¹³¹I-MIBG therapy

Indications

• Neuroblastoma: relapsed or refractory high-risk MIBG-avid disease (EANM 2008 lists stage III–IV neuroblastoma). Front-line use during induction remains investigational (COG ANBL1531).
• Phaeochromocytoma and paraganglioma: metastatic, recurrent or inoperable MIBG-avid disease needing systemic therapy, for tumour control and control of catecholamine excess.
• Other MIBG-avid tumours listed by EANM 2008: inoperable carcinoid tumours and metastatic or recurrent medullary thyroid cancer (now rarely treated this way).
• All indications need adequate uptake and retention on a pre-therapy diagnostic MIBG scan; EANM notes there is no agreed definition of adequate uptake.
• US label (Azedra, high-specific-activity iobenguane, FDA July 2018): patients aged 12 or over with iobenguane-scan-positive, unresectable, locally advanced or metastatic PPGL needing systemic anticancer therapy. Production stopped: Lantheus announced discontinuation in August 2023 and made no Azedra after 1 March 2024.

Contraindications

• Absolute (EANM 2008): pregnancy; breastfeeding; life expectancy <3 months unless for intractable bone pain; renal insufficiency needing dialysis in the short term.
• Relative (EANM 2008): unacceptable medical risk from isolation; unmanageable urinary incontinence; rapidly deteriorating renal function (GFR <30 mL/min); progressive haematological or renal toxicity from prior treatment; WBC <3.0 ×10⁹/L or platelets <100 ×10⁹/L.
• Azedra label: no formal contraindications, but do not give the first dose with platelets <80 ×10⁹/L or ANC <1.2 ×10⁹/L. It was not studied in severe renal impairment (creatinine clearance <30 mL/min).
• Disease without MIBG uptake (common in SDHB-related PPGL): consider other options, such as PRRT if SSTR-positive (still used in research or compassionate programmes for PPGL, EANM/SNMMI 2019).

• Thyroid blockade (EANM 2008): potassium iodide 130 mg/day in adults, 65 mg (15–50 kg), 32 mg (5–15 kg) or 16 mg (<5 kg); or potassium iodate 170/80/40/20 mg; or Lugol 1% 1 drop/kg/day (maximum 40 drops). Start 24–48 h before and continue for 10–15 days. Potassium perchlorate (400/300/200/100 mg) may be added to speed washout. The Azedra label asks for inorganic iodine from at least 24 h before to 10 days after each dose.
• Whole-body absorbed dose from serial retention measurements is the surrogate for marrow dose. Individual absorbed-dose estimates are expected in Europe; the EANM dosimetry SOP (2020) gives the method.
• Whole-body-dose protocols can reach administered activities above 30 GBq in larger children (EANM dosimetry SOP 2020).
• EANM 2008 recommends high specific activity (up to 1.48 GBq/mg) for therapy. Azedra was a no-carrier-added product (about 92.5 GBq/mg).
• Drug interference (US and EU differ): EANM 2008 gives drug-specific withdrawal times (for example labetalol 72 h, tricyclics 24–48 h, decongestants 24–48 h, depot antipsychotics 1 month) and advises keeping α- and β-blockade unchanged in catecholamine-secreting tumours. The Azedra label asks for withdrawal for at least 5 half-lives before any dose and no restart until 7 days after. For diagnostic imaging, EANM/SNMMI 2019 advises stopping labetalol 10 days before.

• Early: nausea and vomiting in the first 2 days; sialadenitis and dry mouth (39% and 48% with Azedra); fatigue.
• Myelosuppression is dose-limiting, typically at 4–6 weeks (EANM 2008). It is often an isolated thrombocytopenia in children after chemotherapy and is less frequent in adults. Risk rises with marrow involvement, high whole-body dose, delayed renal clearance and prior chemotherapy. With Azedra: grade 4 thrombocytopenia 33%, neutropenia 16%, anaemia 7%, febrile neutropenia 5%; neutrophil nadir at a median of 36 days after the first dose and 43 days after the second.
• Catecholamine surge: hypertension during or within 24 h of infusion (worsening in 11% with Azedra). Manage by slowing or stopping the infusion and giving short-acting α- or β-blockers.
• Hypothyroidism despite blockade (3.4% with Azedra; usually from inadequate blockade). Check TSH yearly.
• Renal: renal failure or acute kidney injury in 7% and a clinically significant GFR fall in 22% at 6–12 months with Azedra; rare deterioration after prior cisplatin or ifosfamide (EANM 2008).
• Pneumonitis: rare but fatal once, 9 weeks after one dose in the Azedra expanded-access programme; do not give a second dose after pneumonitis.
• Liver: sinusoidal obstruction syndrome when MIBG is followed closely by busulfan–melphalan, which is why the front-line pilot required a 10-week gap.
• Late: MDS or acute leukaemia in 6.8% of Azedra-treated patients (12 months to 7 years); second solid cancers; persistent cytopenias; infertility (gonadal doses after a cumulative 37 GBq are in the range that causes temporary or permanent infertility).

• Treat as an inpatient in an approved shielded single room with en-suite facilities, as national legislation usually requires (EANM 2008). Discharge follows local release criteria; for example, the US NRC allows release when the dose to others is unlikely to exceed 5 mSv, with written instructions if it could exceed 1 mSv (10 CFR 35.75).
• Urinary excretion is the main contamination route in the first 5 days: rigorous toilet hygiene, double flushing, and washing heavily soiled clothing separately for 1 week. Catheterise incontinent patients for 3–4 days.
• Child-and-parent model: parents are encouraged to care for their child and act as willing, informed comforters and carers. They need training, protective clothing, time and distance rules, no eating or drinking in the room, and a pocket dosimeter, with a urine check for internal contamination if needed. Their dose constraint is set nationally (EANM 2008 gives, for example, 5 mSv per year), and repeated treatments in a year must be counted. Female carers must not be pregnant or breastfeeding.
• Carers' doses can be significant: in one series of parents of children with neuroblastoma, the mean external dose was 5.8 mSv, and 16.4 mSv for carers of children under 4 years (Han 2017). Internal dose was negligible.
• ICRP 94: young children, infants and visitors who are not giving care are members of the public; a dose constraint of a few mSv per episode applies to adult carers at home.
• Avoid pregnancy for at least 4 months (EANM 2008; Azedra label 7 months for women, 4 months for men); stop breastfeeding (Azedra label: until 80 days after the last dose).
• Give a written card: radiation detectors at borders and airports can detect ¹³¹I for weeks. Medical emergencies take priority over radiation precautions.