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Radionuclide therapy

²²³Ra-dichloride (Xofigo)

Source: EANM 2018 / Xofigo US PI / EU SmPC · confirm locally
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Educational aid — verify against EANM/SNMMI/ATA/NCCN, the drug label and local protocol. Session-only.
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Before planning therapy

2

On the day of treatment

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After treatment & follow-up

Background & evidence

²²³Ra is an α emitter (T½ 11.4 d) that mimics calcium and binds hydroxyapatite where bone turnover is high. Its α range is under 100 µm, so dose goes to the metastasis–bone interface and marrow is relatively spared. In ALSYMPCA it prolonged survival and delayed symptomatic skeletal events in mCRPC with symptomatic bone metastases and no visceral disease. Since 2018 the EU licence reserves it for later lines; fracture risk makes bone protection essential. For the physics alongside the β-emitters, see the short read Bone Radiopharmaceuticals Compared.

Indications & contraindications

Indications

  • Castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases (US PI; also EANM 2018).
  • EU: as above, and only in progression after ≥2 prior systemic lines for mCRPC (other than LHRH analogues) or when no other systemic mCRPC treatment is suitable. Monotherapy or with an LHRH analogue.
  • Benefit is greatest with a high osteoblastic burden. EU SmPC: not recommended for only asymptomatic bone metastases or for <6 metastases.
  • With enzalutamide as first-line mCRPC therapy (PEACE-3): survival benefit shown with mandatory bone protection, but the combination is not in the US or EU label as of September 2026.

Contraindications

  • Combination with abiraterone plus prednisone/prednisolone: contraindicated in the EU; not recommended in the US (ERA 223: more fractures and deaths).
  • Known visceral metastases (outside the licence).
  • Pregnancy or possible pregnancy; the drug is not indicated in women.
  • Blood counts below the label thresholds (first dose: ANC 1.5, platelets 100 ×10⁹/L, Hb 10 g/dL; later doses: ANC 1.0, platelets 50 ×10⁹/L).
  • Untreated imminent or established spinal cord compression, or an unstabilised fracture, until treated.
  • Use with caution: acute inflammatory bowel disease, compromised marrow reserve, superscan (EOD4), high baseline fracture risk.
  • Other systemic cancer therapy apart from LHRH analogues: EU, not recommended; US, safety and efficacy not established. Stop ²²³Ra if chemotherapy, another systemic radionuclide or hemibody radiotherapy is given (US PI).
Activity, dosing & administration
ItemUS (FDA prescribing information)EU (SmPC)
Activity and schedule55 kBq/kg (1.49 µCi/kg) IV every 4 weeks × 655 kBq/kg IV every 4 weeks × 6
Line of therapyAny line within the indicationAfter ≥2 prior systemic mCRPC lines, or no other option
Before dose 1ANC ≥1.5; platelets ≥100 ×10⁹/L; Hb ≥10 g/dLANC ≥1.5; platelets ≥100 ×10⁹/L; Hb ≥10.0 g/dL
Before doses 2–6ANC ≥1.0; platelets ≥50 ×10⁹/LANC ≥1.0; platelets ≥50 ×10⁹/L
No count recoveryDiscontinue if not recovered within 6–8 weeksWithin 6 weeks; otherwise continue only after careful benefit–risk review
Abiraterone + prednisone/prednisoloneNot recommended (warning)Contraindicated; wait ≥5 days after abiraterone
Bone-protecting agentNot addressed in the labelConsider bisphosphonate or denosumab before starting or resuming
Next systemic therapyNo interval statedNot for ≥30 days after the last dose
Male contraceptionCondoms plus partner contraception for 6 monthsEffective contraception for 6 months
  • ALSYMPCA papers quote 50 kBq/kg. NIST revised the ²²³Ra standard in 2015 (a 10.5% numerical change). The same physical activity is now labelled 55 kBq/kg, so there is no difference in the dose given.
  • Typical patient activity is below 8 MBq. The vial holds 6.6 MBq at the reference date (1100 kBq/mL).
  • A fixed, weight-based activity. There is no dosimetry-based adjustment, and no dose change for age, renal or hepatic impairment.
  • Denosumab 120 mg SC or zoledronic acid 4 mg IV every 4 weeks were the regimens compared in men with CRPC bone metastases; denosumab caused more hypocalcaemia (13% vs 6%).
Key trials & evidence
Trial / studyPopulationResultReference
ALSYMPCA (phase 3)921 men with symptomatic CRPC, ≥2 bone metastases, no known visceral disease; prior docetaxel, or unsuitable for or declined itMedian OS 14.9 vs 11.3 months with placebo; HR 0.70 (95% CI 0.58–0.83)Parker, NEJM 2013
ALSYMPCA skeletal eventsSame trialTime to first symptomatic skeletal event 15.6 vs 9.8 months; HR 0.66. Fewer spinal cord compressions (HR 0.52)Sartor, Lancet Oncol 2014
ALSYMPCA docetaxel subgroups526 with and 395 without prior docetaxelOS benefit either way (HR 0.70 and 0.69); grade 3–4 thrombocytopenia 9% vs 3% placebo after prior docetaxelHoskin, Lancet Oncol 2014
ALSYMPCA 3-year safety600 treated with ²²³RaNo AML, MDS or new primary bone cancer; one case of aplastic anaemiaParker, Eur Urol 2018
ERA 223 (phase 3)806 chemo-naive, asymptomatic or mildly symptomatic CRPC on abiraterone plus prednisone/prednisoloneNo gain in symptomatic skeletal event-free survival (HR 1.12); fractures 29% vs 11%; unblinded earlySmith, Lancet Oncol 2019
PEACE-3 (EORTC 1333; phase 3)446 with first-line mCRPC, ≥4 bone metastases, no visceral disease; enzalutamide ± ²²³Ra × 6rPFS 19.4 vs 16.4 months (HR 0.69). Final OS 38.2 vs 32.6 months (HR 0.76). Grade ≥3 AEs 69.3% vs 57.6%Tombal, Ann Oncol 2025; Gillessen, Ann Oncol 2026
PEACE-3 bone-protection safety analysisSame trial; bone protection mandated from 2018 (use rose from 46.1% to 97%)Fractures fell significantly in both arms. Enzalutamide alone: 15.6% to 2.6% at 1 year with a bone-protecting agentGillessen, Eur Urol 2025
REASSURE (post hoc)779 treated in routine practiceALP decline at week 12 linked to longer OS: 18.1 vs 14.2 months (HR 0.74)O'Sullivan, Br J Cancer 2025
Toxicity & its management
  • Marrow: thrombocytopenia, neutropenia, leucopenia, pancytopenia. ALSYMPCA grade 3–4 thrombocytopenia 6.3% vs 2% (placebo), and higher after docetaxel. Bone marrow failure or ongoing pancytopenia in 2%.
  • Nadirs at 2–3 weeks after a dose (phase I). Most recover by 6–8 weeks. Check counts before every injection.
  • Gastrointestinal: nausea 36%, diarrhoea 25%, vomiting 19% (US PI), from faecal excretion. Watch for dehydration (3%).
  • Fractures: the risk is higher with osteoporosis, <6 metastases and steroids, and fractures can occur up to 24 months after the first dose. With abiraterone plus prednisone/prednisolone, fractures were about three times as frequent. Bisphosphonates or denosumab reduce the risk.
  • Osteonecrosis of the jaw: 0.67% vs 0.33% (placebo). All cases had prior or concomitant bisphosphonate and prior chemotherapy.
  • Peripheral oedema 13%; injection-site reactions about 1%.
  • Secondary malignancy: osteosarcoma occurred in rats. No treatment-related cancer was seen in up to 3 years of clinical follow-up.
  • Hold or stop: counts below the thresholds; no recovery within 6–8 weeks (US) or 6 weeks (EU); life-threatening marrow failure.
Radiation protection & discharge
  • Radiation protection follows national and local rules. External dose rate is low because activity is usually below 8 MBq and the emission is mainly α. It is normally given as a day case.
  • Excretion is mainly faecal. At 48 h cumulative faecal excretion was 13% (range 0–34%) and urine 2% (US PI); median 52% was in the bowel at 24 h (Carrasquillo 2013). Slow transit raises bowel dose.
  • Patient advice (US PI): hygiene for at least 1 week after the last injection; use a toilet and flush several times; wash soiled clothing promptly and separately; carers wear gloves and wash their hands. No restriction on personal contact.
  • Plan ahead for faecal or urinary incontinence and stoma care with local radiation-protection staff. PEACE-3 excluded patients with faecal incontinence.
  • Staff: gloves and gowns; the γ emissions from the daughters allow contamination monitoring with standard instruments; decontaminate spills with 0.01 M EDTA. Treat all administration materials as radioactive waste.
  • Men: condoms plus partner contraception during treatment and for 6 months after. It is not for use in women who are, or may be, pregnant or breastfeeding.

References

  1. Poeppel TD, Handkiewicz-Junak D, Andreeff M, et al. EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2018;45(5):824-45.
  2. Handkiewicz-Junak D, Poeppel TD, Bodei L, et al. EANM guidelines for radionuclide therapy of bone metastases with beta-emitting radionuclides. Eur J Nucl Med Mol Imaging. 2018;45(5):846-59.
  3. Bayer HealthCare Pharmaceuticals. Xofigo (radium Ra 223 dichloride) injection: US prescribing information. DailyMed; 2026 [cited 2026 Sep 29]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a398400e-bd31-41a9-9696-4f7c06569ede
  4. European Medicines Agency. Xofigo: EPAR – product information (summary of product characteristics). Updated 2026 Jul 30 [cited 2026 Sep 29]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/xofigo
  5. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-23.
  6. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014;15(7):738-46.
  7. Hoskin P, Sartor O, O'Sullivan JM, et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014;15(12):1397-406.
  8. Parker CC, Coleman RE, Sartor O, et al. Three-year safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases from phase 3 randomized Alpharadin in Symptomatic Prostate Cancer trial. Eur Urol. 2018;73(3):427-35.
  9. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):408-19.
  10. Tombal B, Choudhury A, Saad F, et al. Enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer: results of the EORTC 1333/PEACE-3 trial. Ann Oncol. 2025;36(9):1058-67.
  11. Gillessen S, Gallardo E, Choudhury A, et al. Final overall survival results from EORTC 1333/PEACE-3 trial of enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer. Ann Oncol. 2026;37(5):736-42.
  12. Gillessen S, Tombal B, Turco F, et al. Decrease in fracture rate with mandatory bone-protecting agents in the EORTC 1333/PEACE-3 trial comparing radium-223 combined with enzalutamide versus enzalutamide alone: a safety analysis. Eur Urol. 2025;87(3):285-8.
  13. O'Sullivan JM, Heinrich D, Castro E, et al. Alkaline phosphatase decline and pain response as predictors of overall survival benefit in patients treated with radium-223: a post hoc analysis of the REASSURE study. Br J Cancer. 2025;132(4):354-60.
  14. Carrasquillo JA, O'Donoghue JA, Pandit-Taskar N, et al. Phase I pharmacokinetic and biodistribution study with escalating doses of 223Ra-dichloride in men with castration-resistant metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2013;40(9):1384-93.
  15. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813-22.
  16. US Nuclear Regulatory Commission. NRC Information Notice 2016-03: revision to the National Institute of Standards and Technology standard for radium-223 and impact on dose calibration for the medical use of radium-223 dichloride. Washington (DC): NRC; 2016 Jan 12. Available from: https://www.nrc.gov/docs/ml1526/ml15264b095.pdf
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