European Nuclear Medicine Guide
Radiopharmaceutical: [90Y]Y-microspheres [48].
Nuclide: Yttrium-90 is a β emitter, 2.2 MeV, with a half-life of 2.67 days. Absorbed radiation dose of 28 mGy MBq-1.
Activity: Patient specific.
Administration: injection into the hepatic artery.
Intra-arterial locoregional liver therapies have their rationale in the fact that liver lesions are fed mainly by the arterial stream, while normal parenchyma is supplied by portal vein blood flow. The [90Y]Y-microspheres become trapped in the liver capillaries, distribute according to vascularity, and ideally lodge in the arterioles in and around the tumours. Thus, a high local radiation absorbed dose is delivered while sparing the normal liver parenchyma.
General:
Relative:
The treatment includes preparatory angiography followed by treatment 1-2 weeks later. For both procedures, patients may be hospitalized on the day before angiography with adequate pre- and post-hydration considering the tendency for renal insufficiency in the cirrhotic patient with hyperdynamic circulation and the considerable amounts of contrast that may be administered. Patients are discharged approximately 24 h after the intervention unless complications occur.
During the preparatory procedure the patient is subjected to an angiography of the upper abdominal vessels. The coeliac trunk and upper mesenteric artery must be visualized followed by coiling of relevant (aberrant) vessels, especially branches of the coeliac axis supplying extra-hepatic tissue. After successful angiography and coiling of the relevant vasculature, the position of the catheter is documented and a test dose of 150 MBq [99mTc]Tc-MAA is injected into the hepatic arteries (note: for a selective approach the activity may be split). Directly after the procedure (within 60 min of administration), a SPECT/CT is acquired to determine the distribution to the lungs or other non-target organs (extra-hepatic deposition). Planar imaging of the thorax and abdomen is performed, as well as SPECT/CT of the abdomen (approximately 45 min acquisition time).
1-2 weeks following the preparatory angiography patients will receive the prescribed activity of [90Y]Y-microspheres. The catheter is positioned at exactly the same location as during the preparatory angiography to avoid technique-induced differences in biodistribution between the test dose and the therapeutic dose.
Prophylactic proton pump inhibition (e.g. pantoprazol 40 mg) is recommended, starting on the day of the preparatory procedure for a period of 6 weeks.
When extra-hepatic depositions are observed in stomach, duodenum or pancreas this should be monitored carefully during follow-up.
Tumour absorbed doses can vary widely and have been reported as high as 1000 Gy [175]. Dosimetry is simplified by the assumption that the microspheres are trapped so that only physical decay occurs.
Correlations between the absorbed doses delivered and toxicity and response have been reported both for hepatocellular carcinoma, colorectal metastases and intrahepatic cholangiocarcinoma [176–181]. The absorbed dose in tumour associated with improved outcome dependent on the used device (glass or resin labelled microspheres). For instance, improved survival was reported in HCC for tumour absorbed doses ≥ 205 Gy when using 90Y-labelled glass microspheres and ≥ 120 Gy when using 90Y-labelled resin microspheres [177,182].
With current recommendations dosimetry is often used as a basis for treatment planning, although methods for dose prescription vary. All vendors allow the determination of the therapeutic activity administration according to predictive dosimetry based on 99Tc-MAA SPECT/CT data assuming the MAA distribution in the targeted liver predicts the therapeutic 90Y microsphere activity distribution.
The accuracy with which a pre-therapy [99mTc]Tc-MAA study can predict the absorbed doses delivered at therapy has been reported with conflicting results. Standardization of PET imaging, and particularly for bremsstrahlung imaging with SPECT, is needed as is standardization of dosimetry procedures to facilitate direct comparisons of results obtained from different centres. Recent results from the prospective Dosisphere-01 trial outlined the promising indications of absorbed dose effect relationships for tumour response in HCC [183]. Furthermore, improved overall survival associated with personalized dosimetry was shown in ICC [184]. Indeed, more multicentre prospective studies are needed to extend the evidence of the benefits deriving from the dosimetry-based treatment personalization in all radioembolization procedures of hepatic malignancies in which different types of microspheres are used. A possible approach for treatment planning would consist on delivering the highest tolerable dose to healthy tissue aiming to maximize the treatment efficacy [185]. An EANM guidance document on recommended procedures for 99mTc-MAA pre- and 90Y post-therapy dosimetry is under evaluation.
Many studies already have demonstrated a competitive outcome of transarterial radioembolization (TARE) with respect to conventional treatment modalities, both in intermediate and advanced hepatocellular carcinoma (HCC) stages and metastases [186,187].
At present, Yttrium-90 radioembolization (RE) is indicated in a salvage setting only and when all other treatments (according to national guidelines) have failed. Alternatively, it may act as a bridge to liver transplant or as a bridge / adjunct to curative resection (i.e., radiation segmentectomy). Treatment in a first line setting in patients with liver metastasis of a colorectal carcinoma is currently under investigation.
Toxicity is of particular importance, as patient death from radioembolization-induced liver disease leading to liver failure can be a consequence of a standard treatment. Dosimetry for normal liver is performed from quantitative Technetium-99m, Yttrium-90 bremsstrahlung or Yttrium-90 PET imaging. Lung dosimetry is also of importance as this can cause severe toxicity and may also be performed with imaging, with suitable corrections for photon attenuation [188].
The common adverse events after administration of radioactive microspheres to the liver are fever, abdominal pain, nausea, vomiting and fatigue. These adverse events are all part of the so-called post-RE syndrome. An abnormality of liver function tests is also likely to occur. This may be up to grade 3 or 4 (CTCAE version 4.03) in the case of AST/SGOT and ALT/SGPT, without direct clinical relevance. In general, these effects are transient. The frequency of radiation hepatitis or RE-induced liver disease (REILD) is low (<5%) due to the inhomogeneous distribution of activity that may be anticipated. Veno-occlusive disease may occur following radiation damage to the central veins. This is caused by activation of the coagulation system probably by radiation-induced endothelial damage.
General prophylactic medication consists of pre- and post-hydration, corticosteroids (dexamethasone 10 mg i.v. 1 h before angiography), anti-emetics (ondansetron 8 mg i.v. 1 h before angiography).
The following effects are directly related to inadvertent deposition of the microspheres in organs other than the liver and should therefore be classified as technique related. The development of acute peptic ulceration (<5%) is suggested by the symptoms of ulceration and diagnosed by endoscopy. The post treatment SPECT/CT will determine if there are microspheres lodged in the pancreas or other organs, but additional tests such as serum amylase are also indicated if pancreatitis is suspected (<1%). High levels of implanted radiation and/or excessive shunting to the lungs may lead to radiation pneumonitis (<1%). This may be suspected if patients develop a non-productive cough several days or weeks after the implantation of the microspheres and is diagnosed by function tests and imaging. A rare complication is a radiation-induced cholecystitis (<1%). This side effect may be expected a few weeks after the intervention.
[90Y]Y-glass microspheres and [90Y]Y-resin microspheres are approved in the EU to treat liver primary tumours and liver metastases.