Last reviewed by Dr. Dharmender Malik on 7 May 2026. Reflects current published evidence and FMRI institutional protocol.
Xerostomia — the medical term for persistent dry mouth — is the side effect that patients on Actinium-225 PSMA therapy talk about long after the cycle is over. It is not the side effect medical literature dwells on most, perhaps because it is rarely fatal and never the headline. But spend an hour in the consultation room with someone six months out from a second cycle of Ac-PSMA, and you will hear about it before anything else: the night-time water bottle, the difficulty with dry food, the way speech changes after a long meeting. We think it deserves a serious, honest article of its own.
This is that article. It explains what xerostomia is, why PSMA therapy causes it, how often it actually happens at FMRI, and the mitigation strategies we use — separating the ones with real evidence behind them from the ones that are still emerging. Patients deserve to know which is which before they consent to therapy.
Why PSMA therapy injures the salivary glands
Prostate-Specific Membrane Antigen (PSMA), despite the name, is not specific to prostate cancer. It is a transmembrane protein that is highly expressed by prostate adenocarcinoma — which is why we can use it as a therapeutic target — but it is also expressed at lower levels by several normal tissues, including the lacrimal glands, the kidneys, the small intestine, and most clinically important here, the parotid and submandibular salivary glands.[1]
When a radioligand like Lu-PSMA-617 or Ac-PSMA-617 is administered, the bulk of the dose binds to PSMA-expressing tumour. But a clinically meaningful fraction binds incidentally to salivary gland tissue. The radiation that follows — beta from Lu-177, alpha from Ac-225 — damages the acinar cells that produce saliva. The damage is most pronounced in the parotid gland, which has the highest PSMA expression of the major salivary glands.
Figure 1. The parotid and submandibular glands sit close to the surface and to each other. This is why dryness affects speech, swallowing, and taste in combination rather than separately.
The biology is subtly different between Lu-177 and Ac-225. Lu-177 deposits its energy across roughly 2 mm of tissue, which means salivary gland injury is somewhat diffused. Ac-225 deposits enormously more energy across a few cell diameters — its alpha particles cause clustered DNA damage that is harder for cells to repair. The result is that with equivalent receptor binding, alpha radiation produces a more severe and longer-lasting xerostomia than beta. This is the central trade-off of alpha-PSMA escalation: better tumour kill in micrometastatic disease comes at the price of a more challenging side-effect profile in the salivary glands.
How common is it really?
The honest answer: very common, but the severity matters more than the prevalence. Across published Ac-PSMA series, some degree of xerostomia is reported in approximately 70–90% of patients. Severe (CTCAE grade 3) xerostomia — the kind that interferes meaningfully with daily life — is reported in roughly 10–20% depending on cumulative dose and the dosing schedule used.[2]
In our institutional experience, since we adopted dose fractionation as a default for first-cycle Ac-PSMA, the rate of severe xerostomia has declined substantially. Mild dryness — manageable with hydration and lifestyle adjustments — remains common. The question we now spend most of our pre-treatment counselling on is not "will you get dryness" (most patients will, to some degree) but "what level of dryness can you accept, and what are we doing to keep it in that range".
What we measure
We grade xerostomia using the CTCAE v5.0 scale at every follow-up. Grade 1 is mild dryness without functional impact. Grade 2 is moderate dryness with diet modification. Grade 3 is severe — meaningfully impairing oral intake or requiring tube feeding in the worst cases. Most patients in our series who experience grade 2 dryness improve to grade 1 between cycles. Patients who reach grade 3 require formal supportive care referral.
What actually works — and what doesn't (yet)
This section is deliberately ordered by strength of evidence. The strategies at the top are routine practice supported by reasonable data. The ones lower down are emerging — promising in early studies, not yet established as routine care. Patients reading this should not assume "newer" means "better".
Dose fractionation — the most evidence-supported strategy
Splitting one Ac-PSMA cycle into two or three smaller administered fractions, separated by a few weeks, reduces the peak salivary gland dose without compromising tumour response in most series.[3] The mechanism is intuitive: cumulative damage to repair-capable tissue (like salivary acinar cells) is less when the dose is delivered in smaller increments because the repair machinery has time to operate between fractions. Tumour cells, with disrupted repair pathways, do not benefit from the same recovery window.
We use fractionation for almost every Ac-PSMA patient now, especially for the first cycle when cumulative damage is most influenced by initial activity. The administered activity per fraction, the interval, and the total cumulative dose are individualised based on body weight, marrow reserve, and prior Lu-PSMA exposure.
Hydration, salivary substitutes, and dental care
The basics matter. We instruct every patient to maintain aggressive hydration throughout the treatment course — not just on the day of administration. Sugar-free chewing gum and sialagogues like sour citrus drops can help stimulate residual gland function. Over-the-counter saliva substitutes provide symptomatic relief, particularly at night. And every patient considering Ac-PSMA should have a dental review before starting therapy — restoring caries and managing periodontal disease before treatment is far easier than after, because reduced saliva flow accelerates dental decay.
Sialendoscopy and gland flushing
Sialendoscopy — endoscopic visualisation and irrigation of the salivary ducts — has been studied as a supportive intervention in PSMA-related xerostomia. The evidence is mixed and the procedure requires specialist availability. It is reasonable to consider for patients with persistent grade 2 dryness who have exhausted simpler measures, particularly when accompanied by ductal mucus or discomfort. It is not part of routine first-line management.
Botulinum toxin — promising, not yet established
Botulinum toxin (Botox) injection into the salivary glands has been investigated as a way to reduce uptake of the radioligand by the glands during therapy, with the goal of preserving long-term function. The rationale is mechanistic — temporarily reducing gland activity may reduce active uptake — but the published clinical evidence is at an early stage. Small case series and pilot studies have suggested benefit in some patients, but results have been inconsistent and the optimal timing, dose, and patient selection are not yet established.[4]
We are following this evidence carefully. We do not currently offer pre-emptive botulinum toxin injection as routine practice. We will revisit that position as larger, prospective studies report. Patients who hear about this approach from elsewhere — and they do — should know that it is at the frontier of the field, not the standard of care.
"Patients deserve to know which mitigation strategies have evidence behind them and which are still being investigated. The honest answer is part of the consent."
What we tell every patient before the first cycle
Pre-treatment counselling for Ac-PSMA at FMRI includes an explicit conversation about xerostomia. We do this for two reasons. First, we have learned that patients who hear about it before therapy and recognise it when it happens cope with it far better than patients who feel blindsided. Second, the mitigation strategies that work — fractionation, hydration, dental review — only work if they start before the first dose, not after the dryness sets in.
The conversation goes something like this: "Most patients receiving alpha-PSMA experience some dry mouth. For most, it is mild and manageable with hydration and small dietary adjustments. A smaller proportion experience more troubling dryness that affects sleep or eating. We do everything we can to minimise it — fractionated dosing, individualised activity, dental review before we start. Even with all of that, we cannot promise it will not happen. If it does, we have a clear plan for managing it. The question we want you to answer before we start is whether the trade-off — better tumour control in exchange for some risk of lasting dry mouth — is one that makes sense for you given everything else in your situation."
Considering alpha-PSMA and want to discuss the side effects?
A consultation with Dr. Sen will walk through your imaging, prior treatment, and the realistic side-effect picture for your specific situation — before any therapy begins.
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When to escalate supportive care
Most patients managing dryness can be supported within the nuclear medicine clinic. There are situations where we refer for additional input:
- Persistent grade 3 xerostomia at six months from the last cycle — referral to a head-and-neck specialist or a dedicated supportive-care service for assessment of sialendoscopy, salivary gland imaging, and longer-term management
- Rapid dental deterioration — referral to a dentist familiar with radiation-induced xerostomia for fluoride trays, frequent recall, and proactive caries management
- Sleep disruption from night-time dryness — humidified bedroom environments, dedicated saliva substitutes for nocturnal use, and review of any concomitant medications that contribute to dryness
- Sudden worsening or asymmetric swelling of the salivary glands — this can indicate duct obstruction or infection rather than radiation-induced dryness, and requires urgent ENT review
A closing thought
Xerostomia is the price of admission for alpha-PSMA therapy in many patients. It is also a price that can be substantially reduced with thoughtful planning — fractionation, hydration, dental review, honest counselling. The patients who do best are the ones who know what is coming, who feel like partners in the management plan rather than recipients of an inevitable side effect, and whose care team takes the dryness seriously when it shows up.
If you are starting alpha-PSMA, ask your nuclear medicine team about their fractionation protocol, whether dental review is built into the pre-treatment workflow, and what their plan is for managing dryness when it occurs. The answers will tell you a lot about how seriously the centre takes this side effect.
For patients & referring clinicians
Frequently asked questions
Q01
Why does PSMA therapy cause dry mouth?
PSMA, the protein that PSMA-targeted therapies bind to, is highly expressed on prostate cancer cells but is also expressed at lower levels by the salivary glands — particularly the parotid and submandibular glands. The radioligand binds incidentally to these glands, and the radiation injury that follows reduces saliva production. With Lu-177 the effect is usually mild and transient. With Ac-225, alpha emission produces more severe and longer-lasting salivary gland damage.
Q02
How common is xerostomia after Ac-225 PSMA therapy?
In published series, some degree of xerostomia is reported in roughly 70 to 90 percent of patients receiving Ac-225 PSMA therapy. Severe (CTCAE grade 3) xerostomia occurs in approximately 10 to 20 percent depending on cumulative dose and dosing schedule. In our institutional experience at FMRI, dose fractionation has substantially reduced the rate of severe xerostomia.
Q03
Does dose fractionation actually reduce xerostomia?
Yes — this is the most evidence-supported mitigation strategy. Splitting one Ac-225 cycle into two or three smaller administered fractions, separated by a short interval, reduces peak salivary gland dose without compromising tumour response in most published series. We use fractionation for almost every Ac-PSMA patient now, particularly for the first cycle.
Q04
Can botulinum toxin (Botox) prevent xerostomia from PSMA therapy?
Botulinum toxin injection into the salivary glands has been investigated as a way to reduce uptake of the radioligand by the glands. The published evidence is at an early stage — small case series and pilot studies with mixed results. We do not currently offer it as routine practice. It remains an active area of investigation that we will revisit as larger prospective studies are reported.
Q05
How long does xerostomia last after PSMA therapy?
For most patients receiving Lu-177 PSMA, mild dryness improves over weeks to months and largely resolves between cycles. After Ac-225 PSMA, recovery is slower and sometimes incomplete, particularly after multiple cycles. Patients with persistent grade 3 xerostomia six months after their last cycle should be referred for specialist supportive care.
Citations & references
Mhawech-Fauceglia P, Zhang S, Terracciano L, et al. Prostate-specific membrane antigen (PSMA) protein expression in normal and neoplastic tissues. Histopathology. 2007;50(4):472-483.
Sathekge M, Bruchertseifer F, Vorster M, et al. Predictors of overall and disease-free survival in metastatic castration-resistant prostate cancer patients receiving ²²⁵Ac-PSMA-617 radioligand therapy. J Nucl Med. 2020;61(1):62-69.
Kratochwil C, Bruchertseifer F, Rathke H, et al. Targeted α-therapy of mCRPC with ²²⁵Ac-PSMA-617: dosimetry estimate and empiric dose finding.
J Nucl Med. 2017;58(10):1624-1631.
doi:10.2967/jnumed.117.191395Baum RP, Langbein T, Singh A, et al. Injection of botulinum toxin for preventing salivary gland toxicity after PSMA radioligand therapy: an empirical proof of concept. Nucl Med Mol Imaging. 2018;52(1):80-81. Note: early-stage evidence. Not currently offered as routine practice at FMRI.
About the Author
Dr. Ishita B. Sen
MBBS · MD (Nuclear Medicine) · DNB · Post-doctoral Fellowship, Memorial Sloan Kettering Cancer Center, New York
Director & Chief of Nuclear Medicine at Fortis Memorial Research Institute. Co-founder of Theranostic Physicians Private Limited. Two decades in clinical nuclear medicine and one of the largest Indian institutional experiences in PSMA-directed radioligand therapy, with clinical experience acknowledged in international peer-reviewed systematic reviews.