Researchers at the National University of Singapore have developed a promising dual-therapy approach to combat one of the most debilitating side effects of advanced prostate cancer treatment. The combination of botulinum toxin injections and transdermal scopolamine patches significantly reduces radiation-induced salivary gland damage in patients receiving PSMA-targeted radioligand therapy, according to findings presented at the Society of Nuclear Medicine and Molecular Imaging 2025 Annual Meeting.
The study addresses a critical treatment challenge in metastatic prostate cancer care. While PSMA-targeted radioligand therapy using alpha-emitter ²²⁵Ac-PSMA and beta-emitter ¹⁷⁷Lu-PSMA has demonstrated remarkable anti-tumor efficacy, the inadvertent radiation exposure to salivary glands causes severe xerostomia (chronic dry mouth), often forcing patients to discontinue otherwise effective treatments.
Novel Protective Strategy Shows Significant Results
The research team enrolled 14 patients with metastatic castration-resistant prostate cancer, with a mean age of 68.0 ± 8.1 years, scheduled for combined ²²⁵Ac- and ¹⁷⁷Lu-PSMA radioligand therapy. The cohort was heavily pretreated, with a median PSA level of 59 ng/mL (range 17.2 to 2130.0 ng/mL) and a mean Karnofsky performance score of 85.0 ± 11.6.
The protective protocol involved percutaneous injections of 250 units of botulinum toxin (IncoA, Xeomin) administered to one parotid gland and the contralateral submandibular glands 3-4 weeks before radioligand therapy. Patients also received transdermal scopolamine patches behind the ears starting 72 hours before treatment and continuing until 2 hours post-therapy.
Molecular imaging assessments using SPECT/CT revealed significant reductions in PSMA tracer accumulation in treated salivary glands. Botox-injected parotid glands showed a mean 30% decrease in radioligand uptake compared to untreated contralateral glands, while treated submandibular glands demonstrated a 17% reduction. Crucially, tumor uptake of PSMA radioligands remained unaffected, preserving therapeutic efficacy.
Mechanism and Clinical Impact
The therapeutic approach leverages complementary pharmacological mechanisms. Botulinum toxin, administered via ultrasound-guided injections, inhibits acetylcholine release at presynaptic neuromuscular junctions, reducing salivary gland secretory activity and blood flow. This likely diminishes retention and uptake of PSMA-targeted radioligands in these tissues. Transdermal scopolamine provides systemic anticholinergic effects, further reducing parasympathetic stimulation and enhancing glandular protection.
"This study demonstrates that Botox, administered at recommended doses in combination with a nausea patch, offers a promising therapeutic strategy for reducing radiation-induced salivary gland toxicity without compromising PSMA tumor uptake," said Dr. Jingjing Zhang, assistant professor at the Theranostics Centre of Excellence. "The significance of this work lies in its direct patient benefit and its potential to expand the therapeutic utility of PSMA radiopharmaceutical therapy, particularly with alpha-emitting radionuclides like ²²⁵Ac."
Safety Profile and Treatment Adherence
The combined regimen demonstrated excellent tolerability, with patients experiencing only mild localized injection discomfort and no serious systemic adverse events. Most importantly, no participants discontinued radioligand therapy due to xerostomia, representing a substantial improvement in treatment adherence and quality of life compared to historical outcomes.
The cohort received 1 to 2 cycles of treatment with ¹⁷⁷Lu (5.05 ± 1.09 GBq) and ²²⁵Ac (6.87 ± 3.14 MBq) per cycle, with a total of 16 botulinum toxin treatments administered. Four patients received only botulinum toxin, while the remaining patients received both agents.
Broader Therapeutic Implications
The findings have far-reaching implications for PSMA-targeted radiopharmaceutical therapy. By addressing dose-limiting salivary gland toxicity, clinicians may be able to deliver higher or more frequent therapeutic doses, potentially enhancing oncologic outcomes without compromising patient well-being. This is particularly relevant for potent alpha emitters like ²²⁵Ac, where salivary gland protection could broaden the therapeutic index.
"Our approach leverages readily available, FDA-approved medications to pioneer a protective strategy against radiation-induced salivary gland damage," Dr. Zhang emphasized. "This innovation could rapidly be adopted in clinical centers equipped to perform PSMA radioligand therapy, thereby enhancing patient care on a global scale."
Research assistant Tianzhi Zhao noted the quality of life implications: "In order for patients to maintain a good quality of life and continue with their treatments, it's essential to address these serious dry mouth issues. Our study explored the use of Botox paired with a nausea patch on reducing radiation uptake to the salivary glands."
The dual blockade represents a significant advancement over previous monotherapies or physical cooling methods that failed to achieve meaningful glandular protection. The synergy between botulinum toxin's local neuromuscular blockade and scopolamine's systemic parasympathetic inhibition likely orchestrates a multifaceted reduction in salivary gland perfusion, secretion, and consequent PSMA radioligand uptake.
