, CC25, CC13, TM30010, TM30011, TM30012) and three different plane-parallel ionization chambers (PPC-40, PPC-05, TM34001) by means of a cross-calibration procedure. Generally, standard measurement uncertainties of 1.1% could be achieved. Deviations of less than 1.2% were found between the experimental and the tabulated k Q values. Moreover, the consideration of the experimental values with their smaller uncertainties in updated versions of the dosimetric protocols might enable a substantial reduction of the uncertainties in the dosimetry of carbon ion beams.

Opportunistic dose amplification for proton and carbon ion therapy via capture of internally generated thermal neutrons.

This paper presents Neutron Capture Enhanced Particle Therapy (NCEPT), a method for enhancing the radiation dose delivered to a tumour relative to surrounding healthy tissues during proton and carbon ion therapy by capturing thermal neutrons produced inside the treatment volume during irradiation. NCEPT utilises extant and in-development boron-10 and gadolinium-157-based drugs from the related field of neutron capture therapy. Using Monte Carlo simulations, we demonstrate that a typical proton or carbon ion therapy treatment plan generates an approximately uniform thermal neutron field within the target volume, centred around the beam path. The tissue concentrations of neutron capture agents required to obtain an arbitrary 10% increase in biological effective dose are estimated for realistic treatment plans, and compared to concentrations previously reported in the literature. We conclude that the proposed method is theoretically feasible, and can provide a worthwhile improvement in the dose delivered to the tumour relative to healthy tissue with readily achievable concentrations of neutron capture enhancement drugs.

Clinical trials involving carbon-ion radiation therapy and the path forward.

To describe the international landscape of clinical trials in carbon-ion radiotherapy (CIRT), the authors reviewed the current status of 63 ongoing clinical trials (median, 47 participants) involving CIRT identified from the US clinicaltrials.gov trial registry and the World Health Organization International Clinical Trials Platform Registry. The objectives were to evaluate the potential for these trials to define the role of this modality in the treatment of specific cancer types and identify the major challenges and opportunities to advance this technology. A significant body of literature suggested the potential for advantageous dose distributions and, in preclinical biologic studies, the enhanced effectiveness for CIRT compared with photons and protons. In addition, clinical evidence from phase I/II trials, although limited, indicated the potential for CIRT to improve cancer outcomes. However, current high-level phase III randomized clinical trial evidence does not exist. Although there has been an increase in the number of trials investigating CIRT since 2010, and the number of countries and sites offering CIRT is slowly growing, this progress has excluded other countries. Several recommendations are proposed to study this modality to accelerate progress in the field, including: 1) increasing the number of multinational randomized clinical trials, 2) leveraging the existing CIRT facilities to launch larger multinational trials directed at common cancers combined with high-level quality assurance; and 3) developing more compact and less expensive next-generation treatment systems integrated with radiobiologic research and preclinical testing.

Optimisation of the design of SOI microdosimeters for hadron therapy quality assurance.

Silicon-on-insulator (SOI) microdosimeters offer a promising method for routine quality assurance (QA) for hadron therapy due to their ease of operation and high spatial resolution. However, one complication which has been shown previously is that the traditional use of the mean chord length, [Formula: see text], calculated using Cauchy's formula, for SOI devices in clinical carbon ion fields is not appropriate due to the strong directionality of the radiation field. In a previous study, we demonstrated that the mean path length, [Formula: see text], which is the mean path of charged particles in the sensitive volume (SV), is a more appropriate method to obtain microdosimetric quantities and biological relevant values, namely the relative biological effectiveness (RBE) by means of the microdosimetric kinetic model. The previous work, which was limited to mono-energetic [Formula: see text] ion beams typical of heavy ion therapy (HIT), is extended here to investigate the [Formula: see text] in a pristine proton beam as well as for spread out Bragg peaks (SOBP) for both proton and carbon ion clinical beams. In addition, the angular dependence of the SOI device for a number of different SV designs is also investigated to quantify the effects which the alignment has on the [Formula: see text]. It is demonstrated that the [Formula: see text] can be accurately estimated along the depth of a pristine or SOBP using the energy deposition spectra for both proton and [Formula: see text] ion beams. This observation allows a quick and accurate estimation of the [Formula: see text] for experimental use.