Last reviewed by Dr. Dharmender Malik on 13 May 2026 · this article reflects the published evidence and current clinical practice at FMRI Gurugram.
Introduction
PSMA-targeted radioligand therapies — Lu-177 PSMA (Pluvicto) and Ac-225 PSMA — are among the most effective options available for metastatic castration-resistant prostate cancer that has progressed on prior treatment. They work by binding to prostate-specific membrane antigen (PSMA) on cancer cells and delivering targeted radiation directly to those cells. Because the targeting is molecularly specific, the side-effect profile is meaningfully different from systemic chemotherapy: most patients tolerate PSMA therapy well, and most side effects are mild to moderate. But every effective therapy has adverse effects, and a clear, honest conversation about them is part of good informed consent.
This guide is a complete clinical breakdown of what to expect on PSMA therapy — the common side effects every patient should know about, the less common ones that need attention if they occur, and the rare but important ones that the team monitors for. It covers both Lu-177 PSMA (the established beta-emitter therapy) and Ac-225 PSMA (the alpha-emitter salvage option), with notes on how their profiles differ.
Why PSMA therapy has the side effects it has
PSMA is highly expressed on prostate cancer cells, which is what makes PSMA therapy work. But PSMA is also expressed at lower levels on a few normal tissues — particularly the salivary glands (parotid and submandibular), the lacrimal glands, parts of the small bowel, and the proximal renal tubules. The radioligand binds these tissues incidentally as it circulates, and the radiation delivered to them is what produces most of the off-target side effects. This biology is important: the side-effect profile reflects PSMA expression in normal tissue, and the protective measures (hydration, sialagogue prophylaxis where indicated, monitoring) target these specific tissues.
Common side effects on Lu-177 PSMA
The most common side effects of Lu-177 PSMA, drawn from the VISION trial and real-world experience, are:
- Fatigue — affects approximately 40 to 50 percent of patients, typically mild to moderate, often peaking in the days after each infusion and recovering over the following one to two weeks.
- Dry mouth (xerostomia) — affects approximately 40 percent of patients, usually mild, reflecting PSMA expression in salivary glands. Most cases improve over weeks; a smaller proportion experience persistent mild dryness.
- Nausea — affects approximately 30 percent, usually mild and well controlled with standard antiemetics.
- Reduced appetite and mild weight changes — particularly in the days after each cycle.
- Anaemia, thrombocytopenia, and neutropenia — bone marrow effects, generally mild and recovering between cycles. Severe (Grade 3 or 4) cytopenia occurs in a smaller proportion of patients, particularly those with prior extensive chemotherapy.
- Constipation — often mild.
None of these is typically a reason to stop treatment. The course proceeds with supportive care and any necessary dose timing adjustments.
Less common but important side effects on Lu-177 PSMA
Several less common side effects need attention if they occur:
- Dry eyes (xerophthalmia) — reflects PSMA expression in lacrimal glands. Usually mild but warrants the use of preservative-free artificial tears, particularly during and immediately after treatment cycles.
- More significant cytopenia — Grade 3 or 4 reductions in haemoglobin, platelets, or neutrophils occur in approximately 5 to 10 percent of patients, more commonly in those heavily pre-treated with chemotherapy or those with extensive bone marrow involvement. Management may include transfusion, growth factor support, or treatment delay.
- Renal function decline — small reductions in glomerular filtration rate are common; clinically significant kidney dysfunction is uncommon (approximately 1 to 3 percent in published series).
- Mild liver function abnormalities — usually transient.
Rare but serious adverse effects
Rare but serious adverse effects that the team monitors for include:
- Severe xerostomia (Grade 3) — significant persistent dry mouth affecting eating, speaking, or sleep. Uncommon with Lu-177 PSMA (approximately 1 to 2 percent), more common with Ac-225 PSMA (10 to 20 percent — see next section).
- Myelodysplastic syndrome (MDS) or acute leukaemia — late effects of radiation exposure to the bone marrow. The cumulative incidence at 5-year follow-up is approximately 1 to 2 percent. Risk is higher in patients with extensive prior chemotherapy or radiotherapy.
- Significant kidney dysfunction — uncommon, but a recognised concern that justifies the careful kidney function monitoring throughout the treatment course.
- Salivary gland infections or stone formation — uncommon late effects associated with chronically reduced salivary flow.
These are monitored for, screened for, and managed actively when they occur. They are not common reasons to avoid treatment, but they are reasons for thorough informed consent before treatment begins.
Differences with Ac-225 PSMA therapy
Ac-225 PSMA produces a meaningfully different side-effect profile from Lu-177 PSMA because alpha particles deposit far more energy per micrometre of tissue. The most clinically notable difference is xerostomia: severe (Grade 3) xerostomia affecting eating, speaking, and quality of life occurs in 10 to 20 percent of Ac-225 PSMA patients in published series, compared with 1 to 2 percent on Lu-177. Bone marrow effects, kidney effects, and fatigue are all more pronounced on Ac-225.
The increased toxicity is the main reason Ac-225 PSMA is not used as first-line therapy. It is reserved for patients who have progressed on Lu-177 and where the disease still expresses PSMA on a follow-up PET-CT. Dose fractionation strategies — splitting the Ac-225 dose into smaller, repeated administrations — have substantially reduced severe xerostomia in published series and are now our standard practice at FMRI. Ac-225 PSMA is delivered under the Helsinki Declaration framework with written informed consent that explicitly covers the toxicity profile.
How adverse effects are managed at FMRI
The management framework at FMRI is built around three things: thorough pre-treatment counselling so that nothing about the side effects comes as a surprise; active monitoring during and between cycles, with blood tests, kidney function, and clinical review at every visit; and prompt management of any side effects that occur, including dose modification or treatment delay where indicated. The radiation safety instructions for the household are explained clearly before discharge after each cycle.
For patients on Ac-225 PSMA, we use dose fractionation as our standard approach and we monitor salivary function and salivary gland imaging where indicated. Sialagogue strategies, salivary gland cooling during cycle infusion, and amifostine prophylaxis are options that have been explored in published series; we tailor the protective approach to the individual patient based on their disease and prior treatments.
If you are considering PSMA therapy and want a realistic conversation about side effects, the most useful approach is a consultation with the nuclear medicine team that will deliver the treatment. We will walk you through what to expect, what we monitor for, and how we manage every side effect on the list above. The right informed-consent conversation is what makes treatment go smoothly.
For patients & referring clinicians
Frequently asked questions
Q01
What are the most common side effects of Lu-177 PSMA therapy?
In the VISION trial and in real-world experience, the most common side effects are fatigue (40-50% of patients, typically mild to moderate), dry mouth or xerostomia (about 40%, usually mild), nausea (about 30%, easily controlled), mild reductions in blood counts (anaemia, thrombocytopenia, neutropenia — usually transient between cycles), reduced appetite, and constipation. Most of these are mild and resolve between cycles. They are not typically reasons to stop treatment.
Q02
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 improves over weeks to months. With Ac-225, alpha emission produces more severe and longer-lasting salivary gland injury.
Q03
How serious is the bone marrow effect?
Mild reductions in haemoglobin, platelets, and neutrophils are common and usually recover between cycles. Severe (Grade 3 or 4) cytopenia occurs in approximately 5 to 10 percent of Lu-177 PSMA patients, more commonly in those with heavy prior chemotherapy or extensive bone marrow involvement. Management may include transfusion, growth factor support, or treatment delay. Late myelodysplastic syndrome or acute leukaemia is a rare but recognised long-term concern (approximately 1-2% cumulative incidence at 5-year follow-up).
Q04
How is Ac-225 PSMA different in side effects?
Ac-225 PSMA produces a meaningfully different side-effect profile from Lu-177 PSMA because alpha particles deposit far more energy per micrometre of tissue. Severe (Grade 3) xerostomia occurs in 10 to 20 percent of Ac-225 patients (compared with 1-2% on Lu-177). Bone marrow effects, kidney effects, and fatigue are all more pronounced. This is the main reason Ac-225 is used as salvage therapy after Lu-177 progression rather than as first-line therapy. Dose fractionation strategies have substantially reduced severe xerostomia in published series.
Q05
What can be done to reduce dry mouth?
For Lu-177 PSMA, where xerostomia is typically mild, supportive measures include staying well hydrated, frequent sips of water, sugar-free chewing gum or lozenges to stimulate saliva, avoiding alcohol-based mouthwashes, and humidifying the bedroom. For Ac-225 PSMA, additional strategies have been explored: dose fractionation (our standard approach at FMRI), salivary gland cooling during infusion, and pharmacological prophylaxis with agents such as amifostine — though the evidence base for these is still developing.
Q06
How is kidney function protected?
Lu-177 PSMA is cleared through the kidneys, and the proximal tubules can absorb a small amount of the radioligand. Although clinically significant kidney dysfunction is uncommon (approximately 1-3% in published series), the team monitors kidney function before and between cycles. Patients with borderline baseline kidney function may receive dose modification, intensified hydration during cycles, or fractionated cycles. Severe baseline kidney dysfunction (GFR below 30 mL/min) is generally a contraindication.
Q07
When should I call my team during treatment?
Call your nuclear medicine team for: persistent fever or signs of infection; new or worsening shortness of breath; unusual bleeding or bruising; severe persistent nausea or vomiting; severe persistent fatigue beyond what was discussed; significant dry mouth or dry eyes interfering with daily function; new pain or change in pain pattern; or any symptom that feels worrying or different. The team is available throughout the treatment course, and earlier contact about a problem is always better than later contact.
Citations & references
Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer (VISION).
N Engl J Med. 2021;385(12):1091-1103.
ReferenceKratochwil C, Bruchertseifer F, Rathke H, et al. Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with
225Ac-PSMA-617: Swimmer-Plot Analysis Suggests Efficacy Regarding Duration of Tumor Control.
J Nucl Med. 2018;59(5):795-802.
Reference
About the Author
Dr. Ishita B. Sen
MBBS · MD (Nuclear Medicine) · DNB · Post-doctoral Fellowship, Memorial Sloan Kettering Cancer Center, New York
Director and Chief of Nuclear Medicine at Fortis Memorial Research Institute. Co-founder of Theranostic Physicians Private Limited (TPPL). Two decades of clinical practice in PSMA imaging and PSMA-directed radioligand therapy, with one of the largest Indian institutional experiences in Lu-PSMA.