What is the treatment protocol for radium-228 (Radium-223 dichloride, Xofigo) in prostate cancer?

Radium-223 Treatment Protocol for Prostate Cancer

Radium-223 dichloride (Xofigo) is administered as 55 kBq/kg (1.49 microcurie/kg) intravenously every 4 weeks for 6 cycles in patients with castration-resistant prostate cancer who have symptomatic bone metastases without visceral disease, and all patients must receive mandatory concomitant bone-protective therapy with denosumab or zoledronic acid. 1, 2

Patient Selection Criteria

Strict inclusion requirements must be met:

• Castration-resistant prostate cancer with castrate testosterone levels 3, 2
• Symptomatic bone metastases requiring regular opioid pain medications (≥2 bone metastases) 3, 2
• No visceral metastatic disease - this is an absolute contraindication 3, 1, 2
• Good performance status (ECOG 0-1) regardless of prior docetaxel exposure 2
• Adequate baseline hematologic parameters before initiating therapy 3

Pre-Treatment Laboratory Requirements

Before the initial dose, patients must have: 3

• Absolute neutrophil count ≥ 1.5 × 10⁹/L
• Platelet count ≥ 100 × 10⁹/L
• Hemoglobin ≥ 10 g/dL

Before each subsequent dose, patients must have: 3

• Absolute neutrophil count ≥ 1 × 10⁹/L
• Platelet count ≥ 50 × 10⁹/L (though this threshold may be too low in clinical practice) 3

Dosing and Administration Protocol

Standard dosing regimen: 1, 3, 4

• Dose: 55 kBq/kg (1.49 microcurie/kg) body weight
• Route: Slow intravenous injection over 1 minute 1
• Frequency: Every 4 weeks
• Total cycles: 6 injections
• Flush IV line with isotonic saline before and after each injection 1

The volume calculation requires decay correction factors based on days from the reference date, as radium-223 has a half-life of 11.4 days 1. Administration must occur in appropriately licensed facilities, typically nuclear medicine or radiation therapy departments 3.

Important note: A randomized phase II trial demonstrated that higher doses (88 kBq/kg) or extended schedules (12 cycles) provided no additional benefit and resulted in significantly more grade ≥3 adverse events (48-53% vs 34%), with more treatment discontinuations (16-17% vs 9%) 4. Therefore, the standard 6-cycle regimen remains the evidence-based protocol.

Mandatory Concomitant Bone Protection

Critical safety requirement - this is non-negotiable: 2

• All patients must receive concomitant denosumab or zoledronic acid throughout radium-223 treatment 2, 3
• The ERA 223 trial demonstrated catastrophic fracture rates without bone protection: 45.9% at 1.5 years with radium-223 plus enzalutamide versus 22.3% with enzalutamide alone 2
• There are no restrictions on combining radium-223 with denosumab or bisphosphonates 3

Monitoring During Treatment

Hematologic evaluation must be performed: 3

• Before treatment initiation
• Before each subsequent dose according to FDA labeling 3

Discontinuation criteria: 3

• If blood counts do not recover to required levels within 6-8 weeks after treatment, discontinue radium-223 3
• Discontinue in patients who experience life-threatening complications despite supportive care 1

Absolute Contraindications and Restrictions

Do NOT use radium-223 in the following situations:

• Visceral metastatic disease - absolute contraindication 3, 2, 1
• In combination with chemotherapy (such as docetaxel) outside clinical trials due to additive myelosuppression 3
• In combination with abiraterone plus prednisone/prednisolone - FDA warning due to increased fractures and mortality 1
• In combination with enzalutamide without mandatory bone protection 2
• Asymptomatic or minimally symptomatic patients - not indicated 2

Expected Outcomes and Efficacy

Survival benefit (ALSYMPCA trial): 3

• Median overall survival: 14.9 months vs 11.3 months with placebo (HR 0.70, p<0.001) 3
• Time to first skeletal-related event: 15.6 months vs 9.8 months (HR 0.66, p=0.00037) 5
• Radium-223 is the first bone-targeting agent to provide a survival advantage 3

Safety Profile and Adverse Events

Hematologic toxicity is notably low: 3

• Grade 3/4 neutropenia: 2-3% 3
• Grade 3/4 thrombocytopenia: 3-6% 3
• Grade 3/4 anemia: 6-13% 3

Non-hematologic side effects are generally mild: 3

• Nausea, diarrhea, and vomiting (related to fecal elimination) 3
• These are typically manageable with supportive care 3

Clinical Positioning

NCCN Category 1 recommendation: 3

• First-line or second-line option for patients with symptomatic bone metastases and no visceral disease 3
• Particularly attractive for patients too frail to receive docetaxel 3
• 57% of patients in the pivotal trial had received prior docetaxel 3

Common Pitfalls to Avoid

Critical errors that compromise patient safety:

• Never omit bone-protecting agents - fracture risk increases dramatically without them 2
• Never use in patients with visceral metastases - this violates the FDA indication 3, 2, 1
• Never combine with docetaxel or other chemotherapy outside clinical trials 3
• Never use in asymptomatic patients - not indicated for minimally symptomatic disease 2
• Do not delay treatment beyond 6-8 weeks if blood counts fail to recover - discontinue instead 3

Re-treatment Considerations

Re-treatment with radium-223 (up to 6 additional injections) has been studied in selected patients who completed initial therapy without progression and later developed bone progression 6. At 2-year follow-up, re-treatment was well tolerated with minimal hematologic toxicity and provided continued disease control (median rPFS 9.9 months, median OS 24.4 months) 6. However, this should only be considered in carefully selected patients who meet strict eligibility criteria and have not received intervening chemotherapy 6.