Radionuclide Therapy
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Solve questions (31) →Contents
- 26.1 I-131 Treatment of Hyperthyroidism
- 26.2 I-131 Treatment of Thyroid Cancer (Ablation, Metastases)
- 26.3 I-131 MIBG Therapy (Neuroblastoma, Phaeochromocytoma)
- 26.4 Lu-177 DOTATATE (PRRT – Neuroendocrine Tumours)
- 26.5 Lu-177 PSMA (Metastatic Prostate Cancer)
- 26.6 Ra-223 Dichloride (Bone Metastases)
- 26.7 Y-90 Microspheres (Radioembolisation – Liver)
- 26.8 Sr-89 and Sm-153 (Palliation of Bone Pain)
- 26.9 Ho-166 Microspheres (Liver)
- 26.10 Y-90 Ibritumomab (Radioimmunotherapy)
- 26.11 Radiosynovectomy (Er-169, Y-90, Re-186)
- 26.12 Treatment Dosimetry and Patient Management
- Key Points for the Board
- Current guidelines on this chapter's topics
Learning objectives and modules6 modules · about 4 h 40 min
Learning objectives
After this chapter you will be able to:
- Explain the indications, patient preparation, activity selection and adverse effects of I-131 therapy in hyperthyroidism and differentiated thyroid cancer.
- Explain the indications for and preparation for I-131 MIBG therapy.
- Explain patient selection, protocol, renal protection and toxicity in Lu-177 DOTATATE and Lu-177 PSMA therapy.
- Compare Ra-223 and the radionuclides used for bone pain palliation in terms of emission type, indication and toxicity.
- Explain patient selection, the lung shunt fraction and methods of activity calculation in liver radioembolisation.
- Explain the principle of radioimmunotherapy and radiosynovectomy and the basic elements of therapy dosimetry and patient management.
Modules
The chapter is divided into study modules without changing the order of the text: read, watch the animations, then answer the questions linked to those headings.
- Module 126.1 I-131 Treatment of Hyperthyroidism30 min · 11 questionsAnswer the questions →
- Module 226.2–26.3 I-131 Treatment of Thyroid Cancer (Ablation, Metastases) · I-131 MIBG Therapy (Neuroblastoma, Phaeochromocytoma)50 min · 22 questionsAnswer the questions →
- Module 326.4 Lu-177 DOTATATE (PRRT – Neuroendocrine Tumours)35 min · 1 animation · 14 questionsAnswer the questions →
- Module 426.5–26.6 Lu-177 PSMA (Metastatic Prostate Cancer) · Ra-223 Dichloride (Bone Metastases)50 min · 21 questionsAnswer the questions →
- Module 526.7–26.9 Y-90 Microspheres (Radioembolisation – Liver) · Sr-89 and Sm-153 (Palliation of Bone Pain) · Ho-166 Microspheres (Liver)55 min · 2 animations · 20 questionsAnswer the questions →
- Module 626.10–26.12 Y-90 Ibritumomab (Radioimmunotherapy) · Radiosynovectomy (Er-169, Y-90, Re-186) · Therapy Dosimetry and Patient Management · Key Points for the Board1 h · 18 questionsAnswer the questions →
Times are estimates: 130 words per minute, 3 min per animation, 1.5 min per question.
MOST FREQUENTLY ASKED IN THIS CHAPTER
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Fixed dose in Graves: 10-15 mCi, in TMNG: 15-30 mCi
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Calculated dose formula: 3 parameters → target dose (µCi/g), gland weight (g), 24-hour RAIU (%)
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Antithyroid drugs: methimazole stopped 2-5 days before; PTU 2-8 weeks before with fixed activity ( 4-7 days with a dosimetric approach) (radioprotective effect)
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Graves ophthalmopathy: mild active → I-131 can be given with steroid prophylaxis; moderate-severe active → I-131 should be avoided
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Most important risk factor (worsening ophthalmopathy): smoking
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Most common outcome: hypothyroidism (50-80%)
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In toxic adenoma the surrounding tissue is spared → suppressed tissue does not take up iodine
26.1 I-131 Treatment of Hyperthyroidism11 questions
General Principles
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I-131 → therapeutic effect through beta particles (mean beta energy: 0.192 MeV, maximum: 0.606 MeV)
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Beta range in tissue: mean 0.4 mm, maximum 2.4 mm → localised tissue damage
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Gamma emission (364 keV) → used for imaging and dosimetry
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Physical half-life: 8.02 days
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NIS (sodium-iodide symporter)-mediated active uptake in the thyroid gland
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Effective half-life: ~5-6 days in the thyroid gland (combination of physical + biological half-life)
Indications
Graves Disease:
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Most common cause of hyperthyroidism
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Diffuse increased uptake (RAIU usually 40-80%)
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I-131 therapy → a first-line treatment option (especially in the USA)
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Aim: to induce hypothyroidism (ablation) or achieve euthyroidism
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RAI in childhood Graves disease: avoided under 5 years of age; acceptable between 5-10 years if the activity is <10 mCi (370 MBq); a suitable option above 10 years. The goal is ablation (ATA 2016)
Toxic Multinodular Goitre (TMNG):
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Multiple autonomous nodules
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RAIU variable (15-50%)
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Higher doses may be needed (than in Graves)
Toxic Adenoma (Plummer Disease):
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Single autonomous functioning nodule
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On scintigraphy: "hot" nodule + suppressed surrounding tissue
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I-131 → selective damage to the nodule; surrounding tissue is spared (being suppressed, it takes up no iodine)
Dose Calculation Methods
Fixed-Dose Method:
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Graves: 370-555 MBq (10-15 mCi) → most widely used
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TMNG: 555-1110 MBq (15-30 mCi) → higher dose
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Toxic adenoma: 370-740 MBq (10-20 mCi)
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Simple, practical, widely used
Calculated-Dose Method:
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Target dose for Graves: 80-200 µCi/g (usually 150 µCi/g)
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Target dose for TMNG: 150-300 µCi/g
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Gland weight: estimated by US
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RAIU: 24-hour uptake value is used
Dose (µCi) = Target dose (µCi/g) × Gland weight (g) / [RAIU (%) / 100]
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Marinelli formula in Europe (EANM): A (MBq) = Target dose (Gy) × target volume (mL) × 24.67 / [maximum uptake (%) × effective T½ (days)]; uptake and effective half-life are measured with a radioiodine test
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EANM 2023 target doses: in Graves' disease at least 200 Gy for definitive treatment, up to 300 Gy for large glands and marked hyperthyroidism; ~150 Gy in mild disease when euthyroidism is the aim (hyperthyroidism resolves in 74%/81%/88% with 150/200/300 Gy). The ablative approach is preferred because definitive success is >90% versus <70% with the functional approach. Simplified calculation (assuming Teff 5.5 days): A (MBq) ≈ 6, 8 or 12 × mass (g) / 24-h RAIU (for 150, 200, 300 Gy); e.g. 35 g, 65% RAIU, 200 Gy → 8 × 35 / 0.65 ≈ 430 MBq. Non-toxic goitre 100-175 Gy (3.7-14 MBq/g corrected for RAIU)
Try it in the calculator: I-131 (hyperthyroidism) →
BOARD TIP
▸
"Which parameters are needed to calculate the I-131 dose in Graves?"
→ 3 parameters: (1) target dose (µCi/g), (2) gland weight (g), (3) 24-hour RAIU (%).
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"Is the fixed or calculated dose more common?"
→ The fixed dose is more common and practical.
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"Why is the surrounding tissue spared in toxic adenoma?"
→ Suppressed tissue does not take up iodine → it is protected from I-131 damage.
Figure 26.1: Relationship of the calculated I-131 dose in Graves disease to gland weight and 24-hour RAIU (target dose 150 µCi/g).
Did this figure help you understand the topic?
Patient Preparation and Contraindications
Patient Preparation:
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Antithyroid drugs: methimazole (thiamazole) is stopped 2-5 days before treatment. Because the radioprotective effect of PTU is more marked, stopping it 2-8 weeks before is recommended with the fixed-activity method; 4-7 days is sufficient with the dosimetric approach (EANM)
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Radioprotective effect → reduces treatment efficacy
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Can be restarted 3-7 days after treatment (if needed)
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Low-iodine diet: started 1-2 weeks before treatment → RAIU increased
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Beta-blocker: may be continued for symptom control (does not affect treatment efficacy)
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In elderly patients, those with heart disease or severe thyrotoxicosis, achieving euthyroidism with methimazole and giving a beta-blocker before RAI is recommended; this reduces the risk of post-RAI exacerbation of thyrotoxicosis (ATA 2016)
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Pregnancy test: mandatory in women of childbearing age
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Pregnancy is planned at least 6 months after RAI. TRAb may remain high for months after RAI (risk of fetal and neonatal Graves); surgery may therefore be preferred in a patient with high TRAb who wishes to become pregnant soon
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EANM 2023: in benign disease pregnancy is avoided for 4-6 months after RAI (mainly to avoid pregnancy during uncontrolled hypothyroidism; radiation concerns are limited). In fertile women serum hCG is checked within 72 hours before RAI; breastfeeding is stopped at least 6 weeks before RAI (breast dose). Iodised salt and iodine-rich foods are reduced for at least 7 days and iodine-containing products stopped; oral RAI is given fasting, with fasting for 1-2 hours afterwards and plenty of fluids for 24-48 hours
Absolute Contraindications:
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Pregnancy (fetal thyroid damage → congenital hypothyroidism)
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Hyperthyroidism in pregnancy is treated with antithyroid drugs: PTU in the first trimester (risk of methimazole embryopathy), methimazole thereafter; surgery in the 2nd trimester if needed
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Breastfeeding (passage into milk)
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Uncooperative patient (radiation safety cannot be ensured)
Relative Contraindications:
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Very large goitre (>80 g) → surgery may be preferred
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Active, moderate-severe Graves ophthalmopathy → I-131 may worsen ophthalmopathy
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The risk can be reduced with steroid prophylaxis
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Suspected malignancy
Graves Ophthalmopathy and I-131
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I-131 therapy may worsen Graves ophthalmopathy (15-20%)
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Mechanism: release of thyroid antigens → increased autoimmune response → orbital inflammation
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Risk factors: smoking, high TRAb, severe hyperthyroidism, post-treatment hypothyroidism
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Clinically evident ophthalmopathy occurs in ~25-30% of Graves patients; the severe form is more common in men and older patients
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Prevention: in mild active ophthalmopathy (especially with risk factors) → oral corticosteroid prophylaxis (prednisolone 0.3-0.5 mg/kg, 3 months)
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EANM 2023: for prophylaxis in patients at high risk of developing or worsening ophthalmopathy, prednisone 0.2 mg/kg daily for 6 weeks after RAI is recommended (low-dose regimen). Thyroid function is monitored in the first weeks after RAI; because uncorrected hypothyroidism can worsen ophthalmopathy, early levothyroxine from 2 weeks has been proposed. In Graves' disease with RAIU <20%, lithium (900 mg/day for 7 days) can prolong I-131 retention in the thyroid
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Steroid is started 1-3 days after RAI and tapered off over ~3 months; in low-risk patients 0.2 mg/kg/day for 6 weeks is also effective. Stopping smoking and prompt correction of post-RAI hypothyroidism are recommended
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In mild ophthalmopathy → I-131 can be given (with or without steroid)
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In severe, active ophthalmopathy → I-131 should be avoided → surgery or antithyroid drugs are preferred
Post-Treatment Follow-up
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Hypothyroidism: most common side effect → develops in 50-80% of patients (Graves)
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Usually within 2-6 months
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Lifelong levothyroxine replacement is required
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Transient thyroiditis: within 1-2 weeks → neck pain, transient worsening of thyrotoxicosis
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Thyroid storm: very rare but serious → risk increases in severe hyperthyroidism
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After RAI for benign disease, reduced fertility or an increase in congenital or genetic anomalies in subsequent children has not been shown
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TSH, fT4, fT3 checks: started after 4-6 weeks and repeated every 3-6 months
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Because TSH may remain suppressed for months after RAI, early follow-up relies on fT4 and fT3. If clinical improvement is ongoing, temporary methimazole is used while waiting; a second dose is mostly given at 6 months (at the earliest after 3 months if the response is very poor)
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Treatment failure: still hyperthyroid after 6 months → second dose of I-131
EANM Notes (Benign Thyroid Disease):
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Activity: 3.7-11.1 MBq per mL of thyroid tissue, or a fixed activity of 370-740 MBq
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If clinically possible, thiamazole is stopped 2-5 days before and PTU 2-8 weeks before with the fixed-activity method ( 4-7 days with the dosimetric approach); beta-blockers need not be stopped
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After iodinated contrast, treatment is deferred by 6-8 weeks (if renal function is normal; 3-6 months after lipid-soluble contrast)
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Dosimetric targets: 300-400 Gy in autonomous (toxic) adenoma and >150 Gy in toxic multinodular goitre are associated with high success
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EANM 2023: in a toxic nodule the measured uptake is corrected by the nodule/whole-gland ratio and the target is 300-400 Gy (hyperthyroidism resolves in 85-100%, hypothyroidism 10-20%). In TMNG 150-300 Gy is used to correct hyperthyroidism; if the target mass cannot be determined, 100-150 Gy to the whole gland. Formula: A (MBq) ≈ 4, 6, 8, 12 or 16 × mass (g) / 24-h RAIU (for 100, 150, 200, 300, 400 Gy). In non-toxic goitre rhTSH (0.1 or 0.3 mg, 24 hours before RAI) increases RAIU, but routine use is not supported and it is not EMA-approved
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Also used to reduce volume in selected non-toxic multinodular goitres; the effect mostly appears within 3-6 months
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In nodular goitre, TRAb-positive Graves-like immunogenic hyperthyroidism may rarely develop after I-131 (~1-5%, mostly in the first 3-6 months)
BOARD TIP
▸
"Is I-131 therapy safe in Graves ophthalmopathy?"
→ In mild ophthalmopathy yes (with steroid prophylaxis). In moderate-severe or severe active ophthalmopathy → I-131 should be avoided (antithyroid drugs or surgery).
▸
"Most important risk factor worsening ophthalmopathy?"
→ Smoking.
26.2 I-131 Treatment of Thyroid Cancer (Ablation, Metastases)14 questions
General Principles
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Differentiated thyroid cancer (DTC): papillary and follicular thyroid cancer
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DTC cells express NIS → take up I-131
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I-131 therapy: remnant ablation, adjuvant therapy, treatment of metastatic disease
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Medullary and anaplastic thyroid cancer → no NIS expression → I-131 therapy ineffective
Pre-Treatment Preparation
TSH Stimulation (Two Methods):
1. Thyroid hormone withdrawal (THW):
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Levothyroxine (T4) → stopped 3-4 weeks before
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Or T4 is stopped and T3 (liothyronine) given for 2 weeks → T3 stopped → wait 2 weeks
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Target TSH: >30 mIU/L
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Disadvantage: hypothyroid symptoms (fatigue, weight gain, depression)
2. Recombinant human TSH (rhTSH – Thyrogen):
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0.9 mg IM → on 2 consecutive days (24 and 48 hours before treatment)
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Diagnostic protocol: rhTSH on days 1 and 2, radioiodine on day 3, whole-body scan and stimulated Tg on day 5 (72 hours after the last injection)
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Levothyroxine is not stopped → no hypothyroid symptoms
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rhTSH is preferred especially when endogenous TSH cannot rise (hypopituitarism, long-term glucocorticoids, large remnant or functioning metastases) or when prolonged hypothyroidism would not be tolerated (severe cardiac or psychiatric disease, advanced age)
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Approved for remnant ablation; according to ATA 2025 it is preferred over hormone withdrawal for ablation and adjuvant therapy (strong recommendation)
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With known distant metastases, either THW or rhTSH can be used (ATA 2025)
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In brain or spinal metastases, a rise in TSH may cause tumour oedema and neurological signs; steroid prophylaxis is given before TSH stimulation and RAI, and surgery or EBRT is considered first
Low-Iodine Diet:
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Started 1-2 weeks before treatment
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Daily iodine intake <50 µg is targeted
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Aim: to reduce the body iodine pool → increase I-131 uptake
Pregnancy Test:
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Mandatory in women of childbearing age
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Pregnancy should be avoided for at least 6 months after treatment (ATA 2025)
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Breastfeeding: RAI is not given to a breastfeeding woman. Under ATA 2025, treatment may be deferred until at least 3 months after breastfeeding or pumping has stopped; the SNMMI 2025 appropriate use criteria recommend at least 4 (preferably 6) weeks. In a recently lactating woman, breast uptake can be shown with diagnostic I-123 and treatment deferred. Breastfeeding is not resumed for that child after treatment; it is possible with later pregnancies
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Iodine load (SNMMI/EANM 2022): treatment is given at least 4-6 weeks after iodinated contrast and iodine-based antiseptics; amiodarone is replaced with another antiarrhythmic and clearance of the iodine load is followed with serum or urinary iodine over 3-6 months. Spot urinary iodine <100 µg/L is adequate and <50 µg/L optimal; in advanced disease treatment is discussed even if the optimal value is not reached
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Pregnancy test (SNMMI/EANM 2022): in women aged 12-50, within 72 hours before RAI (before the first injection if rhTSH is used); not required after hysterectomy or menopause. RAI is scheduled at least 4 weeks after surgery
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In renal failure the excretion of RAI is reduced; dosimetry-guided treatment is considered (ATA 2025)
Figure 26.2: TSH stimulation before DTC therapy: thyroid hormone withdrawal (THW) and rhTSH schedules, low-iodine diet and timing of the post-therapy scan (schematic).
Did this figure help you understand the topic?
BOARD TIP
▸
"What is the stunning effect?"
→ Giving a diagnostic I-131 dose (>3 mCi) before treatment → reduces NIS expression → treatment efficacy falls.
▸
"How is it prevented?"
→ (1) Use I-123 for diagnosis (no stunning), (2) use low-dose I-131 (≤3 mCi / ≤111 MBq), (3) keep the interval between the diagnostic dose and treatment under 72 hours.
BOARD TIP
▸
"I-131 therapy in a breastfeeding woman?"
→ Not given; it may be deferred until at least 3 months after breastfeeding stops (ATA 2025). Breastfeeding is not resumed for that child.
▸
"When can RAI be given after iodinated contrast?"
→ At least 4-6 weeks later; urinary iodine <100 µg/L is adequate, <50 µg/L optimal.
Treatment Indications and Doses
Remnant Ablation:
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Destruction of thyroid tissue remaining after total thyroidectomy (remnant)
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With a large remnant ablation success falls and the risk of radiation thyroiditis and oedema rises; completion thyroidectomy before RAI is therefore preferred
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Aim: (1) to facilitate thyroglobulin follow-up, (2) to increase the sensitivity of whole-body scanning, (3) to treat microscopic residual disease
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Low risk: routine remnant ablation is not recommended (strong recommendation); if given in a selected patient, 30-50 mCi (1.1-1.85 GBq) (ATA 2025)
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Low risk in ATA 2025: unifocal T1-T2 (≤4 cm), pN0 or no more than 5 micrometastases (all ≤2 mm), negative margins or only a microscopically positive anterior margin. Unifocal papillary microcarcinoma without additional risk features belongs to this group; routine ablation is not recommended
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Low-intermediate and intermediate-high risk: RAI may be considered; 30-100 mCi (1.1-3.7 GBq)
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High risk: recommended routinely; 100-150 mCi (3.7-5.55 GBq)
Adjuvant Therapy:
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Known or suspected microscopic residual disease
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Dose: ≤150 mCi (≤5.55 GBq) for suspected microscopic residual disease (ATA 2025)
Treatment of Metastatic Disease:
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Local recurrence, lymph node metastasis, distant metastases (lung, bone)
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Best responders to RAI: radiographically occult (micronodular), RAI-avid lung metastases in young patients. Cure is rare in macronodular lung and bone metastases; for brain metastases surgery or EBRT takes priority
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Dose: for pulmonary and bone metastases, empiric 100-200 mCi (3.7-7.4 GBq; 100-150 mCi for pulmonary metastases in patients over 70) or by dosimetry; empiric activities above 150 mCi are avoided in patients over 70 and in renal failure (ATA 2025)
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Repeated doses can be given (cumulative dose must be tracked)
ATA Risk of Recurrence Classification (2025):
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Low (<10%): T1-T2 (≤4 cm), unifocal; pN0, or cN0 and pN1a (≤5 lymph nodes, all ≤2 mm); negative margins or only a microscopically positive anterior margin (R1)
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Low-intermediate (10-15%): T3a, or T1-T2 with any of: unilateral multifocality, microscopic extrathyroidal extension (ETE), cN1a or pN1a (>2 mm or >5 lymph nodes), microscopically positive posterior margin
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Intermediate-high (16-30%): T1, T2 or T3a with any of: bilateral multifocality >1 cm, clinically evident lateral lymph node metastases (cN1b) <3 cm, two or more low-intermediate risk features, aggressive histology, vascular invasion
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High (>30%): T3a with microscopic ETE, T3b or T4; or any T with: poorly differentiated or high-grade tumour, gross incomplete resection (R2), cN1 ≥3 cm, extranodal extension, distant metastasis
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In follicular carcinoma, invasive encapsulated follicular variant and oncocytic carcinoma: a minimally invasive tumour with capsular invasion only is low risk, limited vascular invasion (<4 vessels) low-intermediate, and a widely invasive tumour or vascular invasion of ≥4 vessels high risk
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It replaces the three-tier system of 2015. The classification is made within about 3 months of surgery together with the AJCC stage, postoperative imaging and Tg/anti-Tg, and is updated according to the response to therapy. Age and sex are not part of the risk-of-recurrence classification (age is part of AJCC staging)
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Classic prognostic scores: AMES, AGES and MACIS (age, metastases, completeness of resection, invasion, tumour size); today the ATA classification is used for recurrence risk and TNM (AJCC) for mortality
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In AJCC 8 (TNM) staging the age threshold is 55: under 55 years there are only stage I (M0) or stage II (M1); age at diagnosis is one of the strongest determinants of mortality in DTC
Figure 26.3: I-131 activity ranges in benign thyroid diseases and differentiated thyroid cancer (logarithmic scale).
Did this figure help you understand the topic?
Post-Therapy Whole-Body Scan (Post-Therapy WBS)
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Performed after the I-131 therapy dose, generally between days 2 and 10 (ATA 2025)
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High activity of the therapy dose → more sensitive than the diagnostic scan
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Previously undetected metastases may be seen (10-26% additional foci)
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Adding SPECT/CT → improves localisation accuracy
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EANM: in DTC the therapeutic activity is mostly a fixed activity of 1.11-7.4 GBq; success of ablative treatment is ~90% or higher
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In metastatic disease, superiority of a high dosimetrically determined activity over a fixed activity has not yet been established
Side Effects and Complications
Early Side Effects:
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Sialadenitis: most common side effect → NIS-mediated I-131 uptake in the salivary glands
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Dry mouth, swelling, pain
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Prevention: sour sweets (lemon drops) → increase saliva flow → reduce I-131 retention in the gland
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Timing is debated: some sources recommend avoiding acid stimulation in the first 24 hours (may increase gland uptake)
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Nausea/vomiting: usually mild, first 24-48 hours
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Neck pain/swelling: radiation thyroiditis (in remnant tissue)
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Transient bone marrow suppression: usually mild, self-limiting
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Taste/smell changes: transient
Late Side Effects:
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Chronic sialadenitis/xerostomia: risk increases with cumulative dose
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Nasolacrimal duct obstruction: epiphora (tearing)
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Pulmonary fibrosis: with high-dose I-131 in diffuse lung metastases
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Bone marrow suppression: at high cumulative doses
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Secondary malignancies: leukaemia (especially AML), bladder cancer → risk increases with a cumulative dose >600 mCi; according to ATA 2025 the absolute increase in risk attributable to RAI is small and does not warrant additional cancer screening
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Infertility: transient oligospermia in men (usually reversible), transient amenorrhoea in women
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In men: cumulative dose >400 mCi → risk of permanent infertility increases → sperm banking recommended
BOARD TIP
▸
"Most common side effect of I-131 therapy?"
→ Sialadenitis (inflammation of the salivary glands).
▸
"Most serious late complication?"
→ Secondary malignancy (AML) → risk increases with a cumulative dose >600 mCi.
▸
"When does the risk of pulmonary fibrosis increase?"
→ High-dose I-131 in diffuse lung metastases → risk is high if retained activity is >80 mCi (at 48 hours).
Empirical vs Dosimetric Treatment
Empirical Approach:
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Fixed doses are used (30-200 mCi)
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Dose determined by risk classification
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Practical, widely used
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Disadvantage: individual differences are ignored
Dosimetric Approach:
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Individual patient dosimetry is performed
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Maximum tolerated activity (MTA): ≤200 cGy to bone marrow, lung retention at 48 hours ≤80 mCi
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Lesion-based dosimetry: ≥8000 cGy (80 Gy) to the tumour is targeted
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Advantage: individualised, safe maximum dose
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Disadvantage: complex, time-consuming, not feasible in every centre
Figure 26.4: I-131 cumulative activity thresholds and determination of the maximum tolerated activity (MTA) with the dosimetric approach (schematic).
Did this figure help you understand the topic?
Radioiodine-Refractory (RAI-Refractory) Thyroid Cancer
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Definition: DTC unlikely to respond to RAI; the diagnosis cannot be made in a patient who has not received a therapeutic dose of RAI (ATA 2025)
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Strong criteria (ATA 2025):
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No I-131 uptake on the post-therapy scan despite disease confirmed on structural imaging or FDG PET
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Progression within 6 months after an appropriate therapeutic dose that showed uptake
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Supporting criteria: no uptake on a diagnostic scan (in some of these patients the post-therapy scan is still positive) or uptake in only some foci (a multimodal approach is needed)
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No further empiric RAI is given to a patient with RAI-refractory disease; asymptomatic, stable or minimally progressive disease can be monitored on TSH suppression with imaging every 3-12 months
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Treatment: tyrosine kinase inhibitors (sorafenib, lenvatinib) → DECISION and SELECT trials
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EANM – Redifferentiation: MEK and BRAF inhibitors (selumetinib, vemurafenib, dabrafenib, dabrafenib + trametinib) are used to try to restore NIS expression and I-131 uptake
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Uptake and lesion dosimetry are assessed with I-124 PET/CT before and after treatment; mutation status is important
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Administration schedules are not standardised; the method is still at the research stage. ATA 2025: it may be considered in selected patients with progressive RAI-refractory disease harbouring targetable mutations (clinical trial participation is encouraged); it is not recommended with adjuvant RAI in high-risk patients who have not been selected by genotype
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FDG PET/CT → prognostic value in RAI-refractory disease ("flip-flop" phenomenon: I-131 uptake falls, FDG uptake rises → dedifferentiation)
BOARD TIP
▸
"What is the flip-flop phenomenon?"
→ Dedifferentiation in differentiated thyroid cancer → I-131 uptake falls, FDG uptake rises.
▸
"Treatment in RAI-refractory disease?"
→ Tyrosine kinase inhibitors (lenvatinib, sorafenib).
▸
"When is FDG PET/CT indicated?"
→ High Tg + negative I-131 scan (TENIS syndrome).
26.3 I-131 MIBG Therapy (Neuroblastoma, Phaeochromocytoma)8 questions
General Principles
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MIBG (meta-iodobenzylguanidine): norepinephrine analogue
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Active uptake in neuroendocrine cells mediated by the norepinephrine transporter (NET/uptake-1)
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I-131 MIBG → therapeutic (beta emission)
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I-123 MIBG → diagnostic (gamma emission, no risk of stunning)
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Target tumours: neuroblastoma, phaeochromocytoma, paraganglioma, carcinoid, medullary thyroid cancer
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Contraindications (EANM 2008):
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Absolute: pregnancy and breastfeeding; life expectancy <3 months (except for intractable bone pain); renal failure requiring dialysis in the short term
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Relative: unacceptable medical risk of isolation, unmanageable urinary incontinence, rapidly deteriorating renal function (GFR <30 mL/min), progressive haematological or renal toxicity from prior treatment, myelosuppression (white cells <3.0 × 10⁹/L, platelets <100 × 10⁹/L)
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With low blood counts, extensive marrow involvement or impaired renal function, the activity is reduced and toxicity is followed closely
Treatment of Neuroblastoma
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The most common extracranial solid tumour of childhood
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MIBG uptake: positive in 90-95% of neuroblastomas
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High-risk neuroblastoma: I-131 MIBG therapy indicated
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Dose: 444-666 MBq/kg (12-18 mCi/kg) → usually a single dose or repeated doses
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Before treatment: thyroid blockade is mandatory (SSKI or potassium iodide → started 24-48 hours before treatment, continued for 10-14 days)
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Response rates: 30-40% (neuroblastoma), can be increased with combination therapies
Treatment of Phaeochromocytoma and Paraganglioma
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Surgically unresectable or metastatic disease
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I-131 MIBG → for palliative or therapeutic purposes
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Azedra (iobenguane I-131): FDA approved (2018; production discontinued in 2024) → age 12 and over, MIBG-positive phaeochromocytoma/paraganglioma
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Dose: 3.7-11.1 GBq (100-300 mCi) → repeated doses can be given
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Response rates: symptomatic improvement 60-70%, objective tumour response 30-40%
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Drug interactions: drugs that reduce MIBG uptake should be stopped before treatment:
–
Withdrawal times: antipsychotics → ~3-4 weeks (longest); labetalol → 10 days; TCA → 1-3 days
–
Cocaine, amphetamine
–
Reserpine, labetalol
–
Calcium channel blockers (some)
–
Sympathomimetics (ephedrine, pseudoephedrine)
–
EANM 2008: in catecholamine-secreting tumours (phaeochromocytoma, paraganglioma), withdrawing alpha and beta blockade may provoke symptoms, so the diagnostic scan and treatment are performed without changing the medication, accepting that beta-blockers and calcium channel blockers may reduce efficacy. In other patients MIBG is given slowly and the infusion is stopped if hypertension occurs
BOARD TIP
▸
"Why is thyroid blockade needed in I-131 MIBG therapy?"
→ Free I-131 is taken up by the thyroid gland → risk of thyroid damage. Thyroid blockade is done with SSKI or potassium iodide.
▸
"Drugs that reduce MIBG uptake?"
→ Tricyclic antidepressants, labetalol, antipsychotics, reserpine, sympathomimetics → inhibit uptake-1 or disrupt vesicular storage.
BOARD TIP
▸
"Absolute contraindications to I-131 MIBG therapy?"
→ Pregnancy and breastfeeding, life expectancy <3 months (except intractable bone pain), renal failure requiring dialysis in the short term (EANM 2008).
▸
"How long is pregnancy avoided after MIBG therapy?"
→ At least 4 months.
Figure 26.5: Drug withdrawal times and timing of thyroid blockade before I-131 MIBG therapy.
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Side Effects
•
Bone marrow suppression: most important dose-limiting toxicity → thrombocytopenia, neutropenia
•
Nausea/vomiting
•
Hypertensive crisis: catecholamine release from the tumour (especially phaeochromocytoma) → alpha-blocker preparation
•
Hypothyroidism: with inadequate thyroid blockade
•
Sialadenitis
EANM Notes (I-131 MIBG):
•
Thyroid blockade: started 24-48 hours before administration and continued for 10-15 days after treatment
•
The absorbed tumour dose ranges from <5 Gy to >300 Gy; the limit for red marrow is 2 Gy, and in selected protocols the whole-body dose is raised up to 4 Gy
•
The whole-body absorbed dose correlates with myelotoxicity, not tumour response; infusion is slow (~1-4 hours), with blood pressure and pulse monitored meanwhile
•
Response: morphological response 30-47% and symptomatic response 75-90% in phaeochromocytoma and paraganglioma; ~30% objective response in MTC; 58% in neuroblastoma with individualised treatment
•
Radiation safety (EANM 2008): in most countries legislation requires in-patient treatment in a shielded room with an en-suite bathroom. The patient receives verbal and written information, and the rules for reducing unnecessary exposure of the family and the public are explained
–
If carers such as parents looking after a child are expected to exceed the 1 mSv/year constraint, their informed consent is obtained and an annual constraint (e.g. 5 mSv) is set, taking into account that several treatments may be given in a year. Carers keep time short and distance long, do not eat or drink in the isolation room and wear protective clothing; their dose can be monitored with a pocket dosimeter. Female carers use effective contraception and do not breastfeed
–
Pregnancy is avoided for at least 4 months after treatment (also 4 months in ARSAC 2026); sperm banking is offered to male patients before treatment. Transient myelosuppression typically occurs at 4-6 weeks; blood counts are monitored to plan further cycles
26.4 Lu-177 DOTATATE (PRRT – Neuroendocrine Tumours)14 questions
General Principles
•
PRRT (Peptide Receptor Radionuclide Therapy): treatment of somatostatin receptor-positive tumours
•
Lu-177 DOTATATE (Lutathera): FDA approved (2018)
–
In April 2024 the FDA also approved Lu-177 DOTATATE for SSTR-positive GEP-NETs in children aged 12 years and older (NETTER-P: dosimetry and safety data, efficacy extrapolated from NETTER-1; same dose as adults, 7.4 GBq × 4, 8 weeks apart). In September 2026 the FDA approved two equivalent Lu-177 DOTATATE products (Bexlutry, Bravnetsa); Lu-177 edotreotide (DOTATOC) is not yet approved
•
Lu-177: beta emitter (Eβmax = 0.497 MeV, range ~2 mm) + gamma emission (208 keV → imaging)
•
Physical half-life: 6.7 days
•
DOTATATE: somatostatin receptor type 2 (SSTR2) ligand → high affinity
•
Target: gastroenteropancreatic neuroendocrine tumours (GEP-NET)
NETTER-1 Trial
•
Phase III, randomised, controlled trial
•
Advanced, SSTR-positive midgut NET
•
Lu-177 DOTATATE + octreotide LAR vs high-dose octreotide LAR
•
PFS: markedly superior in the Lu-177 DOTATATE arm (median PFS not reached vs 8.4 months)
•
Response rate: 18% vs 3%
•
20-month PFS: 65.2% vs 10.8%
•
Conclusion: Lu-177 DOTATATE → standard treatment in advanced midgut NET
•
Final overall survival analysis (2021): median 48.0 vs 36.3 months (HR 0.84; not statistically significant). 36% of the control group received PRRT after progression (crossover); the 11.7-month difference was considered clinically meaningful. MDS 2% on long-term follow-up
Treatment Protocol
•
Dose: 7.4 GBq (200 mCi) IV infusion
•
Cycles: 4 cycles, 8 weeks apart
–
EANM/IAEA/SNMMI 2026: the interval is 8 ± 1 weeks; it can be extended to 16 weeks to manage severe adverse reactions, and if a delay beyond 16 weeks is needed, treatment is usually discontinued permanently. With dose-limiting haematological, renal or hepatic toxicity, the activity per cycle is reduced to 3.7 GBq (100 mCi). Administration takes about 30 minutes, co-infused with the amino acid solution
–
Retreatment (2026): in patients progressing after initial PRRT, salvage PRRT up to a cumulative 60.5 GBq has been found safe and effective. The decision is made at the tumour board; the degree and duration of response to the first treatment (ideally at least 12 months), progression from new or existing lesions, Ki-67 on re-biopsy and FDG uptake are decisive
•
Total cumulative dose: 29.6 GBq (800 mCi)
•
Amino acid infusion: for renal protection → IV infusion of lysine and arginine
–
Started 30 minutes before treatment, continued for 4 hours
–
Competitively inhibits reabsorption of Lu-177 DOTATATE in the proximal tubule
–
Reduces the renal dose by 40-50%
•
Antiemetic: the amino acid infusion can cause nausea → ondansetron
•
EANM: 25 g lysine and 25 g arginine are started 30-60 minutes before PRRT and last 4-6 hours
•
Contraindications (EANM/IAEA/SNMMI 2026): absolute: pregnancy, severe acute concomitant illness, severe bone marrow disorder (aplastic syndrome), severe unmanageable psychiatric disorder. Relative: breastfeeding; chronically compromised renal function; severely compromised bone marrow
–
Kidney: Lu-177 DOTATATE is generally well tolerated without adjusting the activity in mild or moderate renal impairment (eGFR ≥40 mL/min/1.73 m²); the patient is well hydrated and monitored closely after each administration. With eGFR <40, or a 40% drop in eGFR between cycles, activity reduction is considered, especially with risk factors (age >65, hypertension, diabetes, previous chemotherapy or PRRT); safety with eGFR <30 has not been established. Y-90 peptides require age-adjusted normal renal function. In the 2013 guidance, creatinine clearance <40 mL/min was an exclusion criterion
–
Bone marrow: PRRT is not given if haemoglobin is <8 g/dL, white cells <3000/µL with absolute neutrophils <1000/µL, or platelets <75,000/µL; deviations from these values are discussed at the tumour board
–
Special warnings: in brain, leptomeningeal or spinal cord metastases, treatment-related swelling may cause mass effect (neurosurgical consultation and steroids are considered); mesenteric or peritoneal disease carries a risk of bowel obstruction (steroid prophylaxis is considered; PRRT is avoided in extensive peritoneal disease); hydronephrosis is corrected before treatment; PRRT may be safe even with more than 75% liver involvement; in carcinoid syndrome and VIPoma, fluid, electrolyte and protein deficits are corrected first
•
NETTER-2 (Lancet 2024): in newly diagnosed, advanced, well-differentiated, higher grade 2 (Ki-67 10-20%) and grade 3 (Ki-67 20-55%) SSTR-positive GEP-NETs, first-line Lu-177 DOTATATE (4 × 7.4 GBq, 8 weeks apart) + octreotide LAR 30 mg was compared with high-dose octreotide LAR 60 mg. Median PFS 22.8 vs 8.5 months (HR 0.28), objective response 43% vs 9%; response 48% in grade 3 tumours. It is the first randomised phase 3 trial to show the efficacy of radioligand therapy in the first line. Hormonal (carcinoid) crisis occurs in ~1% (rare but can be fatal)
Patient Selection
•
Somatostatin receptor positivity: must be confirmed with Ga-68 DOTATATE PET/CT or Octreoscan
•
Tumour uptake must be at least at liver level (Krenning score ≥2)
•
Well-differentiated NET (Grade 1-2, Ki-67 ≤20%)
•
Well-differentiated grade 3 NET (Ki-67 ≤55%) → first-line PRRT was effective in NETTER-2 (objective response 48%); evidence is insufficient above Ki-67 55% and in poorly differentiated neuroendocrine carcinoma (NEC), where platinum-based chemotherapy takes precedence
•
Adequate bone marrow reserve, renal and hepatic function
•
COMPETE (Lancet 2026): progressive grade 1-2 GEP-NETs; non-carrier-added (n.c.a.) Lu-177 edotreotide (DOTATOC; 4 × 7.5 GBq, 12 weeks apart) was compared with everolimus. Median PFS 23.9 vs 14.1 months (HR 0.67), objective response 21.9% vs 4.2%; treatment-related adverse events 82% vs 97%. It is the first phase 3 trial to compare PRRT head-to-head with a targeted drug and supports the use of PRRT in earlier lines
•
Hepatic arterial (intra-arterial) PRRT: in liver-dominant disease, Lu-177 DOTATATE is given into the hepatic artery through a microcatheter; the aim is to increase first-pass tumour uptake and reduce systemic (kidney, bone marrow) dose. Single-centre dosimetry studies reported a tumour dose between 60% and about 3-fold higher than with intravenous administration. However, in the within-patient randomised phase 2 LUTIA trial (2024; 27 patients, one lobe intra-arterial, the contralateral lobe as control) the tumour-to-normal liver uptake ratio did not increase significantly (17.4 vs 16.2; mean increase 17%). The method is safe but has not entered routine practice; it is used within research. Radioembolisation (Y-90, Ho-166) is a separate local option for liver metastases (→ 26.7, 26.9)
BOARD TIP
▸
"How is renal protection achieved in PRRT?"
→ Lysine and arginine amino acid infusion → competitively inhibits reabsorption in the proximal tubule → reduces the renal dose by 40-50%.
▸
"What did the NETTER-1 trial show?"
→ Lu-177 DOTATATE → markedly increased PFS in advanced midgut NET (compared with high-dose octreotide).
▸
"Which imaging is required for patient selection?"
→ Ga-68 DOTATATE PET/CT → SSTR positivity must be confirmed.
Step one shows a single tumour cell: Lu-177 DOTATATE leaves the capillary, binds the seven-transmembrane SSTR2, is internalised through a clathrin-coated pit, the receptor recycles and Lu-177 stays in the lysosome. Step two shows tissue at true scale: β tracks run across tens of cells and reach cells without receptors. Step three shows glomerular filtration and megalin-mediated reabsorption in the proximal tubule, compared with lysine-arginine.
Continuous stream · no seeking
Lu-177 DOTATATE binds SSTR2, is internalised and stays in the lysosome; β⁻ travels tens of cell diameters and irradiates neighbours too; lysine-arginine protects the kidney by reducing megalin-mediated reabsorption.
Source: book 26.4 (EANM); SSTR2 internalisation Reubi 2003 (Endocr Rev), Cescato 2006 (J Nucl Med); megalin-mediated reabsorption de Jong 2005, Vegt 2010 (J Nucl Med); β spectrum ENSDF, ranges NIST ESTAR (water). Timing and reabsorption probabilities representative.
How to use: a single click on the drawing pauses and resumes; in the third step ↑ ↓ or the buttons below switch the amino acid infusion on and off; ← → change steps.
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Figure 26.6: SSTR2 targeting with Lu-177 DOTATATE and the mechanism of renal protection by lysine/arginine infusion (schematic).
Side Effects
•
Bone marrow suppression: lymphopenia (most common), thrombocytopenia, anaemia → usually Grade 1-2
•
Nausea/vomiting: due to the amino acid infusion
•
Nephrotoxicity: long term → reduced by amino acid protection
•
Hepatotoxicity: risk increases with diffuse liver metastases
•
Hormonal crisis: carcinoid crisis → serotonin release → prophylaxis with octreotide
•
Myelodysplastic syndrome/AML: rare in the long term (2-3%)
–
EANM/IAEA/SNMMI 2026: subacute haematological toxicity occurs 4-8 weeks after each administration and is mostly grade 1-2; persistent cytopenia or myelodysplastic disease has been reported in 2-6%. Severe renal toxicity is virtually absent with Lu-177 peptides (it is marked with Y-90 peptides). Exacerbation of the hormonal syndrome occurs in up to 10%; in symptomatic patients blood pressure and pulse are monitored during infusion. Temporary infertility in men and mild temporary alopecia may occur
Y-90 DOTATOC and Alpha-Emitter PRRT (EANM)
Y-90 DOTATOC:
•
A pure, high-energy beta emitter (travels at most ~11 mm in tissue); more effective in bulky disease, but more toxic than Lu-177
•
Activity: fixed activity or 1.85-3.7 GBq/m² by body surface area
•
The critical organ is the kidney: 1.2-5.1 Gy/GBq; the ~37-40 Gy BED limit is important for renal toxicity, so renoprotective amino acid infusion is essential
•
Post-treatment imaging is difficult because it can only be done with Bremsstrahlung radiation (or low-yield PET); currently used in clinical research
Alpha Emitters (Ac-225, Pb-212):
•
Alpha particles have energies of 4-9 MeV and travel <0.1 mm in tissue; they cause dense local DNA damage. Administered activities are far lower than those of beta emitters; for daughter recoil and the "in vivo generator" see 2.1.1
•
Ac-225 DOTATATE (RYZ101): disease control was first reported in small series of patients refractory to Lu-177 therapy. In the phase 3 ACTION-1 trial, comparing it with standard therapy in SSTR-positive GEP-NETs progressing after Lu-177 PRRT, PFS was significantly prolonged at interim analysis (topline announcement, October 2026; numerical results not yet published). The phase 3 dose is 10.2 MBq every 8 weeks for 4 cycles. It is the first positive phase 3 result reported for a targeted alpha-emitting radiopharmaceutical; not yet approved
•
Pb-212 DOTAMTATE (AlphaMedix): in the phase 2 ALPHAMEDIX-02 trial, 2.5 MBq/kg (67.6 µCi/kg) every 8 weeks for 4 cycles gave an objective response of 54% in PRRT-naive patients and 31% in patients previously treated with Lu-177 PRRT (ESMO 2025). The FDA granted breakthrough therapy designation in February 2024; not yet approved. Pb-212 has a half-life of 10.6 hours; Bi-212/Po-212 in its decay chain emit the alpha particle
WHY IT MATTERS · Lu-177m impurity
•
What it is: Direct production by neutron capture on Lu-176 (carrier-added, c.a. Lu-177) also produces the long-lived isomer Lu-177m. The indirect route Yb-176 → Yb-177 → Lu-177 (no-carrier-added, n.c.a.) contains almost none.
•
In numbers: Lu-177m T½ 160.4 days (Lu-177 6.65 days). Its share of the product is very small (usually below 0.015% on certificates).
•
Why it matters clinically: It adds negligibly to the patient's dose, but persists in waste: waste and retention samples containing Lu-177m may have to be stored for years; in the US the decay-in-storage route is limited to radionuclides with half-lives of 120 days or less. The production route is asked about when choosing a product and supplier.
•
In the exam: "A disadvantage of carrier-added Lu-177?" → Long-lived waste due to Lu-177m (and lower specific activity).
•
Sources: Vogel et al., Eur J Nucl Med Mol Imaging 2021; Balzer et al., EJNMMI Radiopharm Chem 2023; US NRC 10 CFR 35.92; ENSDF.
26.5 Lu-177 PSMA (Metastatic Prostate Cancer)12 questions
General Principles
•
PSMA (Prostate-Specific Membrane Antigen): transmembrane glycoprotein overexpressed in prostate cancer cells
•
Lu-177 PSMA-617 (Pluvicto): approved by the FDA (March 2022) and the EMA (December 2022). Lu-177 PSMA-I&T has similar pharmacokinetics and dosimetry; its level of evidence is lower (EANM/SNMMI 2023)
•
Lu-177 → beta emitter (therapeutic) + gamma emitter (imaging)
•
PSMA-617 → small-molecule ligand with high affinity for PSMA
•
Target: metastatic castration-resistant prostate cancer (mCRPC)
•
In July 2026 the FDA also approved Lu-177 PSMA-617 with an androgen receptor pathway inhibitor (ARPI) in PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Approved settings: mCRPC after a taxane and an ARPI (VISION, 2022), mCRPC after an ARPI and before a taxane (PSMAfore, March 2025), hormone-sensitive disease (PSMAddition, July 2026)
VISION Trial
•
Phase III, randomised, open-label trial
•
PSMA-positive mCRPC (progression after at least one androgen receptor pathway inhibitor and 1-2 taxanes)
•
Lu-177 PSMA-617 + standard of care vs standard of care alone
•
OS: 15.3 months vs 11.3 months (HR 0.62, p<0.001) → ~4 months OS advantage
•
rPFS: 8.7 months vs 3.4 months (HR 0.40, p<0.001)
•
PSA response (≥50% decline): 46% vs 7.1%
•
Conclusion: Lu-177 PSMA-617 → significantly increased both OS and rPFS in mCRPC
TheraP Trial
•
Phase II, randomised trial
•
Lu-177 PSMA-617 vs cabazitaxel (mCRPC, after docetaxel)
•
PSA response (≥50%): 66% vs 37% (p<0.001)
•
PFS: median 5.1 months in both arms, but significantly longer with Lu-177 PSMA (HR 0.63; progression-free at 12 months 19% vs 3%; the benefit emerges after 6 months). Overall survival similar (restricted mean survival to 36 months 19.1 vs 19.6 months)
•
Fewer Grade 3-4 adverse events in the Lu-177 PSMA arm
•
Conclusion: Lu-177 PSMA-617 → better PSA response and less toxicity than cabazitaxel
PSMAfore Trial
•
Phase III, randomised trial
•
PSMA-positive mCRPC, after an androgen receptor pathway inhibitor (taxane-naive)
•
Lu-177 PSMA-617 vs change of androgen receptor pathway inhibitor
•
rPFS: 12.0 months vs 5.6 months (HR 0.43, p<0.0001)
•
Conclusion: Lu-177 PSMA-617 → also effective in taxane-naive mCRPC → expanded indication
•
PSMAddition (ESMO 2025): PSMA-positive metastatic hormone-sensitive prostate cancer, treatment-naive or treated for at most 45 days (1144 patients); ADT + ARPI ± Lu-177 PSMA-617 (7.4 GBq × 6, 6 weeks apart). rPFS was significantly prolonged (HR 0.72; medians not yet reached); a positive trend in overall survival (HR 0.84, not significant). The most common adverse event was dry mouth; grade ≥3 cytopenias 14.4% vs 5.0%. It is the first phase 3 evidence for radioligand therapy in the hormone-sensitive setting
•
SPLASH (ESMO 2024): chemotherapy-naive mCRPC after an ARPI; Lu-177 PSMA-I&T (PNT2002; 6.8 GBq × 4, 8 weeks apart) was compared with a change of ARPI. rPFS 9.5 vs 6.0 months (HR 0.71); no overall survival difference was shown (crossover in the control group). ECLIPSE: Lu-177 PSMA-I&T (7.4 GBq × 6, 6 weeks apart) versus a change of ARPI; the primary endpoint (rPFS) was met (announced November 2024); as of November 2026 no numerical results have been published and there is no approval
Treatment Protocol
•
Dose: 7.4 GBq (200 mCi) IV infusion
•
Cycles: 6 cycles, 6 weeks apart
•
Total cumulative dose: 44.4 GBq (1200 mCi)
•
Before treatment: PSMA positivity must be confirmed with Ga-68 PSMA-11 or F-18 DCFPyL (Pylarify) PET/CT
•
PSMA-positive (VISION criterion): uptake greater than liver in at least 1 metastatic lesion + no PSMA-negative lesion meeting the size criteria (solid organ ≥1 cm, lymph node short axis ≥2.5 cm, bone lesion with a soft-tissue component ≥1 cm)
Patient Selection
•
PSMA PET/CT-positive mCRPC
•
Has received at least one androgen receptor pathway inhibitor (abiraterone or enzalutamide)
•
Has received at least one taxane (VISION criteria) OR taxane-naive (PSMAfore criteria)
•
EANM/SNMMI 2023 recommended pre-taxane use only for patients unsuitable for docetaxel (moderate recommendation; the benefit-risk balance was uncertain in patients able to tolerate docetaxel). After PSMAfore, the US approval was extended in March 2025 to include pre-taxane use
•
FDG-positive/PSMA-negative lesions → poor prognosis, no benefit from Lu-177 PSMA
•
Adequate bone marrow, renal and hepatic function. According to EANM/SNMMI 2023 no absolute contraindications are defined; relative contraindications: life expectancy <3 months (unless the aim is palliation), ECOG ≥3, unmanageable urinary incontinence, acute urinary tract obstruction or hydronephrosis (baseline Tc-99m MAG3 or DTPA scintigraphy if at risk), GFR <30 mL/min or creatinine >2 × upper limit, liver enzymes >5 × upper limit, acute infection, WBC <2.5/nL, ANC <1.5/nL, platelets <75/nL (tumour-related cytopenia, e.g. in a superscan, can be treated with close blood count monitoring)
BOARD TIP
▸
"Which imaging is mandatory before Lu-177 PSMA therapy?"
→ PSMA PET/CT (Ga-68 PSMA-11 or F-18 DCFPyL).
▸
"What do PSMA-negative lesions mean?"
→ Dedifferentiation → no benefit from Lu-177 PSMA → assess with FDG PET/CT.
▸
"OS difference in the VISION trial?"
→ 4 months (15.3 vs 11.3 months).
Side Effects
•
Bone marrow suppression: anaemia, thrombocytopenia and lymphopenia are the most common serious (grade ≥3) toxicities; overall, the most common side effects are fatigue, dry mouth and nausea
•
Xerostomia (dry mouth): PSMA expression in salivary glands → Lu-177 uptake
•
Salivary gland protection: cold compresses, sialagogues → efficacy debated
•
Renal toxicity: PSMA expression in the proximal tubule → usually mild
•
Fatigue
•
Nausea
•
MDS/AML: rare in the long term
•
Management of side effects (EANM/SNMMI 2023): grade ≥3 side effects occur in fewer than 10% of patients. Grade 3-4 haematological toxicity between cycles: the next cycle is postponed by 2 weeks and cancelled if there is no recovery (at least 2 weeks between G-CSF and radioactivity); grade ≥2 haematological toxicity on the treatment day or an eGFR fall of >40% (still >30 mL/min): activity reduced by 20%; GFR <30 mL/min, life-threatening toxicity not resolving within 4 weeks or AST/ALT >5 × upper limit: treatment discontinued. Artificial saliva for mild xerostomia; no general recommendation for salivary gland protection measures (oral glutamate, atropine, pre-dosing with unlabelled ligand). Pain may flare in the first week (steroids or NSAIDs)
EANM Notes (Lu-177 PSMA):
•
Patient selection: uptake in metastatic lesions on PSMA PET/CT must be clearly higher than that of normal liver. EANM/SNMMI 2023: PSMA expression is assessed preferably with PSMA PET (otherwise Tc-99m PSMA SPECT) together with CT, MRI or bone scan to exclude PSMA-negative nodal, visceral or lytic bone lesions (strong recommendation). Patients with a lesion ≥1 cm whose uptake is below half that of the parotid (approximately liver level with Ga-68 PSMA-11) are not treated; response is most likely when most lesions show uptake above the parotid (approximately SUV >10). FDG PET is not mandatory for everyone; it helps with lesions of uncertain viability or suspected PSMA negativity, especially liver metastases (which may convert to a PSMA-negative phenotype). PSMA immunostaining of a single biopsy does not replace PET
•
Approved regimen: 7.4 GBq every 6 (±1) weeks, up to 6 cycles; in clinical practice 6-9.3 GBq and intervals of 4-10 weeks have been found safe and effective (EANM/SNMMI 2023)
•
Administration (EANM/SNMMI 2023): ADT is continued (bisphosphonates or denosumab permitted); large-field external beam RT, chemotherapy and bone-seeking radiopharmaceuticals are stopped at least 4 weeks before. Hydration with 500-1000 mL of 0.9% saline (250 mL/h) starting 30 min before; the drug is given slowly IV over >30 seconds with saline flushes before and after; frequent voiding during the first 6-10 hours. Depending on local legislation, 48-72 hours of isolation may be needed; outpatients are observed for ~2 hours. At least one planar scan is acquired >2 hours after treatment (extravasation and biodistribution; medium-energy collimator for 208 keV). Contraception during and for 3 months after therapy
•
Blood counts and creatinine are checked 2-3 weeks after each cycle (expected nadir) and 4-6 weeks after the last cycle; laboratory tests no older than 5 days (blood count, creatinine/eGFR, AST, ALT, bilirubin, albumin, ALP, LDH, PSA, CRP) are required before each cycle. PSA is measured at each cycle; because of possible flare or delayed response it becomes reliable 2-3 weeks after the 2nd cycle, after which a >25% rise should prompt restaging (PCWG3). Restaging is usually performed every 12 weeks with PSMA PET/CT plus a second modality able to show PSMA-negative lesions (diagnostic CT, bone scan or FDG PET); patient-reported well-being is the key criterion for continuing therapy (EANM/SNMMI 2023)
•
Imaging: the gamma photons of Lu-177 are 113 and 208 keV, and its half-life is 6.6 days; this allows multi-time-point quantitative SPECT/CT dosimetry
•
Imaging times: 1-4 hours, 18-24 hours and 5-7 days (an image at 90-96 hours improves renal dosimetry)
•
Most common side effects: fatigue, dry mouth, nausea. In the USA the approval was extended to taxane-naive patients in March 2025
Lu-177 PSMA Mean Absorbed Doses (EANM):
| Organ/Tissue | Absorbed Dose (Gy/GBq) |
|---|---|
| Red bone marrow | 0.03 |
| Kidney | 0.4-0.8 |
| Salivary glands | 0.5-1.9 |
| Lacrimal glands | 0.4-3.8 |
| Tumour lesions | ~1-8 |
•
VISION dosimetry sub-study (29 patients, first cycle): lacrimal glands 2.1, salivary glands 0.63, kidneys 0.43, red marrow 0.035 Gy/GBq; cumulative over six cycles ~19 Gy to the kidneys and ~1.5 Gy to the marrow. Patient-specific dosimetry is not mandatory for approved fixed-activity use; in the EU (2013/59/Euratom art. 56) at least one post-therapy scan is required (EANM/SNMMI 2023)
Ac-225 PSMA-617 (EANM)
•
Ac-225: half-life 9.9 days; 4 alpha particles are emitted in its decay chain; range in tissue 47-85 µm (high LET)
•
Activity used in studies: ~100 kBq/kg per cycle, 6-8 weeks apart
•
Patient selection: mCRPC patients with high PSMA expression who have exhausted, or are unsuitable for, approved options
•
May be preferred especially in patients progressing despite Lu-177 PSMA and with diffuse bone marrow involvement (the bone marrow dose is low because the alpha range is short)
•
Exclusion criteria: unmanageable urinary tract obstruction, GFR <30 mL/min, marked organ dysfunction, severe myelosuppression
•
In a meta-analysis a PSA decline of ≥50% was seen in ~60% of cases; the most common toxicity is xerostomia (dose-limiting organs: salivary glands, kidney and bone marrow)
•
Post-treatment imaging and dosimetry are difficult because of the low photon yield
Figure 26.7: Comparison of the tissue ranges of therapeutic radionuclides: alpha (µm) and beta (mm) emitters.
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26.6 Ra-223 Dichloride (Bone Metastases)9 questions
General Principles
•
Ra-223 (Xofigo): FDA approved (2013)
•
Alpha emitter → high LET, short range ( 100 µm in tissue / 10 cell diameters)
•
Calcium mimetic → incorporates into hydroxyapatite in bone matrix → selective uptake in osteoblastic metastases
•
Physical half-life: 11.4 days
•
Emission of 4 alpha particles (decay chain: Ra-223 → Rn-219 → Po-215 → Pb-211 → Bi-211)
•
Target: castration-resistant prostate cancer with symptomatic bone metastases (mCRPC)
Figure 26.8: Ra-223 decay chain and short-range alpha irradiation after incorporation into hydroxyapatite in an osteoblastic metastasis (schematic).
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ALSYMPCA Trial
•
Phase III, randomised, double-blind, placebo-controlled trial
•
mCRPC with symptomatic bone metastases (no known visceral metastases)
•
Ra-223 + best standard of care vs placebo + best standard of care
•
OS: 14.9 months vs 11.3 months (HR 0.70, p<0.001) → ~3.6 months OS advantage
•
Symptomatic skeletal event (SSE): delayed (15.6 months vs 9.8 months)
•
OS advantage in all subgroups
•
Conclusion: Ra-223 → the first alpha emitter to increase OS in mCRPC with bone metastases
Treatment Protocol
•
Dose: 55 kBq/kg (1.49 µCi/kg) IV injection
•
Cycles: 6 cycles, 4 weeks apart
•
Before treatment: bone metastases must be confirmed with bone scintigraphy or NaF PET/CT
•
Absence of visceral metastases → important selection criterion (in the ERA-223 trial, abiraterone + Ra-223 combination → increased fracture risk → should not be used concurrently with abiraterone)
Figure 26.9: Standard cycle schedules for Lu-177 DOTATATE, Lu-177 PSMA-617 and Ra-223 therapies.
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Indications and Contraindications
Indications:
•
mCRPC + symptomatic bone metastases
•
No known visceral metastases
•
≥2 bone metastases on scintigraphy (symptomatic disease)
Contraindications:
•
Presence of visceral metastases (liver, lung, brain)
•
Bone marrow failure (ANC <1500, PLT <100,000, Hb <10)
•
SNMMI/EANM 2023: before subsequent cycles (within 2 weeks) neutrophils ≥1 × 10⁹/L and platelets ≥50 × 10⁹/L are required; if they do not recover within 6-8 weeks treatment is usually stopped. Because of the survival benefit, a life expectancy of ≥6 months is preferred. CT of the chest, abdomen and pelvis is obtained before starting to exclude visceral disease. Retreatment with Ra-223 is not approved; among Sr-89, Sm-153 and Ra-223 only Ra-223 has shown a survival benefit
•
Crohn's disease and ulcerative colitis are relative contraindications (because it is excreted via the GI tract there is a risk of flare and mucosal damage; as no data exist, benefit-risk should be weighed carefully)
•
Combination with abiraterone/prednisolone → contraindicated (ERA-223: increased fracture risk)
BOARD TIP
▸
"Why is Ra-223 effective only in bone metastases?"
→ Alpha emitter → very short range (100 µm) → acts only at the bone surface, cannot reach soft-tissue metastases.
▸
"Is the Ra-223 plus abiraterone combination safe?"
→ NO → ERA-223 trial → increased fracture risk → contraindicated.
▸
"OS difference in ALSYMPCA?"
→ 3.6 months (14.9 vs 11.3 months).
Figure 26.10: Results of the key randomised trials in radionuclide therapy (NETTER-1, VISION, TheraP, PSMAfore, ALSYMPCA).
Did this figure help you understand the topic?
Side Effects
•
Bone marrow suppression: thrombocytopenia (most common dose-limiting), anaemia, neutropenia
•
GI: nausea, diarrhoea, vomiting → usually mild
•
Transient increase in bone pain (flare): first 1-2 weeks
•
Fracture risk: especially in combination with abiraterone (ERA-223)
•
Myelosuppression: cumulative, must be monitored every cycle
EANM Notes (Ra-223):
•
~95% of the energy is delivered by alpha particles; excretion is mainly faecal, with ~5% excreted in urine
•
Before the first administration: Hb ≥10 g/dL, platelets ≥100×10⁹/L, ANC ≥1.5×10⁹/L; before subsequent administrations: ANC ≥1.0×10⁹/L, platelets ≥50×10⁹/L
•
Haematological values, ALP and PSA are checked before each administration; fracture risk is monitored for at least 24 months after treatment
–
For assessment of treatment response with Ra-223 (ALP, PSA, flare on bone scintigraphy), see 26.12
•
Blood counts mostly reach their nadir at weeks 2-3; use together with other systemic therapies is not recommended
•
PEACE-3 (EORTC 1333; Ann Oncol 2025-2026): in first-line mCRPC with bone metastases, enzalutamide + Ra-223 (6 cycles) was compared with enzalutamide alone. rPFS 19.4 vs 16.4 months (HR 0.69); overall survival was prolonged (final analysis HR 0.76). After the ERA-223 results, a bone-protecting agent (zoledronic acid or denosumab) was made mandatory in March 2018; the fracture rate was 24.3% with the combination and 13.4% with enzalutamide, and fell markedly with a bone-protecting agent. If Ra-223 is given with an ARPI, a bone-protecting agent is mandatory; combination with abiraterone remains contraindicated
26.7 Y-90 Microspheres (Radioembolisation – Liver)10 questions
General Principles
•
Y-90 (Yttrium-90): pure beta emitter (Eβmax = 2.28 MeV, mean 0.94 MeV)
•
Beta range in tissue: mean 2.5 mm, maximum 11 mm
•
Physical half-life: 64.1 hours (2.67 days)
•
No gamma emission → imaging with Bremsstrahlung SPECT or PET/CT (internal pair production)
•
Microspheres are injected into the hepatic artery via a catheter → distributed according to tumour vascularity
•
Tumours are supplied mainly by the hepatic artery, normal liver parenchyma mainly by the portal vein → selective tumour targeting
WHY IT MATTERS · Y-90 imaging: bremsstrahlung SPECT and internal pair PET
See the animation: Figure 26.11 →
•
What it is: Y-90 emits no gamma rays. It is imaged in two ways: by the continuous-spectrum braking radiation produced as beta particles slow down in tissue (bremsstrahlung SPECT), or by the annihilation of the positron from the very rare internal pair production from the excited 0⁺ level of Zr-90 (PET).
•
In numbers: Internal pair production occurs in only 31.86 × 10⁻⁶ per decay (~32 ppm): even at high activity, true coincidences are few, the random fraction is high and long acquisitions per bed position are needed; the Lu-176 background of LSO/LYSO crystals adds to the background. The bremsstrahlung spectrum has no photopeak: a wide window, high scatter and septal penetration degrade resolution and quantification.
•
Why it matters clinically: After radioembolisation it is used to confirm microsphere distribution (non-target deposition in stomach, duodenum, lung) and for post-treatment dosimetry; for quantitative dose calculation Y-90 PET/CT is more accurate than bremsstrahlung SPECT/CT. The 2022 EANM guideline recommends post-treatment imaging.
•
In the exam: "How is Y-90 PET possible?" → Very low-probability (~32 × 10⁻⁶) internal pair production at the excited level of Zr-90 produces positrons.
•
Sources: Selwyn et al., Appl Radiat Isot 2007; Conti and Eriksson, EJNMMI Phys 2016; Weber et al. (EANM), Eur J Nucl Med Mol Imaging 2022.
Microsphere Types
Resin Microspheres (SIR-Spheres):
•
Diameter: 20-60 µm (mean 32 µm)
•
Activity/microsphere: 50 Bq
•
Number of microspheres: 40-80 million (per dose)
•
Greater embolic effect (more microspheres)
•
Dose calculated with the BSA (Body Surface Area) method or partition model
•
EANM 2022: whenever possible (tumour can be segmented and data on tumouricidal and maximum tolerated doses exist for the product) multi-compartment (partition) or voxel-based dosimetry is used; for resin microspheres an international expert panel no longer recommends the BSA and single-compartment methods. Non-dosimetric calculation may lead to under- or overtreatment, both of which are harmful. Ho-166 microspheres: the mean whole-liver dose should not exceed 60 Gy; a scout dose (250 MBq) predicts lung shunting more accurately than MAA
Glass Microspheres (TheraSphere):
•
Diameter: 20-30 µm (mean 25 µm)
•
Activity/microsphere: 2500 Bq
•
Number of microspheres: 1.2-8 million (per dose)
•
Less embolic effect (fewer microspheres, higher specific activity)
•
MIRD-based dose calculation → target dose: 80-150 Gy (to the liver lobe)
Left: portal vein and hepatic artery in the liver, an arterially fed tumour and microspheres lodging after injection through the catheter; in step two part of the MAA particles reaching the lungs through tumour shunts. Right: resin versus glass microspheres, the measured shunt and the dose adjustment by shunt fraction.
Continuous stream · no seeking
Y-90 microspheres lodge in arterially fed tumour and irradiate it in place; the lung shunt measured with MAA sets the dose (>20% contraindicated).
Source: microsphere properties, shunt formula and dose adjustment from the book (26.7); circulation from OpenStax A&P 2e §20.5, §23.6. Distribution ratios and particle counts representative. β⁻ range window: energy from the Y-90 spectrum (ENSDF), track from NIST ESTAR energy loss with multiple scattering; over 3000 decays the mean net distance is 3.1 mm, the longest 9.5 mm; path length at Emax 11.3 mm. Microsphere not to scale.
How to use: a single click on the drawing pauses and resumes; ↑ ↓ or the buttons below change the microsphere type in the first step and the shunt fraction in the second; ← → change steps.
Did this animation help you understand the topic?
Figure 26.11: The dual blood supply principle underlying Y-90 radioembolisation and the properties of resin/glass microspheres (schematic).
Indications
•
Hepatocellular carcinoma (HCC): not a candidate for surgery or transplantation, unsuitable for TACE
–
Bridging therapy (downstaging before transplantation)
–
In the presence of portal vein thrombosis (Y-90 can be given whereas TACE is contraindicated)
•
Liver metastases: colorectal cancer, neuroendocrine tumour, breast cancer, etc.
–
In combination with or after chemotherapy
•
Intrahepatic cholangiocellular carcinoma
•
Contraindications: lung shunt >20% (or a lung dose >30 Gy), uncorrectable GI flow, decompensated liver failure (bilirubin >2 mg/dL, ascites), widespread extrahepatic disease, angiography contraindicated
•
EANM 2022 contraindications: pregnancy and breastfeeding, life expectancy <3 months, clinical liver failure (ascites, jaundice, encephalopathy), disseminated extrahepatic disease (hilar nodes ≤2 cm and up to 5 lung nodules ≤1 cm are often accepted), GI activity not correctable angiographically (except gallbladder, lymph nodes, falciform ligament), Child-Pugh >B7, main portal vein thrombosis with poor targeting, AST/ALT >5 × upper limit or raised bilirubin (caution especially with bilobar treatment). After previous external RT, the fraction of liver receiving ≥30 Gy is the strongest predictor of hepatotoxicity; repeat treatment needs an interval of at least 3 months. REILD (rising bilirubin, low albumin, ascites) usually starts at 2-6 months; first review at 2-4 weeks
•
Radiation segmentectomy: in a single HCC ≤8 cm, an ablative dose (glass microspheres) is given to a single segment; the aim is curative (LEGACY). In BCLC 2022 it is an option in early stage if resection or ablation is not suitable
Pre-treatment Assessment
Tc-99m MAA Shunt Study (Mandatory):
•
Tc-99m MAA injection into the hepatic artery via a catheter
•
The hepatopulmonary shunt is calculated:
Shunt (%) = Lung counts / (Lung counts + Liver counts) × 100
•
Shunt <10%: full dose can be given
•
Shunt 10-15%: dose reduced by 20%
•
Shunt 15-20%: dose reduced by 40%
•
Shunt >20%: treatment contraindicated (risk of radiation pneumonitis)
•
Cumulative lung dose limit: ≤30 Gy per session, ≤50 Gy cumulative
•
EANM 2022: the shunt-based dose reduction steps above come from the product information; a lung dose >30 Gy per session or >50 Gy cumulatively is not an absolute contraindication, because non-attenuation-corrected planar MAA overestimates the shunt. If the shunt is >10%, attenuation- and scatter-corrected SPECT/CT including the lungs is suggested. About 150 MBq of Tc-99m MAA is given into the hepatic artery, and imaging is done as early as possible (preferably within 1 hour) because MAA degrades; oral perchlorate beforehand can be considered so that free pertechnetate in the stomach is not mistaken for shunting. Treatment ideally follows the work-up within 15 days. After treatment, Y-90 PET or bremsstrahlung SPECT/CT confirms tumour uptake, lung dose and absence of extrahepatic deposition (Ho-166: SPECT/CT at 2-5 days)
Extrahepatic Shunt Assessment:
•
Tc-99m MAA SPECT/CT → check for aberrant flow to GI organs (stomach, duodenum)
•
If there is a shunt to the GI tract → aberrant vessels are closed by coil embolisation
•
Gastroduodenal artery, right gastric artery, falciform artery → should be embolised
BOARD TIP
▸
"Why is a Tc-99m MAA shunt study mandatory before Y-90 radioembolisation?"
→ (1) The hepatopulmonary shunt is calculated → if >20%, treatment is contraindicated (radiation pneumonitis). (2) Extrahepatic shunting is assessed → if there is aberrant flow to the GI tract → coil embolisation is needed.
▸
"Advantage of Y-90 over TACE?"
→ Can be used in the presence of portal vein thrombosis (TACE contraindicated).
Left: portal vein and hepatic artery in the liver, an arterially fed tumour and microspheres lodging after injection through the catheter; in step two part of the MAA particles reaching the lungs through tumour shunts. Right: resin versus glass microspheres, the measured shunt and the dose adjustment by shunt fraction.
Continuous stream · no seeking
Y-90 microspheres lodge in arterially fed tumour and irradiate it in place; the lung shunt measured with MAA sets the dose (>20% contraindicated).
Source: microsphere properties, shunt formula and dose adjustment from the book (26.7); circulation from OpenStax A&P 2e §20.5, §23.6. Distribution ratios and particle counts representative. β⁻ range window: energy from the Y-90 spectrum (ENSDF), track from NIST ESTAR energy loss with multiple scattering; over 3000 decays the mean net distance is 3.1 mm, the longest 9.5 mm; path length at Emax 11.3 mm. Microsphere not to scale.
How to use: a single click on the drawing pauses and resumes; ↑ ↓ or the buttons below change the microsphere type in the first step and the shunt fraction in the second; ← → change steps.
Did this animation help you understand the topic?
Figure 26.12: Calculation of the hepatopulmonary shunt with Tc-99m MAA and Y-90 dose adjustment according to the shunt fraction.
Dose Calculation
BSA Method (Resin Microspheres):
A (GBq) = (BSA − 0.2) + Tumour volume / (Tumour volume + Normal liver volume)
MIRD Method (Glass Microspheres):
A (GBq) = [D (Gy) × M (kg)] / 50
•
D: target absorbed dose (usually 80-150 Gy)
•
M: mass of the target liver lobe
Partition Model:
•
Dose is calculated separately for the tumour, normal liver and lung compartments
•
The most accurate but most complex method
Side Effects
•
Post-radioembolisation syndrome: fatigue, nausea, fever, abdominal pain → most common (20-70%)
•
Radiation pneumonitis: with high hepatopulmonary shunt → dose limits must be observed
•
GI ulceration: if extrahepatic shunting is not controlled → gastric/duodenal ulcer
•
Radiation hepatitis (REILD): rare but serious → excess dose to normal liver parenchyma
•
Biliary complications: cholangitis, biliary stricture
•
Lymphopenia: common but usually clinically insignificant
EANM Notes (Y-90 Radioembolisation):
•
For treatment the catheter should be placed at the position where the MAA test dose was given; prophylactic PPI is usually given for 6 weeks
•
Tumour dose associated with better outcome in HCC: ≥205 Gy with glass microspheres, ≥120 Gy with resin microspheres
•
Exclusion criterion for SIR-Spheres: lung shunt >20% or a predicted single-session lung dose >30 Gy
•
Follow-up and response (EANM 2022): the first laboratory tests and clinical evaluation take place 2-4 weeks after treatment (follow-up is planned according to the prior state of the liver, e.g. cirrhosis, and the fraction of liver treated); the first cross-sectional imaging is at about 3 months. Metabolic response on FDG PET may be seen at 4-6 weeks, whereas anatomical response may take 2-3 months. Because size-based RECIST ignores necrosis and decreased perfusion, mRECIST, which measures viable tumour, is used in HCC; in neuroendocrine metastases RECIST response is associated with survival, and mRECIST may help in hypervascular tumours; in intrahepatic cholangiocarcinoma EASL, mRECIST or Choi criteria are associated with survival. Radioembolisation-induced liver disease (REILD: hyperbilirubinaemia, hypoalbuminaemia, ascites) typically develops at 2-6 months without disease progression. For repeated treatment, an interval of at least 3 months is left for liver regeneration
I-131 Lipiodol (EANM):
•
In inoperable, histologically confirmed primary HCC, it is given by slow injection into the hepatic artery under fluoroscopy
•
Standard activity 2.22 GBq (60 mCi); after ~1 week distribution and dosimetry are assessed with whole-body imaging
•
Absolute exclusion criteria: pregnancy or breastfeeding, life expectancy <1 month, hepatic encephalopathy, OKUDA III, contrast agent allergy
•
Side effects: fever, pain in the liver region during injection, rarely acute pneumonitis; today it has largely been replaced by Y-90 microspheres
•
In randomised trials it shows efficacy similar to TACE and is better tolerated; when given as adjuvant therapy after curative resection it has been shown to reduce recurrence
26.8 Sr-89 and Sm-153 (Palliation of Bone Pain)7 questions
General Principles
•
Pain palliation in widespread osteoblastic bone metastases
•
Effective in lesions showing increased uptake on bone scintigraphy
•
More effective in osteoblastic > osteolytic metastases
•
Mean beta range in tissue of agents used for bone palliation: Sm-153 ~0.6 mm (shortest), Re-186 ~1.1 mm, Sr-89 ~2.4 mm, Re-188 and P-32 ~3 mm
•
Purely lytic lesions that show no uptake on bone scintigraphy (e.g. multiple myeloma) do not respond to treatment; therefore bone scintigraphy must be positive in the painful region before treatment
•
Most common indication: bone metastases of prostate and breast cancer
Sr-89 Chloride (Metastron)
•
Pure beta emitter (Eβmax = 1.46 MeV)
•
Physical half-life: 50.5 days (long)
•
Calcium analogue → incorporates into hydroxyapatite
•
Dose: 148 MBq (4 mCi) IV or 1.5-2.2 MBq/kg
•
No gamma emission → imaging not possible
–
It does in fact also emit a 909 keV gamma ray, but with an abundance of ~0.01% this is insufficient for imaging; distribution can only be roughly imaged via Bremsstrahlung
•
Pain response: 60-80% (begins within 2-4 weeks)
•
Flare phenomenon: transient increase in pain in the first 48-72 hours (10%); SNMMI/EANM 2023: ~15% with Sr-89, starting 1-5 days after treatment and lasting up to 4 days; 12-20% with Sm-153, mostly within 72 hours
•
Repeat dose: no earlier than 90 days later (because of the long half-life)
•
EANM: standard activity 150 MBq; ~85% of the activity is excreted in urine; given slowly IV over 4 minutes
–
Calcium therapy is stopped at least 2 weeks before; can be used together with bisphosphonates
–
Contraception for 4 months
Sm-153 EDTMP (Quadramet)
•
Beta emitter (Eβmax = 0.81 MeV) + gamma emitter (103 keV → imaging possible)
•
Physical half-life: 46.3 hours (1.9 days) (short)
•
Binds to the bone surface via phosphonate (EDTMP) (mechanism similar to MDP)
•
The fraction not bound to bone (~35%) is excreted in urine in the first ~6 hours; the kidneys and bladder may therefore be seen on images. In patients with incontinence, catheterisation is used to prevent contamination
•
Dose: 37 MBq/kg (1 mCi/kg) IV
•
Pain response: 60-70% (begins within 1 week → faster than Sr-89)
•
Gamma emission → post-treatment imaging possible (dose distribution is confirmed)
•
Repeat dose: after 8 weeks (short half-life)
•
EANM: given as a bolus with good hydration; the metastasis/normal bone ratio is ~5:1; blood counts reach their nadir at ~week 4 and recover in 6-8 weeks
Re-186 / Re-188 HEDP (EANM)
•
The HEDP complex binds to hydroxyapatite; excreted mainly in urine (because excretion is rapid in the first 12-24 hours, attention must be paid to urinary contamination)
•
Free perrhenate (ReO₄⁻), like pertechnetate, is taken up via NIS in the thyroid, stomach and salivary glands; thyroid blockade with perchlorate is therefore considered for Re-labelled agents
•
Half-life: Re-186 HEDP 3.7 days, Re-188 HEDP 17 hours
•
Pain decreases in 60-80%; wait at least 6-8 weeks before retreatment; blood counts reach their nadir at weeks 3-5; flare ~10%
Sr-89 vs Sm-153 Comparison
| Feature | Sr-89 (Metastron) | Sm-153 (Quadramet) |
|---|---|---|
| Emission | Pure beta | Beta + gamma |
| T½ | 50.5 days | 46.3 hours |
| Mechanism | Ca analogue | Phosphonate (EDTMP) |
| Imaging | Not possible | Possible (103 keV) |
| Onset of response | 2-4 weeks | 1 week |
| Repeat dose | ≥90 days | ≥8 weeks |
| Myelosuppression | More marked (long T½) | Milder (short T½) |
Common Side Effects
•
Bone marrow suppression: most important side effect → thrombocytopenia, leucopenia
–
More marked and prolonged with Sr-89 (long half-life)
–
Milder and shorter with Sm-153
•
Nadir: 3-5 weeks with Sm-153, 12-16 weeks with Sr-89 (US prescribing information; EANM: platelet nadir with Sr-89 at 4-6 weeks, recovery in 3-6 months)
•
Flare phenomenon: transient increase in pain (first 48-72 hours)
•
Contraindications: severe myelosuppression (PLT <60,000, WBC <2400 — US prescribing information), life expectancy <3 months, DIC, renal failure (Sr-89 renal excretion)
•
EANM relative contraindication thresholds (more cautious in Europe): Hb <90 g/L, leucocytes <3.5×10⁹/L, platelets <100×10⁹/L
•
EANM: not given if creatinine is >180 µmol/L and/or GFR <30 mL/min; life expectancy should preferably be >3 months (not suitable if <4 weeks)
•
Common preparation (SNMMI/EANM 2023): a bone scan, preferably within the last 3 months, to show uptake at painful sites; blood count within 2 weeks before treatment. Myelosuppressive chemotherapy is stopped 6-8 weeks (long-acting) or ~4 weeks (other) before; hemibody external RT is stopped 2-4 weeks before and deferred afterwards until counts recover. Thresholds for Sm-153: platelets >60,000/µL (preferably >100,000), WBC >2,400/µL (preferably >5,000), neutrophils >2,000/µL, Hb >10 g/dL. Active DIC is a risk factor for severe thrombocytopenia. The agent is given slowly IV over 1 minute through an indwelling catheter; outpatient treatment, no fasting, good hydration. Pain relief begins within 1-4 weeks (little benefit if life expectancy is <1 month). Sm-153 can be repeated as early as 8 weeks later (up to 3 times in total) if counts recover; it can be combined with bisphosphonates. Pregnancy and breastfeeding are absolute contraindications
•
In metastatic invasion causing neurological deficit (e.g. spinal cord compression), urgent external RT or neurosurgery is required; radionuclide therapy is not appropriate
BOARD TIP
▸
"Most important difference between Sr-89 and Sm-153?"
→ Sr-89 is a pure beta emitter (no imaging, long T½), Sm-153 is beta + gamma (imaging possible, short T½).
▸
"Which acts faster?"
→ Sm-153 (1 week vs 2-4 weeks).
▸
"Which causes more marked myelosuppression?"
→ Sr-89 (long half-life → higher cumulative bone marrow dose).
Figure 26.13: Sr-89 and Sm-153 EDTMP: how the difference in physical half-life is reflected in onset of response, repeat-dose interval and myelosuppression.
Did this figure help you understand the topic?
26.9 Ho-166 Microspheres (Liver)3 questions
General Principles
•
Ho-166 (Holmium-166): beta emitter (Eβmax = 1.85 MeV) + gamma emitter (81 keV)
•
Physical half-life: 26.8 hours
•
QuiremSpheres: Ho-166-loaded poly-L-lactic acid (PLLA) microspheres
•
Diameter: 20-50 µm
•
Differences from Y-90 microspheres:
–
Gamma emission → SPECT imaging possible (not possible with Y-90)
–
Paramagnetic → MR imaging possible
•
Scout dose: a low-activity scout dose can be given with the same microspheres (instead of Tc-99m MAA)
Advantages
•
Triple imaging: SPECT (gamma), MR (paramagnetic), CT (high Z)
•
Scout dose: scout dose with Ho-166 microspheres → reflects the true microsphere distribution (more accurate than Tc-99m MAA)
•
Dosimetry: the actual post-treatment dose distribution can be calculated
•
EANM: a test (scout) dose of ~250 MBq is given (preSIRT); after 1-2 weeks the treatment microspheres are given from the same catheter positions
–
EANM 2022: the scout dose (250 MBq, about 3 million microspheres) is safe and predicts the lung shunt fraction and intrahepatic distribution more accurately than Tc-99m MAA. Scout and treatment are given from the same angiographic position, slowly over 20-30 seconds; treatment is ideally performed within 15 days of the work-up. A typical treatment is 20-30 million microspheres; the catheter is placed more than 3-4 cm distal to the gastroduodenal artery and any artery supplying the gastrointestinal tract
–
Activity calculation is similar to the MIRD method for glass Y-90 microspheres: 1 GBq of Ho-166 delivers 15.87 Gy by beta rays in 1 kg of tissue. The mean absorbed dose to the perfused volume may exceed 60 Gy, provided the mean dose to the whole liver does not exceed 60 Gy
•
In personalised dosimetry a tumour dose of at least ~60 Gy is targeted
Indications
•
Same indications as Y-90: HCC, liver metastases
•
Contraindications (EANM 2022; shared with Y-90, see 26.7): pregnancy and breastfeeding, life expectancy <3 months, clinical liver failure (ascites, jaundice, encephalopathy), disseminated extrahepatic disease, gastrointestinal activity on the scout study that cannot be corrected angiographically; requiring caution: poor targeting of main portal vein thrombosis, creatinine clearance <30 mL/min, contraindication to hepatic artery catheterisation (uncorrectable coagulation disorder, severe contrast allergy), prior external beam RT to the liver
•
Especially where a dosimetry and imaging advantage is wanted
Side Effects
•
Profile similar to Y-90 microspheres
•
Risk of post-radioembolisation syndrome, radiation hepatitis, GI ulceration
•
Post-treatment imaging (EANM 2022): SPECT/CT (medium-energy collimator, down-scatter window) is performed between days 2 and 5 depending on the activity; immediately after treatment, activity above about 1420 MBq in the field markedly increases dead time. Because Ho-166 is paramagnetic, it can be quantified on MRI with T2* (recovery in the liver >95% when there are no surgical clips); however, the susceptibility artefact may obscure gadolinium enhancement and viable residual tumour on follow-up MRI. Radioembolisation-induced liver disease (REILD) usually begins at 2-6 months
•
Radiation safety (EANM 2022): because of its gamma emission, the dose rate from the patient after treatment is clearly higher than with Y-90, and this must be taken into account. Staff whole-body doses of <3 µSv/GBq and maximum finger doses of 2.9 µSv/MBq for preparation and 2.5 µSv/MBq for administration have been reported; ring dosimeters are poorly sensitive to beta rays and may underestimate the actual dose. Contamination during preparation or administration can cause high skin doses. Pregnancy is avoided for at least 4 months after treatment
BOARD TIP
▸
"Imaging advantage of Ho-166 microspheres over Y-90?"
→ SPECT/CT through gamma emission (days 2-5) and MRI quantification through paramagnetism; a scout dose (250 MBq) of the same microspheres predicts the shunt more accurately than MAA.
▸
"Does radiation safety differ between Ho-166 and Y-90?"
→ Yes; because of gamma emission the dose rate from the patient is clearly higher.
26.10 Y-90 Ibritumomab (Radioimmunotherapy)3 questions
General Principles
•
Y-90 ibritumomab tiuxetan (Zevalin): radioimmunotherapy agent
•
Anti-CD20 monoclonal antibody (ibritumomab) + Y-90 (beta emitter)
•
CD20: B-lymphocyte surface antigen → expressed in B-cell non-Hodgkin lymphoma (NHL)
•
Tiuxetan: chelator → binds Y-90 to the antibody
•
Crossfire effect: Y-90 beta range ~5 mm → also kills neighbouring tumour cells not bound by antibody
•
Pretargeting: first an unlabelled bispecific or biotinylated antibody, then a bridging or clearing agent (avidin/streptavidin), and finally a small radiolabelled hapten (biotin) are given; the tumour/blood ratio is high and the bone marrow dose low
Indications
•
Relapsed/refractory low-grade or follicular B-cell NHL
•
Consolidation therapy in follicular lymphoma (after first remission)
•
Must be CD20-positive
•
Patients previously treated with rituximab or rituximab-refractory
•
Exclusion criteria (EANM 2007; EU product information):
–
Pregnancy and breastfeeding; hypersensitivity to ibritumomab tiuxetan, yttrium chloride, rituximab or other murine proteins; age under 18
–
Lymphoma involving >25% of the bone marrow (on an iliac crest biopsy >2 cm long taken within 3 months or after the last progression), prior external beam RT involving >25% of the active marrow, prior bone marrow or stem cell transplantation
–
Neutrophils <1500/mm³; platelets <100,000/mm³ for monotherapy and <150,000/mm³ for consolidation after induction chemotherapy; detectable HAMA depending on titre (HAMA is tested in patients who have previously received murine proteins). The blood count limits are not absolute but increase the risk of severe and prolonged myelosuppression; treatment is usually not given if creatinine or bilirubin exceeds 2.5 times the upper limit
–
Growth factors such as G-CSF are not given for 2 weeks before and 2 weeks after treatment (rapidly dividing myeloid cells are radiosensitive)
Treatment Protocol
Day 1:
•
Rituximab 250 mg/m² IV (to deplete the B-cell pool → optimise Y-90 distribution)
Day 7-9 (day 8 in the EANM schedule):
•
Rituximab 250 mg/m² IV (repeat)
•
Followed by Y-90 ibritumomab IV:
–
PLT ≥150,000 → 14.8 MBq/kg (0.4 mCi/kg) (maximum 1184 MBq / 32 mCi)
–
PLT 100,000-149,000 → 11.1 MBq/kg (0.3 mCi/kg)
–
PLT <100,000/μL → contraindicated
Figure 26.14: Y-90 ibritumomab tiuxetan treatment protocol and activity selection according to platelet count (schematic).
Did this figure help you understand the topic?
Prior Imaging with In-111 Ibritumomab (No Longer Mandatory)
•
Previously, biodistribution was assessed before treatment with In-111-labelled ibritumomab
•
Aim: confirmation of appropriate biodistribution, check for excessive bone marrow uptake
•
No longer mandatory today (FDA 2011 update)
•
EANM schedule: rituximab 250 mg/m² is given on days 1 and 8; within 4 hours after the day-8 rituximab, Y-90 ibritumomab is given IV over 10 minutes
–
Activity is 11 or 14 MBq/kg according to platelet count, at most 1200 MBq
•
EANM: no relationship between tumour dose and response has been shown (routine dosimetry is not performed)
•
The EU marketing authorisation expired on 4 January 2024
Side Effects
•
Bone marrow suppression: most important toxicity → delayed and prolonged
•
Nadir: 7-9 weeks (thrombocytopenia), 5-7 weeks (neutropenia) (FDA prescribing information; EANM: 4-6 weeks)
•
Recovery: 3-4 months
–
Bone marrow involvement >25% → contraindicated
•
Infection risk: immunosuppression (B-cell depletion + myelosuppression)
•
MDS/AML: long term (2-5%)
•
Cytopenias: weekly full blood count monitoring after treatment required
•
Pregnancy, breastfeeding and follow-up: women and men use effective contraception during treatment and for 12 months afterwards; breastfeeding is stopped (FDA label: for 6 months after the last dose). Live viral vaccines are not recommended for 12 months. Semen cryopreservation may be offered to male patients. Cytopenias and their complications (febrile neutropenia, haemorrhage) are monitored for up to 3 months; drugs affecting platelet function or coagulation are avoided
•
Radiation safety: as a pure beta emitter it is given as an outpatient treatment without isolation; little activity is excreted in the urine in the first 7 days (about 3-7%). For one week the toilet is flushed twice, splashed urine is wiped with paper and flushed, hands are washed after using the toilet, men urinate sitting down, condoms are used during intercourse, and blood from a cut is rinsed away (NVNG 2016)
BOARD TIP
▸
"What is the crossfire effect of Y-90 ibritumomab?"
→ Y-90 beta range ~5 mm → also kills neighbouring tumour cells not bound by antibody → advantage in heterogeneous antigen expression.
▸
"How is the dose adjusted to PLT?"
→ PLT ≥150K → 0.4 mCi/kg, PLT 100-149K → 0.3 mCi/kg, PLT <100K → contraindicated.
▸
"Most important side effect?"
→ Delayed myelosuppression (nadir 7-9 weeks).
BOARD TIP
▸
"Exclusion criteria for Y-90 ibritumomab therapy?"
→ Marrow involvement >25%, prior RT to >25% of active marrow, prior stem cell transplantation, neutrophils <1500/mm³, platelets <100,000/mm³ (<150,000 for consolidation), hypersensitivity to murine proteins, pregnancy and breastfeeding.
▸
"Contraception period after Zevalin?"
→ 12 months for women and men.
26.11 Radiosynovectomy (Er-169, Y-90, Re-186)5 questions
General Principles
•
Intra-articular radionuclide injection → radiation ablation of synovial tissue
–
Because the synovium is not removed, EANM 2022 recommends the term radiosynoviorthesis (RSO) instead of 'radiosynovectomy'. The effect begins with phagocytosis of the colloid by the superficial macrophages of the inflamed synovium
•
Treatment of chronic inflammatory synovitis
•
Alternative to surgical synovectomy → less invasive
•
Mechanism: beta radiation → synovial cell necrosis → fibrosis → reduced inflammation
Indications
•
Rheumatoid arthritis (synovitis resistant to medical treatment)
•
Haemophilic arthropathy (recurrent haemarthroses)
•
Pigmented villonodular synovitis (PVNS)
•
Osteoarthritis (if the synovitis component is marked)
•
Other: psoriatic arthritis, ankylosing spondylitis (peripheral joint involvement)
Contraindications (EANM 2022)
•
Absolute: pregnancy, breastfeeding, local skin infection or septic arthritis, ruptured popliteal (Baker's) cyst, joint surgery or arthroplasty within the last 6 weeks (fresh surgical scar), uncontrolled bleeding (including massive haemarthrosis; except in patients with haemophilia)
•
Relative: extensive joint instability with bone destruction, high-grade bone destruction; under the age of 20 the benefit must clearly outweigh the potential harm and the alternatives
•
Women of childbearing age avoid pregnancy for at least 4 months after treatment; breastfeeding is stopped before treatment (transfer of Y-90 colloid into breast milk has been shown)
•
A Baker's cyst alone is not a contraindication (seen in 5-19% of knees on MRI and 25% on ultrasound); only a cyst ruptured at the time of treatment is a contraindication. With strict immobilisation no activity accumulation in the cyst has been shown; radiosynoviorthesis may also reduce the volume of an existing cyst
Choice of Radionuclide (by Joint Size)
| Joint Size | Radionuclide | T½ | Beta Range | Example Joints |
|---|---|---|---|---|
| Large | Y-90 silicate/citrate | 64.1 hours | Max 11 mm | Knee |
| Medium | Re-186 sulphide | 3.7 days | Max 3.6 mm | Shoulder, hip, elbow, wrist, ankle |
| Small | Er-169 citrate | 9.4 days | Max 1 mm | MCP, MTP, PIP joints |
•
Recommended activities (EANM 2022; with the dose of triamcinolone acetonide injected into the joint at the same time):
–
Y-90 citrate: knee 185-222 MBq (5-6 mCi) + 40 mg; Y-90 is used for the knee only
–
Re-186 sulfide: hip and shoulder 74-148 MBq (2-4 mCi), elbow 74-111 MBq (2-3 mCi), wrist 37-74 MBq (1-2 mCi), ankle and subtalar joint 74 MBq (2 mCi)
–
Er-169 citrate: MCP 20-40 MBq (0.5-1.1 mCi), PIP 10-20 MBq (0.3-0.5 mCi), DIP 10-15 MBq (0.3-0.4 mCi), MTP 30-40 MBq (0.8-1.1 mCi), thumb carpometacarpal joint 20-80 MBq (0.5-2.2 mCi)
–
The glucocorticoid bridges the delay between injection and onset of effect and reduces the risk of radiation synovitis and leakage out of the joint
Technique
•
Intra-articular injection under fluoroscopic or ultrasound guidance
•
EANM: to reduce extra-articular leakage the particle size should be at least 5-10 µm; an arthrogram is requested before the procedure
•
EANM: the treated joint is kept strictly immobilised for 48 hours; colloid particles are phagocytosed by synoviocytes
•
Absorption of ~100 Gy by the synovium can produce an effect similar to surgical synovectomy
•
After injection: joint immobilisation for 48-72 hours (to prevent leakage of the radionuclide out of the joint)
–
EANM 2022: the joint is immobilised with a rigid splint for about 48 hours; bed rest is not required. For large and medium-sized joints of the lower limb (hip, knee, ankle), thromboprophylaxis may be needed, especially in patients at risk of thromboembolism or when two adjacent joints are treated together. If immobilisation cannot be ensured, inpatient treatment is considered
•
Before treatment: if there is a joint effusion → aspiration is performed
•
Pre-treatment assessment (EANM 2022): the aim is to confirm synovitis and exclude contraindications. A radiograph in two planes or CT of the joint to be treated, at most 4-6 months old, is available (to exclude fracture, bone tumour, loose bodies and severe bone destruction); in haemophilia older imaging may be accepted
–
In the knee, rupture of a Baker's cyst is excluded with ultrasound. Arthroscintigraphy can be used in selected patients: Tc-99m nanocolloid is injected into the joint, and if leakage into the popliteal soft tissue is seen after movement, the cyst is considered ruptured and treatment is strictly not performed
–
Multiphase bone scintigraphy is performed only when polyarticular disease is suspected or when there is no other evidence of synovitis (unnecessary irradiation is avoided, especially in children)
–
Contrast medium used with Y-90 in the knee must be free of EDTA (EDTA dissolves the colloid binding); the knee is therefore usually treated without contrast. With Er-169 the amount of intra-articular contrast is also kept to a minimum
•
After treatment: distribution is checked with Bremsstrahlung (Y-90) or gamma (Re-186) imaging; because Er-169 is an almost pure β⁻ emitter, imaging it is not practical
–
EANM 2022: the distribution of Re-186 (gamma) and Y-90 (Bremsstrahlung; for Y-90 also PET/CT) is imaged immediately after injection, which also excludes a para-articular (misplaced) injection. An image at 48 hours can help show lymphatic drainage from the treated joint
Efficacy and Outcomes
•
Success rate: 60-80% (reduction in pain and swelling)
•
Knee: pain relief or clinical improvement of 80-81% at 6 months and 76-87% at 12 months has been reported with Y-90; in a multicentre comparison pain relief at 3, 6 and 12 months was 86%, 72%, 46% with radiosynoviorthesis versus 67%, 46%, 21% with intra-articular glucocorticoid (EANM 2022)
•
There is no consistent difference in success by joint size: in a series of 577 joints in RA, a good or excellent response was seen in 57% of knees, 63% of shoulders, 60% of wrists, 64% of ankles, 55% of MCP and 54% of PIP joints; in OA at 12 months, 89%, 86% and 79% in small, medium and large joints. Success depends more on the degree of joint damage (73% and 64% in Steinbrocker stages I and II, 52% in stages III-IV) and is better in RA than in OA (EANM 2022)
•
Retreatment: after 6-12 months (if response is inadequate)
–
EANM 2022: retreatment is performed no earlier than 6 months; the response is considered inadequate if pain on a visual analogue scale has not fallen by at least 50%. The annual cumulative activity limit is not exceeded (in Germany 444 MBq for Y-90 and Re-186, 300 MBq for Er-169)
•
In haemophilia (EANM 2022): it is used early, as first-line treatment of chronic synovitis before haemarthropathy develops (synovitis persisting despite 6 months of intensified factor therapy, or 3 joint bleeds a year). Benefit in bleeding frequency, pain, joint function and synovial thickness has been reported in 70-90%. Adequate factor levels are ensured at the time of the procedure according to the haematologist's plan, and intensified factor replacement is continued for at least 3 months; if synovitis persists the procedure can be repeated up to three times, after which surgery is recommended
–
In children: for the knee, Re-186 50-100 MBq before adolescence and Y-90 150-185 MBq in adolescence; ankle Re-186 40-75 MBq; elbow Re-186 30-60 MBq. There is no consensus on a lower age limit (1 or 2 years have been proposed)
Side Effects and Complications
•
Transient arthritis (flare): first 24-48 hours → transient increase in pain and swelling
–
Radiation synovitis is more common with high-energy agents (Y-90); in large joints a small amount of glucocorticoid is injected at the same time (EANM 2022)
•
Radiation necrosis: rare → skin necrosis if leakage occurs out of the joint
–
Beta burns from Re-186 are more limited, usually heal spontaneously within 3-4 weeks, and hyperbaric oxygen helps in severe cases; burns from Er-169 need only conservative treatment (EANM 2022)
•
Extra-articular leakage: prevented by immobilisation → spread via lymphatics to regional lymph nodes
•
Infection: prevented by sterile technique (rare)
•
Radiation safety (EANM 2022): because of their short range, beta emitters give a high surface dose; for staff the personal dose equivalent at the surface, Hp(0.07), is relevant, and a finger ring dosimeter can be used with beta emitters. Contamination monitoring, storage of radionuclides and waste disposal, and discharge information for the patient are mandatory
–
Leakage out of the joint: mean 2.5-3.9% for Re-186 and 0.11 ± 0.3% for Er-169; for Er-169 the whole-body dose is below 1 mGy per 30 MBq. Leaked particles accumulate in the regional lymph nodes and the liver; depending on the degree of leakage, the lymph node dose can reach the deterministic range
–
The incidence of serious adverse events is about 4.5 per 100,000 treated joints (1990-2019, about 1.5 million joints); no increase in cancer risk after radiosynoviorthesis has been reported
•
Chromosomal damage: theoretical risk → clinical significance unclear
Intracavitary Radionuclide Therapy: Cystic Craniopharyngioma
•
A beta-emitting colloid is instilled into the cyst stereotactically (or through an Ommaya reservoir): P-32 chromic phosphate or Y-90 silicate. The cumulative dose aimed at the inner surface of the cyst wall in reported series is 200-300 Gy (in one series 189-250 Gy over five half-lives, mean 224 Gy)
•
The effect is through fibrosis of the cyst wall; the cyst volume shrinks over months. Because the mean range of Y-90 beta particles in soft tissue is ~3.6 mm (maximum 11 mm), the solid component is not affected → the best results are obtained in solitary cysts
•
Meta-analysis (8 studies, 285 patients; 2026): complete cyst reduction 25.6%, partial reduction 53.3%, cyst enlargement 12.9%; neurological complications 4.9%; 5-year overall survival 92.3%. The main risks are visual and endocrine deterioration; if optic atrophy is present before treatment, visual loss is irreversible
BOARD TIP
▸
"Which radionuclide for the knee joint?"
→ Y-90 (large joint, long beta range).
▸
"For a finger joint?"
→ Er-169 (small joint, short beta range).
▸
"Why is the joint immobilised?"
→ To prevent the radionuclide leaking out of the joint → reduces the risk of skin necrosis and lymphatic spread.
BOARD TIP
▸
"Absolute contraindications to radiosynovectomy?"
→ Pregnancy, breastfeeding, local skin infection or septic arthritis, ruptured Baker's cyst, joint surgery within 6 weeks, uncontrolled bleeding (except haemophilia).
▸
"Does an intact Baker's cyst rule out radiosynovectomy?"
→ No; only a cyst ruptured at the time of treatment is a contraindication.
▸
"Y-90 activity for the knee?"
→ 185-222 MBq (5-6 mCi), with 40 mg triamcinolone acetonide.
26.12 Therapy Dosimetry and Patient Management10 questions
Dosimetric Quantities (Therapy-Specific)
•
Absorbed dose (Gy): energy absorbed per unit mass (J/kg)
•
Tumour absorbed dose: determines treatment efficacy → adequate dose = tumour control
•
Critical organ dose: sets the toxicity limit → bone marrow, kidney, lung
•
Cumulative dose: tracking total dose with repeated treatments → late side effects (MDS/AML, renal failure)
MIRD Formalism (Therapy Dosimetry)
•
MIRD (Medical Internal Radiation Dosimetry):
D(target) = Σ Ã(source) × S(target ← source)
•
D: absorbed dose to the target organ (Gy)
•
à (Cumulated activity): total number of decays in the source organ (Bq·s)
–
Area under the time-activity curve
–
Calculated from the biological and physical half-lives
•
S value: absorbed dose to the target organ per unit cumulated activity in the source organ (Gy/Bq·s)
–
Depends on the emission properties of the radionuclide and organ geometry
–
Obtained from MIRD tables or OLINDA/EXM software
•
Patient-specific three-dimensional (voxel-level) dosimetry: performed by dose-point kernel or voxel S-value convolution, or directly by Monte Carlo (Monte Carlo is the most accurate and accounts for tissue heterogeneity); organ-level MIRD gives only the mean organ dose
WHY IT MATTERS · Dose heterogeneity
•
What it is: The "mean absorbed dose" of an organ or tumour is meaningful when activity is evenly distributed in the tissue. If activity is irregular at the microscopic level and the particle range is short, part of the tissue receives far more and part far less than the mean.
•
In numbers: In the kidney, radiopeptides accumulate irregularly within the cortex: the dose distribution calculated for Lu-177 and In-111 follows this irregularity, creating volumes with doses far below and far above the mean kidney dose; with the long-range Y-90 the distribution is smoothed. Y-90 microspheres cluster at the tumour edge: in explanted livers tumour doses ranged from 100 Gy to over 3000 Gy, and normal parenchyma away from tumours showed little radiation effect.
•
Why it matters clinically: Mean-dose limits derived from external beam therapy (e.g. renal BED) are most probably not directly valid for Lu-177 and Auger emitters; this is why voxel-level dosimetry and dose-volume histograms matter.
•
In the exam: "Why may the mean kidney dose not fully reflect toxicity in Lu-177 therapy?" → With short-range beta the dose follows the irregular cortical activity; the mean hides volumes with high and low doses.
•
Sources: Konijnenberg et al., J Nucl Med 2007; Kennedy et al., Int J Radiat Oncol Biol Phys 2004.
Residence Time
τ = Ã / A₀
•
τ: residence time (hours)
•
Ã: cumulated activity
•
A₀: initial activity
•
A time-activity curve is built from serial imaging → area under the curve = Ã
Figure 26.15: Time-activity curve: cumulated activity (Ã) is the area under the curve, residence time τ = Ã/A₀ (schematic).
Did this figure help you understand the topic?
Therapy-Specific Dosimetry Applications
I-131 Thyroid Cancer Dosimetry:
•
Bone marrow dosimetry: blood sampling + whole-body counting → ≤200 cGy (2 Gy) to bone marrow
•
Lung dosimetry: in diffuse lung metastases → retention at 48 hours ≤80 mCi (3 GBq)
•
Lesion-based dosimetry: ≥8000 cGy (80 Gy) to the tumour is targeted
•
Maximum tolerated activity (MTA): determined by the bone marrow and lung limits
Lu-177 DOTATATE Dosimetry:
•
Renal dosimetry: cumulative renal dose ≤23 Gy (BED ≤40 Gy)
•
Bone marrow dosimetry: cumulative ≤2 Gy
•
Serial SPECT/CT imaging (24, 96, 168 hours) → time-activity curve
Y-90 Microsphere Dosimetry:
•
Partition model → tumour, normal liver and lung calculated separately
•
Normal liver dose: ≤70 Gy (healthy liver), ≤40 Gy (cirrhotic liver)
•
Lung dose: ≤30 Gy per session, ≤50 Gy cumulative
BOARD TIP
▸
"Bone marrow dose limit in I-131 therapy?"
→ ≤200 cGy (2 Gy).
▸
"Lung retention limit?"
→ ≤80 mCi at 48 hours.
▸
"Renal dose limit in Lu-177 DOTATATE?"
→ Cumulative ≤23 Gy.
▸
"Cirrhotic liver dose limit in Y-90 radioembolisation?"
→ ≤40 Gy (≤70 Gy in healthy liver).
Theranostics and Regulatory Framework (EANM)
•
Theranostics: imaging or measuring the target before treatment and treating the same target; the leading pair in the clinic is Ga-68 / Lu-177
•
Ideal target: should be specific to the disease or tumour microenvironment, reachable from the circulation, and stably expressed over time and across metastases
•
The strongest evidence for personalised dosimetry is in liver radioembolisation
•
2013/59/Euratom BSS Directive: target volumes should be individually planned, delivery verified, and doses to non-target tissues kept as low as possible
•
Standardised treatment is administration in line with the summary of product characteristics of an EMA- or CE-approved product, or a guideline; investigational and off-label uses are considered non-standardised (a medical physics expert should be closely involved in the process)
EANM Optimisation Levels:
| Level | Prescription | Dosimetry | Use |
|---|---|---|---|
| L1 | Activity-based | Cohort-averaged | Minimum for standard treatments; net activity within ±10% of intended |
| L2 | Activity-based | Patient-specific (organs at risk ± treatment site) | Minimum for non-standardised treatments; uncertainty ~20% |
| L3 | Absorbed-dose-based | Patient-specific + verification | New methods and dose-effect research |
Patient Management – Radiation Safety
Release Criteria after I-131 Therapy:
•
NRC (USA) rule: dose rate at 1 m <7 mR/hour (0.07 mSv/hour) OR residual activity <33 mCi (1.2 GBq) → may be released
Try it in the calculator: I-131 release →
–
Alternative: if patient-specific dosimetry shows that the total dose to any individual will be ≤500 mrem (5 mSv) → may be released even at higher activity
•
Practice: most centres treat as outpatients at doses of 30-200 mCi
Patient Instructions after Release:
•
Distance: ≥1-2 metres from family members (especially the first 2-5 days)
•
Time: minimise time in close contact
•
Sleeping: separate bed (at least 6-11 days, dose-dependent)
•
Children and pregnant women: avoid close contact (at least 1-3 weeks)
•
Toilet hygiene: double flushing, urinating sitting down (men), hand washing
•
Personal items: separate cutlery and towels
•
Work/school: 1-7 days off depending on dose
•
Breastfeeding: must be stopped after I-131 therapy (permanently for that child)
•
Pregnancy: should be avoided for 6-12 months after treatment
Safety in Other Radionuclide Therapies:
•
Lu-177 DOTATATE/PSMA: usually outpatient → urinary excretion (highest in the first 24 hours)
–
Lu-177 DOTATATE (EU product information): for 7 days after each administration, close contact (less than 1 m) with others is limited; close contact with children and pregnant women is kept under 15 minutes a day for 7 days; the patient sleeps in a separate bedroom for 7 days and apart from children and pregnant women for 15 days. Women use effective contraception for 7 months and men for 4 months after the last dose (2026 guidance: 4-7 months in women); breastfeeding is stopped (FDA: for 2.5 months after the last dose)
•
Ra-223: alpha emitter → minimal external radiation risk → no special isolation needed
•
Y-90 microspheres: pure beta emitter → minimal external radiation risk → low Bremsstrahlung
•
Y-90 ibritumomab: pure beta → minimal external radiation risk → outpatient treatment
•
Sr-89 chloride: as a pure beta emitter it is given on an outpatient basis without isolation; because urine is radioactive in the first days, attention is paid to toilet hygiene
Management of Radioactive Contamination
•
Body fluids: urine, sweat, saliva → may be radioactive (especially I-131)
•
Vomiting: in the first 24 hours after I-131 therapy → high contamination risk
•
In case of death: if a radioactive patient dies → the radiation safety officer must be informed → autopsy and burial procedures
•
Airport security: may trigger radiation detectors for 2-3 months after I-131 therapy → a patient information card should be given
Assessment of Treatment Response
I-131 Thyroid Cancer:
•
Thyroglobulin (Tg): tumour marker → should fall after treatment
–
Stimulated Tg <1 ng/mL → excellent response
–
Response according to ATA 2025 (thresholds unchanged from 2015): excellent (suppressed Tg <0.2 or stimulated Tg <1 ng/mL and imaging negative); indeterminate (suppressed 0.2-1, stimulated 1-10); biochemical incomplete (suppressed >1, stimulated >10 or rising anti-Tg); structural incomplete
–
If anti-Tg antibody is positive → Tg unreliable → the antibody trend is followed
•
If faint uptake persists in the thyroid bed despite repeated ablation but Tg is undetectable and anti-Tg is negative, no further RAI is needed; the patient is followed up
•
Diagnostic whole-body scan: not needed routinely during follow-up in low- and low-intermediate-risk patients with an excellent response; at intermediate-high and high risk it can be performed with I-123 or low-activity I-131 when recurrence is suspected (ATA 2025)
•
In a suspicious cervical lymph node, ultrasound-guided FNAB is performed and Tg is measured in the aspirate washout fluid; this measurement is largely unaffected by serum anti-Tg
•
Neck ultrasound: every 6-12 months
•
FDG PET/CT: high Tg + negative I-131 scan (TENIS syndrome)
–
Causes of TENIS: inadequate TSH stimulation, recent iodine load (contrast), small-volume disease, dedifferentiated tumour (produces Tg but does not take up iodine); the first step is neck ultrasound
–
If no focus is found, empirical I-131 (3.7-7.4 GBq) may be considered in selected patients (ATA 2025: without structural disease, patients with stimulated Tg <10 ng/mL after hormone withdrawal or <5 ng/mL with rhTSH are followed without additional treatment); the post-treatment scan shows a focus in some cases, but cure is rare. If the scan is negative the disease is considered RAI-refractory
Lu-177 DOTATATE:
•
Ga-68 DOTATATE PET/CT: after every 2 cycles or at the end of treatment
•
Chromogranin A: biochemical marker
•
RECIST/mRECIST criteria
–
EANM/IAEA/SNMMI 2026: most patients show a response at the first assessment after the last cycle, with the tumour nadir reached at 3-6 months; a small group shows further response at 6-12 months. Clinical evaluation is performed during treatment and 3, 6 and 12 months after treatment, with emphasis on symptom control and quality of life
Lu-177 PSMA:
•
PSA: before each cycle → decline of ≥50% = response
•
PSMA PET/CT: post-treatment assessment
•
RECIST/PCWG3 criteria
Ra-223:
•
ALP (alkaline phosphatase): marker of bone metastasis activity → decline = response
•
PSA: variable (not reliable on its own)
•
Bone scintigraphy: may be misleading early because of the flare phenomenon
BOARD TIP
▸
"What is TENIS syndrome?"
→ Thyroglobulin Elevated, Negative Iodine Scan → high Tg + negative I-131 scan → FDG PET/CT indicated (suggests dedifferentiation).
▸
"Response marker in Ra-223 therapy?"
→ Decline in ALP (alkaline phosphatase).
▸
"Response assessment in Lu-177 DOTATATE?"
→ Ga-68 DOTATATE PET/CT + chromogranin A.
Key Points for the Board
I-131 Treatment of Hyperthyroidism
•
Fixed dose in Graves: 10-15 mCi, in TMNG: 15-30 mCi
•
Calculated dose formula: 3 parameters → target dose (µCi/g), gland weight (g), 24-hour RAIU (%)
•
Antithyroid drugs: methimazole stopped 2-5 days before, PTU 2-8 weeks before with fixed activity ( 4-7 days with the dosimetric approach) (radioprotective effect)
•
Graves ophthalmopathy: mild active → I-131 can be given with steroid prophylaxis; moderate-severe active → avoid I-131
•
Most important risk factor (worsening ophthalmopathy): smoking
•
Most common outcome: hypothyroidism (50-80%)
•
In toxic adenoma the surrounding tissue is spared → suppressed tissue does not take up iodine
•
RAI in paediatric Graves: avoided under age 5; acceptable at age 5-10 if activity is <10 mCi (ATA 2016)
I-131 Treatment of Thyroid Cancer
•
TSH stimulation: THW → TSH >30 mIU/L or rhTSH (Thyrogen) 0.9 mg IM × 2 days
•
Stunning effect: diagnostic I-131 (>3 mCi) → reduces NIS expression → use I-123 or low-dose I-131 (≤3 mCi)
•
Low-risk ablation: 30 mCi, high risk: 100-200 mCi
•
Post-therapy WBS: 5-7 days after treatment → more sensitive than the diagnostic scan
•
Most common side effect: sialadenitis; most serious late complication: secondary malignancy (AML) → cumulative >600 mCi
•
Flip-flop phenomenon: I-131 uptake ↓, FDG uptake ↑ → dedifferentiation
•
TENIS syndrome: high Tg + negative I-131 scan → FDG PET/CT indicated
•
RAI-refractory: tyrosine kinase inhibitors (lenvatinib, sorafenib)
•
ATA 2015 excellent response: suppressed Tg <0.2 or stimulated Tg <1 ng/mL + imaging negative
•
Age threshold 55 in AJCC 8 DTC staging: under 55 only stage I (M0) or II (M1)
I-131 MIBG Therapy
•
Thyroid blockade mandatory (SSKI/potassium iodide)
•
Drugs that reduce MIBG uptake: tricyclic antidepressants, labetalol, reserpine, sympathomimetics
•
MIBG positivity in neuroblastoma: 90-95%
•
Most important dose-limiting toxicity: bone marrow suppression
Lu-177 DOTATATE (PRRT)
•
NETTER-1: advanced midgut NET → marked superiority in PFS
•
Protocol: 7.4 GBq × 4 cycles, 8 weeks apart
•
Renal protection: lysine + arginine amino acid infusion → reduces reabsorption by 40-50%
•
Patient selection: Ga-68 DOTATATE PET/CT positive, well-differentiated (Grade 1-2)
•
Renal dose limit: cumulative ≤23 Gy
Lu-177 PSMA
•
VISION: OS advantage of 4 months in mCRPC (15.3 vs 11.3 months, HR 0.62)
•
PSMAfore: rPFS 12.0 vs 5.6 months in taxane-naive mCRPC
•
Protocol: 7.4 GBq × 6 cycles, 6 weeks apart
•
Patient selection: PSMA PET/CT positive → PSMA-negative lesion = poor prognosis
•
Most common side effects: fatigue, xerostomia, nausea; most common serious (Grade ≥3) toxicity: bone marrow suppression
Ra-223 Dichloride
•
ALSYMPCA: OS advantage of 3.6 months in mCRPC with bone metastases (14.9 vs 11.3 months)
•
Alpha emitter → range 100 µm → acts only at the bone surface
•
Protocol: 55 kBq/kg × 6 cycles, 4 weeks apart
•
Contraindications: visceral metastases, combination with abiraterone (ERA-223 → fracture risk)
•
Response marker: decline in ALP
Y-90 Radioembolisation
•
Tc-99m MAA shunt study mandatory → hepatopulmonary shunt >20% → contraindicated
•
Shunt <10% → full dose; 10-15% → reduce by 20%; 15-20% → reduce by 40%
•
Glass microspheres: high specific activity (2500 Bq), few microspheres, little embolisation
•
Resin microspheres: low specific activity (50 Bq), many microspheres, more embolisation
•
TACE contraindicated in portal vein thrombosis → Y-90 can be given (advantage)
•
Lung dose limit: ≤30 Gy per session, ≤50 Gy cumulative
•
Normal liver dose limit: healthy ≤70 Gy, cirrhotic ≤40 Gy
Sr-89 vs Sm-153
•
Sr-89: pure beta, T½ 50.5 days, Ca analogue, no imaging, response in 2-4 weeks
•
Sm-153: beta + gamma (103 keV), T½ 46.3 hours, phosphonate, imaging possible, response in 1 week
•
Myelosuppression more marked with Sr-89 (long T½)
•
Purely lytic lesions without uptake on bone scintigraphy (e.g. multiple myeloma) do not respond; shortest beta range in tissue is Sm-153 (~0.6 mm)
Y-90 Ibritumomab (Zevalin)
•
Anti-CD20 + Y-90 → B-cell NHL
•
Crossfire effect: beta range ~5 mm → also kills neighbouring cells
•
Dose: PLT ≥150K → 0.4 mCi/kg; PLT 100-149K → 0.3 mCi/kg; PLT <100K → contraindicated
•
Most important toxicity: delayed myelosuppression (nadir 7-9 weeks)
Radiosynovectomy
•
Large joint (knee): Y-90 (range 11 mm)
•
Medium joint (shoulder, hip): Re-186 (range 3.6 mm)
•
Small joint (finger): Er-169 (range 1 mm)
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Immobilisation for 48-72 hours after injection → prevents extra-articular leakage
Therapy Dosimetry
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MIRD formula: D = Ã × S
•
I-131 bone marrow limit: ≤200 cGy (2 Gy)
•
I-131 lung retention: at 48 hours ≤80 mCi
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Lu-177 DOTATATE renal limit: ≤23 Gy
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Y-90 cirrhotic liver limit: ≤40 Gy
Patient Management and Release
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NRC release: <7 mR/hour at 1 metre OR residual activity <33 mCi
•
Avoid pregnancy after I-131: 6-12 months
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Breastfeeding after I-131: must be stopped (permanently for that child)
•
Ra-223, Y-90, Lu-177: minimal external radiation risk → no special isolation needed
Additional Notes from EANM Guidelines:
•
Benign thyroid: stop thiamazole 2-5 days and PTU 2-8 weeks before (4-7 days with the dosimetric approach); wait 6-8 weeks after iodinated contrast; adenoma 300-400 Gy, TMNG >150 Gy
•
Ra-223: for subsequent doses ANC ≥1.0 and PLT ≥50×10⁹/L; excretion mainly faecal
•
Sr-89: standard 150 MBq; GFR <30 mL/min → not given; calcium stopped 2 weeks before
•
Y-90 RE: tumour dose in HCC: glass ≥205 Gy, resin ≥120 Gy; Ho-166 scout ~250 MBq, tumour ≥60 Gy
•
Lu-177 PSMA: highest doses in lacrimal/salivary glands and kidney; Ac-225 PSMA: 100 kBq/kg, xerostomia
•
EANM optimisation levels: L1 (cohort) – L2 (patient-specific dosimetry) – L3 (absorbed-dose-based prescription)
Current guidelines on this chapter's topics
The latest guidelines and consensus documents on the procedures covered in this chapter (official EANM index and primary sources, November 2026). Comparison of the text with these versions is in progress; consult the guideline itself for details.
- 2026Joint EANM, IAEA, and SNMMI practical guidance on somatostatin receptor-targeted radionuclide therapy of neuroendocrine tumours (opens in a new tab)
- 20252025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer (opens in a new tab)
- 2023The EANM guideline on radioiodine therapy of benign thyroid disease (opens in a new tab)
- 2023Joint EANM/SNMMI procedure guideline for the use of 177Lu-labeled PSMA-targeted radioligand-therapy (177Lu-PSMA-RLT) (opens in a new tab)
- 2023SNMMI Procedure Standard/EANM Practice Guideline for Palliative Nuclear Medicine Therapies of Bone Metastases (opens in a new tab)
- 2022Joint SNMMI/EANM practice guideline for Nuclear Medicine Evaluation and Therapy of Differentiated Thyroid Cancer: Abbreviated Version (opens in a new tab)
- 2022EANM dosimetry committee recommendations for dosimetry of 177Lu-labelled somatostatin-receptor- and PSMA-targeting ligands (opens in a new tab)
- 2022EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds (opens in a new tab)
- 2022Joint EANM/SNMMI/IAEA enabling guide: how to set up a theranostics centre (opens in a new tab)
- 2021EANM dosimetry committee series on standard operational procedures: a unified methodology for 99mTc-MAA pre- and 90Y peri-therapy dosimetry in liver radioembolization with 90Y microspheres (opens in a new tab)
- 2021The EANM guideline for radiosynoviorthesis (opens in a new tab)
- 2020EANM Dosimetry Committee series on standard operational procedures for internal dosimetry : Dosimetry for 131I-mIBG treatment of neuroendocrine tumours (opens in a new tab)
- 2017EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer (opens in a new tab)
- 2008EANM procedure guidelines for 131I-meta-iodobenzylguanidine (131I-mIBG) therapy (opens in a new tab)
- 2007EANM procedure guideline for radio-immunotherapy for B-cell lymphoma with 90Y-radiolabelled ibritumomab tiuxetan (Zevalin) (opens in a new tab)
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