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An alternative approach that is particularly suitable for the radiation health risk assessment (HRA) of astronauts is presented. The quantity, Radiation Attributed Decrease of Survival (RADS), representing the cumulative decrease in the unknown survival curve at a certain attained age, due to the radiation exposure at an earlier age, forms the basis for this alternative approach. Results are provided for all solid cancer plus leukemia incidence RADS from estimated doses from theoretical radiation exposures accumulated during long-term missions to the Moon or Mars. For example, it is shown that a 1000-day Mars exploration mission with a hypothetical mission effective dose of 1.07 Sv at typical astronaut ages around 40 years old, will result in the probability of surviving free of all types of solid cancer and leukemia until retirement age (65 years) being reduced by 4.2% (95% CI 3.2; 5.3) for males and 5.8% (95% CI 4.8; 7.0) for females. RADS dose-responses are given, for the outcomes for incidence of all solid cancer, leukemia, lung and female breast cancer. Results showing how RADS varies with age at exposure, attained age and other factors are also presented. The advantages of this alternative approach, over currently applied methodologies for the long-term radiation protection of astronauts after mission exposures, are presented with example calculations applicable to European astronaut occupational HRA. Some tentative suggestions for new types of occupational risk limits for space missions are given while acknowledging that the setting of astronaut radiation-related risk limits will ultimately be decided by the Space Agencies. Suggestions are provided for further work which builds on and extends this new HRA approach, e.g., by eventually including non-cancer effects and detailed space dosimetry.

Objectives: To assess if excess absolute risk (EAR) of radiation-induced solid cancer can be used to rank radiotherapy plans for treatment of Hodgkin lymphoma (HL) in a statistically significant way., Methods: EAR models, calibrated with data from the Life Span Study and HL survivors, have been incorporated into a voxelised risk-calculation software, which is used to compare four treatment modalities planned for five virtual HL patients. Organ-specific parameters are generated repeatedly in a Monte Carlo fashion to model their uncertainties. This in turn enables a quantitative estimation of the EAR uncertainties., Results: Parameter-driven uncertainties on total EAR are around 13%, decreasing to around 2-5% for relative EAR comparisons. Total EAR estimations indicate that intensity modulated proton therapy decreases the average risk by 40% compared to the intensity modulated radiation therapy plan, 28% compared to the volumetric modulated arc therapy plan whereas the three-dimensional conformal radiation therapy plan is equivalent within the uncertainty., Conclusion: Relative EAR is a useful metric for distinguishing between radiotherapy plans in terms of second cancer risk., Advances in Knowledge: Relative EAR is not dominated by model or parameter uncertainties and can be used to guide the choice of radiotherapy for HL patients.

The risk assessment quantities called lifetime attributable risk (LAR) and risk of exposure-induced cancer (REIC) are used to calculate the cumulative cancer incidence risks for astronauts, attributable to radiation exposure accumulated during long term lunar and Mars missions. These risk quantities are based on the most recently published epidemiological data on the Life Span Study (LSS) of Japanese A-bomb survivors, who were exposed to γ-rays and neutrons. In order to analyze the impact of a different neutron RBE on the risk quantities, a model for the neutron relative biological effectiveness (RBE) relative to gammas in the LSS is developed based on an older dataset with less follow-up time. Since both risk quantities are based on uncertain quantities, such as survival curves, and REIC includes deterministic radiation induced non-cancer mortality risks, modelled with data based on the general population, the risks for astronauts may not be optimally estimated. The suitability of these risk assessment measures for the use of cancer risk calculation for astronauts is discussed. The work presented here shows that the use of a higher neutron RBE than the value of 10, traditionally used in the LSS risk models, can reduce the risks up to almost 50%. Additionally, including an excess absolute risk (EAR) baseline scaling also increases the risks by between 0.4% and 8.1% for the space missions considered in this study. Using just an EAR model instead of an equally weighted EAR and excess relative risk (ERR) model can decrease the cumulative risks for the considered missions by between 0.4% and 4.1% if no EAR baseline scaling is applied. If EAR baseline scaling is included, the calculated risks with the EAR- and the mixed model, as well as the risks calculated with just the ERR model are almost identical and only small differences in the uncertainties are visible., (Copyright © 2020. Published by Elsevier B.V.)

Proton therapy has shown dosimetric advantages over conventional radiation therapy using photons. Although the integral dose for patients treated with proton therapy is low, concerns were raised about late effects like secondary cancer caused by dose depositions far away from the treated area. This is especially true for neutrons and therefore the stray dose contribution from neutrons in proton therapy is still being investigated. The higher biological effectiveness of neutrons compared to photons is the main cause of these concerns. The gold-standard in neutron dosimetry is measurements, but performing neutron measurements is challenging. Different approaches have been taken to overcome these difficulties, for instance with newly developed neutron detectors. Monte Carlo simulations is another common technique to assess the dose from secondary neutrons. Measurements and simulations are used to develop analytical models for fast neutron dose estimations. This article tries to summarize the developments in the different aspects of neutron dose in proton therapy since 2017. In general, low neutron doses have been reported, especially in active proton therapy. Although the published biological effectiveness of neutrons relative to photons regarding cancer induction is higher, it is unlikely that the neutron dose has a large impact on the second cancer risk of proton therapy patients.

The European Space Agency (ESA) is currently expanding its efforts in identifying requirements and promoting research towards optimizing radiation protection of astronauts. Space agencies use common limits for tissue (deterministic) effects on the International Space Station. However, the agencies have in place different career radiation exposure limits (for stochastic effects) for astronauts in low-Earth orbit missions. Moreover, no specific limits for interplanetary missions are issued. Harmonization of risk models and dose limits for exploratory-class missions are now operational priorities, in view of the short-term plans for international exploratory-class human missions. The purpose of this paper is to report on the activity of the ESA Topical Team on space radiation research, whose task was to identify the most pertinent research requirements for improved space radiation protection and to develop a European space radiation risk model, to contribute to the efforts to reach international consensus on dose limits for deep space. The Topical Team recommended ESA to promote the development of a space radiation risk model based on European-specific expertise in: transport codes, radiobiological modelling, risk assessment, and uncertainty analysis. The model should provide cancer and non-cancer radiation risks for crews implementing exploratory missions. ESA should then support the International Commission on Radiological Protection to harmonize international models and dose limits in deep space, and guarantee continuous support in Europe for accelerator-based research configured to improve the models and develop risk mitigation strategies., (Copyright © 2019. Published by Elsevier Ltd.)

Obtaining a correct dose-response relationship for radiation-induced cancer after radiotherapy presents a major challenge for epidemiological studies. The purpose of this paper is to gain a better understanding of the associated uncertainties. To accomplish this goal, some aspects of an epidemiological study on breast cancer following radiotherapy of Hodgkin's disease were simulated with Monte Carlo methods. It is demonstrated that although the doses to the breast volume are calculated by one treatment plan, the locations and sizes of the induced secondary breast tumours can be simulated and, based on these simulated locations and sizes, the absorbed doses at the site of tumour incidence can also be simulated. For the simulations of point dose at tumour site, linear and non-linear mechanistic models which predict risk of cancer induction as a function of dose were applied randomly to the treatment plan. These simulations provided for each second tumour and each simulated tumour size the predicted dose. The predicted-dose-response-characteristic from the analysis of the simulated epidemiological study was analysed. If a linear dose-response relationship for cancer induction was applied to calculate the theoretical doses at the simulated tumour sites, all Monte-Carlo realizations of the epidemiological study yielded strong evidence for a resulting linear risk to predicted-dose-response. However, if a non-linear dose-response of cancer induction was applied to calculate the theoretical doses, the Monte Carlo simulated epidemiological study resulted in a non-linear risk to predicted-dose-response relationship only if the tumour size was small (< 1.5 cm). If the diagnosed breast tumours exceeded an average diameter of 1.5 cm, an applied non-linear theoretical-dose-response relationship for second cancer falsely resulted in strong evidence for a linear predicted-dose relationship from the epidemiological study realizations. For a typical distribution of breast cancer sizes, the model selection probability for a resulting predicted-dose linear model was 61% although a non-linear theoretical-dose-response relationship for cancer induction had been applied. The results of this study, therefore, provide evidence that the shapes of epidemiologically obtained dose-response relationships for cancer induction can be biased by the finite size of the diagnosed second tumour, even though the epidemiological study was done correctly.

Epidemiological studies of long term radiotherapy survivors provide useful insights into dose-response relationships for secondary cancer induction risk at high doses. There are uncertainties involved in estimating the dose to the location of the second malignancy, because the dose distributions in radiotherapy patients can be spatially highly heterogeneous and the size of the diagnosed tumor is on the order of a few cm. Therefor it is nearly impossible to obtain the exact dose corresponding to the exact tumor induction location and so organ specific dose-response relationships have large errors not only in the reported risk, but also in the estimated dose. In this work two alternative methods are proposed for future applications involving investigations into dose response relationships for second cancer induction risk, the method of organ sub-division and the method of risk equivalent dose. The method of organ sub-division takes the inevitable inhomogeneous dose distribution into account by applying epidemiological methods to organ sub-divisions which have a nearly homogenous dose. The method of risk equivalent dose combines risk modeling and epidemiological data analysis. Risk models can be optimized by using an iterative procedure assuming a variation of organ specific dose-responses. The advantage of the alternative methods is that the inhomogeneity of the dose in the organs at risk is taken into account. The second method has the additional advantage that the dose to the location of the tumor site must not be known and that epidemiologically obtained risks that were not stratified by organ specific risk can be used., (Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: To investigate second cancer risk (SCR) comparing volumetric modulated arc therapy (VMAT) and 3D conformal radiotherapy (3DCRT) with different high dose fractionation schemes., Methods: VMAT and 3DCRT virtual treatment plans for 25 patients previously treated with radiotherapy for rectal cancer were evaluated retrospectively. Doses prescribed were 25 × 1.8 Gy and 5 × 5 Gy, respectively. SCR was estimated using a carcinogenesis model and epidemiological data for carcinoma and sarcoma induction. SCR was determined by lifetime attributable risk (LAR)., Results: Mean excess LAR was highest for organs adjacent to the PTV. Total LAR for VMAT and 3DCRT was 2.3-3.0 and 2.0-2.7 %, respectively. For 5 × 5 Gy, LAR was 1.4-1.9 % for VMAT and 1.2-1.6 % for 3DCRT. Organ-specific excess LAR was significantly higher for VMAT, and highest for bladder and colon. Size and shape of the PTV influenced SCR and was highest for age ≤ 40 years. For a patient with an additional lifetime risk of 60 years, LAR was 10 % for 25 × 1.8 Gy and 6 % for 5 × 5 Gy., Conclusions: No statistically significant difference was detected in SCR using VMAT or 3DCRT. For bladder and colon, organ-specific excess LAR was statistically lower using 3DCRT, however the difference was small. Compared to epidemiological data, SCR was smaller when using a hypofractionated schedule. SCR was 2 % higher at normal life expectancy., Trial Registration: ClinicalTrials.gov Identifier NCT02572362 . Registered 4 October 2015. Retrospectively registered.

Determinations of the lowest colon dose, D min , below which there is a statistically significant excess relative risk of all solid cancer, when analyses are restricted to the range [0, D min ], are of current interest in research related to radiation protection and risk assessment. In reviewing recent cancer mortality reports on the Life Span Study (LSS) of Japanese A-bomb survivors, reported D min values were found to vary between different reports. The report 12 (follow-up: 1950-1990) found a D min of 50 mGy, but the most recent report 14 (follow-up: 1950-2003) found a D min of 200 mGy. There were small dosimetry changes between report 12, which used DS86, and report 14, which used DS02, but these changes are unlikely to account for a difference in D min of a factor of 4. This short communication examines the reasons for this difference in D min by presenting further investigations into D min using different trial values for D min and various follow-up time spans, all with the same DS02 dosimetry. Magnitudes of the low-dose risks in different dose ranges are also presented. It is shown here that the main influence on D min comes from the length of follow-up and a D min of 50 mGy may also be obtained with the most recent LSS mortality data and DS02, if a restricted follow-up is analyzed. A systematic trend was evident of lower D min values for earlier mortality follow-up periods, consistent with information from earlier LSS reports. Although it may seem surprising that the D min increases with longer follow-up and better statistics, this systematic trend appears to be a consequence of decreasing mortality risks with longer follow-up, even though the error bars on the risks are getting smaller with increasing follow-up. These systematic trends also persisted after accounting for differences between baseline cancer rates for two groups of survivors who were either proximal or distal to the A-bomb hypocenter. Similar systematic trends, although much less pronounced, were also found in the LSS cancer incidence data. Some evidence is provided here that results on low-dose radiation risks from earlier follow-up periods should not be ignored by radiation protection authorities, once the results from the new extended follow-ups are published. This is because of the possibility that the new data for extended follow-up beyond a certain calendar time, which pertain to very long times since exposure, may be contributing to an overall reduction in radiation related risks per unit dose compared to analogous risks determined from earlier follow-up periods, because of the risk effect modification of time since exposure.

Purpose: Phenomenological risk models for radiation-induced cancer are frequently applied to estimate the risk of radiation-induced cancers at radiotherapy doses. Such models often include the effect modification, of the main risk to radiation dose response, by age at exposure and attained age. The aim of this paper is to compare the patterns in risk effect modification by age, between models obtained from the Japanese atomic-bomb (A-bomb) survivor data and models for cancer risks previously reported for radiotherapy patients. Patterns in risk effect modification by age from the epidemiological studies of radiotherapy patients were also used to refine and extend the risk effect modification by age obtained from the A-bomb survivor data, so that more universal models can be presented here., Methods: Simple log-linear and power functions of age for the risk effect modification applied in models of the A-bomb survivor data are compared to risks from epidemiological studies of second cancers after radiotherapy. These functions of age were also refined and fitted to radiotherapy risks. The resulting age models provide a refined and extended functional dependence of risk with age at exposure and attained age especially beyond 40 and 65 yr, respectively, and provide a better representation than the currently available simple age functions., Results: It was found that the A-bomb models predict risk similarly to the outcomes of testicular cancer survivors. The survivors of Hodgkin's disease show steeper variations of risk with both age at exposure and attained age. The extended models predict solid cancer risk increase as a function of age at exposure beyond 40 yr and the risk decrease as a function of attained age beyond 65 yr better than the simple models., Conclusions: The standard functions for risk effect modification by age, based on the A-bomb survivor data, predict second cancer risk in radiotherapy patients for ages at exposure prior to 40 yr and attained ages before 55 yr reasonably well. However, for larger ages, the refined and extended models can be applied to predict the risk as a function of age.

Background: To estimate the risk of radiation induced second cancers after radiotherapy using deep-inspiration breath-hold (DI) technique with three-dimensional conformal (3DCRT) and volumetric arc therapy (VMAT) for patients with Hodgkin's lymphoma (HL)., Methods: Early-stage HL with mediastinal and supraclavicular involvement was studied using an Alderson phantom. A whole body CT was performed and all tissues were delineated. The clinical target volumes and planning target volumes (PTV) were determined according to the German Hodgkin study group guidelines. Free-breathing (FB) technique and DI technique were simulated by different safety margins for the PTV definition. In both cases, 30 Gy in 15 fractions was prescribed. Second cancer risk was estimated for various tissues with a second cancer model including fractionation., Results: When compared with FB-3DCRT, estimated relative life time attributable risk (LAR) of cancer induction after DI-3DCRT was 0.86, 0.76, 0.94 and 0.92 for breast, lung, esophagus and stomach, respectively. With DI-VMAT, the corresponding values were 2.05, 1.29, 1.01, 0.93, respectively. For breast cancer, the LAR observed with DI-VMAT was not substantially distinguishable from the LAR computed for mantle RT with an administered dose of 40 Gy., Conclusions: This study suggests that DI may reduce the LAR of secondary cancers of all OARs and may be a valuable technique when using 3DCRT. Conversely, VMAT may increase substantially the LAR and should be cautiously implemented in clinical practice.

Radiation-related risks of cancer can be transported from one population to another population at risk, for the purpose of calculating lifetime risks from radiation exposure. Transfer via excess relative risks (ERR) or excess absolute risks (EAR) or a mixture of both (i.e., from the life span study (LSS) of Japanese atomic bomb survivors) has been done in the past based on qualitative weighting. Consequently, the values of the weights applied and the method of application of the weights (i.e., as additive or geometric weighted means) have varied both between reports produced at different times by the same regulatory body and also between reports produced at similar times by different regulatory bodies. Since the gender and age patterns are often markedly different between EAR and ERR models, it is useful to have an evidence-based method for determining the relative goodness of fit of such models to the data. This paper identifies a method, using Akaike model weights, which could aid expert judgment and be applied to help to achieve consistency of approach and quantitative evidence-based results in future health risk assessments. The results of applying this method to recent LSS cancer incidence models are that the relative EAR weighting by cancer solid cancer site, on a scale of 0-1, is zero for breast and colon, 0.02 for all solid, 0.03 for lung, 0.08 for liver, 0.15 for thyroid, 0.18 for bladder and 0.93 for stomach. The EAR weighting for female breast cancer increases from 0 to 0.3, if a generally observed change in the trend between female age-specific breast cancer incidence rates and attained age, associated with menopause, is accounted for in the EAR model. Application of this method to preferred models from a study of multi-model inference from many models fitted to the LSS leukemia mortality data, results in an EAR weighting of 0. From these results it can be seen that lifetime risk transfer is most highly weighted by EAR only for stomach cancer. However, the generalization and interpretation of radiation effect estimates based on the LSS cancer data, when projected to other populations, are particularly uncertain if considerable differences exist between site-specific baseline rates in the LSS and the other populations of interest. Definitive conclusions, regarding the appropriate method for transporting cancer risks, are limited by a lack of knowledge in several areas including unknown factors and uncertainties in biological mechanisms and genetic and environmental risk factors for carcinogenesis; uncertainties in radiation dosimetry; and insufficient statistical power and/or incomplete follow-up in data from radio-epidemiological studies.

Background: Purpose of this study is to explore the trade-offs between radio-induced toxicities and second malignant neoplasm (SMN) induction risk of different emerging radiotherapy techniques for Hodgkin's lymphoma (HL) through a comprehensive dosimetric analysis on a representative clinical model., Methods: Three different planning target volume (PTVi) scenarios of a female patient with supradiaphragmatic HL were used as models for the purpose of this study. Five treatment radiation techniques were simulated: an anterior-posterior parallel-opposed (AP-PA), a forward intensity modulated (FIMRT), an inverse intensity modulated (IMRT), a Tomotherapy (TOMO), a proton (PRO) technique. A radiation dose of 30 Gy or CGE was prescribed. Dose-volume histograms of PTVs and organs-at-risk (OARs) were calculated and related to available dose-volume constraints. SMN risk for breasts, thyroid, and lungs was estimated through the Organ Equivalent Dose model considering cell repopulation and inhomogeneous organ doses., Results: With similar level of PTVi coverage, IMRT, TOMO and PRO plans generally reduced the OARs' dose and accordingly the related radio-induced toxicities. However, only TOMO and PRO plans were compliant with all constraints in all scenarios. For the IMRT and TOMO plans an increased risk of development of breast, and lung SMN compared with AP-PA and FIMRT techniques was estimated. Only PRO plans seemed to reduce the risk of predicted SMN compared with AP-PA technique., Conclusions: Our model-based study supports the use of advanced RT techniques to successfully spare OARs and to reduce the risk of radio-induced toxicities in HL patients. However, the estimated increase of SMNs' risk inherent to TOMO and IMRT techniques should be carefully considered in the evaluation of a risk-adapted therapeutic strategy.

Irradiation is a major causative factor among the small subgroup of sarcomas with a known etiology. The prognosis of radiation-induced sarcomas (RIS) is significantly worse than that of their spontaneous counterparts. The most frequent histological subtypes include undifferentiated pleomorphic sarcomas, angiosarcomas, and leiomyosarcomas. A high frequency of MYC amplifications in radiation-induced angiosarcomas, but not in primary angiosarcomas, has recently been described. To investigate whether MYC amplifications are also frequent in RIS other than angiosarcomas, we analyzed the MYC amplification status of 83 RIS and 192 sporadic sarcomas by fluorescence in situ hybridization. We found significantly higher numbers of MYC amplifications in RIS than in sporadic sarcomas (P < 0.0001), especially in angiosarcomas, undifferentiated pleomorphic sarcomas, and leiomyosarcomas. Angiosarcomas were special in that MYC amplifications were particularly frequent and always high level, while other RIS showed low-level amplifications. We conclude that MYC amplifications are a frequent feature of RIS as a group and may contribute to the biology of these tumors., (Copyright © 2012 Wiley Periodicals, Inc.)

Recent findings demonstrate that accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks in cells, which escaped apoptosis due to proliferative stress. In this work, proliferative stress and inflammation-based carcinogenesis at large dose were included in a cancer induction model considering fractionation. At large dose, tissue injury due to irradiation could be so severe that under the regenerative proliferative stress induced by cell loss, the genomic unstable cells generated during irradiation and/or inflammation escape senescence or apoptosis and reenter the cell cycle, triggering enhanced carcinogenesis. This acceleration-modeled to be proportional to the number of repopulated cells-is only significant, however, when tissue injury is severe and thus proportional to the cell loss in the tissue. The general solutions to the resulting differential equations for carcinoma induction were computed. In case of full repopulation or acute low-dose irradiation, the acceleration term disappears from the equation describing cancer induction. The acceleration term is affecting the dose-response curve for carcinogenesis only at large doses. An example for bladder cancer is shown. An existing model for cancer induction after fractionated radiotherapy which is based on cell mutations was extended here by including the effects of inflammation and proliferative stress, and an additional model parameter was established which describes acceleration. The new acceleration parameter affects the dose-response model only at large dose and is only effective when the tissue is not capable of fully repopulating between dose fractions.

There is clinical evidence that second malignancies in radiation therapy occur mainly within the beam path, i.e. in the medium or high-dose region. The purpose of this study was to assess the risk for developing a radiation-induced tumor within the treated volume and to compare this risk for proton therapy and intensity-modulated photon therapy (IMRT). Instead of using data for specific patients we have created a representative scenario. Fully contoured age- and gender-specific whole body phantoms (4 year and 14 year old) were uploaded into a treatment planning system and tumor volumes were contoured based on patients treated for optic glioma and vertebral body Ewing's sarcoma. Treatment plans for IMRT and proton therapy treatments were generated. Lifetime attributable risks (LARs) for developing a second malignancy were calculated using a risk model considering cell kill, mutation, repopulation, as well as inhomogeneous organ doses. For standard fractionation schemes, the LAR for developing a second malignancy from radiation therapy alone was found to be up to 2.7% for a 4 year old optic glioma patient treated with IMRT considering a soft-tissue carcinoma risk model only. Sarcoma risks were found to be below 1% in all cases. For a 14 year old, risks were found to be about a factor of 2 lower. For Ewing's sarcoma cases the risks based on a sarcoma model were typically higher than the carcinoma risks, i.e. LAR up to 1.3% for soft-tissue sarcoma. In all cases, the risk from proton therapy turned out to be lower by at least a factor of 2 and up to a factor of 10. This is mainly due to lower total energy deposited in the patient when using proton beams. However, the comparison of a three-field and four-field proton plan also shows that the distribution of the dose, i.e. the particular treatment plan, plays a role. When using different fractionation schemes, the estimated risks roughly scale with the total dose difference in%. In conclusion, proton therapy can significantly reduce the risk for developing an in-field second malignancy. The risk depends on treatment planning parameters, i.e. an analysis based on our formalism could be applied within treatment planning programs to guide treatment plans for pediatric patients.

Background and Purpose: Today, there is growing concern about radiotherapy induced secondary malignancies. We analysed the incidence and dose dependence of second cancer., Material and Methods: The study includes 12,000 one-year survivors of radiotherapy, treated between 1981 and 2007. For risk estimates a public databank on cancer in Germany served as reference. Contralateral second breast cancer, second oesophageal and colorectal cancer were analysed with retrospective dosimetry. GI-tract data were used for risk modelling., Results: The incidence rate of second cancers (493 cases) was ~1% per year. Contralateral breast cancer was the most frequent entity (relative risk RR=2.8). The scatter-dose gradient (2-3 Gy) across the contralateral breast did not cause a detectable risk gradient. There was an increased risk for second head and neck cancer (RR=5.1) and for male oesophageal cancer (RR=5.8). For both entities, dose response modelling with case-control data predicted maximum curves with peak induction at 1-5 Gy and positive excess absolute risk values at high doses., Conclusions: A survey of second cancer after radiotherapy requires follow-up over decades. Preliminary dose response modelling albeit with low case numbers suggests an increased risk from multiportal techniques. To improve risk assessment, prospective out-of-field dosimetry and long-term multicentre data collection are recommended., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors. Since, for radiation protection purposes, the dose span of main interest is between zero and one Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses larger than one Gy are becoming more important for radiotherapy patients. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation induced solid cancer., Materials and Methods: For various organs and tissues the analysis of cancer induction was extended by an attempted combination of the linear-no-threshold model from the A-bomb survivors in the low dose range and the cancer risk data of patients receiving radiotherapy for Hodgkin's disease in the high dose range. The data were fitted using organ equivalent dose (OED) calculated for a group of different dose-response models including a linear model, a model including fractionation, a bell-shaped model and a plateau-dose-response relationship., Results: The quality of the applied fits shows that the linear model fits best colon, cervix and skin. All other organs are best fitted by the model including fractionation indicating that the repopulation/repair ability of tissue is neither 0 nor 100% but somewhere in between. Bone and soft tissue sarcoma were fitted well by all the models. In the low dose range beyond 1 Gy sarcoma risk is negligible. For increasing dose, sarcoma risk increases rapidly and reaches a plateau at around 30 Gy., Conclusions: In this work OED for various organs was calculated for a linear, a bell-shaped, a plateau and a mixture between a bell-shaped and plateau dose-response relationship for typical treatment plans of Hodgkin's disease patients. The model parameters (α and R) were obtained by a fit of the dose-response relationships to these OED data and to the A-bomb survivors. For any three-dimensional inhomogenous dose distribution, cancer risk can be compared by computing OED using the coefficients obtained in this work.

Purpose: To estimate and compare intensity-modulated radiotherapy (IMRT) with three-dimensional conformal radiotherapy (3DCRT) in terms of second cancer risk (SCR) for postoperative treatment of endometrial and cervical cancer., Methods and Materials: To estimate SCR, the organ equivalent dose concept with a linear-exponential, a plateau, and a linear dose-response model was applied to dose distributions, calculated in a planning computed tomography scan of a 68-year-old woman. Three plans were computed: four-field 18-MV 3DCRT and nine-field IMRT with 6- and 18-MV photons. SCR was estimated as a function of target dose (50.4 Gy/28 fractions) in organs of interest according to the International Commission on Radiological Protection., Results: Cumulative SCR relative to 3DCRT was +6% (3% for a plateau model, -4% for a linear model) for 6-MV IMRT and +26% (25%, 4%) for the 18-MV IMRT plan. For an organ within the primary beam, SCR was +12% (0%, -12%) for 6-MV and +5% (-2%, -7%) for 18-MV IMRT. 18-MV IMRT increased SCR 6-7 times for organs away from the primary beam relative to 3DCRT and 6-MV IMRT. Skin SCR increased by 22-37% for 6-MV and 50-69% for 18-MV IMRT inasmuch as a larger volume of skin was exposed., Conclusion: Cancer risk after IMRT for cervical and endometrial cancer is dependent on treatment energy. 6-MV pelvic IMRT represents a safe alternative with respect to SCR relative to 3DCRT, independently of the dose-response model. 18-MV IMRT produces second neutrons that modestly increase the SCR.

A simple mechanistic model for predicting cancer induction after fractionated radiotherapy is developed. The model is based upon the linear-quadratic model. The inductions of carcinomas and sarcomas are modeled separately. The linear-quadratic model of cell kill is applied to normal tissues which are unintentionally irradiated during a cancer treatment with radiotherapy. Tumor induction is modeled such that each transformation process results in a tumor cell. The microscopic transformation parameter was chosen such that in the limit of low dose and acute exposure, the parameters of the linear-no-threshold model for tumor induction were approached. The differential equations describing carcinoma and sarcoma inductions can be solved analytically. Cancer induction in this model is a function of treatment dose, the cell kill parameters (alpha, beta), the tumor induction variable (mu), and the repopulation parameter (zeta). Carcinoma induction shows a bell shaped behavior as long as cell repopulation is small. Assuming large cell repopulation rates, a plateaulike function is approached. In contrast, sarcoma induction is negligible for low doses and increases with increasing dose up to a constant value. The proposed model describes carcinoma and sarcoma inductions after fractionated radiotherapy as an analytical function of four parameters. In the limit of low dose and for an instant irradiation it reproduces the results of the linear-no-threshold model. The obtained dose-response curves for cancer induction can be implemented with other models such as the organ-equivalent dose model to predict second cancers after radiotherapy.

Background and Purpose: The scattered radiation from the treatment volume might be more significant for children than for adults and, as a consequence, modern radiotherapy treatment techniques such as IMRT and passive proton therapy could potentially increase the number of secondary cancers. In this report, secondary cancer risk resulting from new treatment technologies was estimated for an adult prostate patient and a child., Material and Methods: The organ equivalent dose (OED) concept with a linear-exponential, a plateau and a linear dose-response curve was applied to dose distributions of an adult prostate patient and a child with a rhabdomyosarcoma of the prostate. Conformal radiotherapy, IMRT with 6MV photons and proton therapy were planned. OED (cancer risk) was estimated for the whole body, the rectum and the bladder. In addition, relative cumulative risk was calculated., Results: Secondary cancer risk in the adult is not more than 15% it increased when IMRT or passive proton therapy was compared to conventional treatment planning. In the child, risk remains practically constant or was even reduced for proton therapy. The cumulative risk in the child relative to that in the adult can be as large as 10-15., Conclusions: By a comparison between an adult patient and a child treated for a disease of the prostate, it was shown that modern radiotherapy techniques such as IMRT and proton therapy (active and passive) do not increase the risk for secondary cancers.

Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors who were exposed to gamma-rays and neutrons. Since, for radiation protection purposes, the dose span of main interest is between 0 and 1 Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses above 1 Gy are becoming more important for radiotherapy patients and for long-term manned missions in space research. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation-induced solid cancer. The analysis of the A-bomb survivor's data was extended by including two extra high-dose categories (4-6 Sv and 6-13 Sv) and by an attempted combination with cancer data on patients receiving radiotherapy for Hodgkin's disease. In addition, since there are some recent indications for a high neutron dose contribution, the data were fitted separately for three different values for the relative biological effectiveness (RBE) of the neutrons (10, 35 and 100) and a variable RBE as a function of dose. The data were fitted using a linear, a linear-exponential and a plateau-dose-response relationship. Best agreement was found for the plateau model with a dose-varying RBE. It can be concluded that for doses above 1 Gy there is a tendency for a nonlinear dose-response curve. In addition, there is evidence of a neutron RBE greater than 10 for the A-bomb survivor data. Many problems and uncertainties are involved in combing these two datasets. However, since very little is currently known about the shape of dose-response relationships for radiation-induced cancer in the radiotherapy dose range, this approach could be regarded as a first attempt to acquire more information on this area. The work presented here also provides the first direct evidence that the bending over of the solid cancer excess risk dose response curve for the A-bomb survivors, generally observed above 2 Gy, is due to cell killing effects.

Purpose: To estimate and compare the secondary cancer risk (SCR) due to para-aortic (PA), dogleg field (DLF), or extensive field (EF) radiotherapy (RT) at different dose levels for Stage I testicular seminoma., Methods and Materials: The organ equivalent dose concept with a linear, plateau, and linear-exponential dose-response model was applied to the dose distributions to estimate the SCR. The dose distributions were calculated in a voxel-based anthropomorphic phantom. Three different three-dimensional plans were computed: PA, DLF, and EF. The plans were calculated with 6-MV photons and two opposed fields, using 20 Gy in 10 fractions., Results: The estimated cumulative SCR for a 75-year-old patient treated with PA-RT at age 35 was 23.3% (linear model), 20.9% (plateau model), and 20.8% (linear-exponential model) compared with 19.8% for the general population. Dependent on the model, PA-RT compared with DLF-RT reduced the SCR by 48-63% or 64-69% when normalized to EF-RT. For PA-RT, the linear dose-response model predicted a decrease of 45% in the SCR, using 20 Gy instead of 30 Gy; the linear-exponential dose-response model predicted no change in SCR., Conclusion: Our model suggested that the SCR after PA-RT for Stage I testicular seminoma is reduced by approximately one-half to two-thirds compared with DLF-RT, independent of the dose-response model. The SCR is expected to be equal or lower with 20 Gy than with 30 Gy. In the absence of mature patient data, the organ equivalent dose concept offers the best potential method of estimating the SCR when discussing treatment options with patients.

Purpose: To estimate secondary cancer risk due to dose escalation in patients treated for prostatic carcinoma with three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated RT (IMRT), and spot-scanned proton RT., Methods and Materials: The organ equivalent dose (OED) concept with a linear-exponential, a plateau, and a linear dose-response curve was applied to dose distributions of 23 patients who received RT of prostate cancer. Conformal RT was used in 7 patients, 8 patients received IMRT with 6- and 15-MV photons, and 8 patients were treated with spot-scanned protons. We applied target doses ranging from 70 Gy to 100 Gy. Cancer risk was estimated as a function of target dose and tumor control probability., Results: At a 100-Gy target dose the secondary cancer risk relative to the 3D treatment plan at 70 Gy was +18.4% (15.0% for a plateau model, 22.3% for a linear model) for the 6-MV IMRT plan, +25.3% (17.0%, 14.1%) for the 15-MV IMRT plan, and -40.7% (-41.3%, -40.0%) for the spot-scanned protons. The increasing risk of developing a radiation-associated malignancy after RT with increasing dose was balanced by the enhanced cure rates at a larger dose., Conclusions: Cancer risk after dose escalation for prostate RT is expected to be equal to or lower than for conventional 3D treatment at 70 Gy, independent of treatment modality or dose-response model. Spot-scanned protons are the treatment of choice for dose escalation because this therapy can halve the risk of secondary cancers.

Background and Purpose: There is concern about the increase of radiation-induced malignancies with the application of modern radiation treatment techniques such as intensity-modulated radiotherapy (IMRT) and proton radiotherapy. Therefore, X-ray scatter and neutron radiation as well as the impact of the primary dose distribution on secondary cancer incidence are analyzed., Material and Methods: The organ equivalent dose (OED) concept with a linear-exponential and a plateau dose-response curve was applied to dose distributions of 30 patients who received radiation therapy of prostate cancer. Three-dimensional conformal radiotherapy was used in eleven patients, another eleven patients received IMRT with 6-MV photons, and eight patients were treated with spot-scanned protons. The treatment plans were recalculated with 15-MV and 18-MV photons. Secondary cancer risk was estimated based on the OED for the different treatment techniques., Results: A modest increase of 15% radiation-induced cancer results from IMRT using low energies (6 MV), compared to conventional four-field planning with 15-MV photons (plateau dose-response: 1%). The probability to develop a secondary cancer increases with IMRT of higher energies by 20% and 60% for 15 MV and 18 MV, respectively (plateau dose-response: 2% and 30%). The use of spot-scanned protons can reduce secondary cancer incidence as much as 50% (independent of dose-response)., Conclusion: By including the primary dose distribution into the analysis of radiation-induced cancer incidence, the resulting increase in risk for secondary cancer using modern treatment techniques such as IMRT is not as dramatic as expected from earlier studies. By using 6-MV photons, only a moderate risk increase is expected. Spot-scanned protons are the treatment of choice in regard to secondary cancer incidence.

It is often assumed that radiation-induced secondary cancer after proton therapy forms preferentially close to the distal fall-off of the spread-out Bragg peak because of an increased relative biological effectiveness (RBE) with regard to cancer induction of low-energy protons. In this study we analyze to what extent dose gradients distal to the Planning Target Volume (PTV) may, independently from the RBE, contribute to enhanced radiation carcinogenesis. The study is based on two dogs which, out of 30 dogs treated with proton therapy at the Paul Scherrer Institute (PSI), developed a secondary cancer. Both dogs were originally diagnosed and treated for a fibrosarcoma and developed an osteosarcoma 48 and almost 60 months, respectively, after radiotherapy. From the dose distributions of the initial radiotherapy for both dogs three-dimensional maps of secondary cancer complication probability (SCCP) were computed. The SCCP maps were analyzed in the regions where the dogs developed a secondary cancer. The SCCP maps showed an enhanced risk in the regions of the femur where the secondary cancers were detected, as compared to the SCCP of the total femur. Excess risk of radiation-induced cancer at the distal part of proton radiation fields can thus be explained using SCCP calculations on the basis of the physical dose distributions. Therefore, the occurrence of secondary cancer close to the distal dose gradients of proton therapy is not necessarily due to an increased RBE of low-energy protons. More extensive studies based on more patients will be necessary to further elucidate the factors influencing the development of secondary tumors.

Purpose: Estimates of secondary cancer risk after radiotherapy are becoming more important for comparative treatment planning. Modern treatment planning systems provide accurate three-dimensional dose distributions for each individual patient. These data open up new possibilities for more precise estimates of secondary cancer incidence rates in the irradiated organs. We report a new method to estimate organ-specific radiation-induced cancer incidence rates. The concept of an organ equivalent dose (OED) for radiation-induced cancer assumes that any two dose distributions in an organ are equivalent if they cause the same radiation-induced cancer incidence., Methods and Materials: The two operational parameters of the OED concept are the organ-specific cancer incidence rate at low doses, which is taken from the data of the atomic bomb survivors, and cell sterilization at higher doses. The effect of cell sterilization in various organs was estimated by analyzing the secondary cancer incidence data of patients with Hodgkin's disease who were treated with radiotherapy in between 1962 and 1993. The radiotherapy plans used at the time the patients had been treated were reconstructed on a fully segmented whole body CT scan. The dose distributions were calculated in individual organs for which cancer incidence data were available. The model parameter that described cell sterilization was obtained by analyzing the dose and cancer incidence rates for the individual organs., Results: We found organ-specific cell radiosensitivities that varied from 0.017 for the mouth and pharynx up to 1.592 for the bladder. Using the two model parameters (organ-specific cancer incidence rate and the parameter characterizing cell sterilization), the OED concept can be applied to any three-dimensional dose distribution to analyze cancer incidence., Conclusion: We believe that the concept of OED presented in this investigation represents a first step in assessing the potential risk of secondary cancer induction after the clinical application of radiotherapy.

Purpose: To assess the potential influence of improved dose distribution with proton beams compared to conventional or intensity-modulated (IM) X-ray beams on the incidence of treatment-induced secondary cancers in pediatric oncology., Methods and Materials: Two children, one with a parameningeal rhabdomyosarcoma (RMS) and a second with a medulloblastoma, were used as models for the purpose of this study. After defining the target and critical structures, treatment plans were calculated and optimized, four for the RMS case (conventional X-ray, IM X-rays, protons, and IM protons) and three for the irradiation of the spinal axis in medulloblastoma (conventional X-ray, IM X-rays, protons). Secondary cancer incidence was estimated using a model based on Publication No. 60 of the International Commission on Radiologic Protection. This model allowed estimation of absolute risks of secondary cancer for each treatment plan based on dose-volume distributions for the nontarget organs., Results: Proton beams reduced the expected incidence of radiation-induced secondary cancers for the RMS patient by a factor of >or=2 and for the medulloblastoma case by a factor of 8 to 15 when compared with either IM or conventional X-ray plans., Conclusions: The potential for a significant reduction in secondary cancers with pediatric cancers after using proton beams (forward planned or IM) in the treatment of RMS and MBD in children and adolescents represents an additional argument supporting the development of proton therapy for most radiotherapy indications in pediatric oncology.

Calculations of mortality due to secondary cancer have been investigated for its use in comparative treatment planning. A patient with Hodgkin's disease has been chosen as an example and has been planned with different radiation treatment modalities using photons and protons. The ICRP calculation scheme has been used to calculate mortality from dose distributions. To this purpose target volumes as well as critical structures have been outlined in the CT set of a patient with Hodgkin's disease. Dose distributions have been calculated using conventional as well as intensity modulated treatment techniques using photon and proton radiation. From the mean doses of each organ the mortality has been derived. Our work suggests that calculations of mortality can be useful in comparative treatment planning. Such mortality calculations can be helpful to find decisions between radiotherapy treatment techniques (intensity modulated or conventional treatment) or between different types of radiation (photons, electrons, protons, neutrons).

Probabilities for secondary cancer incidence have been estimated for a patient with Hodgkin's disease for whom treatment has been planned with different radiation modalities using photons and protons. The ICRP calculation scheme has been used to calculate cancer incidence from dose distributions. For this purpose, target volumes as well as critical structures have been outlined in the CT set of a patient with Hodgkin's disease. Dose distributions have been calculated using conventional as well as intensity-modulated treatment techniques using photon and proton radiation. The cancer incidence has been derived from the mean doses for each organ. The results of this work are: (a) Intensity-modulated treatment of Hodgkin's disease using nine photon fields (15 MV) results in nearly the same cancer incidence as treating with two opposed photon fields (6 MV). (b) Intensity-modulated treatment using nine proton fields (maximum energy 177.25 MeV) results in nearly the same cancer incidence as treating with one proton field (160 MeV). (c) Irradiation with protons using the spot scanning technique decreases the avoidable cancer incidence compared to photon treatment by a factor of about two. This result is independent of the number of beams used. Our work suggests that there are radiotherapy indications in which intensity-modulated treatments will result in little or no reduction of cancer incidence compared to conventional treatments. However, proton treatment can result in a lower cancer incidence than photon treatment.