European Nuclear Medicine Guide
Radiopharmaceutical: [166Ho] microspheres
Nuclide: 166Ho is a beta-emitting radionuclide with a physical half-life of approximately 1.1 days (26.8 hours). It emits beta radiation with an energy of 1.85 MeV (50% yield) and 1.77 MeV (49% yield), achieving a maximum tissue penetration of about 8.7 mm (mean 2.2 mm). Additionally, 166Ho emits gamma photons at 81 keV (6.6% yield), which are suitable for dosimetry purposes on post-treatment imaging with a SPECT/CT camera [17]. Furthermore, as a paramagnetic lanthanide, it also allows MRI-based imaging and absorbed dose estimations [18,19].
Administration:
[166Ho]-microspheres are administered via injection into the hepatic artery for whole-liver treatment or into 1–3 branches for lobar therapy, radiosegmentectomy, or direct tumour therapy.
Selective internal radiotherapy (SIRT), also known as trans-arterial radioembolization (TARE), involves radiolabelled microspheres that embolize and deliver localized radiation to tumours.
Liver tumours are predominantly supplied by the hepatic artery, whereas normal liver tissue is mainly perfused by the portal vein. This physiological difference and the high vascularization of tumour tissue are leveraged to concentrate [166Ho]-microspheres in the tumour's microvasculature.
Whole-liver treatment or lobar therapy: Microspheres are infused into the hepatic artery or its branches, ensuring preferential tumor uptake.
Radiosegmentectomy and direct tumour therapy: A catheter selectively administers microspheres directly into tumour-feeding arteries, further increasing radiation concentration within the tumour.
Once embedded, high-energy beta emissions of 166Ho induce localized tumour cell apoptosis while sparing healthy liver tissue [17].
Candidates for [166Ho] microsphere therapy include patients with unresectable liver tumours, such as:
Primary liver cancers: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC)
Metastatic liver tumours: liver metastases from colorectal cancer, neuroendocrine tumours, breast cancer and other malignancies (under evaluation)
A recent arterial-phase abdominal CT scan is recommended for patient selection.
Potential treatment goals:
Palliative or curative therapy for unresectable primary or metastatic liver cancer
Neoadjuvant therapy to downstage tumours before resection
Liver segment hypertrophy induction (to promote future liver remnant growth)
Bridging therapy before liver transplantation [17]
The latest update to the BCLC recommendations advocates early usage in BCLC-0 patients with a single nodule of up to 8 cm diameter [20]. Furthermore, the promising clinical application of SIRT may shape therapy regimens in the future. For example, promising results combining peptide receptor radionuclide therapy (PRRT) and SIRT are reported [21].
[166Ho] microsphere therapy exclusion criteria are like those for [90Y] microspheres.
Absolute contraindications:
Pregnancy or breastfeeding
Life expectancy <3 months
Clinical liver failure (i.e. ascites, icterus, encephalopathy)
Relative contraindications:
Child-Pugh >B7 (severe liver dysfunction)
Extensive intrahepatic tumour burden (treatment may require staged administration)
Significant or progressive extrahepatic disease
Severe renal impairment (creatinine clearance <30 mL/min)
Severe pulmonary disease
Contraindications to catheterization (e.g., unmanageable coagulation disorders, severe renal failure, contrast media allergy, vascular abnormalities)
Abnormal vascular anatomy causing reflux of microspheres into the stomach, pancreas, or bowel (assessed via angiography)
Lung shunting >20% of hepatic arterial blood flow (determined via pre-treatment imaging)
Predicted absorbed lung dose exceeding 30 Gy per session or >50 Gy cumulatively (assessed using 99mTc-MAA scintigraphy)
Following detailed angiographic planning, a treatment plan is established to identify the targeted structures. An angiographic catheter must be positioned according to the selected treatment targets, which may include the whole liver, specific segments, or the tumour itself. If necessary, coiling of extra-hepatic shunts is performed to prevent unintended distribution.
SIRT follows a two-step approach. Before the therapeutic administration, a scout sequence (preSIRT) is conducted to evaluate the safety of subsequent therapeutic doses and to enable precise dosimetry. This preSIRT phase involves the administration of a preliminary dose of 250 MBq of [166Ho] microspheres, which may be delivered through up to three different catheter positions.
Post-injection SPECT/CT or MRI imaging are utilized to confirm microsphere distribution and prospective tumour and liver dose. Lung shunt fraction and intestinal drainage are measured, ensuring minimal side risks.
1–2 weeks later, subsequent therapeutic administration of [166Ho] microspheres is performed after placing the catheter in identical position(s) to those used during preSIRT [19]. The infusion is administered at a controlled rate (≤5 mL/min) as a series of small microboluses, with intermittent angiographic verification of arterial flow to ensure patency and consistent microsphere deposition.
In patients with reduced hepatic or renal function, hospitalization to administer adequate hydration as well as post-therapeutic surveillance may be feasible for about 24 hours after treatment. To avoid dead time issues, post-therapeutic scans are recommended to be performed 2 to 5 days after SIRT, but not more than 6 days after the procedure.
Advanced imaging techniques such as SPECT/CT and MRI enable precise dosimetry calculations based on the assumption that the microspheres are trapped and only physical decay of radioactivity occurs. Utilizing multicompartmental and voxel-based models, dosimetry is vital in individualized therapy planning. It ensures that each tumour receives a minimum absorbed dose of 60 Gy (preferably significantly higher with curative intention, sometimes reaching several hundred Gy) while sparing healthy liver tissue from excessive radiation exposure (ideally much lower than 60 Gy).
On a patient-by-patient basis using both multicompartmental and voxel-based advanced dosimetry models, the necessary therapeutic activity is determined by a vendor-specific program to optimize tumour dose. In the same step, possible side effects resulting from radioembolization of lung or intestine are evaluated.
[166Ho] microspheres have the distinct advantage of being the same size in preSIRT and SIRT, hence improving absorbed dose accuracy. Additionally, the emitted gamma ray photons facilitate precise dosimetry and reliability. Other SIRT-compound procedures follow a scouting process employing macroaggregated albumin, thereby rendering the process less accurate due to differences in activity distribution in pre-diagnostic vs. diagnostic imaging. Post-therapy dosimetry is also facilitated with 166Ho due to gamma ray emission and MRI-enabling properties [22]. Therefore, individual prediction of absorbed doses is expected to be highly reliable in 166Ho SIRT.
While the majority of effectiveness studies focus on [90Y] microspheres, research on 166Ho remains relatively scarce. Respective clinical studies indicate that [166Ho] SIRT leads to significant tumour response rates, extended progression-free survival, and improved overall survival, especially when lesion-specific dosimetry is employed. The preliminary scout dose approach has been instrumental in refining treatment accuracy and optimizing therapeutic outcomes [17]. It has also been demonstrated that treatment response and overall survival are influenced by the absorbed dose of [166Ho] microspheres [23,24].
Common side effects include transient post-embolization symptoms such as fatigue, abdominal discomfort/pain, nausea, and fever. Transient elevation of liver enzymes may occur. Severe complications, including radiation-induced liver disease, gastrointestinal ulceration, upper gastrointestinal bleeding, pancreatitis or radiation pneumonitis, are rare and generally associated with high tumour load or significant intestinal or lung shunt fractions, respectively. To mitigate risks, prophylactic measures such as adequate hydration, corticosteroids, and proton pump inhibitors are routinely recommended. Use of analgesics and prophylactic application of antibiotics to curb opportunistic hepatic inflammation may be considered.
[166Ho] microspheres have been approved for treating primary and metastatic liver tumours in several European countries. The therapy is CE-marked, but not cleared by the FDA. Individualized dosimetry and the use of scout dose techniques enhance treatment precision and patient outcomes considerably, and are recommended whenever available.