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.

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.

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: individualized Monte Carlo vs generic phantom-based calculations.

PURPOSE: The purpose of this work is to calculate individualized dose distributions in patients undergoing 18 F-FDG PET/CT studies through a methodology based on full Monte Carlo (MC) simulations and PET/CT patient images, and to compare such values with those obtained by employing nonindividualized phantom-based methods. METHODS: We developed a MC-based methodology for individualized internal dose calculations, which relies on CT images (for organ segmentation and dose deposition), PET images (for organ segmentation and distributions of activities), and a biokinetic model (which works with information provided by PET and CT images) to obtain cumulated activities. The software vGATE version 8.1. was employed to carry out the Monte Carlo calculations. We also calculated deposited doses with nonindividualized phantom-based methods (Cristy-Eckerman, Stabin, and ICRP-133). RESULTS: Median MC-calculated dose/activity values are within 0.01-0.03 mGy/MBq for most organs, with higher doses delivered especially to the bladder wall, major vessels, and brain (medians of 0.058, 0.060, 0.066 mGy/MBq, respectively). Comparison with values obtained with nonindividualized phantom-based methods has shown important differences in many cases (ranging from -80% to + 260%). These differences are significant (p < 0.05) for several organs/tissues, namely, remaining tissues, adrenals, bladder wall, bones, upper large intestine, heart, pancreas, skin, and stomach wall. CONCLUSIONS: The methodology presented in this work is a viable and useful method to calculate internal dose distributions in patients undergoing medical procedures involving radiopharmaceuticals, individually, with higher accuracy than phantom-based methods, fulfilling the guidelines provided by the European Council directive 2013/59/Euratom.

Development and clinical characterization of a novel 2041 liquid-filled ionization chambers array for high-resolution verification of radiotherapy treatments.

PURPOSE: The aim of this study was to present a novel 2041 liquid-filled ionization chamber array for high-resolution verification of radiotherapy treatments. MATERIALS AND METHODS: The prototype has 2041 ionization chambers of 2.5 × 2.5 mm2 area filled with isooctane. The detection elements are arranged in a central square grid of 43 × 43, totally covering an area of 107.5 × 107.5 mm2 . The central inline and cross-line are extended to 227 mm and the diagonals to 321 mm to be able to perform profile measurements of large fields. We have studied stability, pixel response uniformity, dose rate dependence, depth and field size dependence and anisotropy. We present results for output factors, tongue-and-groove, garden fence, small field profiles, irregular fields, and verification of dose planes of patient treatments. RESULTS: Comparison with other detectors used for small field dosimetry (SFD, CC13, microDiamond) has shown good agreement. Output factors measured with the device for square fields ranging from 10 × 10 to 100 × 100 mm2 showed relative differences within 1%. The response of the detector shows a strong dependence on the angle of incident radiation that needs to be corrected for. On the other hand, inter-pixel relative response variations in the 0.95-1.08 range have been found and corrected for. The application of the device for the verification of dose planes of several treatments has shown gamma passing rates above 97% for tolerances of 2% and 2 mm. The verification of other clinical fields, like small fields and irregular fields used in the commissioning of the TPS, also showed large passing rates. The verification of garden fence and tongue-and-groove fields was affected by volume-averaging effects. CONCLUSIONS: The results show that the liquid filled ionization chamber prototype here presented is appropriate for the verification of radiotherapy treatments with high spatial resolution. Recombination effects do not affect very much the verification of relative dose distributions. However, verification of absolute dose distributions may require normalization to a radiation field which is representative of the dose rate of the treatment delivered.

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.

Dose rate dependence of the PTW 60019 microDiamond detector in high dose-per-pulse pulsed beams.

Recombination effects can affect the detectors used for the dosimetry of radiotherapy fields. They are important when using ionization chambers, especially in liquid-filled ionization chambers, and should be corrected for. The introduction of flattening-filter-free accelerators increases the typical dose-per-pulse used in radiotherapy beams, which leads to more important recombination effects. Diamond detectors provide a good solution for the dosimetry and quality assurance of small radiotherapy fields, due to their low energy dependence and small volume. The group of Università di Roma Tor Vergata has developed a synthetic diamond detector, which is commercialized by PTW as microDiamond detector type 60019. In this work we present an experimental characterization of the collection efficiency of the microDiamond detector, focusing on high dose-per-pulse FFF beams. The collection efficiency decreases with dose-per-pulse, down to 0.978 at 2.2 mGy/pulse, following a Fowler-Attix-like curve. On the other hand, we have found no significant dependence of the collection efficiency on the pulse repetition frequency (or pulse period).

Correction for FDG PET dose extravasations: Monte Carlo validation and quantitative evaluation of patient studies.

PURPOSE: Current procedure guidelines for whole body [18F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) state that studies with visible dose extravasations should be rejected for quantification protocols. Our work is focused on the development and validation of methods for estimating extravasated doses in order to correct standard uptake value (SUV) values for this effect in clinical routine. METHODS: One thousand three hundred sixty-seven consecutive whole body FDG-PET studies were visually inspected looking for extravasation cases. Two methods for estimating the extravasated dose were proposed and validated in different scenarios using Monte Carlo simulations. All visible extravasations were retrospectively evaluated using a manual ROI based method. In addition, the 50 patients with higher extravasated doses were also evaluated using a threshold-based method. RESULTS: Simulation studies showed that the proposed methods for estimating extravasated doses allow us to compensate the impact of extravasations on SUV values with an error below 5%. The quantitative evaluation of patient studies revealed that paravenous injection is a relatively frequent effect (18%) with a small fraction of patients presenting considerable extravasations ranging from 1% to a maximum of 22% of the injected dose. A criterion based on the extravasated volume and maximum concentration was established in order to identify this fraction of patients that might be corrected for paravenous injection effect. CONCLUSIONS: The authors propose the use of a manual ROI based method for estimating the effectively administered FDG dose and then correct SUV quantification in those patients fulfilling the proposed criterion.

Optimised low-dose multidetector CT protocol for children with cranial deformity.

OBJECTIVE: To present an optimised low-dose multidetector computed tomography (MDCT) protocol for the study of children with cranial deformity. METHODS: Ninety-one consecutive MDCT studies were performed in 80 children. Studies were performed with either our standard head CT protocol (group 1, n = 20) or a low-dose cranial deformity protocol (groups 2 and 3). Group 2 (n = 38), initial, and group 3 (n = 33), final and more optimised. All studies were performed in the same 64-MDCT equipment. Cranial deformity protocol was gradationally optimised decreasing kVp, limiting mA range, using automatic exposure control (AEC) and increasing the noise index (NI). Image quality was assessed. Dose indicators such us CT dose index volume (CTDIvol), dose-length product (DLP) and effective dose (E) were used. RESULTS: The optimised low-dose protocol reached the following values: 80 kVp, mA range: 50-150 and NI = 23. We achieved a maximum dose reduction of 10-22 times in the 1- to 12-month-old cranium in regard to the 2004 European guidelines for MDCT. CONCLUSION: A low-dose MDCT protocol that may be used as the first diagnostic imaging option in clinically selected patients with skull abnormalities. KEY POINTS: • MDCT is a very useful tool in the study of skull lesions • Low-dose MDCT minimises child exposure to ionising radiation while maintaining image quality • Low-dose MDCT should be considered as the first imaging option in selected patients.

eIMRT: a web platform for the verification and optimization of radiation treatment plans.

The eIMRT platform is a remote distributed computing tool that provides users with Internet access to three different services: Monte Carlo optimization of treatment plans, CRT & IMRT treatment optimization, and a database of relevant radiation treatments/clinical cases. These services are accessible through a user-friendly and platform independent web page. Its flexible and scalable design focuses on providing the final users with services rather than a collection of software pieces. All input and output data (CT, contours, treatment plans and dose distributions) are handled using the DICOM format. The design, implementation, and support of the verification and optimization algorithms are hidden to the user. This allows a unified, robust handling of the software and hardware that enables these computation-intensive services. The eIMRT platform is currently hosted by the Galician Supercomputing Center (CESGA) and may be accessible upon request (there is a demo version at http://eimrt.cesga.es:8080/eIMRT2/demo; request access in http://eimrt.cesga.es/signup.html). This paper describes all aspects of the eIMRT algorithms in depth, its user interface, and its services. Due to the flexible design of the platform, it has numerous applications including the intercenter comparison of treatment planning, the quality assurance of radiation treatments, the design and implementation of new approaches to certain types of treatments, and the sharing of information on radiation treatment techniques. In addition, the web platform and software tools developed for treatment verification and optimization have a modular design that allows the user to extend them with new algorithms. This software is not a commercial product. It is the result of the collaborative effort of different public research institutions and is planned to be distributed as an open source project. In this way, it will be available to any user; new releases will be generated with the new implemented codes or upgrades.