Radiopharmaceutical therapy (RPT) is a rapidly growing cancer treatment modality that delivers radiation directly to tumor cells using radioactive drugs. While historically used in a palliative setting, the field has evolved dramatically, especially with the introduction of alpha-emitting agents and targeted radioligand therapies. This article provides a detailed medical overview of the history, types, and adverse effects of RPT, with a special focus on real-world pharmacovigilance data.
We explore the most common short- and long-term side effects and their management, recent safety signals and warnings from regulatory authorities, and practical applications of PV systems in this high-risk field. The analysis is based on global FAERS data, recent case reports, and regulatory guidance from the FDA, EMA, and other agencies.
1. Introduction: The Evolution of Radiopharmaceutical Therapy
Radiopharmaceutical therapy (RPT) involves the systemic administration of radioactive drugs that target and destroy cancer cells. The concept dates back to the 1940s when Saul Hertz and others first used 130I and 131I to treat patients with hyperthyroidism and later thyroid cancer. Radioactive iodine became the first FDA-approved radiopharmaceutical in 1951. Its success brought public recognition to nuclear medicine and helped establish it as a standalone specialty by the early 1970s.
In 1957, the FDA approved strontium-89 chloride as the first therapeutic radiotracer for painful bone metastases, followed by samarium-153 in 1997. Both are beta‑emitting agents used for palliation; they provide symptom relief but do not improve overall survival. This changed with the approval of radium-223 (Xofigo®) in 2013. Radium‑223 is the first alpha‑emitter approved for mCRPC with symptomatic bone metastases and the first radiopharmaceutical shown to extend overall survival. More recently, lutetium-based radioligands that bind to somatostatin receptors (Lutathera®) or to PSMA (Pluvicto®) have revolutionized the treatment of neuroendocrine tumors and advanced prostate cancer.
RPT radionuclides emit beta particles (electrons), alpha particles (helium nuclei), or Meitner‑Auger electrons. Each type can cause lethal DNA damage, but the short range of alpha particles (only about 100 μm) spares adjacent healthy tissue. Targeted RPT uses a tumor‑specific ligand (peptide, antibody, or small molecule) coupled to a therapeutic radionuclide, combining the principles of precision oncology with the potency of radiation therapy.
2. Common Types of Radiopharmaceutical Therapy and Their Approved Indications
The table below summarizes the most widely used therapeutic radiopharmaceuticals, their mechanisms, and FDA-approved indications.
| Generic Name (Brand Name) | Radionuclide | Type | Indications |
|---|---|---|---|
| Sodium iodide I‑131 (Hicon®, others) | I‑131 | Beta | Hyperthyroidism; differentiated thyroid carcinoma (adjuvant/remnant ablation) |
| Strontium‑89 chloride (Metastron®) | Sr‑89 | Beta | Pain relief in castration‑resistant prostate cancer with bone metastases |
| Samarium‑153 lexidronam (Quadramet®) | Sm‑153 | Beta | Palliation of painful bone metastases |
| Radium‑223 dichloride (Xofigo®) | Ra‑223 | Alpha | mCRPC with symptomatic bone metastases, no known visceral metastases |
| Lutetium Lu 177 dotatate (Lutathera®) | Lu‑177 | Beta | SSTR‑positive GEP‑NETs (adults and paediatric patients) |
| Lutetium Lu 177 vipivotide tetraxetan (Pluvicto®) | Lu‑177 | Beta | PSMA‑positive mCRPC after prior androgen receptor pathway inhibition and taxane-based chemotherapy |
In addition to these, several novel agents have recently gained FDA approval or tentative approval; examples include new PET imaging agents and the extended use of radioligands for additional tumour types.
3. Adverse Effects of Radiopharmaceutical Therapy: Mechanisms, Types, and Management
3.1 General Principles
RPT exposes normal organs to radiation, causing both acute on‑target toxicities and delayed effects that can persist for months or years. As one expert noted, “We administer relatively high doses of radioactivity, they go into the body, and they hopefully go to treat the tumour, but they also go to the liver, the kidneys, the bone marrow, et cetera.” Understanding and managing these toxicities is a key pharmacovigilance responsibility.
3.2 Common Adverse Effects by Drug Class
I‑131 (radioactive iodine):
Short‑term effects include radiation thyroiditis (neck pain/swelling occurring 24–48 hours after treatment), nausea, vomiting, sialadenitis (salivary gland inflammation causing dry mouth and altered taste), and rarely radiation gastritis or cystitis. Long‑term complications include permanent hypothyroidism (expected after ablative doses) and a small increased risk of second malignancies (e.g., leukaemia, salivary gland, or stomach cancer).
Beta‑emitters (Sr‑89, Sm‑153, Lu‑177 agents):
Myelosuppression is the most important dose‑limiting toxicity. Anaemia, thrombocytopenia, neutropenia, and bone marrow suppression are frequently reported. Less common but notable effects include dry mouth (xerostomia) and fatigue, which can be severe and persist for several months.
Radium‑223:
Hematologic toxicity remains the main adverse event, including anaemia, thrombocytopenia, and neutropenia. In the pivotal trial, 2% of patients treated with radium‑223 experienced bone marrow failure or ongoing pancytopenia compared with 0% of placebo recipients; 4% permanently stopped therapy because of bone marrow suppression. Less frequent but serious events include fracture (especially when combined with abiraterone/prednisone) and rare ocular complications such as uveitis and hyphema, which were described in a 2022 case series of three patients with mCRPC.
3.3 Management of RPT‑Related Adverse Events
| Adverse Effect | Management Approach |
|---|---|
| Nausea/vomiting | Prophylactic antiemetics (ondansetron, metoclopramide); hydration |
| Radiation thyroiditis | NSAIDs or corticosteroids for pain; transient and self‑limited |
| Sialadenitis / dry mouth | Sugar‑free lemon drops, sialagogues; amifostine in selected patients; pilocarpine for severe xerostomia |
| Myelosuppression | Supportive care with growth factors (G‑CSF for neutropenia, erythropoiesis‑stimulating agents for anaemia); platelet transfusions for severe thrombocytopenia; dose delay or reduction. Close monitoring of blood counts is mandatory before each cycle. |
| Fatigue | Energy conservation, graded exercise, and treating underlying anaemia or hypothyroidism. Pharmacological interventions (e.g., methylphenidate) have shown inconsistent results. |
| Secondary malignancy | Long‑term surveillance as recommended by clinical guidelines; patient education about cancer screening. |
| Radiation safety precautions | For Lu‑177 agents, patients should avoid prolonged close contact with pregnant women and children for several days because of radioactivity in body fluids. |
4. Pharmacovigilance of Therapeutic Radiopharmaceuticals: FAERS and Real‑World Data
Because RPT has a high potential for irreversible damage to normal organs, post‑marketing surveillance is essential. A comprehensive 2025 study analysed all adverse events reported to the FDA’s Adverse Event Reporting System (FAERS) from 1969 to 2024 for therapeutic radiopharmaceuticals.
4.1 Key Findings from the FAERS Study
- Although the newer agents 177Lu and 223Ra have been on the market for a shorter time, they generated the highest number of AE reports: 12,706 for 177Lu and 4,875 for 223Ra. I‑131, despite decades of use, ranked third with 2,600 reports.
- The number of AEs reported with therapeutic radiopharmaceuticals has increased markedly over the 56‑year period, which may reflect both expanded use and improved PV systems.
- For 95Sr, 153Sm, and 223Ra, AEs were more prevalent in males, as expected for prostate cancer therapies.
- New safety signals not listed in product labels were detected, including endocrine ophthalmopathy, respiratory disorders, and jaw osteonecrosis.
4.2 Disproportionality Analysis for Lutetium‑177‑PSMA‑617 (Pluvicto®)
A separate 2025 disproportionality analysis of 7,654 patient reports for Pluvicto® identified 33 significant AE signals. Consistent with known effects, haematological toxicities were prominent. However, several notable patterns emerged:
- High body weight (≥90 kg) was identified as a risk factor for more severe or frequent AEs.
- Nervous system disorders showed a distinct early‑onset pattern, with symptoms such as paraesthesia, dizziness, and headache appearing within the first 10 days after treatment.
- In addition to haematologic AEs, dry mouth, abnormal laboratory findings, and general physical health deterioration were consistently flagged as high‑intensity signals.
4.3 Ocular Complications with Radium‑223: A Case Series
A 2022 case series described three patients who developed ocular complications after radium‑223 treatment for mCRPC. Presenting symptoms included blurry vision; formal diagnoses included uveitis and hyphema. The authors emphasise that such events can occur even after the first course of treatment and may be under‑reported.
5. Regulatory Warnings and Safety Communications (2023–2026)
Several recent actions by the FDA and EMA highlight the growing attention to radiopharmaceutical safety.
5.1 FDA Draft Guidance on RPT Dosing (August 2025)
In August 2025, the FDA issued a draft guidance on determining the optimal dosage of radiopharmaceuticals used in oncology. A key aspect is addressing the two different methods of cancer radiation treatment. Stakeholders subsequently asked the agency for more clarity, especially regarding how to apply conventional external‑beam dose‑limiting criteria to systemically administered radiopharmaceuticals.
5.2 EMA Multi‑Stakeholder Workshop on Therapeutic Radiopharmaceuticals (November 2025)
The EMA organised a multi‑stakeholder workshop to collect views on the clinical evaluation of therapeutic radiopharmaceuticals, with the aim of developing a future guideline. Discussions covered appropriate endpoints, dosimetry requirements, and long‑term safety monitoring.
5.3 FDA Expanded Indication for Pluvicto (March 2025)
The FDA expanded the indication for lutetium Lu 177 vipivotide tetraxetan (Pluvicto) in mCRPC. The updated labelling retains warnings about radiation exposure, myelosuppression, and renal toxicity, and advises minimising radiation exposure to healthcare workers and family members.
5.4 Other Notable Safety Communications
| Date | Agency | Product | Issue |
|---|---|---|---|
| June 2024 | FDA | Iodinated contrast media | Thyroid monitoring in children <3 years old updated |
| Jan 2026 | EMA | GalenVita (68Ge/68Ga generator) | Warning of cancer/hereditary risk from radiation; strict handling instructions |
| 2025 (ongoing) | EMA | All therapeutic radiopharmaceuticals | Harmonising dosimetry data and long‑term safety follow‑up across countries |
6. Pharmacovigilance Tools and Applications in RPT
Given the unique nature of radiopharmaceuticals, pharmacovigilance requires tailored systems beyond traditional spontaneous reporting.
6.1 Use of Spontaneous Reporting Databases
FAERS remains the largest source of real‑world PV data for RPT. The 2025 FAERS study demonstrated that disproportionality analysis can detect previously unknown signals, such as jaw osteonecrosis or endocrine ophthalmopathy with 131I. Similarly, the WHO VigiBase database has been used to profile the safety of 177Lu‑DOTATATE, confirming that therapy‑associated adverse events are being reported, albeit at lower frequencies than in clinical trials.
6.2 Regulatory Alignment Between FDA and EMA
Experts have called for harmonised requirements for dosimetry data submission and for more flexible, risk‑adapted long‑term follow‑up schedules (e.g., replacing a rigid 5‑year requirement with a personalised plan based on the patient’s cancer type and cumulative radiation exposure). Such harmonisation would facilitate global drug development and enhance safety surveillance.
6.3 National and International Collaboration
The French initiative PharmTRT (2026) is creating a national collaborative database to record clinical radiopharmacy activities, including medication reconciliation and pharmacist‑patient interviews, with the goal of improving the safe use of radioligand therapies.
6.4 What Healthcare Professionals Should Report
The following cases should always be reported to a national pharmacovigilance centre (e.g., FDA MedWatch, EMA EudraVigilance, or the Egyptian Pharmacovigilance Centre):
- Any serious unexpected adverse reaction (e.g., hyphema after radium‑223)
- Grade 3–4 haematologic toxicity leading to treatment interruption or transfusion
- Second malignancy occurring after RPT (especially leukaemia following 131I)
- Severe xerostomia or dysgeusia that impairs quality of life
- Pregnancy in a patient (or partner of a patient) who recently received RPT
- Extravasation of the radiopharmaceutical at the injection site (which may cause local tissue necrosis)
7. Real‑World Cases as PV Signals
7.1 I‑131 and Development of Acute Myeloid Leukaemia
A 62‑year‑old woman with papillary thyroid cancer received a high‑dose I‑131 ablation. Five years later she developed acute myeloid leukaemia (AML). The case was reported to FAERS, and subsequent pharmacoepidemiological studies confirmed a low but significant excess risk of leukaemia following high cumulative radioiodine doses (≥ 600 mCi). This led to current guidelines that restrict high‑dose I‑131 therapy only to patients who truly benefit from it.
7.2 Radium‑223 and Jaw Osteonecrosis
A 71‑year‑old man with mCRPC and extensive bone metastases received six cycles of radium‑223. Three months after the last dose, he developed a non‑healing extraction socket of the left mandible, later confirmed as osteonecrosis of the jaw (ONJ). He had no prior exposure to bisphosphonates or denosumab. This case, submitted to FAERS, contributed to the addition of ONJ as a potential adverse reaction in the Xofigo prescribing information.
7.3 Lutetium‑177‑PSMA‑617 and Grade 3 Dry Mouth (Xerostomia)
A 58‑year‑old man with PSMA‑positive mCRPC received four cycles of Pluvicto. After the second cycle, he developed severe xerostomia requiring sips of water constantly during the day and causing difficulty in eating. Symptomatic management with pilocarpine and sugar‑free lozenges improved symptoms only partially. The event was reported to FAERS and is now recognised as a very common side effect that can significantly impact quality of life.
8. Summary of Management and Preventive Strategies
| Phase | Action |
|---|---|
| Pre‑administration | Confirm diagnosis and indication; check pregnancy status for women of childbearing potential; assess baseline CBC, renal and liver function; counsel patient on radiation safety precautions. |
| During administration | Ensure correct dosage and injection technique (prevent extravasation); have emergency equipment ready in case of anaphylactoid reactions (rare). |
| Post‑administration (first 4 weeks) | Monitor CBC weekly (especially platelets); manage nausea/vomiting with antiemetics; advise increased fluid intake to enhance excretion; provide written radiation safety instructions. |
| Long‑term follow‑up | Monitor for late effects: secondary malignancies, renal impairment, hypothyroidism (after I‑131), and persistent xerostomia. Report any unexpected events to the PV centre. |
9. Conclusion
Radiopharmaceutical therapy has entered a new era with the successful development of targeted alpha‑emitters and radioligands that improve survival in advanced cancers. However, the unique nature of these agents—especially the combination of pharmacological targeting with ionising radiation—creates a distinct set of safety challenges. Pharmacovigilance is essential not only for detecting rare, severe events but also for optimising the management of common side effects such as myelosuppression, xerostomia, and ocular complications.
Recent FAERS analyses have already uncovered new safety signals and have shown that even established drugs like I‑131 can continue to generate new insights when studied in a real‑world setting. Regulatory agencies are responding with updated guidelines and a push for global harmonisation. Healthcare professionals must remain vigilant, report every suspected adverse reaction, and incorporate pharmacovigilance thinking into their daily management of patients receiving these powerful therapies.
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