Yttrium-90 Microsphere Therapy

Indication

Y-90 microsphere therapy, also known as transarterial radioembolization (TARE), is indicated for the treatment of inoperable primary and metastatic liver cancers.

What Is Yttrium-90 Microsphere Therapy?

Theranostics is a recently developing field of the medicine. This approach takes body images using a tumor-specific agent to locate the tumor and its metastasis and their potential future locations and it also uses a specific agent with pre-determined therapeutic efficiency for the diseased tissue. This approach enables switching from traditional medicine to contemporary personalized medical procedures.

Regarding liver cancers, 99mTc-MAA liver perfusion scan allows for a pre-treatment trial, helps us plan the optimal dose of treatment and detects pulmonary and gastrointestinal shunts with high sensitivity. On the other hand, tumor tissues can be treated with a targeted therapy approach with Yttrium-90 (Y-90) microsphere. This is a rather new and successful method of theranostic procedures.

How Does Yttrium-90 Microsphere Therapy Work?

If therapeutic agent is applied into the hepatic artery, we have some advantages, as the liver has dual blood supply and 80 to 90% of tumors measuring larger than 3 mm in diameter are fed by the hepatic artery. On the other hand, healthy hepatic parenchyma is mainly fed by the portal vein. For more than 3 decades, this variation has been used when chemotherapy agents are administered through intra-arterial pumps and for tumor embolization. Y-90 microsphere therapy, also called Transarterial Radioembolization (TARE), is an effective treatment for both primary and metastatic malignancies of the liver, and it may be used for better survival and for decreasing the burden in patients for whom surgery or other regional therapies are contraindicated.

This specific vascularization pattern of liver tumors enables quite selective tumor uptake when radioactive particles are infused into the hepatic artery. However, liver metastases can have variable vascularities ranging from avascular hepatic cysts to hypovascular metastatic lesions (colon, pancreas, breast cancer etc.) and hypervascular metastases (renal, neuroendocrine, thyroid cancer etc.). For selective applications, small-sized particles balance the relative “hypovascularity” of metastatic tumors; as a result, the dose absorbed by healthy parenchyma is kept at relatively low levels while metastatic lesions are exposed to high radiation.

Y-90 emits beta-radiation with average 0.94 MeV energy and leads to cell death and tumor necrosis in tumor region. Tissue penetration of Y-90 isotope, which has a half-life of approximately 64 hours, is nearly 1 cm and this short-range limits the radiation exposure to neighboring parenchyma for the benefit of the patient. The advantage of intraarterial infusion of radioactive particles containing Y-90 is less radiation exposure for healthy hepatic parenchyma compared to systemic radiation and delivery of the lowest possible radiation dose to the targeted tumor. In addition, limited tissue penetration makes the patient safer for medical personnel and family members of the patient.

Y-90 Microspheres

Resin microspheres (SIR-Spheres®) are acrylic polymer microspheres measuring 20 to 60 μm in diameter and Y-90 binds to carboxylic group of the polymer after microspheres are prepared.

Glass microspheres (TheraSphere®) have an average size of 20-30 μm; here, 89Y embedded in glass matrix is activated to Y-90 in a nuclear reactor.

The principal difference between glass and resin spheres is the radioactivity varying for each sphere. Radioactivity level is approximately 2.500 Bq in a glass sphere while the figure is approximately 50 Bq in a resin sphere. On the other hand, total radioactivity dose for each commercially available vial is 3-20 GBq for glass microspheres (6 different dose options) and 3 GBq for resin microspheres. Smaller glass microspheres are injected for the targeted activity while probably there is less embolic effect on microcirculatory vessels. Besides, more homogeneous dose distribution and higher biological effect (toxicity and effectiveness) can be potentially achieved with a higher number of resin spheres for the same activity.

166Ho Microspheres

Holmium-166 (166Ho) microspheres (QuiremSpheres®) are poly-l-lactic acid based microspheres that measure 25-35 μm. They have a similar mechanism of action with Y-90 based microspheres and damage the tumor tissue with beta radiation emitted by 166Ho. In addition, 166Ho allows scintigraphic imaging with gamma radiation it generates while MRI can also be scanned as it is quite a paramagnetic element. Today, 166Ho microspheres are not used as commonly as Y-90 based microspheres.

Who is Eligible for Yttrium-90 Microsphere Therapy?

Y-90 microsphere therapy is employed for inoperable primary and metastatic liver cancers.

Hepatocellular Carcinoma (HCC)

For HCC, use of systemic chemotherapy and external radiotherapy is restricted as response rates are low, there are many side-effects and radiosensitive healthy hepatic parenchyma can be easily damaged even with therapeutic doses.

Surgery is a traditional treatment option for localized HCC. However, while some patients are not eligible for surgery, others already have multifocal/bilobar disease at the admission. As HCC is radiosensitive, intraarterial Y-90 microsphere therapy can be successfully used for these cases.

Initial outcomes obtained in case of inoperable HCC cases have demonstrated improvement in tumor vascularity and survival. Subsequent studies compared Y-90 microsphere therapy to other local therapies, such as transarterial coembolization or ablation, for localized diseases and they demonstrated comparable success of treatment.

Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary malignancy of liver. Inoperable cases have poor prognosis. Combined chemotherapy (gemcitabin and cisplatin) may prolong overall survival that is usually associated with systemic toxicity. Cholangiocarcinoma is also a radiosensitive tumor and prolonged median survival associated with limited side-effect can be achieved with palliative Y-90 microsphere.

Colorectal Cancers

Colorectal cancer is globally one of the most common malignancies and the main target of metastasis is liver due to portal venous drainage. Currently, standard treatment method for colorectal cancer is a chemotherapy regime consisting of fluorouracil, leucovorin and oxaliplatin (FOLFOX); besides, combination with Y-90 microsphere therapy can be helpful especially for patients who are refractory to chemotherapy.

Neuroendocrine Tumors (NETs)

Neuroendocrine tumors imply a wide range of malignancies which generally originates from digestive system. Similar to colorectal cancers, they frequently metastasize to liver due to portal venous drainage. Palliative treatment of hepatic metastases with intraarterial embolization without radiotherapy is an option for patients with quite diffuse metastases that are not eligible for surgical resection. Furthermore, as neuroendocrine tumors are radiosensitive, Y-90 microsphere therapy can be successfully employed for those patients.

Down-Staging before Resection or Liver Transplantation

Y-90 microsphere therapy can be used as neoadjuvant treatment to make patients with HCC, metastatic colorectal cancer and cholangiosarcoma operable. Moreover, radioembolization with Y-90 microsphere can be utilized to pave the way for liver transplantation by decreasing tumor burden and decelerate progression of the disease.

Radiation Segmentectomy

For patients with a liver disease confined to one segment and for those who are not eligible for other curative therapies, it is based on the principle of delivering radiation at a higher dose to cure the tumor and resultant radiation necrosis of the segment. Radiation segmentectomy can be employed for malignant diseases that involve only one segment or a part of the segment and when Y-90 microspheres can be infused solely through the artery that feeds the segment.

Is Yttrium-90 Microsphere Therapy Safe?

Y-90 microsphere therapy is a safe treatment that is typically well tolerated. Since Y-90 emits pure beta particles and does not cause gamma radiation, isolation of the patient is not necessary after the treatment.

The most common side-effect of Y-90 microsphere therapy is post-radioembolization syndrome which is characterized by tiredness, nausea, vomiting and/or abdominal pain. Those complaints can be treated with analgesic and anti-emetic drugs.

As is the case with all other minimally invasive hepatic procedures, perihepatic effusion and hepatic abscess can also be observed after this treatment.

Moreover, there are quite rarer side-effects which are listed below and are less likely when the treatment is given by experienced healthcare personnel.

Allergy secondary to use of the contrast agent, nephrotoxicity and vascular injuries may occur that can be faced during all angiographic procedures.

Although many measures are taken to ensure minimum dose exposure for intact liver tissue when doses are planned, variations in patient’s physiology can sometimes cause such complications like “radioembolization-induced liver disease”, hepatic fibrosis and portal hypertension. This risk is higher for patients who receive more than one microsphere therapy or external radiotherapy.

Biliary system is also a potential region of complication in Y-90 microsphere therapy due to close proximity.

Complications such as cholecystitis, duodenal ulcer, pancreatitis, radiation pneumonia and radiation-induced dermatitis on abdominal wall are quite likely secondary to non-targeted radioembolization. These complications can be prevented with prophylactic embolization of relevant blood vessels while an angiogram or suitable catheterization techniques are planned.

Preparation before Yttrium-90 Microsphere Therapy

Patients who are eligible for Y-90 microsphere therapy are selected by a multidisciplinary tumor council consisting of General Surgeon, Medical Oncologist, Gastroenterologist, Interventional Radiologist and Nuclear Medicine Specialist.

Patient Selection

Patients who are eligible for Y-90 microsphere

Disease is located only or predominantly in the liver
Not suitable for surgical resection (inoperable)
Life expectancy > 3 months
ECOG performance score ≤ 2
Patient does not use Capecitabine therapy for more than 3 months

Patients who are not eligible for Y-90 microsphere

Pregnancy and lactation
Ascites or clinical picture of hepatic failure
Child-Pugh score > B7
Acute or severe chronic renal failure
Acute or severe chronic lung disease
AST/ALT > 5 x upper limit of normal
Serum albumin <3 g/dL
Total bilirubin >2 mg/dL
Hepatopulmonary shunt >20% (when the lung dose to be delivered at a single time is >25 Gy for resin microsphere, >30 Gy for glass microsphere or when a cumulative dose is >50 Gy)
History of external radiotherapy to liver
Hepatic tumor load > 60%
Gastrointestinal shunt that cannot be repaired with angiographic techniques
Use of Bevacizumab

ECOG Performance Scale

0	Fully active, able to carry on all pre-disease performance without restriction.
1	Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. e.g., light house work, office work.
2	Ambulatory and capable of all self-care but unable to carry out any work-related activities; up and about more than 50% of waking hours.
3	Capable of only limited self-care; confined to bed or chair more than 50% of waking hours.
4	Completely disabled; cannot carry on any self-care, totally confined to bed or chair.

Child-Pugh Scoring

	1 point	2 points	3 points
Total Bilirubin (mg/dL)	<2	2-3	>3
Albumin (g/dL)	>3,5	2,8-3,5	<2,8
INR or PT	<1.7 or 1-4 s	1.7-2.2 or 4-6 seconds	>2.2 or >6 seconds
Ascites	None	Mild	Severe
Hepatic encephalopathy	None	Grade 1-2	Grade 3-4

Classification	Child – Pugh A	Child – Pugh B	Child – Pugh C
Total Score	5-6	7-9	10-15

Defining Severity of Ascites

Grade 1	Ascites that cannot be defined during physical examination and can only be detected with ultrasound
Grade 2	Ascites that is detectable as a symmetric bulging in abdomen
Grade 3	Ascites that form a remarkable bulging and tenderness in abdomen

Grading Hepatic Encephalopathy

Grade 1	Personality changes, poor attention and concentration, altered sleep pattern, slowing in mental tests
Grade 2	Lethargy, apathy, confusion, disordered time and place orientation (intermittent).
Grade 3	Agitation, aggressive behavior, confusion, severer and continuous time and place disorientation, worsened lethargy, ability to answer simple verbal questions.
Grade 4	Severe lethargy, responsive to painful stimuli while unresponsiveness develops gradually. Signs of cerebral edema can be seen in acute forms.

Pre-treatment Imaging

MRI, CT, 18F-FDG PET/CT

Hepatic and extra-hepatic disease is evaluated.

Angiogram

To plan and administer Y-90 microsphere therapy,
To evaluate the tumor, its feeders and the anatomy of mesenteric and hepatic artery,
For determining and performing coil embolization for extrahepatic accessory/collateral vessels especially gastroduodenal, cystic and right gastric arteries originating from branches of the hepatic artery that feeds the tumor.

99mTc-MAA Liver Perfusion Scan & Vascular Mapping with SPECT/CT

For simulating distribution of Y-microsphere in tumor and healthy liver tissues,
For planning the Y-90 microsphere therapy,
For measuring the hepatopulmonary shunt ratios (increasing due to current or underlying cirrhosis),
For demonstrating the flow towards extrahepatic organs.

Supraumbilical subcutaneous soft tissue leakage can be observed in liver perfusion scan. Should leakage into anterior abdominal wall be detected; vasospasm with cold compress on anterior abdominal wall is recommended during treatment in order to eliminate post-treatment subcutaneous inflammation and radiation damage.

Imaging should be performed within the first 1 hour after 99mTc-MAA is infused. Thus, image artifacts secondary to in-vivo fragmеntation can be minimized.

99mTc- MAA Liver Perfusion Scan – Quantitative Measurements

Tumor/Liver uptake ratio = [Tumor count (count/pixel)]/[Liver count (count/pixel)] threshold value >2.

Hepatopulmonary shunt ratio = √[(Anterior Pulmonary Count) x (Posterior Pulmonary Count)] / √[(Anterior Pulmonary Count + Anterior Hepatic Count) x (Posterior Lung count + Posterior hepatic Count)] x100

Calculating Y-90 Microsphere Dose

For glass microspheres, the dose can be calculated with software that is developed by predicting the volume of hepatic lobe/segment to be treated, ratio of hepatopulmonary shunt and mean dose of 120 Gy to be delivered to the tissue.

For resin microsphere, body surface area method or partition method can be used. For body surface area, patient’s body surface area and volume of tumor and liver are used. Partition method is based on the “medical internal radiation dose” (MIRD) and calculation is done using the volume of tumor and non-tumoral hepatic tissue, activity uptake rates and ratios of hepatopulmonary shunt.

Dose Modification Based on Hepatopulmonary Shunt Ratio in Treatment with Y-90 Resin Microspheres

Hepatopulmonary Shunt Ratio	Y-90 Microsphere Dose to Be Administered
<10%	Standard dose is administered.
10-15%	Dose is decreased by 20%.
15-20%	Dose is decreased by 40%.
>20%	Treatment is not applied.

How is Yttrium-90 Microsphere Therapy Applied?

Procedure

Y-90 microsphere is infused through a catheter that is inserted into the hepatic artery. Microspheres prepared at appropriate doses are placed into application kits provided by the manufacturer company and next, the preparation is slowly infused through the catheter by an interventional radiologist at angiography unit. The treatment can usually be administered into a single lobe, a single segment or subsegmentally into the blood vessel that feeds the tumor depending on spread of disease and arterial vascularization. It is necessary to pay attention to satellite nodules in case of subsegmental practices.

Y-90 Microsphere Imaging After Therapy (Bremsstrahlung Scintigraphy and SPECT/CT or Y-90 PET/CT)

It is used to identify uptake locations of Y-90 microspheres, evaluate Y-90 microsphere uptake in non-targeted regions such as lungs and gastrointestinal system and determine the tumor dose.

Y-90 microsphere therapy is a day procedure. However, patients are generally followed up at inpatient settings for a night due to associated comorbidities. Analgesic, antipyretic and antiemetic drugs, proton pump inhibitors and steroids can be used on the day of treatment, when necessary, for prophylactic or symptomatic treatment.

Follow-up

Week 2	Physical examination and blood tests (complete blood count, hepatic function tests)
Months 1-3	Imaging to evaluate response to therapy; FDG PET/CT, MRI etc.
Month 6	Imaging to evaluate response to therapy; FDG PET/CT, MRI etc.