Arnaud Dieudonné

Clinical Feasibility of Fast 3-Dimensional Dosimetry of the Liver for Treatment Planning of Hepatocellular Carcinoma with 90Y-Microspheres

Several treatment strategies are used for selective internal radiation therapy with 90Y-microspheres. The diversity of approaches does not favor the standardization of the prescribed activity calculation. To this aim, a fast 3-dimensional (3D) dosimetry method was developed for 90Y-microsphere treatment planning and was clinically evaluated retrospectively. Methods: Our 3D approach is based on voxel S values (VSVs) and has been implemented in the software tool VoxelDose. VSVs were previously calculated at a fine voxel size. The time-integrated activity (TIA) map is derived from pretherapeutic 99mTc-macroaggregated-albumin SPECT/CT. The fine VSV map is resampled at the voxel size of the TIA map. Then, the TIA map is convolved with the resampled VSV map to construct the 3D dose map. Data for 10 patients with 12 tumor sites treated by 90Y-microspheres for hepatocellular carcinoma were collected retrospectively. 3D dose maps were computed for each patient, and tumoral liver and nontumoral liver (TL and NTL, respectively) were delineated, allowing the computation of descriptive statistics (i.e., mean absorbed dose, minimum absorbed dose, and maximum absorbed dose) and dose–volume histograms. Mean absorbed doses in TL and NTL from VoxelDose were compared with those calculated with the standard partition model. Results: The estimated processing time for a complete 3D dosimetry calculation is on the order of 15 min, including 10 s for the dose calculation (i.e., VSV resampling and convolution). An additional 45 min was needed for the semiautomatic and manual segmentation of TL and NTL. The mean absorbed dose (±SD) was 422 ± 263 Gy for TL and 50.1 ± 36.0 Gy for NTL. The comparison between VoxelDose and partition model shows a mean relative difference of 1.5% for TL and 4.4% for NTL. Results show a wide spread of voxel-dose values around mean absorbed dose. The minimum absorbed dose within TL ranges from 32 to 267 Gy (n = 12). The fraction of NTL volume irradiated with at least 80 Gy ranges from 4% to 70% (n = 10), and the absorbed dose from which 25% of NTL was the least irradiated ranges from 14 to 178 Gy. Conclusion: This article demonstrates the feasibility of a fast 3D dosimetry method for 90Y-microspheres and highlights the potential value of a 3D treatment planning strategy.

Fine-Resolution Voxel S Values for Constructing Absorbed Dose Distributions at Variable Voxel Size

This article presents a revised voxel S values (VSVs) approach for dosimetry in targeted radiotherapy, allowing dose calculation for any voxel size and shape of a given SPECT or PET dataset. This approach represents an update to the methodology presented in MIRD pamphlet no. 17. Methods: VSVs were generated in soft tissue with a fine spatial sampling using the Monte Carlo (MC) code MCNPX for particle emissions of 9 radionuclides: 18F, 90Y, 99mTc, 111In, 123I, 131I, 177Lu, 186Re, and 201Tl. A specific resampling algorithm was developed to compute VSVs for desired voxel dimensions. The dose calculation was performed by convolution via a fast Hartley transform. The fine VSVs were calculated for cubic voxels of 0.5 mm for electrons and 1.0 mm for photons. Validation studies were done for 90Y and 131I VSV sets by comparing the revised VSV approach to direct MC simulations. The first comparison included 20 spheres with different voxel sizes (3.8–7.7 mm) and radii (4–64 voxels) and the second comparison a hepatic tumor with cubic voxels of 3.8 mm. MC simulations were done with MCNPX for both. The third comparison was performed on 2 clinical patients with the 3D-RD (3-Dimensional Radiobiologic Dosimetry) software using the EGSnrc (Electron Gamma Shower National Research Council Canada)-based MC implementation, assuming a homogeneous tissue-density distribution. Results: For the sphere model study, the mean relative difference in the average absorbed dose was 0.20% ± 0.41% for 90Y and −0.36% ± 0.51% for 131I (n = 20). For the hepatic tumor, the difference in the average absorbed dose to tumor was 0.33% for 90Y and −0.61% for 131I and the difference in average absorbed dose to the liver was 0.25% for 90Y and −1.35% for 131I. The comparison with the 3D-RD software showed an average voxel-to-voxel dose ratio between 0.991 and 0.996. The calculation time was below 10 s with the VSV approach and 50 and 15 h with 3D-RD for the 2 clinical patients. Conclusion: This new VSV approach enables the calculation of absorbed dose based on a SPECT or PET cumulated activity map, with good agreement with direct MC methods, in a faster and more clinically compatible manner.

Spatial gradients of blood vessels and hematopoietic stem and progenitor cells within the marrow cavities of the human skeleton

This report evaluates the spatial profile of blood vessel fragments (BVFs) and CD34(+) and CD117(+) hematopoietic stem and progenitor cells (HSPCs) in human cancellous bone. Bone specimens were sectioned, immunostained (anti-CD34 and anti-CD117), and digitally imaged. Immunoreactive cells and vessels were then optically and morphometrically identified and labeled on the corresponding digital image. The distance of each BVF, or CD34(+) or CD117(+) HSPC to the nearest trabecular surface was measured and binned in 50-microm increments. The relative concentration of HSPCs and BVFs within cancellous marrow was observed to diminish with increasing distance in the marrow space. On average, 50% of the CD34(+) HSPC population, 60% of the CD117(+) HSPC population, and 72% of the BVFs were found within 100 microm of the bone surfaces. HSPCs were also found to exist in close proximity to BVFs, which supports the notion of a shared HSPC and vessel spatial niche.

Comparison Between 2D and 3D Dosimetry Protocols in 90Y-Ibritumomab Tiuxetan Radioimmunotherapy of Patients with Non-Hodgkin's Lymphoma

UNLABELLED We compared the radiation-absorbed dose obtained from a two dimensional (2D) protocol, based on planar whole-body (WB) scans and fixed reference organ masses with dose estimates, using a 3D single-photon emission computed tomography (SPECT) imaging protocol and patient-specific organ masses. METHODS Six (6) patients with follicular non-Hodgkins lymphoma underwent a computed tomography (CT) scan, 5 2D planar WB, and 5 SPECT scans between days 0 and 6 after the injection of (111)In-ibritumomab tiuxetan. The activity values in the liver, spleen, and kidneys were calculated from the 2D WB scans, and also from the 3D SPECT images reconstructed, using quantitative image processing. Absorbed doses after the administration of (90)Y-ibritumomab tiuxetan were calculated from the (111)In WB activity values combined with reference organ masses and also from the SPECT activity values and organ masses as estimated from the patient CT scan. To assess the quantitative accuracy of the WB and SPECT scans, an abdominal phantom was also studied. RESULTS The differences between organ masses estimated from the patient CT and from the reference MIRD models were between -10% and +98%. Using the phantom, errors in organ and tumor activity estimates were between -86% and 10% for the WB protocol and between -43% and -6% for the SPECT protocol. Patient liver, spleen, and kidney activity values determined from SPECT were systematically less than those from the WB scans. Radiation-absorbed doses calculated with the 3D protocol were systematically lower than those calculated from the WB protocol (29%+/-26%, 73%+/-26%, and 33%+/-53% differences in the liver, spleen, and kidney, respectively), except in the kidneys of 2 patients and in the liver of 1 patient. CONCLUSIONS Accounting for patient-specific organ mass and using SPECT activity quantification have both a great impact on estimated absorbed doses.

Study of the Impact of Tissue Density Heterogeneities on 3-Dimensional Abdominal Dosimetry: Comparison Between Dose Kernel Convolution and Direct Monte Carlo Methods

Dose kernel convolution (DK) methods have been proposed to speed up absorbed dose calculations in molecular radionuclide therapy. Our aim was to evaluate the impact of tissue density heterogeneities (TDH) on dosimetry when using a DK method and to propose a simple density-correction method. Methods: This study has been conducted on 3 clinical cases: case 1, non-Hodgkin lymphoma treated with 131I-tositumomab; case 2, a neuroendocrine tumor treatment simulated with 177Lu-peptides; and case 3, hepatocellular carcinoma treated with 90Y-microspheres. Absorbed dose calculations were performed using a direct Monte Carlo approach accounting for TDH (3D-RD), and a DK approach (VoxelDose, or VD). For each individual voxel, the VD absorbed dose, DVD, calculated assuming uniform density, was corrected for density, giving DVDd. The average 3D-RD absorbed dose values, D3DRD, were compared with DVD and DVDd, using the relative difference ΔVD/3DRD. At the voxel level, density-binned ΔVD/3DRD and ΔVDd/3DRD were plotted against ρ and fitted with a linear regression. Results: The DVD calculations showed a good agreement with D3DRD. ΔVD/3DRD was less than 3.5%, except for the tumor of case 1 (5.9%) and the renal cortex of case 2 (5.6%). At the voxel level, the ΔVD/3DRD range was 0%–14% for cases 1 and 2, and –3% to 7% for case 3. All 3 cases showed a linear relationship between voxel bin-averaged ΔVD/3DRD and density, ρ: case 1 (Δ = –0.56ρ + 0.62, R2 = 0.93), case 2 (Δ = –0.91ρ + 0.96, R2 = 0.99), and case 3 (Δ = –0.69ρ + 0.72, R2 = 0.91). The density correction improved the agreement of the DK method with the Monte Carlo approach (ΔVDd/3DRD < 1.1%), but with a lesser extent for the tumor of case 1 (3.1%). At the voxel level, the ΔVDd/3DRD range decreased for the 3 clinical cases (case 1, –1% to 4%; case 2, –0.5% to 1.5%, and –1.5% to 2%). No more linear regression existed for cases 2 and 3, contrary to case 1 (Δ = 0.41ρ – 0.38, R2 = 0.88) although the slope in case 1 was less pronounced. Conclusion: This study shows a small influence of TDH in the abdominal region for 3 representative clinical cases. A simple density-correction method was proposed and improved the comparison in the absorbed dose calculations when using our voxel S value implementation.

Pretreatment Dosimetry in HCC Radioembolization with 90Y Glass Microspheres Cannot Be Invalidated with a Bare Visual Evaluation of 99mTc-MAA Uptake of Colorectal Metastases Treated with Resin Microspheres

TO THE EDITOR: We read with great interest the paper by Ulrich et al. (1) reporting on the predictive value of 99mTcmacroaggregated albumin (99mTc-MAA) uptake in patients with colorectal liver metastasis scheduled for selective internal radiation therapy (SIRT) with 90Y-loaded resin microspheres. Despite the inclusion of an impressive amount of work (66 patients and 435 lesions), the results are disappointing as they found no association between patientor lesion-based response and the overall degree of 99mTc-MAA perfusion (P 5 0.172). The authors conclude that the response cannot be predicted by the degree of perfusion on 99mTc-MAA scintigraphy. This study raises several important methodologic and general concerns that have to be clarified. In our opinion, conclusions made by the authors cannot be supported by data presented in this paper. From a methodologic point of view, we have 4 major concerns: the insufficient quantification method, lack of dosimetric evaluation, inappropriate radiologic evaluation of response, and inadequate definition of catheter position. First, the main issue about imaging 99mTc-MAA perfusion is that it does not sufficiently evaluate the true degree of implantation in small lesions. Mazzaferro et al. (2), using the same Siemens software as Ulrich et al., needed to apply 120 projections, 8 iterations, and 8 subsets without any gaussian postfiltering to maximize the SPECT spatial resolution (7 mm in full width at half maximum measured in water), keeping a reasonable noise level. Nevertheless, under these circumstances, because of the wellknown partial-volume effect, a 20% underestimation of activity was reported for a 1.8-cm-diameter sphere (3 mL in volume) with a 99mTc contrast ratio of 4:1 between sphere and background. The smaller the lesion, the larger the underestimation. For this reason, Mazzaferro et al. excluded lesions with a diameter smaller than 1.8 cm from their voxel dosimetry analysis. The reconstruction parameter described by Ulrich et al. implies worse spatial resolution than that achieved by Mazzaferro et al., with a consequently more pronounced underestimation of the degree of 99mTc-MAA perfusion even in lesions larger than 1.8 cm, whereas their lesion size was 3.39 6 2.12 cm at baseline. Moreover, they adopted the Chang attenuation correction, which is valid for uniform objects and for which accuracy should be validated in regions of nonuniform attenuation (slices containing liver–lung interfaces). The lesion-based analysis relies on MR imaging/SPECT registration, and no description of the registration process is given. Since liver deformation can occur in 30 d, an image mismatch could occur without an elastic deformation registration method. Second, SIRT is a kind of radiation therapy. As such, efficacy should be discussed in terms of absorbed dose and radiobiologic models, not merely in qualitative terms of degree of 99mTc-MAA implantation, which is imageand operator-dependent. The third methodologic concern relates to the response evaluation. According to our experience, the 6-wk interval is definitely too short to observe an appropriate morphologic response. Metabolic assessment of tumor response using 18F-FDG PET can be applied early (6–8 wk) and would probably have been more accurate as an endpoint for assessing a dose–response relationship. In addition, the Response Evaluation Criteria in Solid Tumors (RECIST) are not at all a validated method for the assessment of treatment response in SIRT. “The most common change in the CT-appearance of the liver after SIRT is decreased attenuation in the affected hepatic areas” (3). In these situations, response evaluation must take into account the vascularization of the lesion, as in the criteria of the European Association for the Study of the Liver (EASL) or in modified RECIST. Fourth, regarding catheter position, identification of the vessel by merely specifying right or left artery is not sufficient. The distance between the tip of the catheter and the origin of the artery should also be carefully reproduced, since a 5to 10-mm difference in catheter position can have a major impact on flow distribution (4). In addition to these 4 methodologic issues, 3 general concerns have to be raised. First, the results of this study contradict previously published results on resin microspheres (SIR-Spheres; Sirtex). Using an appropriate dosimetric approach (5), a preliminary study (8 patients) found a good correlation between the tumor-absorbed dose and the response of metastatic disease to 90Y-resin microspheres. On the other hand, more than one study (Wondergem et al. (4), for instance) found a poor correspondence between 99mTc-MAA and 90Y-resin microsphere biodistributions, suggesting that the degree of 99mTc-MAA perfusion could not predict response. Indeed, 99mTc-MAA particles and 90Y-resin microspheres may not have the same distribution, since the number of injected therapeutic particles is about 300 times higher than the number of 99mTc-MAA particles. Moreover, 99mTcMAA is injected as a bolus, whereas the resin microspheres are given as a series of small injections interleaved with checks with contrast medium. In hepatocellular carcinoma (HCC), the results seem more concordant. Using the partition model applied to planar 99mTc-MAA images, Ho et al. (6) reported a response rate of 37.5% for a tumor dose of more than 225 Gy versus only 10.3% for a tumor dose of 225 Gy or less (P, 0.006). Similarly, Kao et al. (7) reported a good correlation between 99mTc-MAA SPECT/CT dosimetry and response after 90Y-resin microsphere therapy. Second, the fact that in Ulrich’s study 26% of the lesions with a low degree of 99mTc-MAA perfusion effectively responded may be explained by at least one factor other than quantification underestimation. Although quantification of bremsstrahlung images of 90Y distribution was not performed, the authors conclude that even in hypovascularized lesions the amount of 90Y-resin microspheres is sufficient to induce an antitumoral effect. We wonder whether, for some patients, this antitumoral effect might have been embolic rather than induced by radiation, once properly quantified. Indeed, even though the absence of histologic signs of embolization in normal liver was demonstrated in a preclinical study (8), the potential embolic effect on tumoral neovascularization is still a matter of debate. Third, Ulrich et al., despite their poor methodology, suggest that “. . .in 99mTc-MAA SPECT no prediction of response in colorectal COPYRIGHT

A gate evaluation of the sources of error in quantitative90Y PET

PURPOSE Accurate reconstruction of the dose delivered by 90 Y microspheres using a postembolization PET scan would permit the establishment of more accurate dose-response relationships for treatment of hepatocellular carcinoma with 90 Y. However, the quality of the PET data obtained is compromised by several factors, including poor count statistics and a very high random fraction. This work uses Monte Carlo simulations to investigate what impact factors other than low count statistics have on the quantification of90 Y PET. METHODS PET acquisitions of two phantoms-a NEMA PET phantom and the NEMA IEC PET body phantom-containing either 90 Y or 18 F were simulated using gate. Simulated projections were created with subsets of the simulation data allowing the contributions of random, scatter, and LSO background to be independently evaluated. The simulated projections were reconstructed using the commercial software for the simulated scanner, and the quantitative accuracy of the reconstruction and the contrast recovery of the reconstructed images were evaluated. RESULTS The quantitative accuracy of the 90 Y reconstructions were not strongly influenced by the high random fraction present in the projection data, and the activity concentration was recovered to within 5% of the known value. The contrast recovery measured for simulated 90 Y data was slightly poorer than that for simulated 18 F data with similar count statistics. However, the degradation was not strongly linked to any particular factor. Using a more restricted energy range to reduce the random fraction in the projections had no significant effect. CONCLUSIONS Simulations of 90 Y PET confirm that quantitative 90 Y is achievable with the same approach as that used for 18 F, and that there is likely very little margin for improvement by attempting to model aspects unique to 90 Y, such as the much higher random fraction or the presence of bremsstrahlung in the singles data.

Absorbed-dose calculation for treatment of liver neoplasms with 90Y-microspheres

The aim of this review article is to present a state-of-the-art of the absorbed-dose calculation for the selective internal radiation therapy (SIRT) of liver neoplasms with 90Y-microspheres. The review focuses on the following aspects: activity quantification, partition model, medical internal radiation dose (MIRD) formalism, three-dimensional dosimetry, micro-scale dosimetry, and radiobiological modeling. 99mTc-macro-aggregated albumin (MAA) with single-photon emission tomography (SPECT) serves as a surrogate for 90Y-microspheres for treatment planning and predictive dosimetry. Iterative reconstruction with physic modeling to compensate quantification biases is now a standard for activity quantification. For post-implantation dosimetry, direct 90Y quantification with time of flight positron emission tomography has demonstrated good accuracy. The partition model is a simple and well-known approach for tumor, normal liver, and lung dosimetry measured from 99mTc-MAA-SPECT, while the MIRD equations can provide more detailed schemes for pre- and post-implantation dosimetry. 3D dosimetry allows considering heterogeneous activity and material distribution thanks to voxel-based quantification and energy deposition modeling. For the latter, dose-kernel convolution or local energy deposition approaches are widespread. Micro-scale dosimetry studies have highlighted high-absorbed-dose heterogeneities at the microscopic level. Microscopic models were developed and can be incorporated into macro-scale dosimetry. More recently, radiobiological models have been applied to calculate the biological effective dose. 90Y-microspheres dosimetry for SIRT is an active field of research in all its aspects. Its ease of implementation in a clinical setting along with the development of microscopic and radiobiological models should contribute to better handle treatment outcomes.

Implementation and validation of collapsed cone superposition for radiopharmaceutical dosimetry of photon emitters.

Two collapsed cone (CC) superposition algorithms have been implemented for radiopharmaceutical dosimetry of photon emitters. The straight CC (SCC) superposition method uses a water energy deposition kernel (EDKw) for each electron, positron and photon components, while the primary and scatter CC (PSCC) superposition method uses different EDKw for primary and once-scattered photons. PSCC was implemented only for photons originating from the nucleus, precluding its application to positron emitters. EDKw are linearly scaled by radiological distance, taking into account tissue density heterogeneities. The implementation was tested on 100, 300 and 600 keV mono-energetic photons and (18)F, (99m)Tc, (131)I and (177)Lu. The kernels were generated using the Monte Carlo codes MCNP and EGSnrc. The validation was performed on 6 phantoms representing interfaces between soft-tissues, lung and bone. The figures of merit were γ (3%, 3 mm) and γ (5%, 5 mm) criterions corresponding to the computation comparison on 80 absorbed doses (AD) points per phantom between Monte Carlo simulations and CC algorithms. PSCC gave better results than SCC for the lowest photon energy (100 keV). For the 3 isotopes computed with PSCC, the percentage of AD points satisfying the γ (5%, 5 mm) criterion was always over 99%. A still good but worse result was found with SCC, since at least 97% of AD-values verified the γ (5%, 5 mm) criterion, except a value of 57% for the (99m)Tc with the lung/bone interface. The CC superposition method for radiopharmaceutical dosimetry is a good alternative to Monte Carlo simulations while reducing computation complexity.