Out-of-field neutron and leakage photon exposures and the associated risk of second cancers in high-energy photon radiotherapy: current status

Determination and understanding of out-of-field neutron and photon doses in accelerator-based radiotherapy is an important issue since linear accelerators operating at high energies (>10 MV) produce secondary radiations that irradiate parts of the patient's anatomy distal to the target region, potentially resulting in detrimental health effects. This paper provides a compilation of data (technical and clinical) reported in the literature on the measurement and Monte Carlo simulations of peripheral neutron and photon doses produced from high-energy medical linear accelerators and the reported risk and/or incidence of second primary cancer of tissues distal to the target volume. Information in the tables facilitates easier identification of (1) the various methods and measurement techniques used to determine the out-of-field neutron and photon radiations, (2) reported linac-dependent out-of-field doses, and (3) the risk/incidence of second cancers after radiotherapy due to classic and modern treatment methods. Regardless of the measurement technique and type of accelerator, the neutron dose equivalent per unit photon dose ranges from as low as 0.1 mSv/Gy to as high as 20.4 mSv/Gy. This radiation dose potentially contributes to the induction of second primary cancer in normal tissues outside the treated area.     

Out-of-field doses from secondary radiation produced in proton therapy and the associated risk of radiation-induced cancer from a brain tumor treatment

PurposeTo determine out-of-field doses produced in proton pencil beam scanning (PBS) therapy using Monte Carlo simulations and to estimate the associated risk of radiation-induced second cancer from a brain tumor treatment.MethodsSimulations of out-of-field absorbed doses were performed with MCNP6 and benchmarked against measurements with tissue-equivalent proportional counters (TEPC) for three irradiation setups: two irradiations of a water phantom using proton energies of 78–147 MeV and 177–223 MeV, and one brain tumor irradiation of a whole-body phantom. Out-of-field absorbed and equivalent doses to organs in a whole-body phantom following a brain tumor treatment were subsequently simulated and used to estimate the risk of radiation-induced cancer. Additionally, the contribution of absorbed dose originating from radiation produced in the nozzle was calculated from simulations.ResultsOut-of-field absorbed doses to the TEPC ranged from 0.4 to 135 µGy/Gy. The average deviation between simulations and measurements of the water phantom irradiations was about 17%. The absorbed dose contribution from radiation produced in the nozzle ranged between 0 and 70% of the total dose; the contribution was however small in absolute terms. The absorbed and equivalent doses to the organs ranged between 0.2 and 60 µGy/Gy and 0.5–151 µSv/Gy. The estimated lifetime risk of radiation-induced second cancer was approximately 0.01%.ConclusionsThe agreement of out-of-field absorbed doses between measurements and simulations was good given the sources of uncertainties. Calculations of out-of-field organ doses following a brain tumor treatment indicated that proton PBS therapy of brain tumors is associated with a low risk of radiation-induced cancer.     

Three-dimensional quality assurance of IMRT prostate plans using gel dosimetry

Intensity modulated radiotherapy (IMRT) is one of the most modern radiation therapy treatment techniques. Although IMRT can deliver high and complex conformational doses to the tumor volume, its implementation requires rigorous quality assurance (QA) procedures that include a dosimetric pre-treatment verification of individual patient planning. This verification usually involves measuring a small volume of absolute dose with an ionization chamber and checking bi-dimensional fluency with an array of detectors. The planning technique has tri-dimensional characteristics, but no tridimensional dosimetry has been established in the clinical routine. One strategy to perform three-dimensional dosimetry is to use polymeric gels associated with magnetic resonance imaging to evaluate dose distribution. Here, we have compared the results of conventional QA procedures involving one- and two-dimensional dosimetry to the results of three-dimensional dosimetry conducted with MAGIC-f gel in 10 cases of prostate cancer IMRT planning. More specifically, we used the gamma index (3%/3 mm) to compare the results of three-dimensional dosimetry to the expected dose distributions obtained with the treatment planning system. Except for one IMRT treatment plan, the gel dosimetry results agreed with the conventional quality control and provided an overview of dose distribution in the target volume.     

Out-of-field organ doses and associated risk of cancer development following radiation therapy with photons

Innovations in cancer treatment have contributed to the improved survival rate of these patients. Radiotherapy is one of the main options for cancer management nowadays. High doses of ionizing radiation are usually delivered to the tumor site with high energy photon beams. However, the therapeutic radiation exposure may lead to second cancer induction. Moreover, the introduction of intensity-modulated radiation therapy over the last decades has increased the radiation dose to out-of-field organs compared to that from conventional irradiation. The increased organ doses might result in elevated probabilities for developing secondary malignancies to critical organs outside the treatment volume. The organ-specific dosimetry is considered necessary for the theoretical second cancer risk assessment and the proper analysis of data derived from epidemiological reports. This study reviews the methods employed for the measurement and calculation of out-of-field organ doses from exposure to photons and/or neutrons. The strengths and weaknesses of these dosimetric approaches are described in detail. This is followed by a review of the epidemiological data associated with out-of-field cancer risks. Previously published theoretical cancer risk estimates for adult and pediatric patients undergoing radiotherapy with conventional and advanced techniques are presented. The methodology for the theoretical prediction of the probability of carcinogenesis to out-of-field sites and the limitations of this approach are discussed. The article also focuses on the factors affecting the magnitude of the probability for developing radiotherapy-induced malignancies. The restriction of out-of-field doses and risks through the use of different types of shielding equipment is presented.     

Cell survival responses after exposure to modulated radiation fields

In the present study survival responses were determined in cells with differing radiosensitivity, specifically primary fibroblast (AG0-1522B), human breast cancer (MDA-MB-231), human prostate cancer (DU-145) and human glioma (T98G) cells, after exposure to modulated radiation fields delivered by shielding 50% of the tissue culture flask. A significant decrease (P < 0.05) in cell survival was observed in the shielded area, outside the primary treatment field (out-of-field), that was lower than predicted when compared to uniform exposures fitted to the linear-quadratic model. Cellular radiosensitivity was demonstrated to be an important factor in the level of response for both the in- and out-of-field regions. These responses were shown to be dependent on secretion-mediated intercellular communication, because inhibition of cellular secreted factors between the in- and out-of-field regions abrogated the response. Out-of-field cell survival was shown to increase after pretreatment of cells with agents known to inhibit factors involved in mediating radiation-induced bystander signaling (aminoguanidine, DMSO or cPTIO). These data illustrate a significant decrease in survival out-of-field, dependent upon intercellular communication, in several cell lines with varying radiosensitivity after exposure to a modulated radiation field. This study provides further evidence for the importance of intercellular signaling in modulated exposures, where dose gradients are present, and may inform the refinement of established radiobiological models to facilitate the optimization of advanced radiotherapy treatment plans.     

Bystander effects and radiotherapy

Radiation-induced bystander effects are defined as biological effects expressed after irradiation by cells whose nuclei have not been directly irradiated. These effects include DNA damage, chromosomal instability, mutation, and apoptosis. There is considerable evidence that ionizing radiation affects cells located near the site of irradiation, which respond individually and collectively as part of a large interconnected web. These bystander signals can alter the dynamic equilibrium between proliferation, apoptosis, quiescence or differentiation. The aim of this review is to examine the most important biological effects of this phenomenon with regard to areas of major interest in radiotherapy. Such aspects include radiation-induced bystander effects during the cell cycle under hypoxic conditions when administering fractionated modalities or combined radio-chemotherapy. Other relevant aspects include individual variation and genetics in toxicity of bystander factors and normal tissue collateral damage. In advanced radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), the high degree of dose conformity to the target volume reduces the dose and, therefore, the risk of complications, to normal tissues. However, significant doses can accumulate out-of-field due to photon scattering and this may impact cellular response in these regions. Protons may offer a solution to reduce out-of-field doses. The bystander effect has numerous associated phenomena, including adaptive response, genomic instability, and abscopal effects. Also, the bystander effect can influence radiation protection and oxidative stress. It is essential that we understand the mechanisms underlying the bystander effect in order to more accurately assess radiation risk and to evaluate protocols for cancer radiotherapy.     

A multicenter dosimetry study to evaluate the imaging dose from Elekta XVI and Varian OBI kV-CBCT systems to cardiovascular implantable electronic devices (CIEDs)

The increasing use of daily CBCT in radiotherapy has raised concerns about the additional dose delivered to the patient, and it can also become a concern issue for those patients with cardiovascular implantable electronic devices (CIEDs) (Pacemaker [PM] and Implantable Cardioverter Defibrillator [ICD]). Although guidelines highly recommend that the cumulative dose received by CIEDs should be kept as low as possible, and a safe threshold based on patient risk classification needs to be respected, this additional imaging dose is not usually considered. Four centers with different dosimetry systems and different CBCT imaging protocols participated in this multicenter study to investigate the imaging dose to the CIEDs from Elekta XVI and Varian OBI kV-CBCT systems. It was found that although imaging doses received by CIEDs outside the CBCT field are negligible, special attention should be paid to this value when CIEDs are inside the field because the daily use of CBCT can sometimes contribute considerably to the total dose received by a CIED.     

Dosimetry quality control based on percent depth dose rate variation for checking beam quality in radiotherapy

Recently, the quality management inside a radiotherapy department has been crucial to treat cancer efficiently. Thus, many international bodies recommend multiple methods to check in periodically the dosimetry quality beyond the depth of 10 cm as the beam quality index. However, they evade checking out the beam dosimetry quality on both the build-up dose and the electronic equilibrium regions. The objective of this study is to cover the overall variation of the percent depth dose (PDD) by including all sub-regions in the procedure evaluation of the beam quality.In this work, we have studied and examined the dosimetry quality by considering the whole PDD variation. The PDD rate is therefore introduced to determine accurately the quality as an overall notion in external beam radiotherapy according to the field size and photon beam energy. We have presented the reasons and methods to introduce particles contamination, such as electrons and low photon energy in this new approach. The latter enables us to figure the dosimetry quality by extending the International Atomic Energy Agency (IAEA) procedure at any field size less than 25 × 25 cm² under the current conditions without being limited to 10 × 10 cm² on the exponential decay region.     

Configuration and validation of an analytical model predicting secondary neutron radiation in proton therapy using Monte Carlo simulations and experimental measurements

PurposeThis study focuses on the configuration and validation of an analytical model predicting leakage neutron doses in proton therapy.MethodsUsing Monte Carlo (MC) calculations, a facility-specific analytical model was built to reproduce out-of-field neutron doses while separately accounting for the contribution of intra-nuclear cascade, evaporation, epithermal and thermal neutrons. This model was first trained to reproduce in-water neutron absorbed doses and in-air neutron ambient dose equivalents, H*(10), calculated using MCNPX. Its capacity in predicting out-of-field doses at any position not involved in the training phase was also checked. The model was next expanded to enable a full 3D mapping of H*(10) inside the treatment room, tested in a clinically relevant configuration and finally consolidated with experimental measurements.ResultsFollowing the literature approach, the work first proved that it is possible to build a facility-specific analytical model that efficiently reproduces in-water neutron doses and in-air H*(10) values with a maximum difference less than 25%. In addition, the analytical model succeeded in predicting out-of-field neutron doses in the lateral and vertical direction. Testing the analytical model in clinical configurations proved the need to separate the contribution of internal and external neutrons. The impact of modulation width on stray neutrons was found to be easily adjustable while beam collimation remains a challenging issue. Finally, the model performance agreed with experimental measurements with satisfactory results considering measurement and simulation uncertainties.ConclusionAnalytical models represent a promising solution that substitutes for time-consuming MC calculations when assessing doses to healthy organs.     

The effect of changes in dosimetry on cancer mortality risk estimates in the atomic bomb survivors

In the spring of 1986 the Radiation Effects Research Foundation (RERF) received a new atomic bomb dosimetry system. This report presents the comparisons of leukemia and nonleukemia cancer mortality risk estimates under the old and new dosimetries. In terms of total kerma (essentially whole-body gamma plus neutron exposure), risk estimates for both classes of cancer are 75-85% higher with the new dosimetry. This and other summary comparisons allow for possible nonlinearity at high estimated doses. Changes are also considered in relation to organ doses and assumptions about the relative biological effectiveness (RBE) of neutrons. Without regard to RBE, the risk estimates for total organ dose are essentially unchanged by the dosimetry revision. However, with increasing assumed values of RBE, the estimated low-LET risk decreases much less rapidly under the new dosimetry, due to the smaller neutron component. Thus at an assumed constant RBE of 10, for example, the effect of the dosimetry revision is to increase organ dose risk estimates, relative to those based on the old dosimetry, by 30% for nonleukemia and 80% for leukemia. At an RBE of 20 these increases are 72 and 136%, respectively. A number of other issues are discussed. The city difference in dose is no longer statistically significant, even at an RBE of one. Estimation of RBE is even less feasible with new dosimetry. There is substantial question of the linearity in dose response, in the sense of a leveling off at higher doses. Finally, some indication is given of how risks estimated from this dosimetry and the current data may compare to widely used estimates based largely on the RERF data with the previous dosimetry.     

Peripheral organ doses from radiotherapy for heterotopic ossification of non-hip joints: Is there a risk for radiation-induced malignancies?

Radiotherapy, used for heterotopic ossification (HO) management, may increase radiation risk to patients. This study aimed to determine the peripheral dose to radiosensitive organs and the associated cancer risks due to radiotherapy of HO in common non-hip joints. A Monte Carlo model of a medical linear accelerator combined with a mathematical phantom representing an average adult patient were employed to simulate radiotherapy for HO with standard AP and PA fields in the regions of shoulder, elbow and knee. Radiation dose to all out-of-field radiosensitive organs defined by the International Commission on Radiological Protection was calculated. Cancer induction risk was estimated using organ-specific risk coefficients. Organ dose change with increased field dimensions was also evaluated. Radiation therapy for HO with a 7 Gy target dose in the sites of shoulder, elbow and knee, resulted in the following equivalent organ dose ranges of 0.85–62 mSv, 0.28–1.6 mSv and 0.04–1.6 mSv, respectively. Respective ranges for cancer risk were 0–5.1, 0–0.6 and 0–1.3 cases per 10⁴ persons. Increasing the field size caused an average increase of peripheral doses by 15–20%. Individual organ dose increase depends upon the primary treatment site and the distance between organ of interest and treatment volume. Relatively increased risks of more than 1 case per 10,000 patients were found for skin, breast and thyroid malignancies after treatment in the region of shoulder and for skin cancer following elbow irradiation. The estimated risk for inducing any other malignant disease ranges from negligible to low.     

Radiotherapy for non-malignant shoulder syndrome: Is there a risk for radiation-induced carcinogenesis?

PurposeTo estimate the organ-specific probability for carcinogenesis following radiotherapy for non-malignant shoulder syndrome.MethodsPhoton-beam radiation therapy to 6 Gy for shoulder syndrome was simulated with a Monte Carlo code. An androgynous computational phantom representing a typical adult was used to calculate the radiation dose to out-of-field organs having a predilection for carcinogenesis. The organ-specific lifetime attributable risk (LAR) for out-of-field cancer induction was estimated by the organ dose calculations and the proper risk factors introduced by the BEIR-VII report. The average dose (D_av) and organ equivalent dose (OED) of lung, which was partially included within the treatment volume, was found from 3d-conformal radiotherapy plans. The D_av and OED were used to estimate the lung cancer risk with a linear and mechanistic models, respectively. All risk assessments were made for 50- and 60-year-old male and female patients.ResultsMonte Carlo simulations resulted in an out-of-field organ dose range of 0.7–48.4 mGy. The LARs for out-of-field cancer induction were (1.4 × 10⁻⁴)% to (2.8 × 10⁻²)%. These probabilities were at least 403 times lower than the respective lifetime intrinsic risk (LIR) values. The D_av and OED of lung was up to 164.9 and 142.3 mGy, respectively. The LAR for developing lung malignancies varied from 0.11 to 0.18% by the model used and the patient’s age and gender. The lung cancer risks were 36–64 times smaller than the LIRs.ConclusionsThe estimated probabilities for developing malignancies due to radiotherapy for non-malignant shoulder syndrome are minor relative to the natural cancer occurrence rates.     

Comparative dose levels between CT-scanner and slot-scanning device (EOS system) in pregnant women pelvimetry

PurposeTo estimate fetal absorbed doses for pregnant women pelvimetry, a comparative study between EOS imaging system and low-dose spiral CT-scanner was carried out. For this purpose three different studies were investigated: in vivo, in vitro and Monte Carlo calculations.MethodsIn vivo dosimetry was performed, using OSL NanoDot dosimeters, to determine the dose to the skin of twenty pregnant women. In vitro studies were established by using a cubic phantom of water, in order to estimate the out of field doses. In the latter study, OSLDs were placed at depths corresponding to the lowest, average and highest position of the uterus. Monte Carlo calculations of effective doses to high radio-sensitive organs were established, using PCXMC and CTExpo software suites for EOS imaging system and CT-scanner, respectively.ResultsThe EOS imaging system reduces radiation exposure 4 to 8 times compared to the CT-scanner. The entrance skin doses were 74% (p-values <0.01) higher with the CT-scanner than with the EOS system. In the out of field region, the measured doses of the EOS system were reduced by 80% (p-values <0.02).Monte Carlo calculations confirmed that effective doses to organs are less accentuated for EOS than for CT pelvimetry.ConclusionsThe EOS system is less irradiating than the CT exam. The out-of-field dose which is significant, is lower in the EOS than in the CT-scanner and could be reduced even further by optimizing the time used for image acquisition.     

A protocol for absolute dose verification of SBRT/SRS treatment plans using Gafchromic™ EBT-XD films

PurposeTo provide a practical protocol for absolute dose verification of stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery (SRS) treatment plans, based on our clinical experience. It aims to be a concise summary of the main aspects to be considered when establishing an accurate film dosimetry system.MethodsProcedures for film calibration and conversion to dose are described for a dosimetry system composed of Gafchromic™ EBT-XD films and a flatbed document scanner. Factors that affect the film-scanner response are also reviewed and accounted for. The accuracy of the proposed methodology was assessed by taking a set of strips irradiated to known doses and its applicability is illustrated for ten SBRT/SRS treatment plans. The film response was converted to dose using red and triple channel dosimetry. The agreement between the planned and measured dose distributions was evaluated using global gamma analysis with criteria of 3%/2mm 10% threshold (TH), 2%/2mm 10% TH, and 2%/2mm 20% TH.ResultsThe differences between the expected and determined doses from the strips analysis were 0.9 ± 0.6% for the red channel and 1.1 ± 0.7% for the triple channel method. Regarding the SBRT/SRS plans verification, the mean gamma passing rates were 99.5 ± 1.0% vs 99.6 ± 1.0% (3%/2mm 10% TH), 96.9 ± 3.5% vs 99.1 ± 1.3% (2%/2mm 10% TH) and 98.4 ± 1.8% vs 98.8 ± 1.5% (2%/2mm 20% TH) for red and triple channel dosimetry, respectively.ConclusionsThe proposed protocol allows for accurate absolute dose verification of SBRT/SRS treatment plans, applying both single and triple channel methods. It may work as a guide for users that intend to implement a film dosimetry system.     

Dosimetric evaluation of Gafchromic EBT2 film for breast intraoperative electron radiotherapy verification

PurposeQuality assurance (QA) is one of the most important issues that should be addressed for intraoperative electron radiotherapy (IOERT), which is not benefiting from image-based treatment planning system. The aim of this study is to evaluate the dosimetric characteristics of Gafchromic EBT2 film for breast IOERT QA procedure.MethodsDue to the fact that some dedicated accelerators are being used for IOERT, dependence of the film response to energy, field size, dose rate and incidence angle of electron beam from the LIAC IOERT accelerator was studied. Then, film response curve to breast IOERT doses was obtained and its accuracy was evaluated and justified through comparison to the results of ionometric dosimetry.ResultsThe results of this study indicated that there are no significant differences between the film responses at different energies of 6, 8, 10 and 12 MeV (P-value = 0.99). Similarly, no field size dependency was found when evaluating the response of the film to different field sizes ranging from 4 to 10 cm (P-value = 0.94). Film response was found to be independent of the dose rate of intraoperative electron beam (P-value = 0.12). Film response variations with changing the beam incidence angle were not significant (P-value > 0.8). Calibration curve at the dose range of 8–24 Gy had an acceptable accuracy. The difference between the results of film dosimetry and ionometric dosimetry was around 5% which was in agreement with the results of dose uncertainty estimation.ConclusionThe EBT2 film was found to be a potentially appropriate tool for breast IOERT verification.     

Risk estimation for fast neutrons with regard to solid cancer.

In the absence of epidemiological information on the effects of neutrons, their cancer mortality risk coefficient is currently taken as the product of two low-dose extrapolations: the nominal risk coefficient for photons and the presumed maximum relative biological effectiveness of neutrons. This approach is unnecessary. Since linearity in dose is assumed for neutrons at low to moderate effect levels, the risk coefficient can be derived in terms of the excess risk from epidemiological observations at an intermediate dose of gamma rays and an assumed value, R(1), of the neutron RBE relative to this reference dose of gamma rays. Application of this procedure to the A-bomb data requires accounting for the effect of the neutron dose component, which, according to the current dosimetry system, DS86, amounts on average to 11 mGy in the two cities at a total dose of 1 Gy. With R(1) tentatively set to 20 or 50, it is concluded that the neutrons have caused 18% or 35%, respectively, of the total effect at 1 Gy. The excess relative risk (ERR) for neutrons then lies between 8 per Gy and 16 per Gy. Translating these values into risk coefficients in terms of the effective dose, E, requires accounting for the gamma-ray component produced by the neutron field in the human body, which will require a separate analysis. The risk estimate for neutrons will remain essentially unaffected by the current reassessment of the neutron doses in Hiroshima, because the doses are unlikely to change much at the reference dose of 1 Gy.     

A new approach in the design of electronic portal imaging devices for portal dosimetry in radiotherapy

A CCD-based EPID using new crystal-assembly X-ray (CAX) converters is investigated for radiotherapy dosimetry. The proposed EPID design consists in replacing the common phosphor X-ray converters of current CCD-based EPIDs with high-stopping-power CAX converters. A Test Imaging Device (TID), consisting of a 30-mm-thick CAX converter made of Bismuth Germanate (BGO), coupled to a highly sensitive CCD camera, was used to evaluate the accessible imaging and dosimetric performance of the proposed design. The system response to dose and its dependence on photon beam energy were investigated. The effects of ghosting, dose rate, field size and phantom thickness were evaluated as well. The same measurements were also performed with our clinically used aSi-EPID so that comparisons of performance could be directly inferred. The TID displayed no detectable ghosting or sensitivity to dose rate. Its response to MU exposure was found to be linear within about ±1%. The level of glare induced in the TID and the aSi-EPID were equivalent. The TID resolution was higher than that of the aSi-EPID on the axis, but was found to decrease with off-axis distance. Finally, the image quality, assessed on the basis of signal-to-noise ratio in low dose radiographs of the larynx of a patient, was higher for the TID. The imaging performance accessible with the TID proved to be satisfying and its dosimetric capability was found to be superior to that of the current aSi-EPID.     

Three-dimensional printer-generated patient-specific phantom for artificial in vivo dosimetry in radiotherapy quality assurance

Pretreatment intensity-modulated radiotherapy quality assurance is performed using simple rectangular or cylindrical phantoms; thus, the dosimetric errors caused by complex patient-specific anatomy are absent in the evaluation objects. In this study, we construct a system for generating patient-specific three-dimensional (3D)-printed phantoms for radiotherapy dosimetry. An anthropomorphic head phantom containing the bone and hollow of the paranasal sinus is scanned by computed tomography (CT). Based on surface rendering data, a patient-specific phantom is formed using a fused-deposition-modeling-based 3D printer, with a polylactic acid filament as the printing material. Radiophotoluminescence glass dosimeters can be inserted in the 3D-printed phantom. The phantom shape, CT value, and absorbed doses are compared between the actual and 3D-printed phantoms. The shape difference between the actual and printed phantoms is less than 1 mm except in the bottom surface region. The average CT value of the infill region in the 3D-printed phantom is −6 ± 18 Hounsfield units (HU) and that of the vertical shell region is 126 ± 18 HU. When the same plans were irradiated, the dose differences were generally less than 2%. These results demonstrate the feasibility of the 3D-printed phantom for artificial in vivo dosimetry in radiotherapy quality assurance.