Safety of High-Dose Botulinum Toxin Injections for Parotid and Submandibular Gland Radioprotection during Ac-PSMA therapy.

Introduction: Incobotulinumtoxin A (IncoA) is approved for sialorrhea treatment in the US and EU and has been used for salivary gland (SG) protection of&nbsp;cancer patients. Radioligand therapies against prostate (or thyroid cancer) may induce salivary gland destruction due to off-target radioligand-uptake. Severe sialotoxicity is one treatment-limiting side-effect of Actinium-225-PSMA (PSMA: Prostate-Specific Membrane Antigen)&nbsp;radioligand therapy. Other treatments (e.g., anticholinergics) have failed so far to overcome this side-effect. Off-target Ac-PSMA salivary gland uptake correlates with the amount of gland destruction and xerostomia (SG function < 50%). This study assesses the safety of increased IncoA doses to achieve PSMA-uptake reduction in the SG.

Methods: Advanced prostate cancer patients (n=10, mean age 68 y) planned for (Ac+Lu-TANDEM-)PSMA-radioligand therapy were selected for prior IncoA injectionsents over a median time of 14 days [range 5&ndash;33 days] before Ac-PSMA therapy. For baseline, saliva production was measured before IncoA application and after radioligand therapies. &nbsp;

Measurement of salivary flow: Unprovoked salivary flow was measured with four dental rolls placed in the orifice of the mouth and retained for 5 minutes. Provoked salivary flow was measured by chewing on a folded compress placed on the tongue for 2 minutes. The difference in weight between the dry and wet rolls was calculated in grams (g).

Ultrasound guided percutaneous IncoA-injection was carried out (26 G, 25 mm needle length). Parotid gland received six injection points and the contralateral submandibular gland received three for maximum coverage (10 mm distance each, same dose, max. 30 units). A maximum total dose of 250 units of IncoA was applied (170 &ndash; parotid; 80 &ndash; submandibular).

Seven patients received additional transdermal scopolamine during a period of 72 h prior radioligand therapy.

Results: Table 1 summarizes IncoA treatment details and side-effects.

PG=parotid gland, SMG=Submandibular gland, *moderate pre-existing xerostomia.

Very mild injection pain was noted, which resolved immediately (parotid > submandibular). The most frequent (side) effect was mild dryness of mouth. One patient developed injection-related local hematoma (thrombocytopenia known). No other local or systemic adverse&nbsp;effects were noted.

Combined unprovoked and provoked saliva production 16&ndash;20 weeks after the first IncoA injection resulted in a mean 29% [range 25&ndash;31%] loss (or mean 71% preservation) of saliva production.

Conclusions: Injection of total 250 units IncoA under ultrasound guidance was tolerated with mild side effects (dry mouth that was temporary and reversable).

After Ac-PSMA, in our cohort loss of saliva&nbsp;production was only about 29% with one application of IncoA (with/without transdermal scopolamine). In comparison, previous studies reported that 26 patients, treated with 2 cycles of Ac-PSMA, experienced approx. 66% loss of parotid and submandibular gland function. A&nbsp;significant reduction of uptake was noted on PSMA PET/CT and&nbsp;Lu-PSMA &nbsp;SPECT/CT during therapy.

Our preliminary data suggests that high-dose (up to 250 IE) application of IncoA in combination with transdermal scopolamine provides significant SG protection and good tolerability. In conclusion, this treatment strategy can improve the tolerability of Ac-PSMA therapy.