# Y-90 Radioembolization for Hepatic Malignancies

## Introduction

Yttrium-90 (Y-90) radioembolization, also called selective internal radiation therapy (SIRT), delivers high-dose radiation directly to hepatic tumors via the hepatic arterial supply using Y-90-labeled microspheres. This locoregional therapy exploits the dual blood supply of the liver: tumors derive more than 90% of their blood supply from the hepatic artery, while normal parenchyma is predominantly supplied by the portal vein. Y-90 radioembolization is an established treatment for unresectable hepatocellular carcinoma (HCC) and liver-dominant colorectal cancer metastases.

## Y-90 Radiophysics

### Yttrium-90 Properties

Y-90 is a pure beta emitter with no gamma photons, meaning there is minimal external radiation hazard. The maximum beta energy is 2.28 MeV with a mean of 0.93 MeV. Maximum tissue penetration is 11 mm with a mean of 2.5 mm, confining the therapeutic radiation to the immediate vicinity of the lodged microsphere. The physical half-life is 64.1 hours (2.67 days), and greater than 90% of the dose is delivered within 11 days.

### Microsphere Products

Two products are commercially available. Glass microspheres (TheraSphere) are 20-30 micrometers in diameter with high specific activity per sphere. Resin microspheres (SIR-Spheres) are 20-60 micrometers with lower specific activity, requiring more spheres per treatment. Both are permanently implanted and lodge in the tumor microvasculature. Unlike chemoembolization, Y-90 microspheres are not truly embolic at therapeutic doses.

| Feature | Glass (TheraSphere) | Resin (SIR-Spheres) |
|---|---|---|
| Diameter | 20–30 μm | 20–60 μm |
| Specific activity | High (~2,500 Bq/sphere) | Low (~50 Bq/sphere) |
| Spheres per treatment | ~1–8 million | ~40–80 million |
| Embolic effect | Minimal | Mild |
| Primary dosimetry | Partition model (MIRD) | BSA method or partition model |
| FDA-approved indications | HCC, metastatic CRC | Metastatic CRC |

## Patient Selection and Workup

### Indications

Y-90 radioembolization is indicated for unresectable HCC (all BCLC stages except terminal), colorectal cancer liver metastases refractory to or intolerant of systemic chemotherapy, neuroendocrine tumor liver metastases, intrahepatic cholangiocarcinoma, and liver-dominant metastatic disease from other primaries including breast cancer and melanoma.

### Contraindications

Absolute contraindications include a hepatopulmonary shunt fraction exceeding 20% or a projected lung dose exceeding 30 Gy per treatment, inability to prevent Y-90 deposition in the gastrointestinal tract via extrahepatic arterial supply, and severe hepatic insufficiency (bilirubin greater than 2 mg/dL in HCC or greater than 3 mg/dL in metastatic disease). Portal vein thrombosis with hepatofugal flow is a relative contraindication, though main portal vein thrombosis may be acceptable in some cases. Poor performance status (ECOG greater than 2) generally precludes treatment.

![Patient selection algorithm for Y-90 radioembolization based on tumor type and hepatic function](images/y90-patient-selection-algorithm.png)

## Pre-Treatment Planning

### Mapping Angiography

Visceral angiography is performed 1-2 weeks before treatment to identify hepatic arterial anatomy and variants. Prophylactic coil embolization of extrahepatic vessels -- including the gastroduodenal artery, right gastric artery, and falciform artery -- prevents non-target microsphere deposition in the stomach, duodenum, and abdominal wall.

### Tc-99m MAA Simulation

Tc-99m macroaggregated albumin (MAA) is injected via the same catheter position planned for Y-90 delivery. MAA particles serve as a surrogate for microsphere distribution. Subsequent planar imaging and SPECT/CT calculate the hepatopulmonary shunt fraction (lung counts divided by lung plus liver counts, multiplied by 100), identify any extrahepatic gastrointestinal deposition (an absolute contraindication if not correctable by coil embolization), and estimate the tumor-to-normal-liver ratio for dosimetry.

### Dosimetry Methods

The partition model (MIRD-based) calculates dose to tumor, normal liver, and lungs based on the MAA distribution. Target tumor doses are typically 100-150 Gy for HCC and 60-80 Gy for metastases. Normal liver tolerance is less than 40 Gy to uninvolved parenchyma. Lung dose limits are less than 30 Gy per treatment and less than 50 Gy cumulatively. The body surface area (BSA) method is used primarily for resin microspheres. Personalized dosimetry using MAA SPECT/CT is increasingly adopted because it produces improved outcomes compared to empiric dosing.

## Treatment Procedure

### Day of Treatment

A catheter is placed in the same arterial position confirmed during mapping angiography. Catheter position is verified with contrast angiography. Y-90 microspheres are administered slowly under fluoroscopic guidance. Because Y-90 is a pure beta emitter, the radiation is contained within the patient and there is no significant external hazard. The procedure is performed on an outpatient basis, with same-day discharge. No radiation isolation is required.

### Post-Treatment Imaging

Y-90 PET/CT is the preferred method for confirming microsphere distribution. Although Y-90 has an extremely low positron emission branching ratio (0.0032%), the ultra-high activity delivered during therapy produces sufficient coincidence events for PET imaging. Bremsstrahlung SPECT is an alternative but offers inferior spatial resolution. Post-treatment imaging verifies tumor targeting, excludes non-target deposition, and enables post-treatment dosimetry that correlates with response.

![Post-treatment Y-90 PET/CT showing microsphere distribution concentrated within hepatic tumor](images/y90-pet-ct-post-treatment.png)

## Clinical Outcomes

### Hepatocellular Carcinoma

Tumor response rates range from 40-70% by mRECIST criteria. Median overall survival is 15-20 months depending on stage and liver function. Y-90 can downstage patients to surgical resection or transplant eligibility. Radiation lobectomy -- where unilobar treatment induces contralateral lobe hypertrophy -- can convert previously unresectable patients to surgical candidates. The SARAH and SIRveNIB trials demonstrated non-inferiority to sorafenib in advanced HCC.

### Colorectal Cancer Liver Metastases

The SIRFLOX, FOXFIRE, and FOXFIRE-Global trials showed that adding Y-90 to first-line chemotherapy improved liver-specific progression-free survival but did not demonstrate an overall survival benefit. The primary role of Y-90 in colorectal metastases is therefore in chemorefractory or salvage settings.

### Neuroendocrine Tumor Liver Metastases

Tumor response rates of 50-60% are achieved with symptom palliation in more than 80% of patients. Hepatic progression-free survival is prolonged in well-differentiated NETs. Y-90 represents an alternative to hepatic artery embolization and PRRT for liver-dominant disease.

## Complications

### Post-Radioembolization Syndrome

Fatigue is the most common side effect, occurring in 50-70% of patients, accompanied by low-grade fever and nausea. The syndrome is self-limited, resolving within 1-2 weeks, and is managed with supportive care and short-course antiemetics.

### Serious Complications

Radiation-induced liver disease (RILD) occurs in 0-4% and presents with jaundice and ascites 4-8 weeks post-treatment. GI ulceration results from non-target microsphere deposition and is preventable with proper mapping and coil embolization. Radiation pneumonitis from excessive hepatopulmonary shunting is rare with proper dosimetry. Biliary complications (stricture, biloma) are more common after repeated treatments. Lymphopenia is common but usually self-limited.

## Emerging Directions

Radiation segmentectomy delivers ultra-selective treatment to single-segment tumors with high doses exceeding 200 Gy, achieving near-complete pathologic necrosis. The DOSISPHERE-01 trial demonstrated that personalized dosimetry based on MAA SPECT/CT, targeting more than 200 Gy to tumor, significantly improves objective response rates compared to empiric dosing. Combination with immunotherapy (checkpoint inhibitors) shows potential synergy. Y-90 as a bridge to transplant or resection is well established. Ho-166 microspheres offer an alternative with gamma emissions enabling real-time SPECT dosimetry during treatment.

![Pre-treatment Tc-99m MAA SPECT/CT and post-treatment Y-90 PET/CT comparison showing concordant microsphere distribution](images/y90-maa-pet-comparison.png)

## Clinical Pearls

Tc-99m MAA simulation is mandatory before Y-90 therapy to calculate the hepatopulmonary shunt fraction (must be less than 20%) and to exclude extrahepatic GI deposition that could cause radiation ulceration. Y-90 is a pure beta emitter with a mean tissue penetration of 2.5 mm, meaning there is no significant external radiation hazard and patients can be discharged on the day of treatment without radiation isolation. Personalized dosimetry using MAA SPECT/CT partition modeling, targeting more than 200 Gy to tumor, improves objective response rates compared to empiric dosing as demonstrated by the DOSISPHERE-01 trial. Radiation lobectomy, where unilobar Y-90 treatment induces contralateral lobe hypertrophy, can convert unresectable HCC patients to surgical candidates.

## References

1. Salem R, et al. "Y90 Radioembolization Significantly Prolongs Time to Progression Compared with Chemoembolization in Patients with Hepatocellular Carcinoma." *Gastroenterology*. 2016;151(6):1155-1163.
2. Vilgrain V, 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): An Open-Label Randomised Controlled Phase 3 Trial." *Lancet Oncol*. 2017;18(12):1624-1636.
3. Garin E, 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.
4. Kennedy A, et al. "Recommendations for Radioembolization of Hepatic Malignancies Using Yttrium-90 Microsphere Brachytherapy: A Consensus Panel Report." *Int J Radiat Oncol Biol Phys*. 2007;68(1):13-23.