Microsphere radioembolization (RE) is applied increasingly in the management of patients with unresectable liver tumors. This type of internal radiation therapy deploys microspheres, loaded with the high-energy β-emitting radioisotope yttrium-90 (90Y, Emax = 2.280 MeV [I = 100.0%]), which are injected into the hepatic artery. The normal liver parenchyma is relatively sensitive to ionizing radiation Citation[1]. However, intra-arterial instillation via a catheter results in a preferential accumulation in the tumorous tissue because liver tumors are exclusively supplied by the hepatic artery, by contrast to normal liver tissue that receives its blood supply predominantly from the portal vein Citation[2]. If the radioactive microspheres are of the appropriate size, they will lodge in the tumors’ microvasculature and will subsequently deliver a high-radiation dose to the tumors.
Two types of 90Y-microspheres are currently in clinical use: TheraSphere® microspheres (MDS Nordion Inc., Kanata, Ontario, Canada), which have a glass matrix with a diameter of 25 ± 10 µm (mean ± SD), and the SIR-Spheres® (SIRTeX Medical Ltd., Sydney, New South Wales, Australia), which are resin-based microspheres and have a diameter of 32 ± 10 µm (mean ± SD). The glass microspheres (Y2O3–Al2O3–SiO2) are produced by forming a mixture of yttrium oxide, aluminum oxide and silicon oxide, which is melted at a temperature close to 1500°C. After cooling down, the glass is crushed into particles of a specific size. These particles are then melted again through a flame sprayer. The glass microspheres are obtained by surface tension. Subsequently, the 89Y glass microspheres are made radioactive by thermal neutron activation in a nuclear reactor Citation[3]. The resin microspheres are produced by tagging 90Y to preformed Aminex® resin (sulfonated divinylbenzene-styrene copolymer) microspheres (Bio-Rad Laboratories, Richmond, CA, USA) through ion exchange reaction. The 90Y is then precipitated inside the resin by washing with phosphate solutions, yielding insoluble 90Y-phosphate Citation[4].
Meanwhile, worldwide, over 15,000 90Y-RE treatments have been performed using either the resin or the glass microspheres. In the USA, the glass microspheres are approved by the US FDA as a humanitarian device for radiation treatment of unresectable hepatocellular carcinoma (HCC) or as a bridge to surgery or liver transplantation. SIR-Spheres® are FDA-approved for the treatment of colorectal cancer metastatic to the liver. In Europe, both microsphere products have a CE marking for the treatment of patients with either primary or metastatic liver cancer.
90Y-RE is generally well tolerated by patients and associated with high overall response rates, especially when used in the first-line setting and in conjunction with effective systemic treatment options Citation[5,6]. The effect on overall survival is not yet known but will obviously depend strongly on the type of cancer that is treated. Quite a few prospective trials are ongoing in which 90Y-RE is tested as a first-line treatment, mostly but not exclusively, for HCC and colorectal liver cancer.
An essential component for the safe use of 90Y-RE is the pretreatment angiography. During this procedure, the hepatic arterial system is minutely mapped out and branches that supply extrahepatic organs, such as the stomach, are occluded using coils Citation[7]. Subsequently, macroaggregated albumin particles labeled with technetium-99m (99mTc-MAA) are injected into the hepatic artery. γ-scintigraphy is performed to assess the biodistribution of the 99mTc-MAA, to assess whether isolation of hepatic flow has indeed been achieved and also to calculate the fraction of the 99mTc-MAA that has shunted to the lungs (if at all). Also, the intrahepatic distribution of the 99mTc-MAA, videlicet tumor-to-liver activity ratio, may be calculated. In principle, the 99mTc-MAA that are used should be a full rheological surrogate for the 90Y microspheres. However, it has been reported in the literature, and it is the authors’ experience as well, that 99mTc-MAA are in fact poor surrogates for the 90Y microspheres Citation[8]; in many cases, the 99mTc-MAA image does not correspond well with the post-90Y-RE Bremsstrahlung image. This is especially true for the intrahepatic distribution. This discrepancy is probably caused by the differences in physical characteristics (density, shape and size) and in the number of particles that are instilled.
Several groups have acknowledged that 99mTc-MAA constitute a suboptimal microdevice for acquiring robust dose estimates for radioembolization and have proposed other imaging surrogates. Avilla-Rodriguez et al. prepared resin microspheres, labeled with the positron emitting radioisotopes copper-64 (64Cu), yttrium-86 (86Y), and zirconium-89 (89Zr) as PET-imaging surrogates for the resin 90Y-microspheres Citation[9]. They performed a radiolabeling and stability study on these PET resin microspheres. Because of the low stability in vivo of the resin microspheres labeled with 64Cu owing to the high affinity of albumin for Cu(II), 64Cu was discarded for further preclinical or clinical research. The radiolabeling efficiency and in vivo stability of both the resin microspheres labeled with 86Y and those labeled with 89Zr were found to be sufficient for clinical applications. However, because 86Y is a non-pure positron emitter and 89Zr has a relatively long physical half-life (T1/2 = 78 h), they redirected their research work to the development of resin microspheres, labeled with the pure positron emitter fluorine-18 (18F, T1/2 = 110 min) Citation[10]. The labeling efficiency proved to be high (95%), as was the in vitro stability of the 18F resin microspheres (>99%). Unfortunately, an in vivo stability study in a rat revealed significant leaching of 18F from the microspheres (15% at 45 min postinjection), and the authors concluded that further research was therefore warranted on the development of resin microspheres tagged with a positron emitter, suited for clinical application.
Gupta and colleagues reported on glass microspheres containing Fe3O4 proposed as surrogates for the glass 90Y-microspheres Citation[8]. They conducted a study in VX2-carcinoma-bearing rabbits, in which MRI was used for in vivo tracking of the transarterial delivery of these superparamagnetic iron oxide labeled microspheres. By using a clinical MRI system (1.5 Tesla), real-time visualization of iron-labeled microsphere delivery, including detection of extrahepatic shunting was proven feasible.
Our group has also developed a radioactive microsphere device, which is also visible on MRI, namely poly(L-lactic acid) (PLLA) microspheres loaded with the highly paramagnetic element holmium (165Ho) Citation[11–13]. Like 90Y microsphere, the neutron-activated form of Ho, 166Ho, emits high-energy β-particles (Emax = 1.77 MeV [I = 48.7%]), 1.85 MeV [I = 50.0%]), suitable for internal radiation therapy. In addition, 166Ho emits low-energy γ-photons (E = 81 keV [I = 6.7%]), suitable for good-quality γ-scintigraphy, which even allows quantitative analysis of the in vivo biodistribution Citation[14]. A small dose of the same 166Ho microspheres of a low specific activity may be used instead of 99mTc-MAA to predict the distribution of the treatment dose. This concept was tested in healthy pigs. After rigid registration of the scintigraphy images, strong relations were found between the distributions of the scout dose of 166Ho-PLLA-microspheres (60 mg) and the total dose of 166Ho-PLLA-microspheres (600 mg) Citation[15]. Recently, a Phase I trial has been initiated, of which the primary end point is to establish the safety and toxicity profile of radioembolization with 166Ho-PLLA-microspheres in patients with metastatic liver cancer.
The third high-energy β-emitting radioisotope (Emax = 2.1 MeV [I = 71.1%]), which has been used recently for microsphere RE, is rhenium-188 (188Re). A clear advantage of the use of 188Re is that it is available in a generator-form (188W/188Re) as 188ReNaO4. A favorable feature of 188Re is that it emits medium-energy γ-photons (E = 155 keV [I = 15.1%]) suitable for scintigraphic imaging. The physical half-life of 188Re is 17.0 h, which is considerably shorter than both 166Ho and 90Y’s (T1/2 = 26.8 and 64.0 h, respectively). Wunderlich and coworkers used commercially available human serum albumin microspheres (Rotop Pharmaka AG, Radeberg, Germany), which are usually used in nuclear medicine for lung perfusion imaging (labeled with 99mTc) Citation[16]. The labeling efficiency was 85–90% and the in vitro stability of the 188Re-labeled human serum albumin microspheres in stabilized blood was found to be above 88%. A series of ten patients with either unresectable primary liver cancer or liver metastases from colorectal primary were treated with these 188Re-microspheres, in a salvage setting Citation[17]. Interestingly, the number of microspheres that were infused was reported to be 2–3 × 105, which is markedly lower than the number of particles that are administered for both the 90Y and 166Ho microspheres, ranging between 4 and 50 × 106. The 188Re microspheres were also of a smaller diameter, with a mean size of 21 µm versus 25–32 µm for the 90Y and 166Ho microspheres.
Based on the research discussed earlier, it may be concluded that although the clinical results of 90Y-RE are very encouraging, a need exists for type(s) of microsphere that allow(s) in vivo imaging both during the pretreatment procedure, as well as during and/or after administration of the treatment dose. High-quality visualization of the microspheres would allow patient-specific dose estimation, which would improve both safety and efficacy of RE. At this moment, the question of which isotope, type of labeling process and type of matrix material is the most efficient in optimizing RE, remains an open question.
Financial & competing interests disclosure
JFW Nijsen and BA Zonnenberg are inventors on several patent applications The assignee of the patents is the University Medical Center Utrecht, The Netherlands. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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