What is Yttrium‑90 (Y‑90) radioembolization therapy for hepatocellular carcinoma?

Yttrium-90 (Y-90) Radioembolization for Hepatocellular Carcinoma

Yttrium-90 radioembolization (TARE) is a locoregional therapy that delivers radioactive microspheres directly into hepatic arteries feeding HCC tumors, providing targeted radiation while sparing healthy liver parenchyma through preferential arterial tumor blood supply. 1, 2, 3

Mechanism and Technical Overview

TARE involves transarterial injection of micron-sized particles (glass-based TheraSphere® or resin-based SIR-Spheres®) loaded with Yttrium-90, a beta-emitting radioisotope that delivers high-dose radiation (typically 100-150 Gy to tumor) with minimal penetration depth (2.5 mm mean tissue penetration). 2, 3, 4

Key Technical Principles

• The procedure exploits the dual blood supply of the liver: tumors derive 80-100% of blood from hepatic arteries, while normal parenchyma receives 70-80% from portal venous flow, allowing selective tumor irradiation 2, 3

• Super-selective catheterization through tumor-feeding arteries is mandatory to maximize tumor dose and minimize radiation-induced liver disease (REILD) 5

• Pre-treatment technetium-99m macroaggregated albumin (MAA) scan is essential to calculate lung shunt fraction (must be <20% to avoid radiation pneumonitis) and identify extrahepatic deposition risk 2, 4

Clinical Indications and Patient Selection

Primary Indications (Based on 2025 EASL Guidelines)

TARE is recommended for unresectable HCC patients with Child-Pugh A liver function (or favorable B7), ECOG performance status 0-1, and any of the following scenarios: 1, 5

• Solitary tumors >6 cm where ablation is not feasible 1, 5
• Segmental or subsegmental portal vein thrombosis (a key advantage over TACE) 1, 5, 6
• Multifocal disease confined to liver with preserved function 5
• TACE refractoriness after 2-3 failed sessions 1, 5, 6
• Bridge to transplantation or downstaging to transplant criteria 1, 7

Optimal Patient Profile

• Child-Pugh A liver function (selected Child-Pugh B7 without ascites may be considered) 1, 5
• ECOG performance status 0-1 1, 5
• Tumor burden localized to allow adequate future liver remnant 1, 5
• ALBI grade 1-2 predicts better outcomes and lower decompensation risk 5

Absolute Contraindications

Do not perform TARE in patients with: 1, 5, 6

• Decompensated cirrhosis (Child-Pugh C or decompensated B8-9)
• Complete main portal vein occlusion
• ECOG performance status ≥2
• Liver volume <1.5 L with inadequate functional reserve
• Tumor involvement >50% of liver volume
• Lung shunt fraction >20% on MAA scan
• Recent systemic therapy within 2 months
• Extensive extrahepatic metastases

Clinical Outcomes and Comparative Efficacy

Survival and Time to Progression

• Y90 radioembolization significantly prolongs time to progression compared with chemoembolization in HCC patients (median TTP 13.3 vs 8.4 months, p=0.046) 1

• The LEGACY study demonstrated median overall survival of 18.6 months in solitary unresectable HCC treated with radiation segmentectomy 1

• TARE achieves pathological complete necrosis in selected patients, particularly with personalized dosimetry approaches 1, 5

Advantages Over TACE

TARE offers superior quality of life and significantly lower post-embolization syndrome (PES) compared to TACE, with less nausea, fatigue, and abdominal pain. [1, @18@]

• Can be safely performed in patients with portal vein thrombosis (contraindication for TACE) 1, 5, 6
• Single-session treatment vs. multiple TACE sessions 1, 3
• Better tolerability in elderly patients and those with large tumors 1
• Lower hepatotoxicity when performed super-selectively 5

Comparative Effectiveness

• Network meta-analysis showed similar survival outcomes between TARE, TACE, RFA, and radiation therapy for local HCC treatment 1
• For tumors >6 cm, TARE demonstrates superior efficacy compared to smaller lesions due to radiation's ability to penetrate larger tumor volumes 5

Safety Profile and Complications

Common Side Effects

• Transient fatigue (most common, self-limited) 1, 2
• Mild abdominal discomfort 2, 3
• Low-grade fever 2
• Nausea (significantly less than TACE) 1

Serious Complications (Rare with Proper Technique)

Radiation-induced liver disease (REILD) occurs in 4-8 weeks post-procedure; risk factors include liver volume <1.5L, Child-Pugh B, tumor burden >50%, and bilateral whole-liver treatment. 1, 5

• Delayed hepatotoxicity may occur up to 6 months post-TARE 1, 8
• Radiation pneumonitis if lung shunt fraction >20% 2
• GI ulceration from non-target embolization (preventable with meticulous angiography) 1, 2
• Biliary injury and fibrosis 2

Critical Safety Measures

• Avoid bilateral whole-liver treatment—markedly increases decompensation risk 5
• Ensure tumor localization and adequate future liver remnant before proceeding 1, 5
• Perform super-selective catheterization to minimize REILD 5
• Screen for and treat esophageal varices before TARE in portal hypertension patients 5

Treatment Algorithm and Follow-Up

Pre-Treatment Workup

• Multiphasic contrast-enhanced CT or MRI for tumor characterization and volumetric analysis 5
• Comprehensive liver function panel: bilirubin, albumin, INR, calculate Child-Pugh and ALBI scores 5
• Baseline AFP measurement 5
• MAA scan with SPECT/CT to assess lung shunt and extrahepatic deposition 2, 4
• Upper GI endoscopy within 6 months if portal hypertension present 5
• Multidisciplinary tumor board confirmation of unresectability 5

Post-Procedure Monitoring

Follow this structured surveillance protocol: 8, 5

• Early imaging at 4-6 weeks: Contrast-enhanced CT/MRI with mRECIST criteria assessment
• Median time to tumor response is 6 months, with early favorable response visible at 4 months 8
• Serial AFP and PIVKA-II every 2-3 months for first year 8
• Liver function surveillance: Repeat Child-Pugh and ALBI scores to detect early decompensation 8
• REILD monitoring: Assess for ascites, jaundice, rising bilirubin between weeks 4-8 and up to 6 months 1, 8
• Long-term imaging: Every 3 months first year, then every 3-6 months if stable 8

Treatment Modification Criteria

Repeat TARE if: 8

• Residual tumor persists with localized disease
• Liver function remains Child-Pugh A
• No evidence of extrahepatic spread

Switch to alternative therapy if: 8, 6

• Progression to Child-Pugh B8 or higher
• ECOG deteriorates to ≥2
• Portal vein invasion develops → consider TACE plus external beam radiation 8
• Extrahepatic metastases emerge → transition to systemic therapy (atezolizumab-bevacizumab) 5, 6

Position in Treatment Hierarchy

The current evidence-based treatment algorithm for unresectable HCC is: 5, 6

1. First-line for intermediate-stage (BCLC B): TACE remains standard for Child-Pugh A, no portal vein thrombosis, tumor burden <4 nodules or <7 cm solitary 6

2. TARE as preferred alternative when:

   • Portal vein thrombosis present 1, 5, 6
   • Large tumor >6 cm 5, 6
   • TACE refractoriness after 2-3 sessions 1, 5, 6

3. Bridge to transplantation: TARE is effective for downstaging and maintaining transplant candidacy 1, 7

4. Radiation lobectomy/segmentectomy: Ablative-dose TARE can induce future liver remnant hypertrophy, enabling subsequent resection in select patients 1, 4

Common Pitfalls to Avoid

• Never treat patients with complete main portal vein occlusion—this is an absolute contraindication due to insufficient hepatic perfusion 5, 6

• Do not offer TARE to Child-Pugh B8-9 or C patients—high risk of fatal hepatic decompensation 1, 5

• Failure to identify lung shunt fraction >20% on MAA scan can result in fatal radiation pneumonitis 5, 2

• Attempting TARE in ECOG ≥2 patients provides no survival benefit and worsens quality of life 5

• Bilateral whole-liver treatment dramatically increases REILD risk and should be avoided 5