Dosimetric Evaluation of the Effect of Receptor Heterogeneity on the Therapeutic Efficacy of Peptide Receptor Radionuclide Therapy: Correlation with DNA Damage Induction and In Vivo Survival (original) (raw)
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Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2021
Rationale: To build a refined dosimetry model for [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE) in vivo experiments enabling the correlation of absorbed dose with double strand breaks (DSBs) induction and cell death. Methods: Somatostatin receptor type-2 (SSTR2) expression of NCI-H69 xenografted mice, injected with 177Lu-DOTATATE, was imaged at 0, 2, 5, 11 days. This was used as input to reconstruct realistic 3 dimensional heterogeneous activity distributions and tissue geometries of both cancer and heathy cells. The resulting volumetric absorbed dose rate distributions were calculated using GATE Monte Carlo code and compared to homogenous dose rate distributions. The absorbed dose (0-2 days) on µm-scale sections was correlated with DSBs induction, measured by γH2AX foci. Moreover, the absorbed dose on larger mm-scale sections delivered over the whole treatment (0-14 days) was correlated to the modelled in vivo survival to determine the radiosensitivity parameters α and β for com...
EJNMMI Physics, 2020
Background Survival and linear-quadratic model fitting parameters implemented in treatment planning for targeted radionuclide therapy depend on accurate cellular dosimetry. Therefore, we have built a refined cellular dosimetry model for [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE) in vitro experiments, accounting for specific cell morphologies and sub-cellular radioactivity distributions. Methods Time activity curves were measured and modeled for medium, membrane-bound, and internalized activity fractions over 6 days. Clonogenic survival assays were performed at various added activities (0.1–2.5 MBq/ml). 3D microscopy images (stained for cytoplasm, nucleus, and Golgi) were used as reference for developing polygonal meshes (PM) in 3DsMax to accurately render the cellular and organelle geometry. Absorbed doses to the nucleus per decay (S values) were calculated for 3 cellular morphologies: spheres (MIRDcell), truncated cone-shaped constructive solid geometry (CSG within MCNP6.1), ...
Pharmaceutics
Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking into account the different characteristics of TRT. For instance, TRT employs radiation with a high linear energy transfer (LET), which results in an increased effectiveness. Furthermore, a heterogeneous radiopharmaceutical distribution could result in a heterogeneous dose distribution at a tissue, cellular as well as subcellular level, which will generally reduce the tumor response. Finally, the dose rate in TRT is protracted, relatively low, and variable over time. This allows cells to repair more DNA damage, which may reduce the effectiveness of TRT. Within this review, an overview is given on how these characteristics can be included in TCP models, while some experimental findings ...
Journal of Radiation Research, 2012
Stereotactic irradiation/IMRT/Intermittent irradiation/Sublethal damage repair/Reoxygenation/ LQ model. Since the dose delivery pattern in high-precision radiotherapy is different from that in conventional radiation, radiobiological assessment of the physical dose used in stereotactic irradiation and intensitymodulated radiotherapy has become necessary. In these treatments, the daily dose is usually given intermittently over a time longer than that used in conventional radiotherapy. During prolonged radiation delivery, sublethal damage repair takes place, leading to the decreased effect of radiation. This phenomenon is almost universarily observed in vitro. In in vivo tumors, however, this decrease in effect can be counterbalanced by rapid reoxygenation, which has been demonstrated in a laboratory study. Studies on reoxygenation in human tumors are warranted to better evaluate the influence of prolonged radiation delivery. Another issue related to radiosurgery and hypofractionated stereotactic radiotherapy is the mathematical model for dose evaluation and conversion. Many clinicians use the linear-quadratic (LQ) model and biologically effective dose (BED) to estimate the effects of various radiation schedules, but it has been suggested that the LQ model is not applicable to high doses per fraction. Recent experimental studies verified the inadequacy of the LQ model in converting hypofractionated doses into single doses. The LQ model overestimates the effect of high fractional doses of radiation. BED is particularly incorrect when it is used for tumor responses in vivo, since it does not take reoxygenation into account. For normal tissue responses, improved models have been proposed, but, for in vivo tumor responses, the currently available models are not satisfactory, and better ones should be proposed in future studies.
Radiosensitizers and Radioprotectors [Working Title], 2019
Radiotherapy is a cornerstone of the modern treatment of many types of cancer, having both curative and palliative roles. It is estimated that more than half of cancer patients will need radiation therapy in the course of evolution. The goal of radiotherapy is to maximize tumor control, reducing adverse effects on normal tissues in close proximity at the same time. Improving the therapeutic ratio is the main goal of the efforts made to improve the technique and accuracy of the radiotherapy by using the targeting of the tumor volume with the help of the imaging guide and the dose conformation around the target volume. The use of the multi-leaf collimator (MLC) allowed a better coverage of the target volume in the irradiation field, thus reducing the unnecessary irradiation of healthy tissues. The use of radioprotective agents and radiosensitizers is another strategy to maximize the effect of radiotherapy. Recently, interest has focused on the design of irradiation protocols that expl...
Accurate Description of the Cell Survival and Biological Effect at Low and High Doses and LET's
Journal of Radiation Research, 2011
Cell survival modelling/RCR model/Dual Poisson process/Inactivation cross-section/High LET/Relative biological effectiveness/Mixed beams. To accurately describe the radiation response over a wide dose and ionization density range Binomial and Poisson statistics have been combined with the recently developed potentially Repairable-Conditionally-Repairable (RCR) damage response model and the combination is shown to have several advantages for the accurate description of the cell survival at both low and very high doses and LET's, especially when compared with the classical Linear and Linear Quadratic cell survival models. Interestingly, the potentially and conditionally repairable damage types of the RCR model may also be linked to the two major radiation damage repair pathways of eukaryotic cells namely Non Homologous End Joining (NHEJ) and Homologous Recombination (HR) respectively. In addition it describes the damage interaction of low and high LET damage in different dose fractions more accurately than any other model (cf. (6) and Fig. 7d). This is of considerable importance when describing the response of tumors and normal tissues during pencil beam scanning with light ion beams where low and high LET dose fractions from the plateau and Bragg peak can interact synergistically when being delivered quasi simultaneously. In conclusion, considering the unique biological properties of light ion beams such as their increased effect on hypoxic tumors, their microdosimetric energy deposition heterogeneity and their pencil beam energy deposition kernels the largest clinical advantages are obtained with medium LET beams (≈ 20-50 eV/nm). This applies even for radiation resistant tumors, at least when the goal is to maximize tumor cure with minimal adverse reactions in normal tissues.
EJNMMI Research
Background: This study's aim was to develop our dosimetric methodology using a commercial workstation for the routine evaluation of the organs at risk during peptide receptor radionuclide therapy (PRRT) with 177 Lu. Methods: First, planar and SPECT sensitivity factors were determined on phantoms. The reconstruction parameters were optimized by SPECT/CT image acquisition using a NEMA IEC phantom containing a 500 ml bottle of 177 Lu, to simulate a kidney. The recovery coefficients were determined on various phantoms. For the red marrow, this was calculated using a NEMA IEC phantom that contained a centrally placed bottle of 80 ml of 177 Lu (to model the L2-L4 red marrow) flanked by two 200 ml bottles with 177 Lu to simulate the kidneys. Then, SPECT/CT images were acquired at 4, 24, 72, and 192 h after injection in 12 patients with neuroendocrine tumors who underwent PRRT with 177 Lu-DOTATATE. SPECT data were reconstructed using the iterative ordered subset expectation maximization (OSEM) method, with six iterations and ten subsets, attenuation, scatter, recovery resolution corrections, and a Gaussian post-filter of 0.11 cm. The liver, spleen, kidneys, and red marrow dose per administered activity (AD/A admin) values were calculated with the Medical Internal Radiation Dose (MIRD) formalism and the residence times (Dosimetry toolkit® application) using standard and CT imaging-based organ masses (OLINDA/EXM® V1.0 software). Results: Sensitivity factors of 6.11 ± 0.01 and 5.67 ± 0.08 counts/s/MBq were obtained with planar and SPECT/CT acquisitions, respectively. A recovery coefficient of 0.78 was obtained for the modeled L2-L4 red marrow. The mean AD/A admin values were 0.43 ± 0.13 mGy/MBq [0.27-0.91] for kidneys, 0.54 ± 0.58 mGy/MBq [0.12-2.26] for liver, 0. 61 ± 0.13 mGy/MBq [0.42-0.89] for spleen, and 0.04 ± 0.02 mGy/MBq [0.01-0.09] for red marrow. The AD/A admin values varied when calculated using the personalized and standard organ mass, particularly for kidneys (p = 1 × 10 −7), spleen (p = 0.0069), and red marrow (p = 0.0027). Intra-patient differences were observed especially in organs close to or including tumor cells or metastases. Conclusions: The obtained AD/A admin values were in agreement with the literature data. This study shows the technical feasibility of patient dosimetry in clinical practice and the need to obtain patient-specific information.