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Radionuclide therapy

⁹⁰Y SIRT (radioembolisation)

Source: EANM 2022 / Levillain 2021 (resin) / Salem 2023 (glass) / BCLC 2022 · confirm locally
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Educational aid — verify against EANM/SNMMI/ATA/NCCN, the drug label and local protocol. Session-only.
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Before planning therapy

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On the day of treatment

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After treatment & follow-up

Background & evidence

SIRT, also called transarterial radioembolisation (TARE), is the injection of ⁹⁰Y-loaded resin or glass microspheres (or ¹⁶⁶Ho poly-L-lactic acid microspheres) into the hepatic artery. The spheres lodge in the tumour microvasculature, which is mainly arterial, and deliver a high local beta dose (⁹⁰Y: half-life 64.1 h, mean tissue range about 2.5–4 mm). It is a liver-directed option across HCC stages and for liver-dominant metastases; outcome depends on patient selection and, above all, on personalised dosimetry.

Indications & contraindications

Indications

  • Early HCC (BCLC 0–A): a single nodule ≤8 cm not suitable for resection or ablation (BCLC 2022, based on LEGACY). US label for TheraSphere (FDA 2021): solitary HCC 1–8 cm, Child–Pugh A, no macrovascular invasion, good performance status.
  • Bridging and downstaging: radiation segmentectomy before transplant, or radiation lobectomy to grow the future liver remnant before resection.
  • Intermediate HCC (BCLC B): an accepted alternative to TACE (AASLD 2023; BCLC 2022).
  • Locally advanced HCC with portal vein invasion: selected Child–Pugh A patients with hepatic reserve ≥30% and good MAA targeting of tumour and thrombus, using multicompartment dosimetry (DOSISPHERE-01). With BSA-based dosing, SIRT did not improve survival over sorafenib (SARAH, SIRveNIB).
  • Colorectal liver metastases: liver-dominant, chemorefractory disease; with second-line chemotherapy it prolongs PFS and hepatic PFS but not overall survival (EPOCH). It is not recommended with first-line chemotherapy in unselected patients (FOXFIRE/SIRFLOX/FOXFIRE-Global). The US resin label indication is unresectable colorectal liver metastases with intra-arterial floxuridine.
  • Other liver tumours: intrahepatic cholangiocarcinoma and neuroendocrine or other liver-dominant metastases, with tumour-dose thresholds in the resin recommendations (Levillain 2021).

Contraindications

  • Absolute (EANM 2022): pregnancy or breastfeeding; life expectancy <3 months; clinical liver failure (ascites, jaundice, encephalopathy); disseminated extrahepatic disease; gastrointestinal deposition on MAA (or cone-beam CT) that cannot be corrected angiographically.
  • Relative (EANM 2022): Child–Pugh >B7 (unless segmental); high intrahepatic tumour burden (often 50–70% cut-off); main portal vein thrombosis with poor MAA targeting; creatinine clearance <30 mL/min; contraindication to hepatic artery catheterisation; lung dose >30 Gy per session or >50 Gy cumulative.
  • US resin label (SIR-Spheres): previous liver external beam radiotherapy; ascites or liver failure; bilirubin >2.0 mg/dL or albumin <3.0 g/dL; lung shunt >20% or lung dose >30 Gy; uncorrectable reflux to stomach, pancreas or bowel; disseminated extrahepatic disease; capecitabine in the previous 2 months or planned afterwards; portal vein thrombosis.
  • US glass label (TheraSphere): uncorrectable gastrointestinal deposition; lung shunt delivering >0.61 GBq to the lungs; pulmonary insufficiency (PaO₂ <60 mmHg or SaO₂ <90%); severe liver dysfunction; type 4 portal vein thrombosis without MAA deposition; ECOG >2; pregnancy.
  • Prior liver external beam radiotherapy needs caution: hepatotoxicity relates most to the liver fraction that received ≥30 Gy (EANM 2022).
Activity, dosing & administration
Product and methodHow the activity is setKey thresholds (source)
⁹⁹ᵐTc-MAA simulationAbout 150 MBq (glass label 75–150 MBq) at the planned catheter positionLung ≤30 Gy per session, ≤50 Gy cumulative (EANM 2022; Levillain 2021; glass label). US resin label: lung ≤30 Gy and LSF >20% contraindicated
Resin — BSA method (US resin label)A (GBq) = (BSA − 0.2) + Vtumour ÷ Vtotal liver; for lobar treatment, multiply by the treated-lobe fraction of liver volumeLabel method in the USA; the 2021 resin recommendations and EANM 2022 prefer personalised dosimetry
Resin — partition model or voxel dosimetry (Levillain 2021)Activity chosen to reach the tumour target while respecting the normal-liver limitNon-tumoural liver ≤40 Gy for whole-liver treatment (≤30 Gy if heavily pretreated or compromised); tumour ≥100–120 Gy for HCC, mCRC and ICC; 100–150 Gy for NET; lobectomy >70 Gy to normal perfused liver; segmentectomy possibly >150 Gy
Glass — single compartment (glass label)A (GBq) = D (Gy) × M (kg) ÷ [50 × (1 − LSF) × (1 − residual)]80–150 Gy to the perfused liver; future liver remnant ≥30%
Glass — radiation segmentectomy (Salem 2023)Ablative dose to ≤2 segments≥400 Gy to the perfused angiosome, no set upper limit
Glass — radiation lobectomy (Salem 2023)Lobar infusion140–150 Gy single-compartment; or >150 Gy lobar if whole-liver dose <150 Gy (Child–Pugh A, reserve >30%); normal perfused liver ≥88 Gy predicts ≥10% hypertrophy
Glass — multicompartment, locally advanced HCC (Salem 2023; DOSISPHERE-01)Tumour-driven activityTumour ≥205 Gy, >250 Gy where possible; normal tissue ≤120 Gy when hepatic reserve ≥30%; whole normal liver <50 Gy if bilirubin ≥1.1 mg/dL, <90 Gy if lower (investigational)
¹⁶⁶Ho microspheres (EANM 2022; HEPAR)250 MBq scout dose, then treatment planned on scout SPECTAimed whole-liver dose 60 Gy (maximum tolerated dose in HEPAR); multicompartment: whole normal liver <60 Gy (unilobar), <40 Gy bilobar; mCRC tumour >90 Gy
  • One GBq of ⁹⁰Y fully decaying in 1 kg of tissue deposits about 50 Gy; the same constant underlies the lung, liver and tumour dose formulas.
  • Planar MAA overestimates the lung shunt. Use patient-specific lung mass when the LSF is close to the cut-off (Levillain R28); EANM 2022 treats the lung limit as a relative, not absolute, contraindication.
  • MAA predicts the normal-liver dose better than the tumour dose, especially for small tumours. Staged lobar treatment allows the second activity to be adjusted using ⁹⁰Y PET dosimetry of the first.
  • Glass spheres carry much more activity per sphere than resin (EANM 2022 Table 1), so far fewer spheres are injected; resin is more embolic.
  • In the EU, activity must be individually planned and optimised (Council Directive 2013/59/Euratom, Article 56), which the resin recommendations use to support personalised dosimetry.
  • US and EU differ: the US resin label is built on the BSA method, whereas EANM 2022 and the 2021 resin recommendations advise the partition model or voxel dosimetry instead.
Key trials & evidence
Trial / studyPopulationResultReference
SARAH (phase 3)459 with locally advanced HCC (BCLC C or after 2 failed TACE); resin SIRT (BSA) vs sorafenibMedian OS 8.0 vs 9.9 months, HR 1.15 (0.94–1.41), p=0.18; 22% of the SIRT arm never received SIRT; fewer grade ≥3 fatigue and diarrhoea with SIRTVilgrain, Lancet Oncol 2017
SIRveNIB (phase 3)360 with locally advanced HCC, Asia-Pacific; resin SIRT vs sorafenibMedian OS 8.8 vs 10.0 months, HR 1.1, p=0.36; 28.6% of the SIRT arm untreated; grade ≥3 AEs 27.7% vs 50.6%Chow, J Clin Oncol 2018
DOSISPHERE-01 (randomised phase 2)60 with locally advanced HCC, ≥1 lesion ≥7 cm, hepatic reserve ≥30%; glassPersonalised (tumour ≥205 Gy) vs standard (120 ± 20 Gy): ORR 71% vs 36% (p=0.0074); median OS 26.6 vs 10.7 months (ITT, HR 0.42); long-term 24.8 vs 10.7 months (HR 0.51)Garin, Lancet Gastroenterol Hepatol 2021; J Nucl Med 2024
LEGACY (retrospective, single arm)162 with solitary HCC ≤8 cm, Child–Pugh A, ECOG 0–1; glass, selective ablative dosingORR 88.3%; 62.2% with response lasting ≥6 months; 3-year OS 86.6% (92.8% after resection or transplant); basis of the 2021 FDA approval and BCLC 2022Salem, Hepatology 2021
TARGET (retrospective)209 with HCC treated with glass; multicompartment dosimetry applied retrospectivelyHigher tumour dose linked to response and OS (HR 0.83 per 100 Gy); grade ≥3 hyperbilirubinaemia 4.8%, not linked to normal-tissue doseLam, Eur J Nucl Med Mol Imaging 2022
SIRFLOX (phase 3)530 with first-line mCRC; mFOLFOX6 ± bevacizumab ± resin SIRTPFS at any site 10.2 vs 10.7 months, HR 0.93, p=0.43; liver PFS 12.6 vs 20.5 months, HR 0.69van Hazel, J Clin Oncol 2016
FOXFIRE + SIRFLOX + FOXFIRE-Global (pooled)1103 with first-line mCRC and liver metastasesOS 22.6 (SIRT) vs 23.3 months, HR 1.04 (0.90–1.19), p=0.61; more grade 3–4 neutropenia with SIRTWasan, Lancet Oncol 2017
EPOCH (phase 3)428 with second-line colorectal liver metastases; chemotherapy ± glass TAREPFS HR 0.69 (8.0 vs 7.2 months); hepatic PFS HR 0.59; OS 14.0 vs 14.4 months, HR 1.07; grade ≥3 AEs 68.4% vs 49.3%Mulcahy, J Clin Oncol 2021
HEPAR (phase 1)15 with chemorefractory liver metastases; ¹⁶⁶Ho dose escalation 20–80 GyMaximum tolerated whole-liver dose 60 GySmits, Lancet Oncol 2012
Toxicity & its management
  • Common (>10%, usually mild): fatigue, abdominal pain, nausea, fever or chills, transient rise in liver enzymes and lymphopenia (EANM 2022). Grade ≥3 lymphopenia occurred in 34–43% in DOSISPHERE-01.
  • REILD (listed by EANM 2022 among severe events at <5%): jaundice and ascites 4–8 weeks after treatment (up to about 6 months) without progression; histology shows sinusoidal obstruction (veno-occlusive disease). In an early series of patients without cirrhosis it occurred in 20%, mainly after prior chemotherapy and with whole-liver treatment (Sangro 2008).
  • REILD risk rises with a high dose relative to the treated volume, reduced reserve (steatosis, steatohepatitis, cirrhosis), raised baseline bilirubin, small tumour burden (<5%), small liver (<1.5 L), prior resection or liver-directed therapy, and heavy prior chemotherapy (US resin label). Mitigate by dosimetry, sequential lobar treatment and activity reduction.
  • Radiation pneumonitis: rare. Onset 1–6 months with dry cough and restrictive defect. In an early series it occurred only with LSF >13% (5 of 80 patients). A later cohort of 58 patients with >30 Gy cumulative lung dose had no pneumonitis, so the limits are conservative (Leung 1995; Salem 2008).
  • Non-target embolisation: radiation gastritis, gastroduodenal ulcer and bleeding, pancreatitis and cholecystitis. Sudden severe abdominal pain during or soon after infusion needs bremsstrahlung or ⁹⁰Y PET imaging and serum amylase (US resin label).
  • Biliary: cholangitis or liver abscess, mainly after previous biliary intervention.
  • Hold or stop: do not treat, or treat more selectively, when liver function deteriorates, gastrointestinal deposition cannot be corrected, or the cumulative lung dose would exceed 50 Gy.
Radiation protection & discharge
  • ⁹⁰Y is a pure beta emitter; the external dose rate from treated patients is low for all products, so isolation is not usually needed. ¹⁶⁶Ho gives a notably higher exposure rate after treatment (EANM 2022). Follow local release rules; in the USA, release is allowed if the dose to others is unlikely to exceed 5 mSv (10 CFR 35.75).
  • The main staff hazard is skin contamination during preparation and administration: use beta shielding, tongs and absorbent covers, and monitor hands.
  • Pregnancy and breastfeeding are absolute contraindications; avoid pregnancy for at least 4 months after treatment (EANM 2022).
  • Long-lived radionuclide impurities in the spheres matter for waste management but not for later surgery or biopsy (EANM 2022). Allow about 1 month of ⁹⁰Y decay before planned surgery (Levillain 2021).
  • Give the patient written instructions and a card stating the nuclide, activity and date. Medical emergencies take priority over radiation precautions.

References

  1. Weber M, Lam M, Chiesa C, Konijnenberg M, Cremonesi M, Flamen P, et al. EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds. Eur J Nucl Med Mol Imaging. 2022;49(5):1682-99.
  2. Levillain H, Bagni O, Deroose CM, Dieudonné A, Gnesin S, Grosser OS, et al. International recommendations for personalised selective internal radiation therapy of primary and metastatic liver diseases with yttrium-90 resin microspheres. Eur J Nucl Med Mol Imaging. 2021;48(5):1570-84.
  3. Salem R, Padia SA, Lam M, Chiesa C, Haste P, Sangro B, et al. Clinical, dosimetric, and reporting considerations for Y-90 glass microspheres in hepatocellular carcinoma: updated 2022 recommendations from an international multidisciplinary working group. Eur J Nucl Med Mol Imaging. 2023;50(2):328-43.
  4. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022;76(3):681-93.
  5. Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023;78(6):1922-65.
  6. Sirtex Medical. SIR-Spheres Y-90 resin microspheres: instructions for use (USA), SSL-US-14. December 2019.
  7. Biocompatibles UK (Boston Scientific). TheraSphere Yttrium-90 glass microspheres: instructions for use, PMA P200029, Rev. 1. March 2021.
  8. Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH). Lancet Oncol. 2017;18(12):1624-36.
  9. Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, et al. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018;36(19):1913-21.
  10. Garin E, Tselikas L, Guiu B, Chalaye J, Edeline J, de Baere T, et al. Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01). Lancet Gastroenterol Hepatol. 2021;6(1):17-29.
  11. Garin E, Tselikas L, Guiu B, Chalaye J, Rolland Y, de Baere T, et al. Long-term overall survival after selective internal radiation therapy for locally advanced hepatocellular carcinomas: updated analysis of DOSISPHERE-01 trial. J Nucl Med. 2024;65(2):264-9.
  12. Salem R, Johnson GE, Kim E, Riaz A, Bishay V, Boucher E, et al. Yttrium-90 radioembolization for the treatment of solitary, unresectable HCC: the LEGACY study. Hepatology. 2021;74(5):2342-52.
  13. Lam M, Garin E, Maccauro M, Kappadath SC, Sze DY, Turkmen C, et al. A global evaluation of advanced dosimetry in transarterial radioembolization of hepatocellular carcinoma with yttrium-90: the TARGET study. Eur J Nucl Med Mol Imaging. 2022;49(10):3340-52.
  14. van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, et al. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016;34(15):1723-31.
  15. Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017;18(9):1159-71.
  16. Mulcahy MF, Mahvash A, Pracht M, Montazeri AH, Bandula S, Martin RCG, et al. Radioembolization with chemotherapy for colorectal liver metastases: a randomized, open-label, international, multicenter, phase III trial. J Clin Oncol. 2021;39(35):3897-907.
  17. Smits ML, Nijsen JF, van den Bosch MA, Lam MG, Vente MA, Mali WP, et al. Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study. Lancet Oncol. 2012;13(10):1025-34.
  18. Sangro B, Gil-Alzugaray B, Rodriguez J, Sola I, Martinez-Cuesta A, Viudez A, et al. Liver disease induced by radioembolization of liver tumors: description and possible risk factors. Cancer. 2008;112(7):1538-46.
  19. Leung TW, Lau WY, Ho SK, Ward SC, Chow JH, Chan MS, et al. Radiation pneumonitis after selective internal radiation treatment with intraarterial 90yttrium-microspheres for inoperable hepatic tumors. Int J Radiat Oncol Biol Phys. 1995;33(4):919-24.
  20. Salem R, Parikh P, Atassi B, Lewandowski RJ, Ryu RK, Sato KT, et al. Incidence of radiation pneumonitis after hepatic intra-arterial radiotherapy with yttrium-90 microspheres assuming uniform lung distribution. Am J Clin Oncol. 2008;31(5):431-8.
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