Harald Paganetti

Range uncertainties in proton therapy and the role of Monte Carlo simulations

The main advantages of proton therapy are the reduced total energy deposited in the patient as compared to photon techniques and the finite range of the proton beam. The latter adds an additional degree of freedom to treatment planning. The range in tissue is associated with considerable uncertainties caused by imaging, patient setup, beam delivery and dose calculation. Reducing the uncertainties would allow a reduction of the treatment volume and thus allow a better utilization of the advantages of protons. This paper summarizes the role of Monte Carlo simulations when aiming at a reduction of range uncertainties in proton therapy. Differences in dose calculation when comparing Monte Carlo with analytical algorithms are analyzed as well as range uncertainties due to material constants and CT conversion. Range uncertainties due to biological effects and the role of Monte Carlo for in vivo range verification are discussed. Furthermore, the current range uncertainty recipes used at several proton therapy facilities are revisited. We conclude that a significant impact of Monte Carlo dose calculation can be expected in complex geometries where local range uncertainties due to multiple Coulomb scattering will reduce the accuracy of analytical algorithms. In these cases Monte Carlo techniques might reduce the range uncertainty by several mm.

A review of dosimetry studies on external-beam radiation treatment with respect to second cancer induction

It has been long known that patients treated with ionizing radiation carry a risk of developing a second cancer in their lifetimes. Factors contributing to the recently renewed concern about the second cancer include improved cancer survival rate, younger patient population as well as emerging treatment modalities such as intensity-modulated radiation treatment (IMRT) and proton therapy that can potentially elevate secondary exposures to healthy tissues distant from the target volume. In the past 30 years, external-beam treatment technologies have evolved significantly, and a large amount of data exist but appear to be difficult to comprehend and compare. This review article aims to provide readers with an understanding of the principles and methods related to scattered doses in radiation therapy by summarizing a large collection of dosimetry and clinical studies. Basic concepts and terminology are introduced at the beginning. That is followed by a comprehensive review of dosimetry studies for external-beam treatment modalities including classical radiation therapy, 3D-conformal x-ray therapy, intensity-modulated x-ray therapy (IMRT and tomotherapy) and proton therapy. Selected clinical data on second cancer induction among radiotherapy patients are also covered. Problems in past studies and controversial issues are discussed. The needs for future studies are presented at the end.

Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer

Proton therapy treatments are based on a proton RBE (relative biological effectiveness) relative to high-energy photons of 1.1. The use of this generic, spatially invariant RBE within tumors and normal tissues disregards the evidence that proton RBE varies with linear energy transfer (LET), physiological and biological factors, and clinical endpoint. Based on the available experimental data from published literature, this review analyzes relationships of RBE with dose, biological endpoint and physical properties of proton beams. The review distinguishes between endpoints relevant for tumor control probability and those potentially relevant for normal tissue complication. Numerous endpoints and experiments on sub-cellular damage and repair effects are discussed. Despite the large amount of data, considerable uncertainties in proton RBE values remain. As an average RBE for cell survival in the center of a typical spread-out Bragg peak (SOBP), the data support a value of ~1.15 at 2 Gy/fraction. The proton RBE increases with increasing LETd and thus with depth in an SOBP from ~1.1 in the entrance region, to ~1.15 in the center, ~1.35 at the distal edge and ~1.7 in the distal fall-off (when averaged over all cell lines, which may not be clinically representative). For small modulation widths the values could be increased. Furthermore, there is a trend of an increase in RBE as (α/β)x decreases. In most cases the RBE also increases with decreasing dose, specifically for systems with low (α/β)x. Data on RBE for endpoints other than clonogenic cell survival are too diverse to allow general statements other than that the RBE is, on average, in line with a value of ~1.1. This review can serve as a source for defining input parameters for applying or refining biophysical models and to identify endpoints where additional radiobiological data are needed in order to reduce the uncertainties to clinically acceptable levels.

Secondary Carcinogenesis in Patients Treated with Radiation: A Review of Data on Radiation-Induced Cancers in Human, Non-human Primate, Canine and Rodent Subjects

Abstract Suit, H., Goldberg, S., Niemierko, A., Ancukiewicz, M., Hall, E., Goitein, M., Wong, W. and Paganetti, H. Secondary Carcinogenesis in Patients Treated with Radiation: A Review of Data on Radiation-Induced Cancers in Human, Non-human Primate, Canine and Rodent Subjects. Radiat. Res. 167, 12–42 (2007). Concern for risk of radiation-induced cancer is growing with the increasing number of cancer patients surviving long term. This study examined data on radiation transformation of mammalian cells in vitro and on the risk of an increased cancer incidence after irradiation of mice, dogs, monkeys, atomic bomb survivors, occupationally exposed persons, and patients treated with radiation. Transformation of cells lines in vitro increased linearly with dose from ∼1 to ∼4–5 Gy. At <0.1 Gy, transformation was not increased in all studies. Dose–response relationships for cancer incidence varied with mouse strain, gender and tissue/organ. Risk of cancer in Macaca mulatta was not raised at 0.25–2.8 Gy. From the atomic bomb survivor study, risk is accepted as increasing linearly to 2 Sv for establishing exposure standards. In irradiated patients, risk of cancer increased significantly from 1 to 45 Gy (a low to a high dose level) for stomach and pancreas, but not for bladder and rectum (1–60 Gy) or kidney (1–15 Gy). Risk for several organs/tissues increased substantially at doses far above 2 Gy. There is great heterogeneity in risk of radiation-associated cancer between species, strains of a species, and organs within a species. At present, the heterogeneity between and within patient populations of virtually every parameter considered in risk estimation results in substantial uncertainty in quantification of a general risk factor. An implication of this review is that reduced risks of secondary cancer should be achieved by any technique that achieved a dose reduction down to −0.1 Gy, i.e. dose to tissues distant from the target. The proportionate gain should be greatest for dose decrement to less than 2 Gy.

TOPAS: An innovative proton Monte Carlo platform for research and clinical applications

PURPOSE While Monte Carlo particle transport has proven useful in many areas (treatment head design, dose calculation, shielding design, and imaging studies) and has been particularly important for proton therapy (due to the conformal dose distributions and a finite beam range in the patient), the available general purpose Monte Carlo codes in proton therapy have been overly complex for most clinical medical physicists. The learning process has large costs not only in time but also in reliability. To address this issue, we developed an innovative proton Monte Carlo platform and tested the tool in a variety of proton therapy applications. METHODS Our approach was to take one of the already-established general purpose Monte Carlo codes and wrap and extend it to create a specialized user-friendly tool for proton therapy. The resulting tool, TOol for PArticle Simulation (TOPAS), should make Monte Carlo simulation more readily available for research and clinical physicists. TOPAS can model a passive scattering or scanning beam treatment head, model a patient geometry based on computed tomography (CT) images, score dose, fluence, etc., save and restart a phase space, provides advanced graphics, and is fully four-dimensional (4D) to handle variations in beam delivery and patient geometry during treatment. A custom-designed TOPAS parameter control system was placed at the heart of the code to meet requirements for ease of use, reliability, and repeatability without sacrificing flexibility. RESULTS We built and tested the TOPAS code. We have shown that the TOPAS parameter system provides easy yet flexible control over all key simulation areas such as geometry setup, particle source setup, scoring setup, etc. Through design consistency, we have insured that user experience gained in configuring one component, scorer or filter applies equally well to configuring any other component, scorer or filter. We have incorporated key lessons from safety management, proactively removing possible sources of user error such as line-ordering mistakes. We have modeled proton therapy treatment examples including the UCSF eye treatment head, the MGH stereotactic alignment in radiosurgery treatment head and the MGH gantry treatment heads in passive scattering and scanning modes, and we have demonstrated dose calculation based on patient-specific CT data. Initial validation results show agreement with measured data and demonstrate the capabilities of TOPAS in simulating beam delivery in 3D and 4D. CONCLUSIONS We have demonstrated TOPAS accuracy and usability in a variety of proton therapy setups. As we are preparing to make this tool freely available for researchers in medical physics, we anticipate widespread use of this tool in the growing proton therapy community.

Accurate Monte Carlo simulations for nozzle design, commissioning and quality assurance for a proton radiation therapy facility

Monte Carlo dosimetry calculations are essential methods in radiation therapy. To take full advantage of this tool, the beam delivery system has to be simulated in detail and the initial beam parameters have to be known accurately. The modeling of the beam delivery system itself opens various areas where Monte Carlo calculations prove extremely helpful, such as for design and commissioning of a therapy facility as well as for quality assurance verification. The gantry treatment nozzles at the Northeast Proton Therapy Center (NPTC) at Massachusetts General Hospital (MGH) were modeled in detail using the GEANT4.5.2 Monte Carlo code. For this purpose, various novel solutions for simulating irregular shaped objects in the beam path, like contoured scatterers, patient apertures or patient compensators, were found. The four-dimensional, in time and space, simulation of moving parts, such as the modulator wheel, was implemented. Further, the appropriate physics models and cross sections for proton therapy applications were defined. We present comparisons between measured data and simulations. These show that by modeling the treatment nozzle with millimeter accuracy, it is possible to reproduce measured dose distributions with an accuracy in range and modulation width, in the case of a spread-out Bragg peak (SOBP), of better than 1 mm. The excellent agreement demonstrates that the simulations can even be used to generate beam data for commissioning treatment planning systems. The Monte Carlo nozzle model was used to study mechanical optimization in terms of scattered radiation and secondary radiation in the design of the nozzles. We present simulations on the neutron background. Further, the Monte Carlo calculations supported commissioning efforts in understanding the sensitivity of beam characteristics and how these influence the dose delivered. We present the sensitivity of dose distributions in water with respect to various beam parameters and geometrical misalignments. This allows the definition of tolerances for quality assurance and the design of quality assurance procedures.

Nuclear interactions in proton therapy: dose and relative biological effect distributions originating from primary and secondary particles

The dose distribution delivered in charged particle therapy is due to both primary and secondary particles. The secondaries, originating from non-elastic nuclear interactions, are of interest for three reasons. First, if fast Monte Carlo treatment planning is envisaged, the question arises whether all nuclear interaction products deliver a significant contribution to the total dose and, hence, need to be tracked. Second, there could be an enhanced relative biological effectiveness (RBE) due to low energy and/or heavy secondaries. Third, neutrons originating from nuclear interactions may deliver dose outside the target volume. The particle yield from different nuclear interaction channels as a function of proton penetration depth was studied theoretically for different proton beam energies. Three-dimensional dose distributions from primary and secondary particles were simulated for an unmodulated 160 MeV proton beam with and without including a slice of bone material and for a spread-out Bragg peak (SOBP) of 3 x 3 x 3 cm3 in water. Secondary protons deliver up to 10% of the total dose proximal to the Bragg peak of an unmodulated proton beam and they affect the flatness of the SOBP. Furthermore, they cause a dose build-up due to forward emission of secondary particles from nuclear interactions. The dose deposited by d, t, 3He and alpha-particles was found to contribute less than 0.1% of the total dose. The dose distal to the target volume caused by liberated neutrons was studied for four proton beam energies in the range of 160-250 MeV and found to be below 0.05% (2 cm distal to SOBP) of the prescribed target dose for a 3 x 3 x 3 cm3 target. RBE values relative to 60Co were calculated proximal to and within the SOBP. The RBE proximal to the Bragg peak (100% dose) is influenced by secondary particles (mainly protons and a-particles) with a strong dose dependency resulting in RBE values up to 1.2 (2 Gy; inactivation of V79). Depending on the endpoint considered, secondary particles cause a shift in RBE by up to 8% at 2 Gy. In contrast, the RBE in the Bragg peak is almost entirely determined by primary protons due to a decreasing secondary particle fluence with depth. RBE values up to 1.3 (2 Gy; inactivation of V79) at 1 cm distal to the Bragg peak maximum were found. The inactivations of human skin fibroblasts and mouse lymphoma cells were also analysed and reveal a substantial tissue dependency of the total RBE. The outcome of this study shows that elevated RBE values occur not only at the distal edge of the SOBP. Although the variations are modest, and in most cases might have no observable clinical effect, they might have to be considered in certain treatment situations. The biological effect downstream of the target caused by neutrons was analysed using a radiation quality factor of 10. The biological dose was found to be below 0.5% of the prescribed target dose (for a 3 x 3 x 3 cm3 SOBP) but depends on the size of the SOBP. This dose should not be significant with respect to late effects, e.g. cancer induction.

Proton vs carbon ion beams in the definitive radiation treatment of cancer patients.

BACKGROUND AND PURPOSE Relative to X-ray beams, proton [(1)H] and carbon ion [(12)C] beams provide superior distributions due primarily to their finite range. The principal differences are LET, low for (1)H and high for (12)C, and a narrower penumbra of (12)C beams. Were (12)C to yield a higher TCP for a defined NTCP than (1)H therapy, would LET, fractionation or penumbra width be the basis? METHODS Critical factors of physics, radiation biology of (1)H and (12)C ion beams, neutron therapy and selected reports of TCP and NTCP from (1)H and (12)C irradiation of nine tumor categories are reviewed. RESULTS Outcome results are based on low dose per fraction (1)H and high dose per fraction (12)C therapy. Assessment of the role of LET and dose distribution vs dose fractionation is not now feasible. Available data indicate that TCP increases with BED with (1)H and (12)C TCPs overlaps. Frequencies of GIII NTCPs were higher after (1)H than (12)C treatment. CONCLUSIONS Assessment of the efficacy of (1)H vs(12)C therapy is not feasible, principally due to the dose fractionation differences. Further, there is no accepted policy for defining the CTV-GTV margin nor definition of TCP. Overlaps of (1)H and (12)C ion TCPs at defined BED ranges indicate that TCPs are determined in large measure by dose, BED. Late GIII NTCP was higher in (1)H than (12)C patients, indicating LET as a significant factor. We recommend trials of (1)H vs(12)C with one variable, i.e. LET. The resultant TCP vs NTCP relationship will indicate which beam yields higher TCP for a specified NTCP at a defined dose fractionation.

Proton Beams to Replace Photon Beams in Radical Dose Treatments

With proton beam radiation therapy a smaller volume of normal tissues is irradiated at high dose levels for most anatomic sites than is feasible with any photon technique. This is due to the Laws of Physics, which determine the absorption of energy from photons and protons. In other words, the dose from a photon beam decreases exponentially with depth in the irradiated material. In contrast, protons have a finite range and that range is energy dependent. Accordingly, by appropriate distribution of proton energies, the dose can be uniform across the target and essentially zero deep to the target and the atomic composition of the irradiated material. The dose proximal to the target is lower compared with that in photon techniques, for all except superficial targets. This resultant closer approximation of the planning treatment volume (PTV) to the CTV/GTV (grossly evident tumor volume/subclinical tumor extensions) constitutes a clinical gain by definition; i.e. a smaller treatment volume that covers the target three dimensionally for the entirety of each treatment session provides a clinical advantage. Several illustrative clinical dose distributions are presented and the clinical outcome results are reviewed briefly. An important technical advance will be the use of intensity modulated proton radiation therapy, which achieves contouring of the proximal edge of the SOBP (spread out bragg peak) as well as the distal edge. This technique uses pencil beam scanning. To permit further progressive reductions of the PTV, 4-D treatment planning and delivery is required. The fourth dimension is time, as the position and contours of the tumor and the adjacent critical normal tissues are not constant. A potentially valuable new method for assessing the clinical merits of each of a large number of treatment plans is the evaluation of multidimensional plots of the complication probabilities for each of ‘n’ critical normal tissues/structures for a specified tumor control probability. The cost of proton therapy compared with that of very high technology photon therapy is estimated and evaluated. The differential is estimated to be ≈1.5 provided there were to be no charge for the original facility and that there were sufficient patients for operating on an extended schedule (6–7 days of 14–16 h) with ≥ two gantries and one fixed horizontal beam.

Simulation of organ-specific patient effective dose due to secondary neutrons in proton radiation treatment.

Cancer patients undergoing radiation treatment are exposed to high doses to the target (tumour), intermediate doses to adjacent tissues and low doses from scattered radiation to all parts of the body. In the case of proton therapy, secondary neutrons generated in the accelerator head and inside the patient reach many areas in the patient body. Due to the improved efficacy of management of cancer patients, the number of long term survivors post-radiation treatment is increasing substantially. This results in concern about the risk of radiation-induced cancer appearing at late post-treatment times. This paper presents a case study to determine the effective dose from secondary neutrons in patients undergoing proton treatment. A whole-body patient model, VIP-Man, was employed as the patient model. The geometry dataset generated from studies made on VIP-Man was implemented into the GEANT4 Monte Carlo code. Two proton treatment plans for tumours in the lung and paranasal sinus were simulated. The organ doses and ICRP-60 radiation and tissue weighting factors were used to calculate the effective dose. Results show whole body effective doses for the two proton plans of 0.162 Sv and 0.0266 Sv, respectively, to which the major contributor is due to neutrons from the proton treatment nozzle. There is a substantial difference among organs depending on the treatment site.