Abstract
Radioligand therapy is a type of internal radiotherapy combining a short-range radioisotope labeled to a carrier with a high affinity for a specific receptor expressed on tumor cells. Targeted alpha therapy (TAT) combines a high-linear energy transfer (LET) emitter (225Ac) with a prostate-specific membrane antigen (PSMA) carrier, specifically binding tumor cells in patients with metastatic castration-resistant prostate cancer. Although the antitumor activity of 225Ac-PSMA is well-documented, this treatment is nowadays only used as salvage therapy because the high incidence of xerostomia limits the therapeutic window. Thus, methods to reduce salivary toxicity and models able to describe xerostomia incidence are needed. We recently studied the efficacy of salivary gland protectors administered in combination with 177Lu-PSMA therapy. Starting from these data, we performed a predictive dosimetric evaluation of 225Ac-PSMA to assess the impact of salivary gland protectors in TAT. 225Ac-PSMA predictive dosimetry was performed in 13 patients treated with 177Lu-PSMA. Sequential whole-body planar images were acquired 0.5–1, 16–24, 36–48, and 120 h post-injection. 177Lu time-activity curves were corrected for 225Ac physical decay and assumed in equilibrium for all daughters. The OLINDA/EXM spherical model was used for dose estimation of the parotid and submandibular glands. The dose for each daughter was calculated and summed for the total dose estimation. The biologically effective dose formalism was extended to high-LET emitters. For the total biologically effective dose formalism extended to high-LET emitters, including the contribution of all daughter isotopes, the brachytherapy formalism for a mixture of radionuclides was implemented. Equivalent doses in 2 Gy/fraction (EQD2) were then calculated and compared with the normal tissue complication probability model derived from external beam radiotherapy for grade ≥2 xerostomia induction. Median predictive doses were 0.86 BdRBE5/MBq for parotid glands and 1.05 BdRBE5/MBq for submandibular glands, with a 53% reduction compared with previously published data. The results show that the radiobiological model implemented is conservative, as it overestimates the complication rate with respect to the clinical data. Our data shows the possibility of reducing salivary gland uptake in TAT with the coadministration of organ protectors, but these results should be confirmed for TAT with 225Ac-PSMA by carrying out prospective trials with defined toxicity endpoints and dosimetry procedures.
Highlights
The combination of a short-range radioisotope labeled to a carrier/ligand highly specific for receptors expressed on tumor cells enables “internal” radioligand therapy (RLT) to be delivered to tumors
Predictive dosimetry evaluation was performed on 13 patients enrolled in the 177Lu-prostate-specific membrane antigen (PSMA) protocol
Without the administration of salivary gland protectors, the predicted probability values of acute G2+ xerostomia based on the normal tissue complication probability (NTCP) model were 97% for Ai equal to 50 kBq/kg and 100% for Ai equal to 100 g, 150, and 200 kBq/kg (Figure 2A)
Summary
The combination of a short-range radioisotope labeled to a carrier/ligand highly specific for receptors expressed on tumor cells enables “internal” radioligand therapy (RLT) to be delivered to tumors. Internal radiotherapy is known as radiometabolic treatment (RMT) when iodine-131 is used in thyroid cancer or peptide receptor radionuclide therapy when radiolabeled peptides such as somatostatin analog are used in neuroendocrine tumors [2]. Prostate-specific membrane antigen (PSMA) is an attractive target for diagnosis and therapy of metastasized prostate cancer [3]. PSMA, known as glutamate carboxypeptidase II, is a membrane protease anchored in the cell membrane of prostate cancer cells but not in normal prostate cells. A radiolabeled version of a PSMA ligand (DotaPSMA-617) has been synthesized and has shown promising properties when labeled with 177Lutetium, a short-range betagamma emitter [4, 5]
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