Salivary gland toxicity (xerostomia) from PSMA radioligand therapy

Prostate-specific membrane antigen is expressed at low levels on normal salivary gland tissue as well as on prostate cancer cells, so PSMA-targeted radioligand therapies deliver an incidental radiation dose to the salivary glands. In the pivotal VISION trial of lutetium-177 vipivotide tetraxetan (Pluvicto), dry mouth (xerostomia) occurred in 39% of patients receiving Pluvicto plus best standard of care versus 0.5-1% on standard of care alone (any grade); no grade 3-4 xerostomia was reported in VISION. Dosimetry sub-studies found a mean salivary gland absorbed dose of roughly 0.5-0.6 Gy/GBq, which is towards the lower end of a wide reported range (0.5-1.9 Gy/GBq), and translates to roughly 25-30 Gy after a full six-cycle course at 7.4 GBq per cycle.

The FDA label for Pluvicto lists dry mouth among the most common adverse reactions (occurring in \u226520% of patients) and specifies dose modifications for recurrent or higher-grade dry mouth: for grade 2, withhold until improvement and consider a 20% dose reduction; for grade 3, withhold and reduce by 20% to 5.9 GBq; recurrent grade 3 dry mouth after one dose reduction is grounds for permanent discontinuation. In the combined PSMAfore/VISION safety population reported in a later label update, dry mouth of any grade occurred in around 46-61% of patients, reflecting longer follow-up and pooled populations.

Management is largely supportive: hydration, sugar-free gum or lozenges to stimulate residual saliva, avoiding alcohol-based mouthwash and irritant foods, and monitoring for secondary dental disease, since dry mouth increases caries risk. Xerostomia typically improves gradually after treatment ends. External radioprotective strategies (external cooling, salivary gland-sparing infusion techniques) are under investigation but are not yet standard of care.