Targeted Alpha Therapy in mCRPC (Metastatic Castration-Resistant Prostate Cancer) Patients: Predictive Dosimetry and Toxicity Modeling of 225Ac-PSMA (Prostate-Specific Membrane Antigen)

Belli, Maria Luisa; Sarnelli, Anna; Mezzenga, Emilio; Cesarini, Francesco; Caroli, Paola; Iorio, Valentina Di; Strigari, Lidia; Cremonesi, Marta; Romeo, Antonino; Nicolini, Silvia; Matteucci, Federica; Severi, Stefano; Paganelli, Giovanni

doi:10.3389/fonc.2020.531660

Cited by 20 publications

(19 citation statements)

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“…Dosimetry using imaging-based measurements of 225 Ac-PSMA-617 uptake is challenging due to the low administered activity and unfavorable physical decay characteristics of 225 Ac with low gamma emission probability and the competing Bremsstrahlung radiation ( 11 ). Therefore, previous dosimetry on 225 Ac-PSMA-617 and 225 Ac-PSMA-I&T extrapolated the uptake of respective 177 Lu-labeled analogs on imaging ( 11 , 12 , 22 ). Alternatively, extrapolation of 68 Ga-PSMA-617 uptake on positron emission tomography was previously used for dosimetry of 213 Bi-PSMA-617 ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

“…Clinical studies that involve 177 Lu-PSMA-617 generally have used 4-9 GBq of radioactivity compared to 4-8 MBq for 225 Ac-PSMA-617 therapy ( 6 , 10 ). The common use of a 1,000-fold lower dose for 225 Ac-PSMA-617 is based on empirical results and extrapolation of organ-level 177 Lu-PSMA-617 dosimetry ( 11 , 12 ). From a physics perspective, the required radioactivity of 225 Ac-PSMA-617 vs. 177 Lu-PSMA-617 to produce a comparable cytotoxic effect on the cellular level remains to be investigated.…”

Section: Introductionmentioning

confidence: 99%

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Prostat Kanserinde 225Ac-PSMA-617 ve 177Lu-PSMA-617’nin Subsellüler Dozimetriye Dayalı Göreceli Etkinliği

Lee¹

2022

Mirt

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Objectives: Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) with alpha-emitting 225 Ac-PSMA-617 has shown clinical efficacy even in cases of failed therapy with beta-emitting 177 Lu-PSMA-617. We investigated the efficacy of 225 Ac-PSMA-617 relative to 177 Lu-PSMA-617 using subcellular dosimetry. Methods: A 3-dimensional model of prostate cancer was constructed. For each decay, the absorbed and equivalent radiation dose to the cell nuclei was calculated. The relative efficacy per administered activity was calculated by taking into account the differences in residence time and tumor uptake. Results: As the tumor size increased, the absorbed dose from 225 Ac-PSMA-617 increased linearly (R2: 0.99) and reached an asymptote near the maximum alpha range (85 µm), whereas the absorbed dose from 177 Lu-PSMA-617 continued to increase linearly (R2: 0.99). The equivalent dose per decay was 2,320, 2,900, and 823-fold higher in favor of 225 Ac-PSMA-617 compared to 177 Lu-PSMA-617 in a single cell, 100 µm-radius micrometastasis, and macroscopic tumor, respectively. Per administered activity, the relative efficacy of 225 Ac-PSMA-617 compared to 177 Lu-PSMA-617 in respective tumor sizes was at least 3,480, 4,350, and 1,230-fold higher, and possibly 11,800, 14,900, and 4,200-fold higher considering differences in tumor uptake. Conclusion: At commonly administered 1,000-fold lower activity of 225 Ac-PSMA-617 relative to 177 Lu-PSMA-617, the equivalent radiation dose deposited by 225 Ac-PSMA-617 is higher in measurable disease and much higher in microscopic disease compared to 177 Lu-PSMA-617.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prostat Kanserinde 225Ac-PSMA-617 ve 177Lu-PSMA-617’nin Subsellüler Dozimetriye Dayalı Göreceli Etkinliği

Lee¹

2022

Mirt

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“…The lack or very low abundance of gamma emission represents a typical drawback of alpha emitter therapies such as 223 Ra, 225 Ac and 213 Bi-MoAbs and 225 Ac-PSMA, jeopardizing the feasibility or reliability of individual dosimetry. In order to overcome this problem, some authors have proposed extrapolations from the dosimetry using the same molecule and different radionuclides, i.e., assuming similar uptake and retention [21,22]. As a general rule, the reliability of the dosimetry information derived must always be assessed specifically for each type of radiolabeled molecule, since different radionuclides might influence the radiochemical stability and the biokinetics.…”

Section: Radiopharmaceuticals In Trtmentioning

confidence: 99%

Personalized Dosimetry in Targeted Radiation Therapy: A Look to Methods, Tools and Critical Aspects

Danieli

Milano

Gallo

et al. 2022

JPM

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Targeted radiation therapy (TRT) is a strategy increasingly adopted for the treatment of different types of cancer. The urge for optimization, as stated by the European Council Directive (2013/59/EURATOM), requires the implementation of a personalized dosimetric approach, similar to what already happens in external beam radiation therapy (EBRT). The purpose of this paper is to provide a thorough introduction to the field of personalized dosimetry in TRT, explaining its rationale in the context of optimization and describing the currently available methodologies. After listing the main therapies currently employed, the clinical workflow for the absorbed dose calculation is described, based on works of the most experienced authors in the literature and recent guidelines. Moreover, the widespread software packages for internal dosimetry are presented and critical aspects discussed. Overall, a selection of the most important and recent articles about this topic is provided.

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“…In addition, the linear–quadratic (LQ) model was recently adapted to 225 Ac-PSMA (prostate-specific membrane antigen) therapy using brachytherapy formalism for a mixture of radionuclides, considering the contribution of all daughter isotopes in the decay chain [ 11 ]. This model could also be applied to 223 RaCl 2 therapy to improve the accuracy of biologically effective dose (BED) calculation.…”

Section: Introductionmentioning

confidence: 99%

“…This model could also be applied to 223 RaCl 2 therapy to improve the accuracy of biologically effective dose (BED) calculation. Thus, to combine low-LET (linear energy transfer) EBRT and high-LET RN absorbed doses, we adapted the radiobiological model recently published for α-particle emitters to determine radiobiological quantities, such as those of BED, and for 2 Gy equieffective dose (EQD2) calculation [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Alpha-Emitter Radiopharmaceuticals and External Beam Radiotherapy: A Radiobiological Model for the Combined Treatment

Sarnelli

Belli

Azzali

et al. 2022

Cancers

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Previously published studies combined external beam radiotherapy (EBRT) treatments with different activities of 223Ra. The data of two-year overall survival (2y-OS) and neutropenia (TOX) incidence when combining EBRT and 223Ra are not homogeneous in literature. We adapted the linear–quadratic model (LQ) to 223Ra therapy using brachytherapy formalism for a mixture of radionuclides, considering the contribution of all daughter isotopes in the decay chain. A virtual cohort of patients undergoing 223Ra therapy was derived using data from the literature. The doses delivered using 223Ra and EBRT were converted into biologically equivalent doses. Fixed-effect logistic regression models were derived for both the 2y-OS and TOX and compared with available literature. Based on the literature search, four studies were identified to have reported the 223Ra injection activity levels varying from the placebo (0) to 80 kBq/kg, associated or not with EBRT. Logistic regression models revealed a dose-dependent increase in both the 2y-OS (intercept = −1.364; slope = 0.006; p-value ≤ 0.05) and TOX (−5.035; 0.018; ≤0.05) using the EBRT schedule of 8 Gy in 1 fr. Similar results were obtained for other schedules. Discrepancies between our TOX model and those derived for EBRT combined with chemotherapy are discussed. Radiobiological models allow us to estimate dose-dependent relationships, to predict the OS and TOX following combined 223Ra + EBRT treatment, which will guide future treatment optimization.

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Targeted Alpha Therapy in mCRPC (Metastatic Castration-Resistant Prostate Cancer) Patients: Predictive Dosimetry and Toxicity Modeling of 225Ac-PSMA (Prostate-Specific Membrane Antigen)

Cited by 20 publications

References 53 publications

Prostat Kanserinde <sup>225</sup>Ac-PSMA-617 ve <sup>177</sup>Lu-PSMA-617’nin Subsellüler Dozimetriye Dayalı Göreceli Etkinliği

Prostat Kanserinde <sup>225</sup>Ac-PSMA-617 ve <sup>177</sup>Lu-PSMA-617’nin Subsellüler Dozimetriye Dayalı Göreceli Etkinliği

Personalized Dosimetry in Targeted Radiation Therapy: A Look to Methods, Tools and Critical Aspects

Alpha-Emitter Radiopharmaceuticals and External Beam Radiotherapy: A Radiobiological Model for the Combined Treatment

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