Botulinum Toxin Plus Transdermal Scopolamine Reduces Salivary Gland Uptake in Patients Undergoing Tandem Radiopharmaceutical Therapy with [ 225 Ac]Ac- and [ 177 Lu]Lu-PSMA Radioligands

Prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical therapy (RPT) has shown remarkable efficacy in advanced metastatic castration-resistant prostate cancer. However, salivary gland toxicity is a major dose-limiting adverse effect, particularly with α-emitting radionuclides such as 225Ac. Although tandem therapy with combined [225Ac]Ac- and [177Lu]Lu-labeled PSMA-targeted RPT in a single low-activity cycle may address certain challenges, effective salivary gland protection remains crucial. In this study, we explored the use of botulinum toxin (BTX) type A (incobotulinumtoxinA) plus transdermal scopolamine as a protective strategy to mitigate salivary gland uptake of PSMA radioligands. Methods: IncobotulinumtoxinA was injected percutaneously, with increasing dosages of up to 300 units distributed into the parotid and submandibular glands under ultrasound guidance, a mean of 24 d before scheduled tandem PSMA RPT. Transdermal scopolamine was applied from 72 h before RPT until 2 h after RPT. Molecular imaging was conducted as per PSMA RPT protocol, with pretreatment PSMA PET/CT to confirm ligand uptake and follow-up PET/CT for restaging. SPECT/CT was conducted as imaging after RPT. PET SUVmean or SPECT counts were measured, and ratios of injected-to-noninjected contralateral glands were calculated and compared before and after BTX. Results: Fourteen patients (mean age, 68.0 ± 8.1 y) were included; 1 patient received 2 injections before his treatment, and another underwent 2 tandem RPT cycles, with BTX administered before each cycle. Mean cumulative administered activity was 5.05 ± 1.09 GBq for 177Lu and 6.87 ± 3.14 MBq for 225Ac. Combination therapy with incobotulinumtoxinA plus transdermal scopolamine was associated with lower PSMA radioligand uptake in BTX-treated salivary glands relative to untreated contralateral glands, with mean reductions of approximately 30% in parotid glands and 17% in submandibular glands compared with untreated glands. Up to 300 units of incobotulinumtoxinA distributed among the major salivary glands was safe. No patient discontinued tandem PSMA therapy because of xerostomia, and no grade 3 or 4 toxicities were observed during PSMA RPT. Conclusion: BTX plus transdermal scopolamine is a promising strategy to reduce salivary gland uptake during PSMA RPT. This approach enhances patient quality of life after PSMA radiopharmaceutical therapy, particularly with α-emitting radionuclides, while preserving its excellent therapeutic efficacy.