Estimation of planning organ at risk volumes for ocular structures in dogs undergoing three-dimensional image-guided periocular radiotherapy with rigid bite block immobilization.

Planning organ at risk volume (PRV) estimates have been reported as methods for sparing organs at risk (OARs) during radiation therapy, especially for hypofractioned and/or dose-escalated protocols. The objectives of this retrospective, analytical, observational study were to evaluate peri-ocular OAR shifts and derive PRVs in a sample of dogs undergoing radiation therapy for periocular tumors. Inclusion criteria were as follows: dogs irradiated for periocular tumors, with 3D-image-guidance and at least four cone-beam CTs (CBCTs) used for position verification, and positioning in a rigid bite block immobilization device. Peri-ocular OARs were contoured on each CBCT and the systematic and random error of the shifts in relation to the planning CT position computed. The formula 1.3×Σ+0.5xσ was used to generate a PRV of each OAR in the dorsoventral, mediolateral, and craniocaudal axis. A total of 30 dogs were sampled, with 450 OARs contoured, and 2145 shifts assessed. The PRV expansion was qualitatively different for each organ (1-4 mm for the dorsoventral and 1-2 mm for the mediolateral and craniocaudal axes). Maximal PRV expansion was ≤4 mm and directional for the majority; most pronounced for corneas and retinas. Findings from the current study may help improve awareness of and minimization of radiation dose in peri-ocular OARs for future canine patients. Because some OARs were difficult to visualize on CBCTs and/ or to delineate on the planning CT, authors recommend that PRV estimates be institution-specific and applied with caution.

A model of radiation action based on nanodosimetry and the application to ultra-soft X-rays.

A radiation action model based on nanodosimetry is presented. It is motivated by the finding that the biological effects of various types of ionizing radiation lack a consistent relation with absorbed dose. It is postulated that the common fundamental cause of these effects is the production of elementary sublesions (DSB), which are created at a rate that is proportional to the probability to produce more than two ionisations within a volume of 10 base pairs of the DNA. The concepts of nanodosimetry allow for a quantitative characterization of this process in terms of the cumulative probability F2. The induced sublesions can interact in two ways to produce lethal damage. First, if two or more sublesions accumulate in a locally limited spherical volume of 3-10 nm in diameter, clustered DNA damage is produced. Second, consequent interactions or rearrangements of some of the initial damage over larger distances (~ µm) can produce additional lethal damage. From the comparison of theoretical predictions deduced from this concept with experimental data on relative biological effectiveness, a cluster volume with a diameter of 7.5 nm could be determined. It is shown that, for electrons, the predictions agree well with experimental data over a wide energy range. The only free parameter needed to model cell survival is the intersection cross-section which includes all relevant cell-specific factors. Using ultra-soft X-rays it could be shown that the energy dependence of cell survival is directly governed by the nanodosimetric characteristics of the radiation track structure. The cell survival model derived in this work exhibits exponential cell survival at a high dose and a finite gradient of cell survival at vanishing dose, as well as the dependence on dose-rate.

Using biologically based objectives to optimize boost intensity-modulated radiation therapy planning for brainstem tumors in dogs.

Irradiated brain tumors commonly progress at the primary site, generating interest in focal dose escalation. The aim of this retrospective observational study was to use biological optimization objectives for a modeling exercise with simultaneously-integrated boost IMRT (SIB-IMRT) to generate a dose-escalated protocol with acceptable late radiation toxicity risk estimate and improve tumor control for brainstem tumors in dogs safely. We re-planned 20 dog brainstem tumor datasets with SIB-IMRT, prescribing 20 × 2.81 Gy to the gross tumor volume (GTV) and 20 × 2.5 Gy to the planning target volume. During the optimization process, we used biologically equivalent generalized equivalent uniform doses (gEUD) as planning aids. These were derived from human data, calculated to adhere to normal tissue complication probability (NTCP) ≤5%, and converted to the herein used fractionation schedule. We extracted the absolute organ at risk dose-volume histograms to calculate NTCP of each individual plan. For planning optimization, gEUD(a = 4)  = 39.8 Gy for brain and gEUD(a = 6.3)  = 43.8 Gy for brainstem were applied. Mean brain NTCP was low with 0.43% (SD ±0.49%, range 0.01-2.04%); mean brainstem NTCP was higher with 7.18% (SD ±4.29%, range 2.87-20.72%). Nevertheless, NTCP of < 10% in brainstem was achievable in 80% (16/20) of dogs. Spearman's correlation between relative GTV and NTCP was high (ρ = 0.798, P < .001), emphasizing increased risk with relative size even with subvolume-boost. Including biologically based gEUD values into optimization allowed estimating NTCP during the planning process. In conclusion, gEUD-based SIB-IMRT planning resulted in dose-escalated treatment plans with acceptable risk estimate of NTCP < 10% in the majority of dogs with brainstem tumors. Risk was correlated with relative tumor size.

The probabilities of one- and multi-track events for modeling radiation-induced cell kill.

In view of the clinical importance of hypofractionated radiotherapy, track models which are based on multi-hit events are currently reinvestigated. These models are often criticized, because it is believed that the probability of multi-track hits is negligible. In this work, the probabilities for one- and multi-track events are determined for different biological targets. The obtained probabilities can be used with nano-dosimetric cluster size distributions to obtain the parameters of track models. We quantitatively determined the probabilities for one- and multi-track events for 100, 500 and 1000 keV electrons, respectively. It is assumed that the single tracks are statistically independent and follow a Poisson distribution. Three different biological targets were investigated: (1) a DNA strand (2 nm scale); (2) two adjacent chromatin fibers (60 nm); and (3) fiber loops (300 nm). It was shown that the probabilities for one- and multi-track events are increasing with energy, size of the sensitive target structure, and dose. For a 2 × 2 × 2 nm3 target, one-track events are around 10,000 times more frequent than multi-track events. If the size of the sensitive structure is increased to 100-300 nm, the probabilities for one- and multi-track events are of the same order of magnitude. It was shown that target theories can play a role for describing radiation-induced cell death if the targets are of the size of two adjacent chromatin fibers or fiber loops. The obtained probabilities can be used together with the nano-dosimetric cluster size distributions to determine model parameters for target theories.

Track-event theory of cell survival with second-order repair.

When fractionation schemes for hypofractionation and stereotactic body radiotherapy are considered, a reliable cell survival model at high dose is needed for calculating doses of similar biological effectiveness. In this work, a simple model for cell survival which is valid also at high dose is developed from Poisson statistics. It is assumed that a cell is killed by an event that is defined by two double-strand breaks on the same or different chromosomes. Two different mechanisms can produce events. A one-track event is always represented by two simultaneous double-strand breaks. A two-track event results in one double-strand break. Therefore, at least two two-track events on the same or different chromosomes are necessary to produce an event. It is assumed that two double-strand breaks can be repaired with a certain repair probability. Both the one-track events and the two-track events are statistically independent. From the stochastic nature of cell killing which is described by the Poisson distribution, the cell survival probability was derived. The model was fitted to experimental data. It was shown that a solution based on Poisson statistics exists for cell survival. It exhibits exponential cell survival at high dose and a finite gradient of cell survival at vanishing dose, which is in agreement with experimental cell studies. The model fits the experimental data as well as the LQ model and is based on two free parameters. It was shown that cell survival can be described with a simple analytical formula on the basis of Poisson statistics. This solution represents in the limit of large dose the typical exponential behavior and predicts cell survival as well as the LQ model.

Risk adaptive planning with biology-based constraints may lead to higher tumor control probability in tumors of the canine brain: A planning study.

BACKGROUND: Classical radiation protocols are guided by physical dose delivered homogeneously over the target. Protocols are chosen to keep normal tissue complication probability (NTCP) at an acceptable level. Organs at risk (OAR) adjacent to the target volume could lead to underdosage of the tumor and a decrease of tumor control probability (TCP). The intent of our study was to explore a biology-based dose escalation: by keeping NTCP for OAR constant, radiation dose was to be maximized, allowing to result in heterogeneous dose distributions. METHODS: We used computed tomography datasets of 25 dogs with brain tumors, previously treated with 10x4 Gy (40 Gy to PTV D50). We generated 3 plans for each patient: A) original treatment plan with homogeneous dose distribution, B) heterogeneous dose distribution with strict adherence to the same NTCPs as in A), and C) heterogeneous dose distribution with adherence to NTCP <5%. For plan comparison, TCPs and TCP equivalent doses (homogenous target dose which results in the same TCP) were calculated. To enable the use of the generalized equivalent uniform dose (gEUD) metric of the tumor target in plan optimization, the calculated TCP values were used to obtain the volume effect parameter a. RESULTS: As intended, NTCPs for all OARs did not differ from plan A) to B). In plan C), however, NTCPs were significantly higher for brain (mean 2.5% (SD±1.9, 95%CI: 1.7,3.3), p<0.001), optic chiasm (mean 2.0% (SD±2.2, 95%CI: 1.0,2.8), p=0.010) compared to plan A), but no significant increase was found for the brainstem. For 24 of 25 of the evaluated patients, the heterogenous plans B) and C) led to an increase in target dose and projected increase in TCP compared to the homogenous plan A). Furthermore, the distribution of the projected individual TCP values as a function of the dose was found to be in good agreement with the population TCP model. CONCLUSION: Our study is a first step towards risk-adaptive radiation dose optimization. This strategy utilizes a biologic objective function based on TCP and NTCP instead of an objective function based on physical dose constraints.

Systematic measurements of whole-body imaging dose distributions in image-guided radiation therapy.

PURPOSE: The full benefit of the increased precision of contemporary treatment techniques can only be exploited if the accuracy of the patient positioning is guaranteed. Therefore, more and more imaging modalities are used in the process of the patient setup in clinical routine of radiation therapy. The improved accuracy in patient positioning, however, results in additional dose contributions to the integral patient dose. To quantify this, absorbed dose measurements from typical imaging procedures involved in an image-guided radiation therapy treatment were measured in an anthropomorphic phantom for a complete course of treatment. The experimental setup, including the measurement positions in the phantom, was exactly the same as in a preceding study of radiotherapy stray dose measurements. This allows a direct combination of imaging dose distributions with the therapy dose distribution. METHODS: Individually calibrated thermoluminescent dosimeters were used to measure absorbed dose in an anthropomorphic phantom at 184 locations. The dose distributions from imaging devices used with treatment machines from the manufacturers Accuray, Elekta, Siemens, and Varian and from computed tomography scanners from GE Healthcare were determined and the resulting effective dose was calculated. The list of investigated imaging techniques consisted of cone beam computed tomography (kilo- and megavoltage), megavoltage fan beam computed tomography, kilo- and megavoltage planar imaging, planning computed tomography with and without gating methods and planar scout views. RESULTS: A conventional 3D planning CT resulted in an effective dose additional to the treatment stray dose of less than 1 mSv outside of the treated volume, whereas a 4D planning CT resulted in a 10 times larger dose. For a daily setup of the patient with two planar kilovoltage images or with a fan beam CT at the TomoTherapy unit, an additional effective dose outside of the treated volume of less than 0.4 mSv and 1.4 mSv was measured, respectively. Using kilovoltage or megavoltage radiation to obtain cone beam computed tomography scans led to an additional dose of 8-46 mSv. For treatment verification images performed once per week using double exposure technique, an additional effective dose of up to 18 mSv was measured. CONCLUSIONS: Daily setup imaging using kilovoltage planar images or TomoTherapy megavoltage fan beam CT imaging can be used as a standard procedure in clinical routine. Daily kilovoltage and megavoltage cone beam computed tomography setup imaging should be applied on an individual or indication based protocol. Depending on the imaging scheme applied, image-guided radiation therapy can be administered without increasing the dose outside of the treated volume compared to therapies without image guidance.

Systematic measurements of whole-body dose distributions for various treatment machines and delivery techniques in radiation therapy.

PURPOSE: Contemporary radiotherapy treatment techniques, such as intensity-modulated radiation therapy and volumetric modulated arc therapy, could increase the radiation-induced malignancies because of the increased beam-on time, i.e., number of monitor units needed to deliver the same dose to the target and the larger volume irradiated with low doses. In this study, whole-body dose distributions from typical radiotherapy patient plans using different treatment techniques and therapy machines were measured using the same measurement setup and irradiation intention. METHODS: Individually calibrated thermoluminescent dosimeters were used to measure absorbed dose in an anthropomorphic phantom at 184 locations. The dose distributions from 6 MV beams were compared in terms of treatment technique (3D-conformal, intensity-modulated radiation therapy, volumetric modulated arc therapy, helical TomoTherapy, stereotactic radiotherapy, hard wedges, and flattening filter-free radiotherapy) and therapy machine (Elekta, Siemens and Varian linear accelerators, Accuray CyberKnife and TomoTherapy). RESULTS: Close to the target, the doses from intensity-modulated treatments (including flattening filter-free) were below the dose from a static treatment plan, whereas the CyberKnife showed a larger dose by a factor of two. Far away from the treatment field, the dose from intensity-modulated treatments showed an increase in dose from stray radiation of about 50% compared to the 3D-conformal treatment. For the flattening filter-free photon beams, the dose from stray radiation far away from the target was slightly lower than the dose from a static treatment. The CyberKnife irradiation and the treatment using hard wedges increased the dose from stray radiation by nearly a factor of three compared to the 3D-conformal treatment. CONCLUSIONS: This study showed that the dose outside of the treated volume is influenced by several sources. Therefore, when comparing different treatment techniques, the dose ratios vary with distance to the isocenter. The effective dose outside the treated volume of intensity-modulated treatments with or without flattening filter was 10%-30% larger when compared to 3D-conformal radiotherapy. This dose increase is much lower than the monitor unit scaled effective dose from a static treatment.

Technical note: spatial resolution of proton tomography: impact of air gap between patient and detector.

PURPOSE: Proton radiography and tomography were investigated since the early 1970s because of its low radiation dose, high density resolution, and ability to image directly proton stopping power. However, spatial resolution is still a limiting factor. In this note, preliminary results of the impact of an air gap between detector system and patient on spatial resolution are presented. METHODS: Spatial resolution of proton radiography and tomography is governed by multiple Coulomb scattering (MCS) of the protons in the patient. In this note, the authors employ Monte Carlo simulations of protons traversing a 20 cm thick water box. Entrance and exit proton coordinate measurements were simulated for improved spatial resolution. The simulations were performed with and without a 5 cm air gap in front of and behind the patient. Loss of spatial resolution due to the air gap was studied for protons with different initial angular confusion. RESULTS: It was found that spatial resolution is significantly deteriorated when a 5 cm air gap between the position sensitive detector and the patient is included. For a perfect parallel beam spatial resolution worsens by about 40%. Spatial resolution is getting worse with increasing angular confusion and can reach 80%. CONCLUSIONS: When proton radiographies are produced by measuring the entrance and exit coordinates of the protons in front of and behind the patient the air gap between the detector and the patient can significantly deteriorate the spatial resolution of the system by up to 80%. An alternative would be to measure in addition to the coordinates also the exit and entrance angles of each proton. In principle, using the air gap size and proton angle, images can be reconstructed with the same spatial resolution than without air gap.

Tumour volume distribution can yield information on tumour growth and tumour control.

BACKGROUND: It is shown that tumour volume distributions can yield information on two aspects of cancer research: tumour induction and tumour control. MATERIALS AND METHODS: From the hypothesis that the intrinsic distribution of breast cancer volumes follows an exponential distribution, firstly the probability density function of tumour growth time was deduced via a mathematical transformation of the probability density functions of tumour volumes. In a second step, the distribution of tumour volumes was used to model the variation of the clonogenic cell number between patients in order to determine tumour control probabilities for radiotherapy patients. RESULTS: Distribution of lag times, i.e. the time from the appearance of the first fully malignant cell until a clinically observable cancer, can be used to deduce the probability of tumour induction as a function of patient age. The integration of the volume variation with a Poisson-TCP model results in a logistic function which explains population-averaged survival data of radiotherapy patients. CONCLUSIONS: The inclusion of tumour volume distributions into the TCP formalism enables a direct link to be deduced between a cohort TCP model (logistic) and a TCP model for individual patients (Poisson). The TCP model can be applied to non-uniform tumour dose distributions.

A concept for anisotropic PTV margins including rotational setup uncertainties and its impact on the tumor control probability in canine brain tumors.

Objective.In this modelling study, we pursued two main goals. The first was to establish a new CTV-to-PTV expansion which considers the closest and most critical organ at risk (OAR). The second goal was to investigate the impact of the planning target volume (PTV) margin size on the tumor control probability (TCP) and its dependence on the geometrical setup uncertainties. The aim was to achieve a smaller margin expansion close to the OAR while allowing a moderately larger expansion in less critical areas further away from the OAR and whilst maintaining the TCP.Approach.Imaging data of radiation therapy plans from pet dogs which had undergone radiation therapy for brain tumor were used to estimate the clinic specific rotational setup uncertainties. A Monte-Carlo methodology using a voxel-based TCP model was used to quantify the implications of rotational setup uncertainties on the TCP. A combination of algorithms was utilized to establish a computational CTV-to-PTV expansion method based on probability density. This was achieved by choosing a center of rotation close to an OAR. All required software modules were developed and integrated into a software package that directly interacts with the Varian Eclipse treatment planning system.Main results.Several uniform and non-isotropic PTVs were created. To ensure comparability and consistency, standardized RT plans with equal optimization constraints were defined, automatically applied and calculated on these targets. The resulting TCPs were then computed, evaluated and compared.Significance.The non-isotropic margins were found to result in larger TCPs with smaller margin excess volume. Further, we presented an additional application of the newly established CTV-to-PTV expansion method for radiation therapy of the spinal axis of human patients.

Comparative simulations of neutron dose in soft tissue and phantom materials for proton and carbon ion therapy with actively scanned beams.

PURPOSE: In the clinical environment phantom materials are usually used to simulate the patient for neutron dosimetric measurements. It is not clear that the results of such phantom measurements represent the actual neutron dose in the patient. The aim of this study was to compare the difference in secondary neutron equivalent dose for different phantom materials to that in human tissue, for both proton and carbon ion radiation therapy. METHODS: In order to compare the neutron equivalent dose induced by primary particles in different materials, Monte Carlo simulations were performed using the FLUKA Monte Carlo package. The scored dosimetric quantities were absorbed dose and neutron ambient dose equivalent for monoenergetic proton and carbon ion beams of clinically relevant energies. It was shown that neutron equivalent dose, for which no scoring routine exists in the current FLUKA release, can be approximated by neutron ambient dose equivalent within 4% for the investigated energies of proton and carbon ion beams. RESULTS: The Monte Carlo simulations performed in this work showed differences in neutron ambient dose equivalent in radiation therapy phantom materials compared to ICRP soft tissue for primary proton and carbon ion beams. For Alderson soft tissue the maximum deviation was 11% for protons and 8% for carbon ions. For water the maximum deviation was 10% for protons and 9% for carbon ions. In the case of RW3 solid water, the maximum deviation compared to ICRP soft tissue was as large as 28% and 21% for protons and carbon ions, respectively. CONCLUSIONS: Alderson soft tissue and water are suitable phantom materials for neutron dosimetry for the accuracy which is achievable. When using solid water phantoms, the chemical and therefore nuclear composition of the phantom material has to be accounted for.

A Novel Analytical Population Tumor Control Probability Model Includes Cell Density and Volume Variations: Application to Canine Brain Tumor.

PURPOSE: Tumor control probability (TCP) models based on Poisson statistics characterize the distribution of surviving clonogens. Thus enabling the calculation of TCP for individuals. To mathematically describe clinically observed survival data of patient cohorts it is necessary to extend the Poisson TCP model. This is typically done by either incorporating variations of model parameters or by using an empirical logistic model. The purpose of this work is the development of an analytical population TCP model by mechanistic extension of the Possion model. METHODS AND MATERIALS: The frequency distribution of gross tumor volumes was used to incorporate tumor volume variations into the TCP model. Additionally the tumor cell density variation was incorporated. Both versions of the population TCP model were fitted to clinical data and compared to existing literature. RESULTS: It was shown that clinically observed brain tumor volumes of dogs undergoing radiotherapy are distributed according to an exponential distribution. The average gross tumor volume size was 3.37 cm3. Fitting the population TCP model including the volume variation using linear-quadratic and track-event model yieldedα=0.36Gy--1a, ß=0.045Gy--2, a=0.9yr--1, TD=5.0d,and p=.36Gy--1, q=0.48Gy--1, a=0.80yr--1, TD=3.0d, respectively. Fitting the population TCP model including both the volume and cell density variation yielded α=0.43Gy--1, ß=0.0537Gy--2, a=2.0yr--1, TD=3.0d, σ=2.5,and p=.43Gy--1, q=0.55Gy--1, a=2.0yr--1, TD=2.0d, σ=3.0,respectively. CONCLUSIONS: Two sets of radiobiological parameters were obtained which can be used for quantifying the TCP for radiation therapy of brain tumors in dogs. We established a mechanistic link between the poisson statistics based individual TCP model and the logistic TCP model. This link can be used to determine the radiobiological parameters of patient specific TCP models from published fits of logistic models to cohorts of patients.

Reducing margins for abdominopelvic tumours in dogs: Impact on dose-coverage and normal tissue complication probability.

Image-guided, intensity modulated radiation therapy (IG-IMRT) reduces dose to pelvic organs at risk without losing dose coverage to the planning target volume (PTV) and might permit margin reductions potentially resulting in lower toxicity. Appropriate PTV margins have not been established for IG-IMRT in abdominopelvic tumours in dogs, and herein we explore if our usual PTV 5 mm margin can be reduced further. Datasets from dogs that underwent IG-IMRT for non-genitourinary abdominopelvic neoplasia with 5 mm-PTV expansion were included in this retrospective virtual study. The clinical target volumes and organs at risk (OAR) colon, rectum, spinal cord were adapted to each co-registered cone-beam computed tomography (CBCT) used for positioning. New treatment plans were generated and smaller PTV margins of 3 mm and 4 mm evaluated with respect to adequate dose coverage and normal tissue complication probability (NTCP) of OAR. Ten dogs with a total of 70 CBCTs were included. Doses to the OAR of each CBCT deviated mildly from the originally planned doses. In some plans, insufficient build-up of the high dose-area at the body surface was found due to inadequate or missing bolus placement. Overall, the margin reduction to 4 mm or 3 mm did not impair dose coverage and led to significantly lower NTCP in all OAR except for spinal cord delayed myelopathy. However, overall NTCP for spinal cord was very low (<4%). PTV-margins depend on patient immobilization and treatment technique and accuracy. IG-IMRT allows treatment with very small margins in the abdominopelvic region, ensuring appropriate target dose coverage, while minimizing NTCP.

Hypofractionated radiotherapy has the potential for second cancer reduction.

BACKGROUND AND PURPOSE: A model for carcinoma and sarcoma induction was used to study the dependence of carcinogenesis after radiotherapy on fractionation. MATERIALS AND METHODS: A cancer induction model for radiotherapy doses including fractionation was used to model carcinoma and sarcoma induction after a radiation treatment. For different fractionation schemes the dose response relationships were obtained. Tumor induction was studied as a function of dose per fraction. RESULTS: If it is assumed that the tumor is treated up to the same biologically equivalent dose it was found that large dose fractions could decrease second cancer induction. The risk decreases approximately linear with increasing fraction size and is more pronounced for sarcoma induction. Carcinoma induction decreases by around 10% per 1 Gy increase in fraction dose. Sarcoma risk is decreased by about 15% per 1 Gy increase in fractionation. It is also found that tissue which is irradiated using large dose fractions to dose levels lower than 10% of the target dose potentially develop less sarcomas when compared to tissues irradiated to all dose levels. This is not observed for carcinoma induction. CONCLUSIONS: It was found that carcinoma as well as sarcoma risk decreases with increasing fractionation dose. The reduction of sarcoma risk is even more pronounced than carcinoma risk. Hypofractionation is potentially beneficial with regard to second cancer induction.

Dose-response relationship for lung cancer induction at radiotherapy dose.

Cancer induction after radiation therapy is a severe side effect. It is therefore of interest to predict the probability of second cancer appearance for the treated patient. Currently there is large uncertainty about the shape of the dose-response relationship for carcinogenesis for most cancer types at high dose levels. In this work a dose-response relationship for lung cancer is derived based on (i) the analysis of lung cancer induction after Hodgkin's disease, (ii) a cancer risk model developed for high doses including fractionation based on the linear quadratic model, and (iii) the reconstruction of treatment plans for Hodgkin's patients treated with radiotherapy. The fitted model parameters for an α/ß=3 Gy were α=0.061Gy(-1) and R=0.84. The value for α is in agreement with analysis of normal tissue complications of the lung after radiation therapy. The repopulation/repair parameter R is large, but seems to be characteristic for lung tissue which is sensitive with regard to fractionation. Lung cancer risk is according to this model for small doses consistent with the finding of the A-bomb survivors, has a maximum at doses of around 15 Gy and drops off only slightly at larger doses. The predicted EAR for lung after radiotherapy of Hodgkin's disease is 18.4/10000PY which can be compared to the findings of several epidemiological studies were EAR for lung varies between 9.7 and 21.5/10000PY.

A complication probability study for a definitive-intent, moderately hypofractionated image-guided intensity-modulated radiotherapy protocol for anal sac adenocarcinoma in dogs.

Previous trials showed the importance of administering radiation therapy (RT) with small doses per fraction in canine pelvic tumours to maintain acceptable toxicity levels. With increased accuracy/precision of RT, namely intensity-modulated RT (IMRT), this approach might be challenged. Theoretical toxicity calculations for a new definitive-intent moderately hypofractionated RT protocol for canine anal sac adenocarcinomas (ASAC) were performed, focussing on the risk of toxicity in pelvic organs at risk (OAR). Computed tomography datasets of 18 dogs with stage 3b ASAC were included. Re-planning with margins for daily image-guidance/IMRT was performed and a new protocol isoeffective to previously described definitive-intent protocols was computed. Dose-volume information were derived from individual plans and used for normal tissue complication probability (NTCP) computations. A 12 × 3.8 Gy protocol was computed for risk estimation. Tumour volumes ranged from 27.9 to 820.4 cm3 (mean 221.3 cm3 ± 188.9). For late rectal toxicity/bleeding ≥grade 2, median risk probability was 2.3% inter quartile range (IQR: 5.9; 95% confidence interval (CI): 1.2, 8.4) (rho = 0.436) and 3.4% (IQR: 0.96; 95%CI: 3.1, 4.0) (rho = 0.565), respectively. Median late toxicities in urinary bladder, kidneys and small bowel were <1%, except in one kidney. Myelopathy/myelonecrosis had a median risk probability of 4.1% (IQR: 23.5; 95%CI: 2.1, 25.2) (rho = 0.366) and 5.6% (IQR: 13.5; 95%CI: 3.1, 14.1) (rho = 0.363), respectively. However, graded risk showed a probability estimate for late spinal cord toxicity of ≥5% in 8/18 patients. The daily-imaging IMRT 12 × 3.8 Gy protocol for canine ASAC seems tolerable for most cases, even in advanced disease. Theoretical dose computations serve as estimate, but are safe measures before implementing new protocols into clinical use.

TRACK EVENT THEORY: A CELL SURVIVAL and RBE MODEL CONSISTENT WITH NANODOSIMETRY.

A simple model for cell survival which is valid also at high dose has been developed. The model parameters can be traced back to measurable quantities from nanodosimetry. It is assumed that a cell is killed by an event which is defined by two or more double strand breaks in differently sized lethal interaction volumes (LIVs). Two different mechanisms can produce events, one-track events by one-particle track and two-track events by two. One- and two-track events are statistically independent. From the stochastic nature of cell killing which is described by the Poisson distribution, the cell survival probability was derived. The ratio of the number of one- and two-track events can be directly expressed in terms of nanodosimetry by the probability F2 that at least two ionizations are produced in a basic interaction volume (5-10 base pairs). From the model, relative biological effectiveness (RBE) can be derived which depends only on F2 and the size of the LIV. The expression for RBE fits experimental data with satisfying quality.

Comparative evaluation of a novel, moderately hypofractionated radiation protocol in 56 dogs with symptomatic intracranial neoplasia.

BACKGROUND: Use of strongly hypofractionated radiation treatments in dogs with intracranial neoplasia did not improve outcomes and yielded increased rates of toxicosis. OBJECTIVES: To evaluate safety and efficacy of a new, moderately hypofractionated radiation protocol of 10 × 4 Gy compared to a standard protocol. ANIMALS: Convenience sample of 56 client-owned dogs with primary symptomatic brain tumors. METHODS: Retrospective observational study. Twenty-six dogs were assigned to the control standard protocol of 20 × 2.5 Gy (group A) and 30 dogs to the new protocol of 10 × 4 Gy (group B), assigned on owners' informed consent. Statistical analysis was conducted under the "as treated" regime, using Kaplan-Meier and Cox-regression analysis. Treatment was delivered with technically advanced image-guided radiation therapy. The 2 treatment groups were compared in terms of outcome and signs of toxicosis. RESULTS: Overall progression-free interval (PFI) and overall survival (OS) time were favorable, with 663 (95%CI: 497;828) and 637 (95%CI: 403;870) days, respectively. We found no significant difference between the two groups: PFI for dogs in group A vs B was 608 (95%CI: 437;779) days and mean (median not reached) 863 (95%CI: 644;1083) days, respectively (P = .89), and OS for dogs in group A vs B 610 (95%CI: 404;816) and mean (median not reached) 796 (95%CI: 586;1007) days (P = .83). CONCLUSION AND CLINICAL IMPORTANCE: In conclusion, 10 × 4 Gy is a safe and efficient protocol for treatment of primary intracranial neoplasia and future dose escalation can be considered.

The impact of dose escalation on secondary cancer risk after radiotherapy of prostate cancer.

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.