Targeted alpha therapy of mCRPC: Dosimetry estimate of 213Bismuth-PSMA-617

Abstract

PurposePSMA-617 is a small molecule targeting the prostate-specific membrane antigen (PSMA). In this work, we estimate the radiation dosimetry for this ligand labeled with the alpha-emitter 213Bi.MethodsThree patients with metastatic prostate cancer underwent PET scans 0.1 h, 1 h, 2 h, 3 h, 4 h and 5 h after injection of 68Ga-PSMA-617. Source organs were kidneys, liver, spleen, salivary glands, bladder, red marrow and representative tumor lesions. The imaging nuclide 68Ga was extrapolated to the half-life of 213Bi. The residence times of 213Bi were forwarded to the instable daughter nuclides. OLINDA was used for dosimetry calculation. Results are discussed in comparison to literature data for 225Ac-PSMA-617.ResultsAssuming a relative biological effectiveness of 5 for alpha radiation, the dosimetry estimate revealed equivalent doses of mean 8.1 Sv RBE5/GBq for salivary glands, 8.1 Sv RBE5/GBq for kidneys and 0.52 Sv RBE5/GBq for red marrow. Liver (1.2 Sv RBE5/GBq), spleen (1.4 Sv RBE5/GBq), bladder (0.28 Sv RBE5/GBq) and other organs (0.26 SvRBE5/GBq) were not dose-limiting. The effective dose is 0.56 Sv RBE5/GBq. Tumor lesions were in the range 3.2–9.0 SvRBE5/GBq (median 7.6 SvRBE5/GBq). Kidneys would limit the cumulative treatment activity to 3.7 GBq; red marrow might limit the maximum single fraction to 2 GBq. Despite promising results, the therapeutic index was inferior compared to 225Ac-PSMA-617.ConclusionsDosimetry of 213Bi-PSMA-617 is in a range traditionally considered reasonable for clinical application. Nevertheless, compared to 225Ac-PSMA-617, it suffers from higher perfusion-dependent off-target radiation and a longer biological half-life of PSMA-617 in dose-limiting organs than the physical half-life of 213Bi, rendering this nuclide as a second choice radiolabel for targeted alpha therapy of prostate cancer.Electronic supplementary materialThe online version of this article (10.1007/s00259-017-3817-y) contains supplementary material, which is available to authorized users.

225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study

“…However, it is well known that kidney damage following radionuclide therapy can manifest in a delayed manner and onset of radiation-induced renal dysfunction may appear years later and might be missed with our short follow-up period. However, considering an estimated kidney dose of 0.7 Sv RBE5 /MBq of 225 Ac-PSMA-617 [21], a cumulative activity of 24 MBq, corresponding to an equivalent dose of 16.8 Sv RBE5 , still keeps a safety margin to the generally accepted tolerable cumulative equivalent dose of 27 Sv RBE5 for kidneys.…”

Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors

“…Their rationale for directly cell-targeted TAT of mCRPC is strong as indicated by the promising results with anti-PSMA ligands labeled with α-emitters [2][3][4][5][6][7][8][9]. While PSMA is detected on the majority of prostate cancer cases, the expression can be heterogenic at all levels; patient, lesion [33] and circulating tumor cells (CTCs).…”

“…Utilizing direct targeting in TAT, e.g., by alpharadioimmunotherapy (α-RIT), could further leverage αparticle-based treatments of mCRPC through increased efficacy and broadened indication. Studies have shown promising results using targeting of the prostate-specific membrane antigen (PSMA) in combination with the αemitters 225 Ac [2][3][4][5][6], 213 Bi [7] and 211 At [8,9]. While the results from reported and ongoing anti-PSMA-studies have been very encouraging, these reports have also pointed out limitations; some mCRPC patients have a low PSMA-expression [10], a fraction of pathologic positive lesion sites can be PSMA-negative [11], i.e., there is heterogeneity in the occurrence and expression of PSMA.…”

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“…Assuming an MTD of 1 Sv RBE5 for the red marrow and 27 Sv RBE5 for the kidneys, the maximum-tolerated adminis-tered activity would be approximately 10.4 MBq for the first hypothesis and 5.3 MBq for the second hypothesis (Table 2; ref. 33). Dose-limiting organs are similar with conventional RIT ( Supplementary Table S8).…”