Ion beam radiobiology and cancer: Time to update ourselves

High-energy protons and carbon ions exhibit an inverse dose profile allowing for increased energy deposition with penetration depth. Additionally, heavier ions like carbon beams have the advantage of a markedly increased biological effectiveness characterized by enhanced ionization density in the individual tracks of the heavy particles, where DNA damage becomes clustered and therefore more difficult to repair, but is restricted to the end of their range. These superior biophysical and biological profiles of particle beams over conventional radiotherapy permit more precise dose localization and make them highly attractive for treating anatomically complex and radioresistant malignant tumors but without increasing the severe side effects in the normal tissue. More than half a century since Wilson proposed their use in cancer therapy, the effects of particle beams have been extensively investigated and the biological complexity of particle beam irradiation begins to unfold itself. The goal of this review is to provide an as comprehensive and up-to-date summary as possible of the different radiobiological aspects of particle beams for effective application in cancer treatment.     

Heavy ion radiography and tomography

In the latest years, radiation therapy with ion beams has been rapidly spreading worldwide. This is mainly due to the favourable interaction properties of ion beams with matter, offering the possibility of more conformal dose deposition with superior sparing of healthy tissue in comparison to conventional photon radiation. Moreover, heavier ions like carbon offer a selective increase of biological effectiveness which can be advantageous for the treatment of tumours being resistant to sparsely ionizing radiation. However, full clinical exploitation of the advantages offered by ion beams is still challenged by the lack of exact knowledge of the beam range within the patient. Therefore, increasing research efforts are being devoted to the goal of reducing range uncertainties in ion beam therapy. In this context, ion transmission imaging is being recognized as a promising modality capable of providing valuable pre- (or even “in-between”) treatment information on the patient-specific stopping properties for indirect in-vivo range verification and low dose image guidance at the treatment site. The more recent availability of energetic ion beam sources at therapeutic treatment facilities, in combination with the advances in detector technologies and computational power, have considerably renewed the interest in this imaging technique. Nowadays, many research efforts are being devoted to the development of novel detector prototypes for heavy ion radiography and tomography, as will be reviewed in this contribution.     

Radiation dose detection by imaging response in biological targets

Imaging was one of the earliest techniques to quantify radiation dose. While films and active fluorescent detectors are still commonly used in physical dosimetry, biological imaging is emerging as a new method to visualize and quantify radiation dose in biological targets. Methods for biological imaging are normally based on molecular fluorescent probes, labeling chromatin-conjugated molecules or specific repair proteins. Examples are chromatin-binding coumarin compounds, which become fluorescent under irradiation, or the H2AX histone, which is rapidly phosphorylated at sites of DNA double-strand breaks and can be visualized by immunostaining. Many other DNA repair proteins can be expressed with fluorescent targets, such as green fluorescent protein, thus becoming visible for dose estimation in vivo. The possibility to visualize radiation damage in living biological targets is particularly important for repair kinetic studies, for estimating individual radiation response, and for remote control of living samples exposed to radiation, for instance in robotic space missions. In vivo dose monitoring in particle therapy exploits the production of positron emitters by nuclear interaction of the incident beam in the patient's body. Positron emission tomography (PET) can then be used to visualize and quantify the particle dose in the patient, and it can in principle also be used for radiotherapy with high-energy X rays. Alternatively, prompt γ rays or scattered secondary particles are under study for in vivo dosimetry of ion beams in therapy.     

Prompt-gamma emission in GEANT4 revisited and confronted with experiment

PurposeThe field of online monitoring of the beam range is one of the most researched topics in proton therapy over the last decade. The development of detectors that can be used for beam range verification under clinical conditions is a challenging task. One promising possible solution are modalities that record prompt-gamma radiation produced by the interactions of the proton beam with the target tissue. A good understanding of the energy spectra of the prompt gammas and the yields in certain energy regions is crucial for a successful design of a prompt-gamma detector. Monte-Carlo simulations are an important tool in development and testing of detector concepts, thus the proper modelling of the prompt-gamma emission in those simulations are of vital importance. In this paper, we confront a number of GEANT4 simulations of prompt-gamma emission, performed with different versions of the package and different physics lists, with experimental data obtained from a phantom irradiation with proton beams of four different energies in the range 70–230 MeV.MethodsThe comparison is made on different levels: features of the prompt-gamma energy spectrum, gamma emission depth profiles for discrete transitions and the width of the distal fall-off in those profiles.ResultsThe best agreement between the measurements and the simulations is found for the GEANT4 version 10.4.2 and the reference physics list QGSP_BIC_HP.ConclusionsModifications to prompt-gamma emission modelling in higher versions of the software increase the discrepancy between the simulation results and the experimental data.     

Transversal dose profile reconstruction for clinical proton beams: A detectors inter-comparison

PurposeThe main purpose of this work is the inter-comparison between different devices devoted to the transversal dose profile recostruction for daily QA tests in proton therapy.MethodsThe results obtained with the EBT3 radiochromic films, used as a reference, and other common quality control devices, have been compared with those obtained with a beam profiling system developed at the “Laboratori Nazionali del Sud” of Italian Institute for Nuclear Physics (INFN-LNS, Catania, Italy). It consists of a plastic scintillator screen (thickness 1 mm), mounted perpendicularly to the beam axis and coupled with a highly sensitive CCD detector in a light-tight box.Results and conclusionThe tests, carried out both at the INFN-LNS and Trento Proton Therapy Center facilities, show, in general, a good agreement between the different detectors. The beam profiling system, in particular, appears to be a promising quality control device for 2-D relative dosimetry, because of its linear response in a dose rate range useful for proton therapy treatments, its high spatial resolution and its short acquisition and processing time.     

Test of a pion range monitor using the radiative capture of pions on protonsπ −p→nγ

Summary The present paper demonstrates that neutron-photon pairs from radiative capture of stopped pions on chemically bound protons can be used to measure the range of negative pions within phantoms or a patient. Experimental results are given for a polyethylene and a water target of realistic size as well as for a Rando phantom. Monte-Carlo calculations were carried out in order to study the influence of various sizes of treatment volumes, detector geometries and neutron scattering within the targets upon the accuracy of the pion range determination. The results reveal clearly that a pion range monitor for the control of therapy plans and for actual patient irradiations can be designed according to the proposed principle. The absorbed dose required for a measurement is of the order of 0.1 Gy for a single pion beam if one aims at an accuracy of range determination of a few millimeters.     

COTS Silicon diodes as radiation detectors in proton and heavy charged particle radiotherapy 1

Modern radiotherapy facilities for cancer treatment such as the Heavy Ion Therapy Center (HIT) in Heidelberg, Germany, allow for sub-millimeter precision in dose deposition. For measurement of such dose distributions and characterization of the particle beams, detectors with high spatial resolution are necessary. Here, a detector based on the commercially available COTS photodiode (BPW-34) is presented. When applied in hadronic beams of protons and carbon ions, the detector reproduces dose distribution well, but its response decreases rapidly by radiation damage. However, for MeV photon beams, the detector exhibits a similar behavior as found in diode detectors usually applied in radiotherapy.     

Real-time monitoring of the Bragg-peak position in ion therapy by means of single photon detection

For real-time monitoring of the longitudinal position of the Bragg-peak during an ion therapy treatment, a novel non-invasive technique has been recently proposed that exploits the detection of prompt γ-rays issued from nuclear fragmentation. Two series of experiments have been performed at the GANIL and GSI facilities with 95 and 305 MeV/u ¹²C⁶⁺ ion beams stopped in PMMA and water phantoms. In both experiments, a clear correlation was obtained between the carbon ion range and the prompt photon profile. Additionally, an extensive study has been performed to investigate whether a prompt neutron component may be correlated with the carbon ion range. No such correlation was found. The present paper demonstrates that a collimated set-up can be used to detect single photons by means of time-of-flight measurements, at those high energies typical for ion therapy. Moreover, the applicability of the technique both at cyclotron and at synchrotron facilities is shown. It is concluded that the detected photon count rates provide sufficiently high statistics to allow real-time control of the longitudinal position of the Bragg-peak under clinical conditions.     

Tumor therapy and track structure

The elevated relative biological effectiveness (RBE) of heavy ions like carbon is the main reason for their use in radiotherapy and is due to the microscopic distribution of dose inside each particle track. High local doses produce lesions that are expected to have a diminished possibility of repair. Thus, RBE depends on track structure and on the biological repair capacity of the tissue that is affected by the irradiation. For tumor treatment planning with heavy ions, the beam quality and the tissue sensitivity have to be taken into account. Using the dependence of radial dose distribution on particle energy and atomic number on the physical side and x-ray dose response for the repair capacity on the biological side, the response to particle irradiation can be calculated in the local effect model (LEM) and used for treatment planning. This article traces the route from electron emission as the basis of track structure to the RBE calculation and the application in treatment planning. Received: 21 April 1999 / Accepted in revised form: 1 September 1999     

Motion mitigation in scanned ion beam therapy through 4D-optimization

The treatment of moving tumors remains challenging, especially with scanned ion beam therapy due to interplay effects and the strong range dependence. This is especially true in the context of radiosurgery with high dose delivered in few or single fractions. Inverse treatment planning on the entire 4D-CT may result in conformal plans inherently adapted to the moving anatomy of the patient. Existing studies on this topic for photon therapy are reviewed, but arguably the benefits for ion beam therapy can be even greater. Compared to the main conformal mitigation technique of beam tracking, 4D-optimization permits a) easier, offline handling of range changes, b) handling of complex motion patterns, and c) improved dose shaping capabilities outside of the target.Different approaches for 4D-optimization in scanned ion beam therapy are proposed and compared, together with delivery methods that provide the necessary synchronization between irradiation and detected patient motion. Potential solutions for the improvement of robustness in 4D-optimization are discussed. A method for delivery of homogenous doses to each motion phase is presented that might be a potential solution for robust conformal dose delivery for future clinical use.In an exemplary lung cancer patient case with a large motion amplitude, 4D-optimization resulted in conformal dose coverage while beam tracking did not.In conclusion, different strategies of 4D-optimization could provide increased OAR sparing and highly conformal dose delivery for targets with complex motion patterns and large amplitudes.     

Computation of cell survival in heavy ion beams for therapy

A simplified method for the calculation of mammalian cell survival after charged particle irradiation is presented that is based on the track structure model of Scholz and Kraft [1, 2]. Utilizing a modified linear-quadratic relation for the x-ray survival curve, one finds that the model yields linear-quadratic relations also for heavy ion irradiation. If survival is calculated as a function of specific energy, z, in the cell nucleus – thus reducing the stochastic fluctuations of energy deposition – the increase in slope of the survival curve and therefore the coefficient β _z can be estimated with sufficient accuracy from the initial slope, α _z . This permits the tabulation of the coefficients α _z for the particle types and energies of interest, and subsequent fast calculations of survival levels at any point in a mixed particle beam. The complexity of the calculations can thereby be reduced in a wide range of applications, which permits the rapid calculations that are required for treatment planning in heavy ion therapy. The validity of the modified computations is assessed by the comparison with explicit calculations in terms of the original model and with experimental results for track-segment conditions. The model is then used to analyze the influence of beam fragmentation on the biological effect of charged particle beams penetrating to different depths in tissue. In addition, cell-survival rates after neutron irradiation are computed from the slowing-down spectra of secondary charged particles and are compared to experimental observations. Received: 10 August 1996 / Accepted in revised form: 16 December 1996     

A novel pencil beam model for carbon-ion dose calculation derived from Monte Carlo simulations

An accurate kernel model is of vital importance for pencil-beam dose algorithm in charged particle therapy using precise spot-scanning beam delivery, in which an accurate depiction of the low dose envelope is especially crucial. Based on the Monte Carlo method, we investigated the dose contribution of secondary particles to the total dose and proposed a novel beam model to depict the lateral dose distribution of carbon-ion pencil beam in water. We demonstrated that the low dose envelope in single-spot profiles in water could be adequately modelled with the addition of a logistic distribution to a double Gaussian one, which was verified in both single carbon-ion pencil beam and superposed fields of different sizes with multiple pencil beams. Its superiority was mainly manifested at medium depths especially for high-energy beams with small fields compared with single, double and triple Gaussian models, where the secondary particles influenced the total dose considerably. The double Gaussian-logistic model could reduce the deviations from 4.1%, 1.7% to 0.3% in the plateau and peak regions, and from 19.2%, 4.9% to 1.2% in the tail region compared for the field size factor (FSF) calculations of 344 MeV/u carbon-ion pencil beam with the single and double Gaussian models. Compared with the triple Gaussian one, our newly-proposed model was on a par with it, even better than it in the plateau and peak regions. Thus our work will be helpful for improving the dose calculation accuracy for carbon-ion therapy.     

Quality assurance of carbon ion and proton beams: A feasibility study for using the 2D MatriXX detector

PurposeThe quality assurance (QA) procedures in particle therapy centers with active beam scanning make extensive use of films, which do not provide immediate results. The purpose of this work is to verify whether the 2D MatriXX detector by IBA Dosimetry has enough sensitivity to replace films in some of the measurements.MethodsMatriXX is a commercial detector composed of 32 × 32 parallel plate ionization chambers designed for pre-treatment dose verification in conventional radiation therapy. The detector and GAFCHROMIC® films were exposed simultaneously to a 131.44 MeV proton and a 221.45 MeV/u carbon-ion therapeutic beam at the CNAO therapy center of Pavia – Italy, and the results were analyzed and compared.ResultsThe sensitivity MatriXX on the beam position, beam width and field flatness was investigated. For the first two quantities, a method for correcting systematic uncertainties, dependent on the beam size, was developed allowing to achieve a position resolution equal to 230 μm for carbon ions and less than 100 μm for protons. The beam size and the field flatness measured using MatriXX were compared with the same quantities measured with the irradiated film, showing a good agreement.ConclusionsThe results indicate that a 2D detector such as MatriXX can be used to measure several parameters of a scanned ion beam quickly and precisely and suggest that the QA would benefit from a new protocol where the MatriXX detector is added to the existing systems.     

Evaluations of a flat-panel based compact daily quality assurance device for proton pencil beam scanning (PBS) system

PurposeTo evaluate the flat-panel detector quenching effect and clinical usability of a flat-panel based compact QA device for PBS daily constancy measurements.Materials & MethodThe QA device, named Sphinx Compact, is composed of a 20x20 cm² flat-panel imager mounted on a portable frame with removable plastic modules for constancy checks of proton energy (100 MeV, 150 MeV, 200 MeV), Spread-Out-Bragg-Peak (SOBP) profile, and machine output. The potential quenching effect of the flat-panel detector was evaluated. Daily PBS QA tests of X-ray/proton isocenter coincidence, the constancy of proton spot position and sigma as well as the energy of pristine proton beam, and the flatness of SOBP proton beam through the 'transformed' profile were performed and analyzed. Furthermore, the sensitivity of detecting energy changes of pristine proton beam was also evaluated.ResultsThe quenching effect was observed at depths near the pristine peak regions. The flat-panel measured range of the distal 80% is within 0.9 mm to the defined ranges of the delivered proton beams. X-ray/proton isocenter coincidence tests demonstrated maximum mismatch of 0.3 mm between the two isocenters. The device can detect 0.1 mm change of spot position and 0.1 MeV energy changes of pristine proton beams. The measured transformed SOBP beam profile through the wedge module rendered as flat.ConclusionsEven though the flat-panel detector exhibited quenching effect at the Bragg peak region, the proton range can still be accurately measured. The device can fulfill the requirements of the daily QA tests recommended by the AAPM TG224 Report.     

Evaluation of the effects of implementing a diode transmission device into the clinical workflow

PurposeThis work investigated effects of implementing the Delta⁴ Discover diode transmission detector into the clinical workflow.MethodsPDD and profile scans were completed with and without the Discover for a number of photon beam energies. Transmission factors were determined for all beam energies and included in Eclipse TPS to account for the attenuation of the Discover. A variety of IMRT plans were delivered to a Delta⁴ Phantom+ with and without the Discover to evaluate the Discover’s effects on IMRT QA. An imaging QA phantom was used to assess the detector’s effects on MV image quality. OSLDs placed on the Phantom+ were used to determine the detector’s effects on superficial dose.ResultsThe largest effect on PDDs after d_max was 0.5%. The largest change in beam profile symmetry and flatness was 0.2% and 0.1%, respectively. An average difference in gamma passing rates (2%/2 mm) of 0.2% was observed between plans that did not include the Discover in the measurement and calculation to plans that did include the Discover in the measurement and calculation. The Discover did not significantly change the MV image quality, and the largest observed increase in the relative superficial dose when the Discover was present was 1%.ConclusionsThe effects the Discover has on the linac beam were found to be minimal. The device can be implemented into the clinic without the need to alter the TPS beam modeling, other than accounting for the device’s attenuation. However, a careful workflow review to implement the Discover should be completed.     

Dosimetric characterization of a small-scale (Zn,Cd)S:Ag inorganic scintillating detector to be used in radiotherapy

PurposeIn modern radiotherapy techniques, to ensure an accurate beam modeling process, dosimeters with high accuracy and spatial resolution are required. Therefore, this work aims to propose a simple, robust, and a small-scale fiber-integrated X-ray inorganic detector and investigate the dosimetric characteristics used in radiotherapy.MethodsThe detector is based on red-emitting silver-activated zinc-cadmium sulfide (Zn,Cd)S:Ag nanoclusters and the proposed system has been tested under 6 MV photons with standard dose rate used in the patient treatment protocol. The article presents the performances of the detector in terms of dose linearity, repeatability, reproducibility, percentage depth dose distribution, and field output factor. A comparative study is shown using a microdiamond dosimeter and considering data from recent literature.ResultsWe accurately measured a small field beam profile of 0.5 × 0.5 cm² at a spatial resolution of 100 µm using a LINAC system. The dose linearity at 400 MU/min has shown less than 0.53% and 1.10% deviations from perfect linearity for the regular and smallest field. Percentage depth dose measurement agrees with microdiamond measurements within 1.30% and 2.94%, respectively for regular to small field beams. Besides, the stem effect analysis shows a negligible contribution in the measurements for fields smaller than 3x3 cm². This study highlights the drastic decrease of the convolution effect using a point-like detector, especially in small dimension beam characterization. Field output factor has shown a good agreement while comparing it with the microdiamond dosimeter.ConclusionAll the results presented here anticipated that the developed detector can accurately measure delivered dose to the region of interest, claim accurate depth dose distribution hence it can be a suitable candidate for beam characterization and quality assurance of LINAC system.     

Heavy charged particle radiobiology: using enhanced biological effectiveness and improved beam focusing to advance cancer therapy

Ionizing radiation causes many types of DNA damage, including base damage and single- and double-strand breaks. Photons, including X-rays and γ-rays, are the most widely used type of ionizing radiation in radiobiology experiments, and in radiation cancer therapy. Charged particles, including protons and carbon ions, are seeing increased use as an alternative therapeutic modality. Although the facilities needed to produce high energy charged particle beams are more costly than photon facilities, particle therapy has shown improved cancer survival rates, reflecting more highly focused dose distributions and more severe DNA damage to tumor cells. Despite early successes of charged particle radiotherapy, there is room for further improvement, and much remains to be learned about normal and cancer cell responses to charged particle radiation.     

The SiFi-CC project – Feasibility study of a scintillation-fiber-based Compton camera for proton therapy monitoring

One of the big challenges for proton therapy is the development of tools for online monitoring of the beam range, which are suited to operate in clinical conditions and can be included in the clinical practice. A Compton camera based on stacks of heavy scintillating fibers used for prompt-gamma imaging is a promising approach for this task. It provides full, three-dimensional information on the deposited dose distribution while showing a high detection efficiency and rate capability due to its high granularity. The investigation of the rate capability and detection efficiency of such a camera under clinical conditions by means of Geant4 simulations is presented along with the event construction algorithm. The results hint towards a very low pile-up rate in the detector and a relatively high detection efficiency, so that imaging of a single proton beam spot appears to be an achievable goal.     

Clinical gain from improved beam delivery systems

Summary The feasibility of dynamic conformal heavy charged particle radiotherapy has been investigated at UCLBL, and shows high promise of: 1. an improved therapeutic ratio and 2. reduction in the number of treatment portals required for efficient treatment delivery. Assessment of dose to tumor and critical structures for several anatomical sites have been carried out using a normal tissue complication algorithm developed at LBL. For high-LET charged particle treatment delivery, dynamic conformal therapy using a raster scanned beam with variable modulation and multileaf collimator appears to be the optimal technique for treatment delivery.Paper given on the fourth workshop on Heavy Charged Particles in Biology and Medicine GSI, Darmstadt, FRG, September 23–25,1991. Supported in part by NIH-NCI Grant CA19138 and DOE Contract DE-AC03-76SF00098