[18F]-FMISO PET/MRI Imaging Shows Ischemic Tissue around Hematoma in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH), being the most severe cerebrovascular disease, accounts for 10-15% of all strokes. Hematoma expansion is one of the most important factors associated with poor outcome in intracerebral hemorrhage (ICH). Several studies have suggested that an "ischemic penumbra" might arise when the hematoma has a large expansion, but clinical studies are inconclusive. We performed a preclinical study to demonstrate the presence of hypoxic-ischemic tissue around the hematoma by means of longitudinal [18F]-fluoromisonidazole ([18F]-FMISO) PET/MRI studies over time in an experimental ICH model. Our results showed that all [18F]-FMISO PET/MRI images exhibited hypoxic-ischemic tissue around the hematoma area. A significant increase of [18F]-FMISO uptake was found at 18-24 h post-ICH when the maximum of hematoma volume is achieved and this increase disappeared before 42 h. These results demonstrate the presence of hypoxic tissue around the hematoma and open the possibility of new therapies aimed to reduce ischemic damage associated with ICH.

Texture analysis of high-resolution dedicated breast 18 F-FDG PET images correlates with immunohistochemical factors and subtype of breast cancer.

PURPOSE: This study aims to determine whether PET textural features measured with a new dedicated breast PET scanner reflect biological characteristics of breast tumors. METHODS: One hundred and thirty-nine breast tumors from 127 consecutive patients were included in this analysis. All of them underwent a 18F-FDG PET scan before treatment. Well-known PET quantitative parameters such as SUV m a x , SUV m e a n , metabolically active tumor volume (MATV) and total lesion glycolysis (TLG) were extracted. Together with these parameters, local, regional, and global heterogeneity descriptors, which included five textural features (TF), were computed. Immunohistochemical classification of breast cancer considered five subtypes: luminal A like (LA), luminal B like/HER2 - (LB -), luminal B like/HER2+ (LB+), HER2-positive-non-luminal (HER2pnl), and triple negative (TN). Associations between PET features and tumor characteristics were assessed using non-parametric hypothesis tests. RESULTS: Along with well-established associations, new correlations were found. HER2-positive tumors had significantly higher uptake (p < 0.001, AUCs > 0.70) and presented different global and regional heterogeneity (p = 0.002, p = 0.016, respectively, AUCs < 0.70). Nine out of ten analyzed features were significantly associated with immunohistochemical subtype. Uptake was lower for LA tumors (p < 0.001) with AUCs ranging from 0.71 to 0.88 for each subgroup comparison. Heterogeneity metrics were significantly associated when comparing LA and LB - (p < 0.01), being regional heterogeneity metrics more discriminative than any other parameter (AUC = 0.80 compared to AUC = 0.71 for SUV). LB+ and HER2pnl tumors also showed more regional heterogeneity than LA tumors (AUCs = 0.79 and 0.84, respectively). After comparison with whole-body PET studies, we observed an overall improvement in the classification ability of both non-heterogeneity metrics and textural features. CONCLUSIONS: PET parameters extracted from high-resolution dedicated breast PET images showed new and stronger correlations with immunohistochemical factors and immunohistochemical subtype of breast cancer compared to whole-body PET.

Adaptive biokinetic modelling of iodine-131 in thyroid cancer treatments: implications on individualised internal dosimetry.

Nowadays therapies involving radioiodine (I-131) represent 84% of the total metabolic treatments in Europe, according to the last report of the European Association of Nuclear Medicine in relation to treatment planning for molecular radiotherapy. Last recommendations of the European Council, i.e. 2013/59/Euroatom, mandates that metabolic treatments should be planned according to the radiation doses delivered to individual patients, analogous to external beam radiotherapy. In this work, we present a novel biokinetic model for I-131 that allows on to obtain realistic activity distributions for particular patients with thyroid cancer in absence of metastasis. Other models existing in the literature present either a too simple metabolic description to obtain realistic results or a too complex one for adapting the model to individual patients, and many of these models are not indicated for metabolic treatments. The individualisation of activity distribution is obtained by an optimisation method that adjusts our model to a set of experimental measurements. Significant differences in terms of absorbed doses are observed between our model and the standard generalist models, especially in terms of red marrow absorbed dose.

Characterising endourologist learning curve during percutaneous nephrolithotomy: implications on occupational dose and patients.

In this study we have characterised the learning curve for percutaneous nephrolithotomy procedures over 301 cases for six years. Different surrogate parameters of clinical expertise have been used, such as dose area product, total procedure time, fluoroscopy time and personal equivalent doses. In addition, two different endourologists have been monitored; one of whom had specific Radiation Protection training (ICRP 85). Eye lens dose was estimated from thermoluminescent dosimeters. Significant differences were observed between both endourologists, especially in the fluoroscopy time. Finally, both entrance skin dose and effective doses of patients have been determined.

Characterizing endourologist learning curve during percutaneous nephrolithotomy: implications on occupational dose and patients.

In this study we have characterized the learning curve of percutaneous nephrolithotomy procedures over 301 cases for six years. Different surrogate parameters of clinical expertise have been used, such as dose area product, total procedure time, fluoroscopy time and personal equivalent doses. In addition, two different endourologists have been monitored; one of whom was subjected to a specific Radiation Protection training (ICRP 85). Eye lens dose is estimated from thermoluminescent dosimeters. Significant differences are observed between both endourologists, especially in the fluoroscopy time. Finally, both entrance skin dose and effective doses of patients have been determined.

Evaluation and optimization of occupational eye lens dosimetry during positron emission tomography (PET) procedures.

The last recommendations of the International Commission on Radiological Protection for eye lens dose suggest an important reduction on the radiation limits associated with early and late tissue reactions. The aim of this work is to quantify and optimize the eye lens dose associated to nurse staff during positron emission tomography (PET) procedures. PET is one of the most important diagnostic methods of oncological and neurological cancer disease involving an important number of workers exposed to the high energy isotope F-18. We characterize the relevant stages as preparation and administration of monodose syringes in terms of occupational dose. A direct reading silicon dosimeter was used to measure the lens dose to staff. The highest dose of radiation was observed during preparation of the fluorodesoxyglucose (FDG) syringes. By optimizing a suitable vials' distribution of FDG we find an important reduction in occupational doses. Extrapolation of our data to other clinical scenarios indicates that, depending on the work load and/or syringes activity, safety limits of the dose might be exceeded.

Radiobiological Meta-Analysis of the Response of Prostate Cancer to Different Fractionations: Evaluation of the Linear-Quadratic Response at Large Doses and the Effect of Risk and ADT.

The purpose of this work was to investigate the response of prostate cancer to different radiotherapy schedules, including hypofractionation, to evaluate potential departures from the linear-quadratic (LQ) response, to obtain the best-fitting parameters for low-(LR), intermediate-(IR), and high-risk (HR) prostate cancer and to investigate the effect of ADT on the radiobiological response. We constructed a dataset of the dose-response containing 87 entries/16,536 patients (35/5181 LR, 32/8146 IR, 20/3209 HR), with doses per fraction ranging from 1.8 to 10 Gy. These data were fit to tumour control probability models based on the LQ model, linear-quadratic-linear (LQL) model, and a modification of the LQ (LQmod) model accounting for increasing radiosensitivity at large doses. Fits were performed with the maximum likelihood expectation methodology, and the Akaike information criterion (AIC) was used to compare the models. The AIC showed that the LQ model was superior to the LQL and LQmod models for all risks, except for IR, where the LQL model outperformed the other models. The analysis showed a low α/ß for all risks: 2.0 Gy for LR (95% confidence interval: 1.7-2.3), 3.4 Gy for IR (3.0-4.0), and 2.8 Gy for HR (1.4-4.2). The best fits did not show proliferation for LR and showed moderate proliferation for IR/HR. The addition of ADT was consistent with a suppression of proliferation. In conclusion, the LQ model described the response of prostate cancer better than the alternative models. Only for IR, the LQL model outperformed the LQ model, pointing out a possible saturation of radiation damage with increasing dose. This study confirmed a low α/ß for all risks.

A Biomathematical Model of Tumor Response to Radioimmunotherapy With αPDL1 and αCTLA4.

There is evidence of synergy between radiotherapy and immunotherapy. Radiotherapy can increase liberation of tumor antigens, causing activation of antitumor T-cells. This effect can be boosted with immunotherapy. Radioimmunotherapy has potential to increase tumor control rates. Biomathematical models of response to radioimmunotherapy may help on understanding of the mechanisms affecting response, and assist clinicians on the design of optimal treatment strategies. In this work we present a biomathematical model of tumor response to radioimmunotherapy. The model uses the linear-quadratic response of tumor cells to radiation (or variation of it), and builds on previous developments to include the radiation-induced immune effect. We have focused this study on the combined effect of radiotherapy and αPDL1/ αCTLA4 therapies. The model can fit preclinical data of volume dynamics and control obtained with different dose fractionations and αPDL1/ αCTLA4. A biomathematical study of optimal combination strategies suggests that a good understanding of the involved biological delays, the biokinetics of the immunotherapy drug, and the interplay between them, may be of paramount importance to design optimal radioimmunotherapy schedules. Biomathematical models like the one we present can help to interpret experimental data on the synergy between radiotherapy and immunotherapy, and to assist in the design of more effective treatments.

Variation of the relative biological effectiveness with fractionation in proton therapy: Analysis of prostate cancer response.

BACKGROUND: In treatment planning for proton therapy a constant Relative Biological Effectiveness (RBE) of 1.1 is used, disregarding variations with linear energy transfer, clinical endpoint, or fractionation. PURPOSE: To present a methodology to analyze the variation of RBE with fractionation from clinical data of tumor control probability (TCP) and to apply it to study the response of prostate cancer to proton therapy. METHODS AND MATERIALS: We analyzed the dependence of the RBE on the dose per fraction by using the LQ model and the Poisson TCP formalism. Clinical tumor control probabilities for prostate cancer (low and intermediate risk) treated with photon and proton therapy for conventional fractionation (2 Gy(RBE)×37 fractions), moderate hypofractionation (3 Gy(RBE)×20 fractions) and hypofractionation (7.25 Gy(RBE)×5 fractions) were obtained from the literature and analyzed aiming at obtaining the RBE and its dependence on the dose per fraction. RESULTS: The theoretical analysis of the dependence of the RBE on the dose per fraction showed three distinct regions with RBE monotonically decreasing, increasing or staying constant with the dose per fraction, depending on the change of (α, ß) values between photon and proton irradiation (the equilibrium point being at (αp /ßp ) = (αX /ßX )(αX /αp )). An analysis of the clinical data showed RBE values that decline with increasing dose per fraction: for low risk RBE≈1.124, 1.119, and 1.102 for 1.82 Gy, 2.73 Gy and 6.59 Gy per fraction (physical proton doses), respectively; for intermediate risk RBE≈1.119 and 1.102 for 1.82 Gy and 6.59 Gy per fraction (physical proton doses), respectively. These values are nonetheless very close to the nominal 1.1 value. CONCLUSIONS: In this study, we have presented a methodology to analyze the RBE for different fractionations, and we used it to study clinical data for prostate cancer and evaluate the RBE versus dose per fraction. The analysis shows a monotonically decreasing RBE with increasing dose per fraction, which is expected from the LQ formalism and the changes in (α, ß) values between photon and proton irradiation. However, the calculations in this study have to be considered with care as they may be biased by limitations in the modeling assumptions and/or by the clinical data set used for the analysis.

Tomotherapy-like versus VMAT-like treatments: a multicriteria comparison for a prostate geometry.

PURPOSE: To perform a methodological comparison of volumetric modulated arc therapy (VMAT)-like and tomotherapy-like techniques for a prostate geometry, exploring the dependence on machine, delivery, and optimization parameters of cost function values optimized for each technique. METHODS: A gradient-descent algorithm is used to optimize tomotherapy-like treatments, while VMAT-like optimization is carried out using a direct-aperture simulated annealing algorithm with 180 control points equispaced at 2° angles. Dose distributions are linked to fluences via a three-dimensional double-gaussian pencil beam model. Plans are optimized for a prostate geometry, outlined according to the CHHiP protocol. The cost function used for optimization contains ten simple functions, each of which describes a single planning objective. These functions are split into three structure groups according to whether they are used to control PTV, rectal or bladder dose levels. Different optimizations have been performed by varying the relative weights of each of these structure groups, exploring in this way a three-dimensional Pareto front. Plan quality is studied according to the value of the optimized cost function and the relative Euclidean distance between the components of the cost function and those of the nearest plan lying on a reference Pareto front obtained for tomotherapy-like plans generated using a 1 cm fan-beam width and 1/3 pitch. RESULTS: The quality of tomotherapy-like optimization depends on the fan-beam width, s, and rotation pitch, p, used to deliver the treatment. These values together define the effective longitudinal resolution with which fluence can be modulated, and lower cost function values are obtained for treatments optimized with tighter pitches and narrower fan-beam widths (higher modulation resolution). On the other hand, the cost function values of VMAT-like optimizations depends on the optimization running time, leaf displacement constraints, and number of arcs employed, as well as on the size of the beamlets used in the optimization (a change in leaf width from 5 to 10 mm clearly worsens the value of the objective function, but only a marginal improvement is observed when the leaf movement discretization step is reduced from 5 to 5/3 mm). However, for no combination of these parameter values did VMAT-like optimizations match the cost function values of optimized tomo-like plans obtained for s = 1 cm and p = 1∕3 (or 1/2). This is the case all across the Pareto front. On the other hand, cost function values of VMAT-like plans are generally lower than those of optimized tomotherapy-like plans obtained for s = 2.5 cm. CONCLUSIONS: Tomotherapy-like plans created for the prostate geometry using a 1 cm fan-beam width and pitches of 1/3 or 1/2 have lower cost function values than VMAT-like plans, although the associated dosimetric improvements are quite small, both techniques generating very good dose distributions. When a 2.5 cm wide fan-beam is used for tomotherapy-like treatments the pattern is reversed, the tomotherapy-like plans having higher cost functions than the VMAT-like ones.

Correction factors for A1SL ionization chamber dosimetry in TomoTherapy: machine-specific, plan-class, and clinical fields.

PURPOSE: Recently, an international working group on nonstandard fields presented a new formalism for ionization chamber reference dosimetry of small and nonstandard fields [Alfonso et al., Med. Phys. 35, 5179-5186 (2008)] which has been adopted by AAPM TG-148. This work presents an experimental determination of the correction factors for reference dosimetry with an Exradin A1SL thimble ionization chamber in a TomoTherapy unit, focusing on: (i) machine-specific reference field, (ii) plan-class-specific reference field, and (iii) two clinical treatments. METHODS: Ionization chamber measurements were performed in the TomoTherapy unit for intermediate (machine-specific and plan-class-specific) calibration fields, based on the reference conditions defined by AAPM TG-148, and two clinical treatments (lung and head-and-neck). Alanine reference dosimetry was employed to determine absorbed dose to water at the point of interest for the fields under investigation. The corresponding chamber correction factors were calculated from alanine to ionization chamber measurements ratios. RESULTS: Two different methods of determining the beam quality correction factor k(Q,Q(0) ) for the A1SL ionization chamber in this TomoTherapy unit, where reference conditions for conventional beam quality determination cannot be met, result in consistent values. The observed values of overall correction factors obtained for intermediate and clinical fields are consistently around 0.98 with a typical expanded relative uncertainty of 2% (k = 2), which when considered make such correction factors compatible with unity. However, all of them are systematically lower than unity, which is shown to be significant when a hypothesis test assuming a t-student distribution is performed (p=1.8×10(-2)). Correction factors k(Q(clin),Q(pcsr) ) (f(clin),f(pcsr) ) and k(Q(clin),Q(msr) ) (f(clin),f(msr) ), which are needed for the computation of field factors for relative dosimetry of clinical beams, have been found to be very close to unity for two clinical treatments. CONCLUSIONS: The results indicate that the helical field deliveries in this study (including two clinical fields) do not introduce changes on the ion chamber correction factors for dosimetry. For those two specific clinical cases, ratios of chamber readings accurately represent field output factors. The values observed here for intermediate calibration fields are in agreement with previously published data based on alanine dosimetry but differ from values recently reported obtained via radiochromic dosimetry.

Numerical modeling of air-vented parallel plate ionization chambers for ultra-high dose rate applications.

PURPOSE: Air-vented ionization chambers have been the secondary standard for radiation dosimetry since the origins of radiation metrology. However, the feasibility of their use in ultra-high dose rate pulsed beams has been a matter of discussion, as large losses are caused by ion recombinations and no suitable theoretical model is available for their correction. The theories developed by Boag and his contemporaries since the 1950s, which have provided the standard ion recombination correction factor in clinical dosimetry, do not provide an accurate description when used under the limit conditions of ultra-high dose rates (UHDRs). Moreover, the high-ion recombination effects of ionization chambers under extreme dose-rate applications are an obstacle to the development of adequate dosimetry standards. METHODS: In this article, the charge carrier transport equations within a parallel plate ionization chamber (PPIC) have been solved numerically with a double aim. First, this numerical model provides a more accurate tool that can be used to evaluate ion recombination correction for established PPICs in pulsed ultra-high dose rate regimes. Second, studying the chamber behavior in detail allow as to explore the limits of new chamber designs in order to improve their performance under UHDRs. The model presented here has been tested by measuring the instantaneous current of one unit of a Roos chamber (i.e., the time-resolved current during and after the irradiation pulse under UHDR conditions) and comparing these results with the absolute value of the simulated current. RESULTS: The experimental data show consistent agreement with the results obtained using the numerical model. The experimental instantaneous current reveals effects such as the variation of the free electron fraction with the dose per pulse that are supported by the numerical model but cannot be explained in the framework of Boag's theory. CONCLUSIONS: Numerical solutions of the charge carrier released and transport in ionization chambers are able to estimate the effects observed when PPICs are irradiated with ultra-high dose rate beams and to provide new insight into processes related to recombination losses at UHDRs. These models can be reliably extended to include regions where current analytical solutions are not valid. An agreement of better than 5 % between the experimental and simulated effective free electron fraction is found. We were able to reproduce the instantaneous current from a Roos chamber. The discrepancies observed between the experimental data and the numerical simulations can be attributed to the uncertainty about the transport parameters involved in the calculation.

Development of an ultra-thin parallel plate ionization chamber for dosimetry in FLASH radiotherapy.

BACKGROUND: Conventional air ionization chambers (ICs) exhibit ion recombination correction factors that deviate substantially from unity when irradiated with dose per pulse magnitudes higher than those used in conventional radiotherapy. This fact makes these devices unsuitable for the dosimetric characterization of beams in ultra-high dose per pulse as used for FLASH radiotherapy. PURPOSE: We present the design, development, and characterization of an ultra-thin parallel plate IC that can be used in ultra-high dose rate (UHDR) deliveries with minimal recombination. METHODS: The charge collection efficiency (CCE) of parallel plate ICs was modeled through a numerical solution of the coupled differential equations governing the transport of charged carriers produced by ionizing radiation. It was used to find out the optimal parameters for the purpose of designing an IC capable of exhibiting a linear response with dose (deviation less than 1%) up to 10 Gy per pulse at 4 µ $\umu$ s pulse duration. As a proof of concept, two vented parallel plate IC prototypes have been built and tested in different ultra-high pulse dose rate electron beams. RESULTS: It has been found that by reducing the distance between electrodes to a value of 0.25 mm it is possible to extend the dose rate operating range of parallel plate ICs to ultra-high dose per pulse range, at standard voltage of clinical grade electrometers, well into several Gy per pulse. The two IC prototypes exhibit behavior as predicted by the numerical simulation. One of the so-called ultra-thin parallel plate ionization chamber (UTIC) prototypes was able to measure up to 10 Gy per pulse, 4 µ $\umu$ s pulse duration, operated at 300 V with no significant deviation from linearity within the uncertainties (ElectronFlash Linac, SIT). The other prototype was tested up to 5.4 Gy per pulse, 2.5 µ $\umu$ s pulse duration, operated at 250 V with CCE higher than 98.6% (Metrological Electron Accelerator Facility, MELAF at Physikalisch-Technische Bundesanstalt, PTB). CONCLUSIONS: This work demonstrates the ability to extend the dose rate operating range of ICs to ultra-high dose per pulse range by reducing the spacing between electrodes. The results show that UTICs are suitable for measurement in UHDR electron beams.

Numbers of beam angles required for near-optimal IMRT: theoretical limits and numerical studies.

PURPOSE: To derive limits on the numbers of beams needed to deliver near-optimal IMRT, and to assess the accuracy of the limits. METHODS: The authors four different limits have been derived. One, K(A), has been obtained by coupling Fourier techniques with a proof used to obtain Bortfeld's limit, K, that if all the cross-profiles of a many-field plan can be represented as polynomials of order (K-1) over the range [-R, + R], then within the radius R circle an identical dose-distribution can be created using just K fields. Two further limits, K(H) and K(N), have been obtained using sampling theory, the K(N) limit describing fields spaced at the Nyquist frequency. K(N) can be generalized to K(N,Fbeamlet), a limit that accounts for the finite size of the beamlets from which modulated fields are constructed. Using Bortfeld's theoretical framework, the accuracy of the limits has been explored by testing how well the cross-profiles of an 8 MV double-Gaussian pencil beam and of 1 and 4 cm wide fields can be approximated by polynomials of orders equal to the different limits minus one. The dependence of optimized cost function values of IMRT plans, generated for a simple geometry and for a head-and-neck (oropharynx) case, on the numbers of beams used to construct the plans has also been studied. RESULTS: The limits are all multiples of R/W (W being the 20%-80% penumbra-width of a broad field) and work out at K = 27, K(A) = 43, K(H) = 34, and K(N) = 68 fields for R = 10 cm and W = 5.3 mm. All and none of the cross-profiles are approximated well by polynomials of order K(N)-1 and K-1, respectively, suggesting some inaccuracy in the assumptions used to derive the limit K. Order K(A)-1 polynomials cannot accurately describe the pencil beam profile, but do approximate the 1- and 4-cm profiles reasonably well because higher spatial frequencies are attenuated in these wider fields. All the profiles are represented well by polynomials of order K(N,Fbeamlet(-1)), which decreases from K(N) as beamlet width increases. Cost functions generated in the IMRT planning study fall as greater numbers of fields are used, before plateauing out around K(N,Fbeamlet) fields. CONCLUSIONS: Numerical calculations suggest that the minimum number of fields required for near-optimal IMRT lies around the generalized Nyquist limit K(N,Fbeamlet). For a clinically realistic 20%-80% penumbra-width of 5.3 mm and a radius of interest of 10 cm, K(N,Fbeamlet) falls from 68 to 47 fields as the beamlet width rises from 0 to 1 cm.

Classification of tolerable/intolerable mucosal toxicity of head-and-neck radiotherapy schedules with a biomathematical model of cell dynamics.

PURPOSE: The purpose of this study is to present a biomathematical model based on the dynamics of cell populations to predict the tolerability/intolerability of mucosal toxicity in head-and-neck radiotherapy. METHODS AND MATERIALS: Our model is based on the dynamics of proliferative and functional cell populations in irradiated mucosa, and incorporates the three As: Accelerated proliferation, loss of Asymmetric proliferation, and Abortive divisions. The model consists of a set of delay differential equations, and tolerability is based on the depletion of functional cells during treatment. We calculate the sensitivity (sen) and specificity (spe) of the model in a dataset of 108 radiotherapy schedules, and compare the results with those obtained with three phenomenological classification models, two based on a biologically effective dose (BED) function describing the tolerability boundary (Fowler and Fenwick) and one based on an equivalent dose in 2 Gy fractions (EQD2 ) boundary (Strigari). We also perform a machine learning-like cross-validation of all the models, splitting the database in two, one for training and one for validation. RESULTS: When fitting our model to the whole dataset, we obtain predictive values (sen + spe) up to 1.824. The predictive value of our model is very similar to that of the phenomenological models of Fowler (1.785), Fenwick (1.806), and Strigari (1.774). When performing a k = 2 cross-validation, the specificity and sensitivity in the validation dataset decrease for all models, from ˜1.82 to Ëœ1.55-1.63. For Fowler, the worsening is higher, down to 1.49. CONCLUSIONS: Our model has proved useful to predict the tolerability/intolerability of a dataset of 108 schedules. As the model is more mechanistic than other available models, it could prove helpful when designing unconventional dose fractionations, schedules not covered by datasets to which phenomenological models of toxicity have been fitted.

Development of a Compartmental Pharmacokinetic Model for Molecular Radiotherapy with 131I-CLR1404.

Pharmacokinetic modeling of the radiopharmaceuticals used in molecular radiotherapy is an important step towards accurate radiation dosimetry of such therapies. In this paper, we present a pharmacokinetic model for CLR1404, a phospholipid ether analog that, labeled with 124I/131I, has emerged as a promising theranostic agent. We follow a systematic approach for the model construction based on a decoupling process applied to previously published experimental data, and using the goodness-of-fit, Sobol's sensitivity analysis, and the Akaike Information Criterion to construct the optimal form of the model, investigate potential simplifications, and study factor prioritization. This methodology was applied to previously published experimental human time-activity curves for 9 organs. The resulting model consists of 17 compartments involved in the CLR1404 metabolism. Activity dynamics in most tissues are well described by a blood contribution plus a two-compartment system, describing fast and slow uptakes. The model can fit both clinical and pre-clinical kinetic data of 124I/131I. In addition, we have investigated how simple fits (exponential and biexponential) differ from the complete model. Such fits, despite providing a less accurate description of time-activity curves, may be a viable alternative when limited data is available in a practical case.

Evaluation of indirect damage and damage saturation effects in dose-response curves of hypofractionated radiotherapy of early-stage NSCLC and brain metastases.

BACKGROUND AND PURPOSE: To investigate the possible contribution of indirect damage and damage saturation to tumour control obtained with SBRT/SRS treatments for early-stage NSCLC and brain metastases. METHODS AND MATERIALS: We have constructed a dataset of early-stage NSCLC and brain metastases dose-response. These data were fitted to models based on the linear-quadratic (LQ), the linear-quadratic-linear (LQL), and phenomenological modifications of the LQ-model to account for indirect cell damage. We use the Akaike-Information-Criterion formalism to compare performance, and studied the stability of the results with changes in fitting parameters and perturbations on dose/TCP values. RESULTS: In NSCLC, a modified LQ-model with a beta-term increasing with dose yields the best-fits for α/ß = 10 Gy. Only the inclusion of very fast accelerated proliferation or low α/ß values can eliminate such superiority. In brain, the LQL model yields the best-fits, and the ranking is not affected by variations of fitting parameters or dose/TCP perturbations. CONCLUSIONS: For α/ß = 10 Gy, a modified LQ-model with a beta-term increasing with dose provides better fits to NSCLC dose-response curves. For brain metastases, the LQL provides the best fit. This might be interpreted as a hint of indirect damage in NSCLC, and damage saturation in brain metastases. The results for NSCLC are strongly dependent on the value of α/ß and may require further investigation, while those for brain seem to be clearly significant. Our results can assist in the design of improved radiotherapy for NSCLC and brain metastases, aiming at avoiding over/under-treatment.

Quantification of internal dosimetry in PET patients II: Individualized Monte Carlo-based dosimetry for [18F]fluorocholine PET.

PURPOSE: To obtain individualized internal doses with a Monte Carlo (MC) method in patients undergoing diagnostic [18F]FCH-PET studies and to compare such doses with the MIRD method calculations. METHODS: A patient cohort of 17 males were imaged after intravenous administration of a mean [18F]FCH activity of 244.3 MBq. The resulting PET/CT images were processed in order to generate individualized input source and geometry files for dose computation with the MC tool GATE. The resulting dose estimates were studied and compared to the MIRD method with two different computational phantoms. Mass correction of the S-factors was applied when possible. Potential sources of uncertainty were closely examined: the effect of partial body images, urinary bladder emptying, and biokinetic modeling. RESULTS: Large differences in doses between our methodology and the MIRD method were found, generally in the range ±25%, and up to ±120% for some cases. The mass scaling showed improvements, especially for non-walled and high-uptake tissues. Simulations of the urinary bladder emptying showed negligible effects on doses to other organs, with the exception of the prostate. Dosimetry based on partial PET/CT images (excluding the legs) resulted in an overestimation of mean doses to bone, skin, and remaining tissues, and minor differences in other organs/tissues. Estimated uncertainties associated with the biokinetics of FCH introduce variations of cumulated activities in the range of ±10% in the high-uptake organs. CONCLUSIONS: The MC methodology allows for a higher degree of dosimetry individualization than the MIRD methodology, which in some cases leads to important differences in dose values. Dosimetry of FCH-PET based on a single partial PET study seems viable due to the particular biokinetics of FCH, even though some correction factors may need to be applied to estimate mean skin/bone doses.

An approach to multiobjective optimization of rotational therapy. II. Pareto optimal surfaces and linear combinations of modulated blocked arcs for a prostate geometry.

PURPOSE: The purpose of this work is twofold: To further develop an approach to multiobjective optimization of rotational therapy treatments recently introduced by the authors [J. Pardo-Montero and J. D. Fenwick, "An approach to multiobjective optimization of rotational therapy," Med. Phys. 36, 3292-3303 (2009)], especially regarding its application to realistic geometries, and to study the quality (Pareto optimality) of plans obtained using such an approach by comparing them with Pareto optimal plans obtained through inverse planning. METHODS: In the previous work of the authors, a methodology is proposed for constructing a large number of plans, with different compromises between the objectives involved, from a small number of geometrically based arcs, each arc prioritizing different objectives. Here, this method has been further developed and studied. Two different techniques for constructing these arcs are investigated, one based on image-reconstruction algorithms and the other based on more common gradient-descent algorithms. The difficulty of dealing with organs abutting the target, briefly reported in previous work of the authors, has been investigated using partial OAR unblocking. Optimality of the solutions has been investigated by comparison with a Pareto front obtained from inverse planning. A relative Euclidean distance has been used to measure the distance of these plans to the Pareto front, and dose volume histogram comparisons have been used to gauge the clinical impact of these distances. A prostate geometry has been used for the study. RESULTS: For geometries where a blocked OAR abuts the target, moderate OAR unblocking can substantially improve target dose distribution and minimize hot spots while not overly compromising dose sparing of the organ. Image-reconstruction type and gradient-descent blocked-arc computations generate similar results. The Pareto front for the prostate geometry, reconstructed using a large number of inverse plans, presents a hockey-stick shape comprising two regions: One where the dose to the target is close to prescription and trade-offs can be made between doses to the organs at risk and (small) changes in target dose, and one where very substantial rectal sparing is achieved at the cost of large target underdosage. Plans computed following the approach using a conformal arc and four blocked arcs generally lie close to the Pareto front, although distances of some plans from high gradient regions of the Pareto front can be greater. Only around 12% of plans lie a relative Euclidean distance of 0.15 or greater from the Pareto front. Using the alternative distance measure of Craft ["Calculating and controlling the error of discrete representations of Pareto surfaces in convex multi-criteria optimization," Phys. Medica (to be published)], around 2/5 of plans lie more than 0.05 from the front. Computation of blocked arcs is quite fast, the algorithms requiring 35%-80% of the running time per iteration needed for conventional inverse plan computation. CONCLUSIONS: The geometry-based arc approach to multicriteria optimization of rotational therapy allows solutions to be obtained that lie close to the Pareto front. Both the image-reconstruction type and gradient-descent algorithms produce similar modulated arcs, the latter one perhaps being preferred because it is more easily implementable in standard treatment planning systems. Moderate unblocking provides a good way of dealing with OARs which abut the PTV. Optimization of geometry-based arcs is faster than usual inverse optimization of treatment plans, making this approach more rapid than an inverse-based Pareto front reconstruction.

Homogenized blocked arcs for multicriteria optimization of radiotherapy: analytical and numerical solutions.

PURPOSE: Homogenized blocked arcs are intuitively appealing as basis functions for multicriteria optimization of rotational radiotherapy. Such arcs avoid an organ-at-risk (OAR), spread dose out well over the rest-of-body (ROB), and deliver homogeneous doses to a planning target volume (PTV) using intensity modulated fluence profiles, obtainable either from closed-form solutions or iterative numerical calculations. Here, the analytic and iterative arcs are compared. METHODS: Dose-distributions have been calculated for nondivergent beams, both including and excluding scatter, beam penumbra, and attenuation effects, which are left out of the derivation of the analytic arcs. The most straightforward analytic arc is created by truncating the well-known Brahme, Roos, and Lax (BRL) solution, cutting its uniform dose region down from an annulus to a smaller nonconcave region lying beyond the OAR. However, the truncation leaves behind high dose hot-spots immediately on either side of the OAR, generated by very high BRL fluence levels just beyond the OAR. These hot-spots can be eliminated using alternative analytical solutions "C" and "L," which, respectively, deliver constant and linearly rising fluences in the gap region between the OAR and PTV (before truncation). RESULTS: Measured in terms of PTV dose homogeneity, ROB dose-spread, and OAR avoidance, C solutions generate better arc dose-distributions than L when scatter, penumbra, and attenuation are left out of the dose modeling. Including these factors, L becomes the best analytical solution. However, the iterative approach generates better dose-distributions than any of the analytical solutions because it can account and compensate for penumbra and scatter effects. Using the analytical solutions as starting points for the iterative methodology, dose-distributions almost as good as those obtained using the conventional iterative approach can be calculated very rapidly. CONCLUSIONS: The iterative methodology is appropriate and useful for computing homogenized blocked arcs, as it produces better dose-distributions than the analytic approaches and their obvious extensions, and can more straightforwardly be used to generate homogenized arcs for concave OARs. However, the analytical solutions provide promising starting points for the iterative algorithm, leading to fast convergence.