290 Background: There is no established way to measure radiation dose deposition during liver radioembolization to help quantify the shortcomings of prescription calculations, which do not consider size, shape, and location of tumors. We aimed to establish a standardized method of radioembolization dose measurement though a novel technique using Positron Emission Tomography and Computed Tomography (PET-CT). Methods: Patients who were recommended for liver radioembolization treatment were enrolled in a prospective single-arm registry study. Index lesions were contoured on the patients’ CT simulation scans. Immediate post-treatment PET/CTs were used to measure the deposited radiation dose by capturing the positron emission from the Yttrium-90’s daughter nuclei. The CT simulation scans were fused to the post-treatment PET/CT scans using rigid registration around the index lesions. The primary dosimetric outcomes were mean dose and dose to 70% of the tumor volume (D70). The optimal mean dose and D70 were > 100 Gy and > 70 Gy, respectively. Results: From November 2014 to November 2015, fifteen consecutive patients with either hepatocellular carcinoma (n = 4) or liver metastases (n = 11) were enrolled in the study. A total of 43 index lesions were contoured with a mean and median size of 18.2 cc and 5.4 cc, respectively. The average mean dose to the index lesions was 99.9 Gy (mean dose range: 2 – 298 Gy; Table). The mean and median D70 were 66.9 Gy and 71 Gy, respectively (range: 1.4 – 211 Gy; standard deviation [SD]: 40.3 Gy). The mean and median D90s were 43 Gy and 41 Gy, respectively. A total of 20 (46.5%) lesions received optimal mean dose and 23 (53.5%) lesions received optimal D70 dose. Conclusions: We established a successful standardized procedure utilizing PET/CT scans to measure the radiation dose delivered during liver radioembolization. The range of the doses received by the tumors underlines the need to collect dosimetric data for future treatment optimization. Dosimetric parameters. Clinical trial information: NCT02088775. [Table: see text]

PURPOSEThe tumor control probability in radiation therapy allows comparing different radiation treatments to each other by means of calculating the probability that a prescribed dose of radiation eradicates or controls the tumor. In the conventional approach, all cancer cells can divide unlimited number of times and the tumor control often means eradicating every malignant cell by the radiation. In recent years however, there is a mounting consensus that in a given tumor volume there is a sub-population of cells, known as cancer stem cells (CSCs) that are responsible for tumor initiation and growth. Other or progenitor cancer cells can only divide limited number of times. This entails that only cancer stem cells may nned to be eliminated in order to control the tumor. Thus one may define TCP as the probability of eliminating CSCs for the given dose of radiation.METHODSUsing stochastic methods, specifically the birth-and-death Markov processes, an infinite system of equations is set for probabilities of having m cancer stem cells at time t after the start of radiation. The TCP is calculated as the probability of no cancer stem cells surviving the radiation. Two scenarios are studied. In the first situation, the TCP is calculated for a unidirectional case when CSC gives birth to another CSC or a progenitor cell. In the second scenario, a bidirectional model is studied where the progenitor cell gives rise to CSC.RESULTSThe proposed calculations show that the calculated TCP for CSC depends on whether one adopts unidirectional or bidirectional conversion models. The bidirectional model shows significantly lower TCP values for the given dose delivered to the tumor.CONCLUSIONIncorporating CSC hypothesis into the TCP modeling may notably influence the dose prescription as well as the concept of the expected TCP after the radiation treatments.

PURPOSE:(90)Y -positron emission tomography (PET) imaging is becoming a recognized modality for postinfusion quantitative assessment following radioembolization therapy. However, the extremely low counts and high random fraction associated with (90)Y -PET may significantly impair both qualitative and quantitative results. The aim of this work was to study image quality and noise level in relation to the quantification and bias performance of two types of Siemens PET scanners when imaging (90)Y and to compare experimental results with clinical data from two types of commercially available (90)Y microspheres. METHODS:Data were acquired on both Siemens Biograph TruePoint [non-time-of-flight (TOF)] and Biograph microcomputed tomography (mCT) (TOF) PET/CT scanners. The study was conducted in three phases. The first aimed to assess quantification and bias for different reconstruction methods according to random fraction and number of true counts in the scan. The NEMA 1994 PET phantom was filled with water with one cylindrical insert left empty (air) and the other filled with a solution of (90)Y . The phantom was scanned for 60 min in the PET/CT scanner every one or two days. The second phase used the NEMA 2001 PET phantom to derive noise and image quality metrics. The spheres and the background were filled with a (90)Y solution in an 8:1 contrast ratio and four 30 min acquisitions were performed over a one week period. Finally, 32 patient data (8 treated with Therasphere(®) and 24 with SIR-Spheres(®)) were retrospectively reconstructed and activity in the whole field of view and the liver was compared to theoretical injected activity. RESULTS:The contribution of both bremsstrahlung and LSO trues was found to be negligible, allowing data to be decay corrected to obtain correct quantification. In general, the recovered activity for all reconstruction methods was stable over the range studied, with a small bias appearing at extremely high random fraction and low counts for iterative algorithms. Point spread function (PSF) correction and TOF reconstruction in general reduce background variability and noise and increase recovered concentration. Results for patient data indicated a good correlation between the expected and PET reconstructed activities. A linear relationship between the expected and the measured activities in the organ of interest was observed for all reconstruction method used: a linearity coefficient of 0.89 ± 0.05 for the Biograph mCT and 0.81 ± 0.05 for the Biograph TruePoint. CONCLUSIONS:Due to the low counts and high random fraction, accurate image quantification of (90)Y during selective internal radionuclide therapy is affected by random coincidence estimation, scatter correction, and any positivity constraint of the algorithm. Nevertheless, phantom and patient studies showed that the impact of number of true and random coincidences on quantitative results was found to be limited as long as ordinary Poisson ordered subsets expectation maximization reconstruction algorithms with random smoothing are used. Adding PSF correction and TOF information to the reconstruction greatly improves the image quality in terms of bias, variability, noise reduction, and detectability. On the patient studies, the total activity in the field of view is in general accurately measured by Biograph mCT and slightly overestimated by the Biograph TruePoint.

Purpose: The accuracy of PET-based post-treatment dosimetry of yttrium-90 microspheres has been improving over the past decade and is now at a stage, permitting volumetric dose-outcome studies. We outline the recent advances and identify the physical limitations to the accuracy of the dose calculations. Methods: Convolution of the measured PET activity density distribution with a pre-calculated voxel-dose-kernel (VDK) is the most widely used method for dose reconstruction. Therefore, accurate knowledge of the beta+ branching ratio as well as the micro-dosimetric characteristics of electron interactions within the microsphere is essential for the computation of the dose kernel. We implement a model of the microspheres used in our clinic to calculate the modified electron energy spectrum at the microsphere’s surface and to determine the impact of self-shielding on the dose reconstruction. The three-dimensional dose distributions obtained for 10 patients treated with radio-embolization with yttrium-90 microspheres are evaluated and various DVH markers are investigated for correlation with outcome. Results: The methods for reducing the overall computation uncertainty are systematically outlined in this presentation. Since the latest experimental data on yttrium-90 beta+ branching ratio has a relative uncertainty of 1.5%, all contributing factors derived from Monte Carlo simulations must be brought to a sub 1% level. The self-shielding within the microspheres is found to be responsible for up to 6% reduction of the reconstructed dose in low-gradient regions and must be taken into account. The contribution of trace amounts of other beta+ emitters introduced during the manufacturing process is also discussed. Conclusion: The accelerating pace of clinical adoption of PET-based post-treatment dosimetry is mainly due to advances in both quantitative PET imaging and physical models of dose deposition. We show that the overall physical dose uncertainty in the convolution step can be further reduced, thus making ongoing multi-institutional dose-outcome studies even more reliable.

Purpose:Accurate range verification is of great importance to fully exploit the potential benefits of ion beam therapies. Current research efforts on this topic include the use of PET imaging of induced activity, detection of emerging prompt gamma rays or secondary particles. It has also been suggested recently to detect the ultrasound waves emitted through the ion energy absorption process. The energy absorbed in a medium is dissipated as heat, followed by thermal expansion that leads to generation of acoustic waves. By using an array of ultrasound transducers the precise spatial location of the Bragg peak can be obtained. The shape and intensity of the emitted ultrasound pulse depend on several variables including the absorbed energy and the pulse length. The main objective of this work is to understand how the ultrasound wave amplitude and shape depend on the initial ion energy and intensity. This would help guide future experiments in ionoacoustic imaging.Methods:The absorbed energy density for protons and carbon ions of different energy and field sizes were obtained using Fluka Monte Carlo code. Subsequently, the system of coupled equations for temperature and pressure is solved for different ion pulse intensities and lengths to obtain the pressure wave shape, amplitude and spectral distribution.Results:The proposed calculations show that the excited pressure wave amplitude is proportional to the absorbed energy density and for longer ion pulses inversely proportional to the ion pulse duration. It is also shown that the resulting ionoacoustic pressure distribution depends on both ion pulse duration and time between the pulses.Conclusion:The Bragg peak localization using ionoacoustic signal may eventually lead to the development of an alternative imaging method with sub‐millimeter resolution. It may also open a way for in‐vivo dose verification from the measured acoustic signal.

Purpose: The linear-quadratic model is the most prevalent model for planning dose fractionation in radiation therapy in the low dose per fraction regimens. However for high-dose fractions, used in SRS/SBRT/HDR treatments the LQ model does not yield accurate predictions, due to neglecting the reduction in the number of sublethal lesions as a result of their conversion to lethal lesions with subsequent irradiation. Proper accounting for this reduction in the number of sublethally damaged lesions leads to the dependence of the survival fraction on the temporal structure of the dose. The main objective of this work is to show that the functional dependence of the dose rate on time in each voxel is an important additional factor that can significantly influence the TCP. Methods: Two SBRT lung plans have been used to calculate the TCPs for the same patient. One plan is a 3D conformal plan and the other is an IMRT plan. Both plans are normalized so that 99.5% of PTV volume receives the same prescription dose of 50 Gy in 5 fractions. The dose rate in each individual voxel is calculated as a function of treatment time and subsequently used in the calculation of TCP. Results: The calculated TCPs show that shorter delivery times lead to greater TCP, despite all delivery times being short compared to the repair half-time for sublethal lesions. Furthermore, calculated TCP(IMRT) =0.308 for the IMRT plan is smaller than TCP(3D) =0.425 for 3D conformal, even though it shows greater tumor hot spots and equal PTV coverage. The calculated TCPs are considerably lower compared to those based on the LQ model for which TCP=1 for both plans. Conclusion: The functional dependence of the voxel-by-voxel dose rate on time may be an important factor in predicting the treatment outcome and cannot be neglected in radiobiological modeling.

Purpose: To study the dosimetric difference resulted in using the pencil beam algorithm instead of Monte Carlo (MC) methods for tumors adjacent to the skull. Methods: We retrospectively calculated the dosimetric differences between RT and MC algorithms for brain tumors treated with CyberKnife located adjacent to the skull for 18 patients (total of 27 tumors). The median tumor sizes was 0.53-cc (range 0.018-cc to 26.2-cc). The absolute mean distance from the tumor to the skull was 2.11 mm (range – 17.0 mm to 9.2 mm). The dosimetric variables examined include the mean, maximum, and minimum doses to the target, the target coverage (TC) and conformality index. The MC calculation used the same MUs as the RT dose calculation without further normalization and 1% statistical uncertainty. The differences were analyzed by tumor size and distance from the skull. Results: The TC was generally reduced with the MC calculation (24 out of 27 cases). The average difference in TC between RT and MC was 3.3% (range 0.0% to 23.5%). When the TC was deemed unacceptable, the plans were re-normalized in order to increase the TC to 99%. This resulted in a 6.9% maximum change in the prescription isodose line. The maximum changes in the mean, maximum, and minimum doses were 5.4 %, 7.7%, and 8.4%, respectively, before re-normalization. When the TC was analyzed with regards to target size, it was found that the worst coverage occurred with the smaller targets (0.018-cc). When the TC was analyzed with regards to the distance to the skull, there was no correlation between proximity to the skull and TC between the RT and MC plans. Conclusions: For smaller targets (< 4.0-cc), MC should be used to re-evaluate the dose coverage after RT is used for the initial dose calculation in order to ensure target coverage.

Purpose: The commercial availability of high-energy accelerators opens new therapeutic opportunities for X-rays with energies in excess of 15MV. Three clinical beams (Varian 18MV, Elekta SL25, and Top Grade LA45) were compared by the production of photo-activated positron emitters in five types of biological tissues. Methods: The activation studies were performed using FLUKA2011 Monte Carlo suite with beam models designed for the three accelerators. Absolute activity density (Bq/ml) distribution in space was obtained from this study. Additionally, the temporal evolution of all activated species was monitored for cooling times up to 30 minutes. Results: The relative activation contrast of tissue pairs was evaluated for 2Gy of dose at 10cm depth for five tissues (normal, hypoxic, adipose, bone, and lung). In bone the sort-lived isotopes O-15 and P-30 dominated the activity at the early cooling stages. In all tissues 15 minutes post-irradiation the C-11 activity became dominant. Tissues with higher carbon-to-oxygen ratio in their elemental composition became clearly visible in a PET scan at longer cooling times. Radiation treatment of a lung tumor with a hypoxic core was simulated in an anthropomorphic phantom using the LA45 beam model. Increase in the PET counts by more than 50% was measured in the hypoxic volume 15 minutes post-irradiation, demonstrating the benefits of the relative activation contrast concept. Conclusion: LA45 beam is found to produce measurable activation distribution for 2Gy of dose, suitable for tissue type discrimination studies. Maximum activation contrast of 1.7 between hypoxic and normal tissues was measured in a simulated treatment. The absolute activity density values obtained from these Monte Carlo studies suggest that the window of opportunity for a PET scan exists up to 60 minutes after 2Gy of dose is deposited by 45MV X-ray beam. Lung-to-tissue activation contrast can be explored for treatment QA purposes as well.

PURPOSEIn the past few years there have been numerous proposals for 3D dose reconstruction from the PET-CT imaging of patients undergoing radioembolization treatment of the liver with yttrium-90 microspheres. One of the most promising techniques uses convolution of the measured PET activity distribution with a pre-calculated Monte Carlo dose deposition kernel. The goal of the present study is to experimentally verify the accuracy of this method and to analyze the significance of various error sources.METHODSOptically stimulated luminescence detectors (OSLD) were used (NanoDot, Landauer) in this experiment. Two detectors were mounted on the central axis of a cylinder filled with water solution of yttrium-90 chloride. The total initial activity was 90mCi. The cylinder was inserted in a larger water phantom and scanned on a Siemens Biograph 16 Truepoint PET-CT scanner. Scans were performed daily over a period of 20 days to build a calibration curve for the measured absolute activity spanning 7 yttrium-90 half-lives. The OSLDs were mounted in the phantom for a predetermined period of time in order to record 2Gy dose. The measured dose was then compared to the dose reconstructed from the activity density at the location of each dosimeter.RESULTSThorough error analysis of the dose reconstruction algorithm takes into account the uncertainties in the absolute PET activity, branching ratios, and nonlinearity of the calibration curve. The measured dose for 105-minute exposure on day 10 of the experiment was 219(11)cGy, while the reconstructed dose at the location of the detector was 215(47)cGy.CONCLUSIONWe present the first experimental verification of the accuracy of the convolution algorithm for absolute dose reconstruction of yttrium-90 microspheres. The excellent agreement between the measured and calculated point doses will encourage the broad clinical adoption of the convolution-based dose reconstruction algorithm, making future quantitative dose/outcome studies possible.

PURPOSE The introduction of radioembolization with microspheres represents a significant step forward in the treatment of patients with metastatic disease to the liver. This technique uses semiempirical formulae based on body surface area or liver and target volumes to calculate the required total activity for a given patient. However, this treatment modality lacks extremely important information, which is the three-dimensional (3D) dose delivered by microspheres to different organs after their administration. The absence of this information dramatically limits the clinical efficacy of this modality, specifically the predictive power of the treatment. Therefore, the aim of this study is to develop a 3D dose calculation technique that is based on the PET imaging of the infused microspheres. METHODS The Fluka Monte Carlo code was used to calculate the voxel dose kernel for 90Y source with voxel size equal to that of the PET scan. The measured PET activity distribution was converted to total activity distribution for the subsequent convolution with the voxel dose kernel to obtain the 3D dose distribution. In addition, dose-volume histograms were generated to analyze the dose to the tumor and critical structures. RESULTS The 3D inpatient dose distribution can be reconstructed from the PET data of a patient scanned after the infusion of microspheres. A total of seven patients have been analyzed so far using the proposed reconstruction method. Four patients underwent treatment with SIR-Spheres for liver metastases from colorectal cancer and three patients were treated with Therasphere for hepatocellular cancer. A total of 14 target tumors were contoured on post-treatment PET-CT scans for dosimetric evaluation. Mean prescription activity was 1.7 GBq (range: 0.58-3.8 GBq). The resulting mean maximum measured dose to targets was 167 Gy (range: 71-311 Gy). Mean minimum dose to 70% of target (D70) was 68 Gy (range: 25-155 Gy). Mean minimum dose to 90% of target (D90) was 53 Gy (range: 13-125 Gy). CONCLUSIONS A three-dimensional inpatient dose reconstruction method has been developed that is based on the PET/CT data of a patient treated with 90Y microspheres. It allows for a complete description of the absorbed dose by the tumor and critical structures. It represents the first step in building predictive models for treatment outcomes for patients receiving this therapeutic modality as well as it allows for better analysis of patients' dose response and will ultimately improve future treatment administration.

Purpose: Radioembolization is an emerging therapeutic option for the treatment of metastatic and primary tumors of the liver. Simple formulas are currently utilized in order to prescribe the appropriate activity. While the activity infused to each patient is known, limited data is available concerning the delivered dose. This makes correlation of response to dose impossible. The aim of this study is to establish a method for calculation of dose delivered to intrahepatic targets. Methods: Six patients were enrolled in this study as part of one approved clinical trial. All patients underwent radioembolization for primary or metastatic liver tumor(s). Each patient underwent a post‐treatment PET‐CT for the quantification of activity of Yttrium‐90 labeled microspheres. The absorbed dose is calculated as the convolution of the pre‐calculated dose kernel with the PET‐measured activity. Results: Four patients underwent treatment with SIR‐Spheres for liver metastases from colorectal cancer and 2 patients were treated with Therasphere for hepatocellular cancer. A total of 11 target tumors were contoured on post‐treatment PET‐CT scans for dosimetric evaluation. Mean prescription activity was 1.51 GBq (range: 0.58 to 3.29 GBq). The resulting mean maximum measured dose to targets was 167 Gy (range: 71 to 311 Gy). Mean minimum dose to 70% of target (D70) was 54 Gy (range: 29 to 83 Gy). Mean minimum dose to 90% of target (D90) was 36 Gy (range: 13 to 58 Gy). The mean maximum dose for Therasphere and SIR‐spheres was 266 Gy versus 111 Gy. Conclusion: This pilot project demonstrates that dose can be calculated in patients after radioembolization, utilizing PET‐CT measured activity. Although this represents preliminary work with a small number of patients, the doses to patients treated with Therasphere may be larger. This process could lay the foundation for more sophisticated dose prescription methods in the future.

Purpose: This study performed an in-depth investigation of two SBRT planning strategies for small lung lesion treatment and evaluated their effectiveness of overcoming the heterogeneity impact on the plan quality. The first approach is to re-normalize the dose by prescribing to a different isodose level in order to achieve the desired target dose coverage after the initial plan is recalculated using the Monte Carlo (MC) method. The second approach is to re-optimize the beam weights of the initial plan based on the MC calculated dose. Methods: Mutiplan that has both the MC calculation method and the ray-tracing algorithm was employed. Sixteen lung cancer patients (PTV4.7-58.5cm3) treated with Cyberknife were recruited. The ray-tracing algorithm was utilized for the initial plan optimization as the only choice provided by the Multiplan. Subsequently, the two planning strategies were performed followed by the dose distribution and plan quality comparison with the initial plan. The single beam dose calculations with the ray-tracing and the MC method were compared for investigating why re-optimization is able to improve the quality of the most plans but not all. Results: Fourteen out of the sixteen cases demonstrate a better plan quality in the re-optimized plan. The average conformity index of the initial, the re-normalized, and the re-optimized plans are 1.14±0.08, 1.48±0.26, and 1.27±0.11, respectively, while the heterogeneity indexes are 1.28±0.07, 1.48±0.09, and 1.42±0.2. The comparison of the critical structure DVH parameters supports that the re-optimized plans can reduce the dose to the critical structures. Conclusions: Both strategies provide plans fulfilling the clinical criteria. Re-optimization achieves a better plan quality, especially for irregular and peripherally located lesions. For small isolated-or low density lesions, re-normalization method provides better plan quality. Algorithms to better accounting for the heterogeneity effect are necessary for the initial plan optimization to further improve the plan quality.

It is shown that the spatial dispersion in composite systems formed by inclusion of finite size spheres may lead to negative group velocity and, subsequently, to negative refraction. Longitudinal and transverse electromagnetic modes exhibiting negative dispersion are found in the system of finite size charged clouds. It is also shown that similar mechanism due to the electric quadrupole coupling leads to excitation of longitudinal and transverse eigenmodes with negative dispersion in a random set of nonmagnetic metal spheres embedded in a dielectric host. It is shown that the negative refraction related to the spatial dispersion effects may alternatively be viewed as a result of simultaneously negative permittivity and permeability.