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Radioembolization for hepatocellular carcinoma

  • Bruno Sangro
    Correspondence
    Corresponding author. Address: Liver Unit, Clinica Universidad de Navarra, Avda. Pio XII 36, 31008 Pamplona, Spain. Tel.: +34 948 296 637; fax: +34 948 296 500.
    Affiliations
    Liver Unit, Clinica Universidad de Navarra, Pamplona, Spain

    Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Pamplona, Spain
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  • Mercedes Iñarrairaegui
    Affiliations
    Liver Unit, Clinica Universidad de Navarra, Pamplona, Spain

    Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Pamplona, Spain
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  • Jose I. Bilbao
    Affiliations
    Interventional Radiology, Clinica Universidad de Navarra, Pamplona, Spain
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Open AccessPublished:August 03, 2011DOI:https://doi.org/10.1016/j.jhep.2011.07.012

      Summary

      Radioembolization is a form of brachytherapy in which intra-arterially injected 90Y-loaded microspheres serve as sources for internal radiation purposes. It produces average disease control rates above 80% and is usually very well tolerated. Main complications do not result from the microembolic effect, even in patients with portal vein occlusion, but rather from an excessive irradiation of non-target tissues including the liver. All the evidence that support the use of radioembolization in HCC is based on retrospective series or non-controlled prospective studies. However, reliable data can be obtained from the literature, particularly since the recent publication of large series accounting for nearly 700 patients. When compared to the standard of care for the intermediate and advanced stages (transarterial embolization and sorafenib), radioembolization consistently provides similar survival rates. Two indications seem particularly appealing in the boundaries of these stages for first-line radioembolization. First, the treatment of patients straddling between the intermediate and advanced stages (intermediate patients with bulky or bilobar disease that are considered poor candidates for TACE, and advanced patients with solitary tumors invading a segmental or lobar branch of the portal vein). Second, the treatment of patients that are slightly above the criteria for resection, ablation or transplantation, for which downstaging could open the door for a radical approach. Radioembolization can also be used to treat patients progressing to TACE or sorafenib. With a number of clinical trials underway, the available evidence shows that it adds a significant value to the therapeutic weaponry against HCC of tertiary care centers dealing with this major cancer problem.

      Keywords

      Linked Article

      Introduction

      The term radioembolization defines those procedures in which intra-arterially injected radioactive microspheres are used for internal radiation purposes [
      • Brown D.B.
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      Transcatheter therapy for hepatic malignancy: standardization of terminology and reporting criteria.
      ]. The artery or arteries in which microspheres are injected define the volume of liver tissue that is exposed to radiation as shown in Fig. 1. A thorough description of the procedures involved in liver radioembolization is beyond the scope of this review and has been recently addressed by an International Working Group [
      • Coldwell D.
      • Sangro B.
      • Wasan H.
      • Salem R.
      • Kennedy A.
      General selection criteria of patients for radioembolization of liver tumors: an International Working Group report.
      ]. Therefore, this review will briefly describe the devices and procedures and then focus mainly on those aspects of dosimetry that concern tumor response and safety, and on the impact in survival across different tumor stages, to provide the rational that supports its use in daily practice and clinical trials in patients with hepatocellular carcinoma (HCC).
      Figure thumbnail gr1
      Fig. 1Liver volume exposed to radiation is defined by the arteries into which radioactive microspheres are injected.
      Radioembolization differs substantially from transarterial chemoembolization (TACE). In TACE, occlusion of medium and large size arteries (with the use of particles 3–10 times larger than those used in radioembolization) results in tumor ischemia that drives an antitumor effect, with drug delivery potentially enhancing tumor cell killing [
      • Sangro B.
      • D’Avola D.
      • Inarrairaegui M.
      • Prieto J.
      Transarterial therapies for hepatocellular carcinoma.
      ]. Radioembolization (also called selective internal radiation therapy or SIRT) is a form of brachytherapy for liver tumors in which the source of radiation has to access the network of tumoral neovessels after being injected into the hepatic arteries. Fig. 2 illustrates the difference between devices and procedures used for radioembolization and TACE. It has to be emphasized that both the beneficial and deleterious effects of radioembolization originate from the radiation delivered by the isotope and the not well-understood effects of microembolization, but not by ischemia due to vessel occlusion.
      Figure thumbnail gr2
      Fig. 2(Chemo)embolization and radioembolization. Upper panel: small (35 μm) isotope-loaded particles are delivered into the smallest intratumoral blood vessels with the aim of delivering short-range irradiation in radioembolization. Medium (100–500 μm) drug-eluting or simple particles are delivered into the medium-size vessels that irrigate tumor nodules with the aim of producing ischemia and eventually expose tumor cells to high concentrations of cytotoxic agents in (chemo)embolization. Lower panel: size comparison between microspheres used for arterial (chemo)embolization and radioembolization.
      HCC is in fact a radiosensitive tumor [
      • Wigg A.J.
      • Palumbo K.
      • Wigg D.R.
      Radiotherapy for hepatocellular carcinoma: systematic review of radiobiology and modeling projections indicate reconsideration of its use.
      ] for which external beam radiation therapy is not used widely because severe liver toxicity can appear when more than 35 Gy of radiation are absorbed by a significant volume of liver tissue [
      • Lawrence T.S.
      • Robertson J.M.
      • Anscher M.S.
      • Jirtle R.L.
      • Ensminger W.D.
      • Fajardo L.F.
      Hepatic toxicity resulting from cancer treatment.
      ]. In fact, we know that liver toxicity after external irradiation depends on the dose of radiation delivered, the volume of liver tissue involved, the presence of cirrhosis, prior liver function and concurrent therapies [
      • Dawson L.A.
      • Ten Haken R.K.
      Partial volume tolerance of the liver to radiation.
      ]. Internal radiation therapy has been developed as an attempt to overcome this problem based on the arterial irrigation of HCC nodules. The aim of internal radiation therapy is to deliver tumoricidal doses of radiation to liver tumors (irrespective of their number, size, and location) while sparing the non-tumoral liver by the injection into the hepatic artery of either embolizing sources of radiation such as Lipiodol or microspheres. Radioembolization has overcome some of the problems of radioactive Lipiodol. With the commercially available microspheres (Table 1) that are made of resin (SIR-Spheres®, Sirtex Medical, Sidney, Australia) or glass (TheraSphere®, MDS Nordion, Toronto, Canada) and loaded with yttrium 90 (90Y), a pure beta emitter, isolation for radioprotection is not needed after treatment. 90Y is a high-energy radiation source with a short half-life (2.67 days), and a short tissue penetration (mean 2.5 mm and maximum 11 mm). Within the 2 weeks following injection, more than 95% of the radiation is delivered into the surrounding tissues of the vessels in which the microspheres get embolized. As summarized in Table 1, glass and resin microspheres differ in several characteristics including the amount of isotope loaded in each microsphere and the number of spheres typically injected in a single treatment (<5 million to 10–30 million) but are very similar in size, and the clinical outcomes are tenaciously similar for both devices.
      Table 1Differences between 90Y microspheres used for radioembolization of HCC.
      MIRD, Medical Internal Radiation Dose Committee. From Gulec et al.
      • Gulec S.A.
      • Sztejnberg M.L.
      • Siegel J.A.
      • Jevremovic T.
      • Stabin M.
      Hepatic structural dosimetry in (90)Y microsphere treatment: a Monte Carlo modeling approach based on lobular microanatomy.
      .

      Dosimetry and radiobiology

      Radioembolization usually induces tumor regressions of varying degrees in targeted lesions, with most series reporting response rates of 25–50% [
      • Carr B.I.
      Hepatic arterial 90Yttrium glass microspheres (Therasphere) for unresectable hepatocellular carcinoma: interim safety and survival data on 65 patients.
      ,
      • Dancey J.E.
      • Shepherd F.A.
      • Paul K.
      • Sniderman K.W.
      • Houle S.
      • Gabrys J.
      • et al.
      Treatment of nonresectable hepatocellular carcinoma with intrahepatic 90Y-microspheres.
      ,
      • Gaba R.C.
      • Lewandowski R.J.
      • Kulik L.M.
      • Riaz A.
      • Ibrahim S.M.
      • Mulcahy M.F.
      • et al.
      Radiation lobectomy: preliminary findings of hepatic volumetric response to lobar yttrium-90 radioembolization.
      ,
      • Inarrairaegui M.
      • Martinez-Cuesta A.
      • Rodriguez M.
      • Bilbao J.I.
      • Arbizu J.
      • Benito A.
      • et al.
      Analysis of prognostic factors after Yttrium-90 radioembolization of advanced hepatocellular carcinoma.
      ,
      • Kulik L.M.
      • Atassi B.
      • van Holsbeeck L.
      • Souman T.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • et al.
      Yttrium-90 microspheres (TheraSphere) treatment of unresectable hepatocellular carcinoma: downstaging to resection, RFA and bridge to transplantation.
      ,
      • Kulik L.M.
      • Carr B.I.
      • Mulcahy M.F.
      • Lewandowski R.J.
      • Atassi B.
      • Ryu R.K.
      • et al.
      Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis.
      ,
      • Lau W.Y.
      • Ho S.
      • Leung T.W.
      • Chan M.
      • Ho R.
      • Johnson P.J.
      • et al.
      Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres.
      ,
      • Lau W.Y.
      • Leung W.T.
      • Ho S.
      • Leung N.W.
      • Chan M.
      • Lin J.
      • et al.
      Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study.
      ,
      • Salem R.
      • Lewandowski R.J.
      • Atassi B.
      • Gordon S.C.
      • Gates V.L.
      • Barakat O.
      • et al.
      Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): safety, tumor response, and survival.
      ,
      • Salem R.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Riaz A.
      • Ryu R.K.
      • Ibrahim S.
      • et al.
      Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
      ,
      • Sangro B.
      • Bilbao J.I.
      • Boan J.
      • Martinez-Cuesta A.
      • Benito A.
      • Rodriguez J.
      • et al.
      Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma.
      ]. These differences in the magnitude of tumor response may be due to several reasons but two of them seem to be especially relevant. First, tumor shrinkage evolves slowly after radioembolization. Maximal volumetric response is usually observed after 3–6 months [
      • Sangro B.
      • Bilbao J.I.
      • Boan J.
      • Martinez-Cuesta A.
      • Benito A.
      • Rodriguez J.
      • et al.
      Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma.
      ,
      • Riaz A.
      • Kulik L.
      • Lewandowski R.J.
      • Ryu R.K.
      • Giakoumis Spear G.
      • Mulcahy M.F.
      • et al.
      Radiologic–pathologic correlation of hepatocellular carcinoma treated with internal radiation using yttrium-90 microspheres.
      ] and median time to response was 6.6 months (95% CI 5.6–7.6) by WHO criteria in the largest series that has evaluated this parameter [
      • Salem R.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Riaz A.
      • Ryu R.K.
      • Ibrahim S.
      • et al.
      Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
      ]. It should also be noticed that, as it happens after TACE, intratumoral changes in imaging procedures suggesting tumor necrosis or fibrosis may reflect a response to treatment beyond size reduction and response could be better evaluated by mixed criteria as the ones proposed by the European Association for the Study of the Liver (EASL) [
      • Bruix J.
      • Sherman M.
      • Llovet J.M.
      • Beaugrand M.
      • Lencioni R.
      • Burroughs A.K.
      • et al.
      Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver.
      ] as shown in Table 2. Response by necrosis and volume most usually precedes response by volume alone [
      • Riaz A.
      • Memon K.
      • Miller F.H.
      • Nikolaidis P.
      • Kulik L.M.
      • Lewandowski R.J.
      • et al.
      Role of the EASL, RECIST, and WHO response guidelines alone or in combination for hepatocellular carcinoma: radiologic–pathologic correlation.
      ].
      Table 2Overall response rates according to volumetric and combined criteria in large (n >50) series of patients with HCC treated by radioembolization.
      WHO criteria unless otherwise specified. ∗∗EASL criteria unless otherwise specified.
      aRECIST criteria.
      The second factor that may impact the occurrence of a tumor response is the dose of radiation that is actually delivered to tumor tissue. The biological effects of radiotherapy are mediated by the absorbed dose, which is defined as the energy absorbed per unit mass of tissue. In radioembolization, the absorbed dose depends on the amount of 90Y activity that is injected, the hemodynamics of the hepatic artery blood flow, and the vessel density inside the tumors. Activity is a constant value, but hemodynamics varies in different parts of the liver and tumor mass, and vessel density is heterogeneous within the liver and the tumors. In a 3-dimensional computer model with fixed vessel geometry, the type of particle inlet distribution (how particles distribute inside the vessel after injection) and the pressure boundary conditions were major factors influencing the delivery of 90Y-microspheres and, as a result, the total absorbed dose of radiation in the tumor and normal liver tissues [
      • Kennedy A.S.
      • Kleinstreuer C.
      • Basciano C.A.
      • Dezarn W.A.
      Computer modeling of yttrium-90-microsphere transport in the hepatic arterial tree to improve clinical outcomes.
      ]. The problem may be even more intricate since models like this assume a steady blood flow, rigid vessel wall, and non-interacting particles, conditions that are rather variable in the live scenario of radioembolization. However, after injection into the hepatic artery, most microspheres are attracted by the tumor microvasculature that is preferentially supplied by arterial blood. They ultimately accumulate in the tumor nodules in at least a 3:1–20:1 ratio compared with the normal liver, and are preferentially located in the periphery of nodules where the doses of absorbed radiation can go well beyond 500 Gy [
      • Kennedy A.S.
      • Nutting C.
      • Coldwell D.
      • Gaiser J.
      • Drachenberg C.
      Pathologic response and microdosimetry of (90)Y microspheres in man: review of four explanted whole livers.
      ]. Exposure to radiation can then produce irreversible cell damage in tumor epithelial, stromal, and endothelial cells that ultimately leads to compromised tumor growth. Hypovascular HCCs are not likely good candidates for radioembolization since one would expect a preferential deployment of radioactive microspheres in the non-tumoral compartment, although this issue has not been specifically evaluated.
      Unlike other forms of brachytherapy, an accurate dosimetry cannot be predicted in radioembolization. Millions of sources of radiation that are not implanted but rather liberated in the bloodstream make this task impracticable. A simulation of the actual treatment is performed 1–2 weeks prior to radioembolization with technetium-99 m labeled macroaggregated albumin (99mTc-MAA) particles that are roughly the size of the microspheres. 99mTc-MAA allows for planar and/or SPECT gamma-camera imaging, which can be used to measure hepatopulmonary shunting and to anticipate an average dose of radiation that could be delivered to tumor areas (Fig. 3). A number of 3D software packages may take the distribution of 99mTc-MAA or 90Y microspheres for a given patient (from SPECT or PET) and combine it with anatomic information (from CT or MRI) to yield absorbed dose estimates that are specific to that particular patient [
      • Flamen P.
      • Vanderlinden B.
      • Delatte P.
      • Ghanem G.
      • Ameye L.
      • Van Den Eynde M.
      • et al.
      Multimodality imaging can predict the metabolic response of unresectable colorectal liver metastases to radioembolization therapy with Yttrium-90 labeled resin microspheres.
      ]. However, the ability of 99mTc-MAA images to predict actual 90Y activity distribution is probably far from ideal. First, it has been shown using human tissue samples that significant amounts of tissue actually receive either a much lower or a higher dose of radiation than the one calculated by considering a uniform distribution of the injected activity [
      • Fox R.A.
      • Klemp P.F.
      • Egan G.
      • Mina L.L.
      • Burton M.A.
      • Gray B.N.
      Dose distribution following selective internal radiation therapy.
      ]. Second, when the correlation between activities detected by full 3D 90Y and 99mTc-MAA SPECT images was analyzed, the Spearman’s rank correlation values were in the range of 0.451–0.818 (the optimal value being 1.0) [
      • Knesaurek K.
      • Machac J.
      • Muzinic M.
      • DaCosta M.
      • Zhang Z.
      • Heiba S.
      Quantitative comparison of yttrium-90 (90Y)-microspheres and technetium-99m (99mTc)-macroaggregated albumin SPECT images for planning 90Y therapy of liver cancer.
      ]. And third, there are differences between the simulation and the actual treatment procedure in the size and specific gravity of 99mTc-MAA and 90Y microspheres, in the precise site, volume and velocity of injection, and quite importantly in the hemodynamic conditions inside the tumor under which particle injection is performed, that often vary during the procedure. Besides, since vessel density and hemodynamics are heterogeneous within a given tumor nodule, estimates reflect the average dose for a certain volume and not the actual dose as calculated for external or interstitial radiotherapy. Nevertheless, in HCC patients in which activity per mass was actually measured intraoperatively with a beta probe, tumor response correlated with the total dose of radiation delivered to the tumor and could be predicted from the dose estimates provided by the pre-treatment 99mTc-MAA planar scintigraphy [
      • Lau W.Y.
      • Leung T.W.
      • Ho S.
      • Chan M.
      • Leung N.W.
      • Lin J.
      • et al.
      Diagnostic pharmaco-scintigraphy with hepatic intra-arterial technetium-99m macroaggregated albumin in the determination of tumour to non-tumour uptake ratio in hepatocellular carcinoma.
      ]. In patients with HCC, tumor response by EASL criteria was associated with higher calculated mean absorbed doses for both glass [
      • Chiesa C.
      • Maccauro M.
      • Romito R.
      • Spreafico C.
      • Pellizzari S.
      • Negri A.
      • et al.
      Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with 90Y microspheres: the experience of the National Tumor Institute of Milan.
      ] and resin [
      • Strigari L.
      • Sciuto R.
      • Rea S.
      • Carpanese L.
      • Pizzi G.
      • Soriani A.
      • et al.
      Efficacy and toxicity related to treatment of hepatocellular carcinoma with 90Y-SIR spheres: radiobiologic considerations.
      ] microspheres. However, a cut-off point has not been established for the estimated absorbed dose in the tumor that may lead to a tumor response, although there is a general agreement by experts that 120 Gy would suffice [
      • Lau W.Y.
      • Kennedy A.S.
      • Kim Y.H.
      • Lai H.K.
      • Lee R.C.
      • Leung T.W.
      • et al.
      Patient selection and activity planning guide for selective internal radiotherapy with Yttrium-90 resin microspheres.
      ] and it has even been reported that the lowest dose needed to produce an objective tumor response with glass spheres is 40 Gy [
      • Gulec S.A.
      • Mesoloras G.
      • Dezarn W.A.
      • McNeillie P.
      • Kennedy A.S.
      Safety and efficacy of Y-90 microsphere treatment in patients with primary and metastatic liver cancer: the tumor selectivity of the treatment as a function of tumor to liver flow ratio.
      ].
      Figure thumbnail gr3
      Fig. 399mTc-MAA scan of a patient with a large tumor involving the right lobe treated in a lobar fashion. (A) A planar image from where lung shunting is calculated; (B) a SPECT image that reveal an intense uptake by the tumor (high tumor to non-tumor ratio); (C) an MR image of the tumor at baseline; and (D) an MR image of the tumor 2 years later showing an intense partial response after 3 sessions of radioembolization.
      Despite these uncertainties regarding tumor dosimetry, tumor growth of the treated lesions is arrested in more than 90% of the patients [
      • Sangro B.
      • Bilbao J.I.
      • Boan J.
      • Martinez-Cuesta A.
      • Benito A.
      • Rodriguez J.
      • et al.
      Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma.
      ] resulting in disease control rates that range from 77% [
      • Kulik L.M.
      • Carr B.I.
      • Mulcahy M.F.
      • Lewandowski R.J.
      • Atassi B.
      • Ryu R.K.
      • et al.
      Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis.
      ] to 90% and higher [
      • Inarrairaegui M.
      • Martinez-Cuesta A.
      • Rodriguez M.
      • Bilbao J.I.
      • Arbizu J.
      • Benito A.
      • et al.
      Analysis of prognostic factors after Yttrium-90 radioembolization of advanced hepatocellular carcinoma.
      ,
      • Hilgard P.
      • Hamami M.
      • Fouly A.E.
      • Scherag A.
      • Muller S.
      • Ertle J.
      • et al.
      Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.
      ]. It has been suggested that the intensity of tumor shrinkage does not define the possibility of achieving a better survival [
      • Inarrairaegui M.
      • Martinez-Cuesta A.
      • Rodriguez M.
      • Bilbao J.I.
      • Arbizu J.
      • Benito A.
      • et al.
      Analysis of prognostic factors after Yttrium-90 radioembolization of advanced hepatocellular carcinoma.
      ]. However, in a recent study, in which patients treated by TACE or radioembolization were jointly analyzed, response by EASL criteria at 6 months significantly predicted a better survival [
      • Memon K.
      • Kulik L.
      • Lewandowski R.J.
      • Wang E.
      • Riaz A.
      • Ryu R.K.
      • et al.
      Radiographic response to locoregional therapy in hepatocellular carcinoma predicts patient survival times.
      ]. Progression to radioembolization is almost always the result of new lesions growing inside or outside the liver [
      • Lau W.Y.
      • Ho S.
      • Leung T.W.
      • Chan M.
      • Ho R.
      • Johnson P.J.
      • et al.
      Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres.
      ,
      • Sangro B.
      • Bilbao J.I.
      • Boan J.
      • Martinez-Cuesta A.
      • Benito A.
      • Rodriguez J.
      • et al.
      Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma.
      ] and occurs after different intervals according to the extension and aggressiveness of the disease. Reported median time to progression ranges from 7.9 months (95% CI 6.0–10.3) to 10.0 months (95% CI 6.1–16.4) for entire cohorts of patients and from 11.8 months (95% CI 6.1–17.2) to 15.5 months (95% CI 10.7–25.9) when only those patients free from portal vein invasion are considered [
      • Salem R.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Riaz A.
      • Ryu R.K.
      • Ibrahim S.
      • et al.
      Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
      ,
      • Hilgard P.
      • Hamami M.
      • Fouly A.E.
      • Scherag A.
      • Muller S.
      • Ertle J.
      • et al.
      Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.
      ]. The identification of those patients that are at a high chance of early progression is relevant since it is in this group that combination with systemic targeted agents makes more sense. This early progression is not affected by treatment-related factors but rather depends on baseline characteristics of the tumor that denote a more aggressive behavior at baseline including the presence of a large number of (>5) nodules, bilobar disease and increased alpha-fetoprotein [
      • Inarrairaegui M.
      • Martinez-Cuesta A.
      • Rodriguez M.
      • Bilbao J.I.
      • Arbizu J.
      • Benito A.
      • et al.
      Analysis of prognostic factors after Yttrium-90 radioembolization of advanced hepatocellular carcinoma.
      ]. This observation and the finding of a similar rate of new lesions in targeted and non-targeted areas of the liver in patients treated in a lobar fashion strongly suggest that radioembolization is not effective against microscopic disease probably due to the absence of predominantly arterial vasculature.

      Tolerability and safety

      Side-effects are not common after radioembolization. A post-embolization syndrome like the one that appears after TACE is not seen, but in large series [
      • Salem R.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Riaz A.
      • Ryu R.K.
      • Ibrahim S.
      • et al.
      Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
      ,
      • Hilgard P.
      • Hamami M.
      • Fouly A.E.
      • Scherag A.
      • Muller S.
      • Ertle J.
      • et al.
      Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.
      ,
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after (90) Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: a European evaluation.
      ] several rather mild procedure-related symptoms may ensue including fatigue (54–61%), abdominal pain (23–56%), nausea and vomiting (20–32%) and low-grade fever (3–12%) that usually last only a few hours. Mild-to-moderate lymphopenia is commonly seen after radioembolization but not associated with increased susceptibility to infections [
      • Carr B.I.
      Hepatic arterial 90Yttrium glass microspheres (Therasphere) for unresectable hepatocellular carcinoma: interim safety and survival data on 65 patients.
      ]. Radioembolization is safe in patients with portal vein thrombosis [
      • Inarrairaegui M.
      • Thurston K.G.
      • Bilbao J.I.
      • D’Avola D.
      • Rodriguez M.
      • Arbizu J.
      • et al.
      Radioembolization with use of yttrium-90 resin microspheres in patients with hepatocellular carcinoma and portal vein thrombosis.
      ] in whom TACE may lead to complications such as liver abscess or decompensation of cirrhosis [
      • Chan A.O.
      • Yuen M.F.
      • Hui C.K.
      • Tso W.K.
      • Lai C.L.
      A prospective study regarding the complications of transcatheter intraarterial lipiodol chemoembolization in patients with hepatocellular carcinoma.
      ] and results from a small series suggest that it could also be safe in asymptomatic patients with lobar or segmental biliary tract obstruction but normal or near-normal bilirubin [
      • Gaba R.C.
      • Riaz A.
      • Lewandowski R.J.
      • Ibrahim S.M.
      • Ryu R.K.
      • Sato K.T.
      • et al.
      Safety of yttrium-90 microsphere radioembolization in patients with biliary obstruction.
      ] although its use in patients with main bile duct obstruction or stenting should not be encouraged. Safety in these special situations is probably the result of the lack of significant ischemia, as observed in animal models [
      • Bilbao J.I.
      • de Martino A.
      • de Luis E.
      • Diaz-Dorronsoro L.
      • Alonso-Burgos A.
      • Martinez de la Cuesta A.
      • et al.
      Biocompatibility, inflammatory response, and recanalization characteristics of nonradioactive resin microspheres: histological findings.
      ]. However, radioembolization may produce relevant toxic effects as a result of radiation of non-target organs including cholecystitis [
      • Carr B.I.
      Hepatic arterial 90Yttrium glass microspheres (Therasphere) for unresectable hepatocellular carcinoma: interim safety and survival data on 65 patients.
      ], gastrointestinal ulceration [
      • Carretero C.
      • Munoz-Navas M.
      • Betes M.
      • Angos R.
      • Subtil J.C.
      • Fernandez-Urien I.
      • et al.
      Gastroduodenal injury after radioembolization of hepatic tumors.
      ,
      • Naymagon S.
      • Warner R.R.
      • Patel K.
      • Harpaz N.
      • Machac J.
      • Weintraub J.L.
      • et al.
      Gastroduodenal ulceration associated with radioembolization for the treatment of hepatic tumors: an institutional experience and review of the literature.
      ], pneumonitis [
      • Leung T.W.
      • Lau W.Y.
      • Ho S.K.
      • Ward S.C.
      • Chow J.H.
      • Chan M.S.
      • et al.
      Radiation pneumonitis after selective internal radiation treatment with intraarterial 90yttrium-microspheres for inoperable hepatic tumors.
      ], and most importantly for HCC patients, liver toxicity.
      Two consequences of cirrhosis may affect radioembolization in the cirrhotic liver, at least theoretically. On one hand, the usual distribution of microspheres can be profoundly altered by the vascular changes that occur in the cirrhotic liver. This altered microvascular pattern and the presence of anatomical arterio-portal and arterio-venous shunts may modify the radiation dose absorbed by the tumor and the non-tumoral liver and therefore affect treatment tolerance and effectiveness. On the other hand, the cirrhotic liver has a reduced functional reserve that produces an increased risk of liver failure after extensive resection, or liver insults including toxic or viral acute hepatitis, or external irradiation [
      • Furuse J.
      • Ishii H.
      • Nagase M.
      • Kawashima M.
      • Ogino T.
      • Yoshino M.
      Adverse hepatic events caused by radiotherapy for advanced hepatocellular carcinoma.
      ]. This reduced functional reserve is the consequence of the reduction in total liver mass and liver blood flow, together with the profound changes that occur in liver cell functions. A direct liver cell injury and a further compromise of liver blood supply produced by a radiation-mediated blood vessel damage could all result in a higher risk of clinically relevant liver toxicity after radioembolization in comparison with non-cirrhotic livers.
      Again, the lack of an adequate dosimetry hinders the analysis of a dose–tolerance relationship in radioembolization. When hepatic structural dosimetry was studied in a 3-dimensional liver model, doses absorbed by the portal area were much higher than those absorbed around the central venules [
      • Gulec S.A.
      • Sztejnberg M.L.
      • Siegel J.A.
      • Jevremovic T.
      • Stabin M.
      Hepatic structural dosimetry in (90)Y microsphere treatment: a Monte Carlo modeling approach based on lobular microanatomy.
      ]. This heterogeneous distribution could explain in part the higher doses of radiation tolerated in radioembolization when compared with external beam irradiation. However, this and other models assume that microspheres are always positioned in the distal arterial branches and are uniformly scattered throughout the entire liver parenchyma in a non-clustered distribution. Actually, microspheres can be found in portal and hepatic veins in the normal liver and in the fibrotic septa in the cirrhotic liver, where they not infrequently form clusters, and are every so often distributed in a rather heterogeneous way. This may explain the lack of a clear dose-event relationship in liver tolerance, as happens with tumor response. Yet, the general agreement is that in macrodosimetry, the dose absorbed by the non-tumoral liver tissue should be kept below 50 Gy for patients with cirrhosis [
      • Lau W.Y.
      • Kennedy A.S.
      • Kim Y.H.
      • Lai H.K.
      • Lee R.C.
      • Leung T.W.
      • et al.
      Patient selection and activity planning guide for selective internal radiotherapy with Yttrium-90 resin microspheres.
      ].
      In non-cirrhotic patients, a form of sinusoidal obstruction syndrome appearing 4–8 weeks after radioembolization as jaundice, mild ascites and a moderate increase in GGTP and alkaline phosphatase has been described as radioembolization-induced liver disease (REILD) [
      • Sangro B.
      • Gil-Alzugaray B.
      • Rodriguez J.
      • Sola I.
      • Martinez-Cuesta A.
      • Viudez A.
      • et al.
      Liver disease induced by radioembolization of liver tumors: description and possible risk factors.
      ]. The actual incidence of this complication in cirrhotics and non-cirrhotics is difficult to establish because most published series report on changes in individual laboratory values along different periods of time, from 30 days to the entire follow-up period (Table 3). In a population enriched in cirrhotics in whom abnormal liver function tests are frequently present at baseline and liver failure may develop as a result of the progression of the chronic liver disease, such differences in reporting criteria do not help to clarify the actual incidence of REILD. Nevertheless, in the two largest series ever published [
      • Salem R.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Riaz A.
      • Ryu R.K.
      • Ibrahim S.
      • et al.
      Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
      ,
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after (90) Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: a European evaluation.
      ], grade 3 or higher CTCAE bilirubin levels (a hallmark of REILD) were observed within 3 months after therapy in 14% of patients treated with glass spheres (mostly in a lobar fashion) and in nearly 6% of patients treated with resin spheres (almost half of them treated in a bilobar fashion). Although a causal relationship with radioembolization could only be confirmed in controlled clinical trials in which adverse events are recorded prospectively and compared to those occurring in the control arm, it is very likely that the increased bilirubin levels reflect some kind of REILD. This opinion is further supported by the fact that increasing bilirubin does not appear in association with other changes that may reflect abating liver function such as decreased albumin levels or prothrombin activity [
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after (90) Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: a European evaluation.
      ]. In fact, an increase in CTCAE grade of albumin and INR within 3 months after therapy was observed in 19% and 15% of patients, and relevant changes (grade 3 or higher) were observed in only 0.8% and 1.8% of patients, respectively. These recent findings underscore the good safety profile of radioembolization in HCC patients.
      Table 3Liver-related side effects reported after radioembolization in HCC patients.
      Interval: days after radioembolization. SAE: serious adverse events. n.r.: not reported. RILD: radiation-induced liver disease. CTC (>3 times the upper normal limit). ∗∗SWOG (>200% increase from baseline).
      • Lau W.Y.
      • Ho S.
      • Leung T.W.
      • Chan M.
      • Ho R.
      • Johnson P.J.
      • et al.
      Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres.
      ,
      • Dancey J.E.
      • Shepherd F.A.
      • Paul K.
      • Sniderman K.W.
      • Houle S.
      • Gabrys J.
      • et al.
      Treatment of nonresectable hepatocellular carcinoma with intrahepatic 90Y-microspheres.
      ,
      • Geschwind J.F.
      • Salem R.
      • Carr B.I.
      • Soulen M.C.
      • Thurston K.G.
      • Goin K.A.
      • et al.
      Yttrium-90 microspheres for the treatment of hepatocellular carcinoma.
      ,
      • Carr B.I.
      Hepatic arterial 90Yttrium glass microspheres (Therasphere) for unresectable hepatocellular carcinoma: interim safety and survival data on 65 patients.
      ,
      • Salem R.
      • Lewandowski R.J.
      • Atassi B.
      • Gordon S.C.
      • Gates V.L.
      • Barakat O.
      • et al.
      Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): safety, tumor response, and survival.
      ,
      • Goin J.E.
      • Salem R.
      • Carr B.I.
      • Dancey J.E.
      • Soulen M.C.
      • Geschwind J.F.
      • et al.
      Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: a risk-stratification analysis.
      ,
      • Sangro B.
      • Bilbao J.I.
      • Boan J.
      • Martinez-Cuesta A.
      • Benito A.
      • Rodriguez J.
      • et al.
      Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma.
      ,
      • Kulik L.M.
      • Carr B.I.
      • Mulcahy M.F.
      • Lewandowski R.J.
      • Atassi B.
      • Ryu R.K.
      • et al.
      Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis.
      ,
      • Hilgard P.
      • Hamami M.
      • Fouly A.E.
      • Scherag A.
      • Muller S.
      • Ertle J.
      • et al.
      Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.
      ,
      • Kooby D.A.
      • Egnatashvili V.
      • Srinivasan S.
      • Chamsuddin A.
      • Delman K.A.
      • Kauh J.
      • et al.
      Comparison of yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma.
      ,
      • Salem R.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Riaz A.
      • Ryu R.K.
      • Ibrahim S.
      • et al.
      Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
      ,
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after (90) Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: a European evaluation.

      Treatment outcomes and potential roles according to tumor stages

      All the evidence that supports the use of radioembolization in HCC is based on retrospective series or non-controlled prospective studies (levels of evidence II-2 and II-3) [

      Force UPST. Guide to clinical preventive services: report of the US Preventive Services Task Force. In: Publishing D, editor; 1998. p. 24.

      ], and no randomized controlled trials have been published comparing radioembolization with other loco-regional or systemic therapies or best supportive care. Nevertheless, sound data can be drawn from the analysis of the literature, particularly since the recent publication of three large series accounting for nearly 700 patients [
      • Salem R.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Riaz A.
      • Ryu R.K.
      • Ibrahim S.
      • et al.
      Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
      ,
      • Hilgard P.
      • Hamami M.
      • Fouly A.E.
      • Scherag A.
      • Muller S.
      • Ertle J.
      • et al.
      Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.
      ,
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after (90) Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: a European evaluation.
      ]. These data provide a valuable source of information to allow comparison with other treatment options for most subgroups of patients. It should also be kept in mind that the proof of principle that internal radiation therapy is active in the treatment of HCC was produced with the use of radioactive Lipiodol. Two randomized controlled trials conducted in the 1990s showed that in patients with unresectable HCC, radioactive Lipiodol resulted in response rates and overall survival comparable to TACE with fewer side effects, and prolonged survival among patients with portal vein thrombosis when compared to best supportive care [
      • Raoul J.L.
      • Guyader D.
      • Bretagne J.F.
      • Duvauferrier R.
      • Bourguet P.
      • Bekhechi D.
      • et al.
      Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support.
      ,
      • Raoul J.L.
      • Guyader D.
      • Bretagne J.F.
      • Heautot J.F.
      • Duvauferrier R.
      • Bourguet P.
      • et al.
      Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma.
      ].
      By and large, most series of radioembolization for HCC have reported on the outcome of patients at different stages that had progressed or relapsed after TACE or were considered poor candidates for TACE due to the presence of portal vein invasion or bulky tumors. This is particularly true for series published before 2008, when the multi-tyrosine kinase inhibitor sorafenib [
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ] was shown to prolong survival even in this population of patients with mixed intermediate and advanced stages. A case-control analysis of a small cohort of patients with this profile showed that survival was significantly better in the group that received radioembolization as first-line treatment than in a control group matched for liver function and tumor burden, treated with conventional or experimental therapies or no therapy (16 vs. 8 months; p <0.05) [
      • D’Avola D.
      • Lnarrairaegui M.
      • Bilbao J.I.
      • Martinez-Cuesta A.
      • Alegre F.
      • Herrero J.I.
      • et al.
      A retrospective comparative analysis of the effect of Y90-radioembolization on the survival of patients with unresectable hepatocellular carcinoma.
      ]. These findings provide some evidence that radioembolization can prolong survival over no specific therapy in this population of patients not amenable for TACE. This evidence is further supported by the comparison of numerous studies reporting survivals in the range of 9–16 months [
      • Dancey J.E.
      • Shepherd F.A.
      • Paul K.
      • Sniderman K.W.
      • Houle S.
      • Gabrys J.
      • et al.
      Treatment of nonresectable hepatocellular carcinoma with intrahepatic 90Y-microspheres.
      ,
      • Lau W.Y.
      • Ho S.
      • Leung T.W.
      • Chan M.
      • Ho R.
      • Johnson P.J.
      • et al.
      Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres.
      ,
      • Hilgard P.
      • Hamami M.
      • Fouly A.E.
      • Scherag A.
      • Muller S.
      • Ertle J.
      • et al.
      Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.
      ] in groups of patients with similar characteristics to that of 7.9 months in the group of patients in the SHARP trial randomized to receive placebo. As illustrated in Fig. 4, among similar populations, radioembolization provides a very similar survival as sorafenib [
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ,
      • Bruix J.
      • Raoul J.L.
      • Sherman M.
      • Shan M.
      • Lentini G.
      • Nadel A.
      Efficacy and safety of sorafenib in patients with hepatocellular carcinoma (HCC): subanalysis of Sharp trial based on Barcelona Clinic Liver Cancer (BCLC) stage.
      ,
      • Galle P.
      • Blanc J.
      • Van Laethem J.L.
      • et al.
      Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and prior antitumor therapy: a subanalysis from the SHARP trial.
      ,
      • Raoul J.L.
      • Santoro A.
      • Beaugrand M.
      • et al.
      Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to ECOG performance status: a subanalysis from the SHARP trial.
      ,
      • Sherman M.
      • Mazzaferro V.
      • Amadori D.
      • Seitz J.
      • Moscovici M.
      • Shan M.
      • et al.
      Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and vascular invasion or extrahepatic spread: a subanalysis from the SHARP trial.
      ].
      Figure thumbnail gr4
      Fig. 4Comparison between median overall survival observed in comparable subgroups of patients treated by radioembolization and sorafenib. Data for 299 sorafenib-treated patients was obtained from subanalysis of the SHARP trial. Data for 189 radioembolization-treated patients was obtained from subanalysis of a cohort of patients fulfilling the same inclusion criteria, namely Child-Pugh class A and either BCLC stage C or BCLC stage B with prior TACE or bulky disease (bilobar or >5 nodules) [
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after (90) Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: a European evaluation.
      ,
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ,
      • Bruix J.
      • Raoul J.L.
      • Sherman M.
      • Shan M.
      • Lentini G.
      • Nadel A.
      Efficacy and safety of sorafenib in patients with hepatocellular carcinoma (HCC): subanalysis of Sharp trial based on Barcelona Clinic Liver Cancer (BCLC) stage.
      ,
      • Galle P.
      • Blanc J.
      • Van Laethem J.L.
      • et al.
      Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and prior antitumor therapy: a subanalysis from the SHARP trial.
      ,
      • Raoul J.L.
      • Santoro A.
      • Beaugrand M.
      • et al.
      Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to ECOG performance status: a subanalysis from the SHARP trial.
      ,
      • Sherman M.
      • Mazzaferro V.
      • Amadori D.
      • Seitz J.
      • Moscovici M.
      • Shan M.
      • et al.
      Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and vascular invasion or extrahepatic spread: a subanalysis from the SHARP trial.
      ].
      Since both the aim and outcomes of radioembolization can be quite different across tumor stages, we will review the available evidence supporting its potential role in the different stages of HCC using the Barcelona Clinic Liver Cancer (BCLC) classification as the framework since it has been endorsed by the two main Western hepatology societies [
      • Bruix J.
      • Sherman M.
      • Llovet J.M.
      • Beaugrand M.
      • Lencioni R.
      • Burroughs A.K.
      • et al.
      Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver.
      ,
      • Bruix J.
      • Sherman M.
      Management of hepatocellular carcinoma: an update.
      ]. In doing so, it has to be stressed that similar to other treatments, prognosis after radioembolization largely depends on liver function and tumor burden (inside and outside the liver) before treatment [
      • Salem R.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Riaz A.
      • Ryu R.K.
      • Ibrahim S.
      • et al.
      Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
      ,
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after (90) Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: a European evaluation.
      ] and probably on the response to treatment [
      • Memon K.
      • Kulik L.
      • Lewandowski R.J.
      • Wang E.
      • Riaz A.
      • Ryu R.K.
      • et al.
      Radiographic response to locoregional therapy in hepatocellular carcinoma predicts patient survival times.
      ].

      Advanced stage

      Sorafenib is the mainstay for treating advanced HCC, defined by the presence of vascular invasion, extrahepatic disease or deteriorated performance status in a patient with at least partially preserved liver function. As shown in Fig. 5, patients in the advanced stage treated by radioembolization have median overall survivals in the range of 6–10 months [
      • Salem R.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Riaz A.
      • Ryu R.K.
      • Ibrahim S.
      • et al.
      Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
      ,
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after (90) Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: a European evaluation.
      ], very similar to those 6.5–10.7 months reported in the phase III clinical trials of sorafenib in the same group of patients [
      • Bruix J.
      • Raoul J.L.
      • Sherman M.
      • Shan M.
      • Lentini G.
      • Nadel A.
      Efficacy and safety of sorafenib in patients with hepatocellular carcinoma (HCC): subanalysis of Sharp trial based on Barcelona Clinic Liver Cancer (BCLC) stage.
      ,
      • Cheng A.L.
      • Kang Y.K.
      • Chen Z.
      • Tsao C.J.
      • Qin S.
      • Kim J.S.
      • et al.
      Efficacy and safety of sorafenib in patients in the Asia–Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
      ]. A compromised portal vein blood flow is usually considered a contraindication for TACE [
      • Bruix J.
      • Sherman M.
      Management of hepatocellular carcinoma: an update.
      ]. Due to the lack of significant macroembolic effect causing liver decompensation [
      • Inarrairaegui M.
      • Thurston K.G.
      • Bilbao J.I.
      • D’Avola D.
      • Rodriguez M.
      • Arbizu J.
      • et al.
      Radioembolization with use of yttrium-90 resin microspheres in patients with hepatocellular carcinoma and portal vein thrombosis.
      ], portal vein thrombosis is not an absolute contraindication to radioembolization. However, patients with main portal vein thrombosis have a poor prognosis after radioembolization, their median overall survival ranging from 3 to 6 months [
      • Kulik L.M.
      • Carr B.I.
      • Mulcahy M.F.
      • Lewandowski R.J.
      • Atassi B.
      • Ryu R.K.
      • et al.
      Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis.
      ,
      • Woodall C.E.
      • Scoggins C.R.
      • Ellis S.F.
      • Tatum C.M.
      • Hahl M.J.
      • Ravindra K.V.
      • et al.
      Is selective internal radioembolization safe and effective for patients with inoperable hepatocellular carcinoma and venous thrombosis?.
      ]. Contrary, patients with branch (segmentary or lobar) portal vein thrombosis may achieve an unforeseeable median survival post-radioembolization of 10 to 14 months [
      • Kulik L.M.
      • Carr B.I.
      • Mulcahy M.F.
      • Lewandowski R.J.
      • Atassi B.
      • Ryu R.K.
      • et al.
      Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis.
      ,
      • Inarrairaegui M.
      • Thurston K.G.
      • Bilbao J.I.
      • D’Avola D.
      • Rodriguez M.
      • Arbizu J.
      • et al.
      Radioembolization with use of yttrium-90 resin microspheres in patients with hepatocellular carcinoma and portal vein thrombosis.
      ]. The effect of liver function seems to be particularly relevant in the subgroup of patients in the advanced stage [
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after (90) Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: a European evaluation.
      ], those patients with portal vein thrombosis and Child-Pugh B surviving a median of 2–5 months [
      • Salem R.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Riaz A.
      • Ryu R.K.
      • Ibrahim S.
      • et al.
      Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
      ].
      Figure thumbnail gr5
      Fig. 5Median overall survival of HCC patients treated with radioembolization, TACE, and sorafenib according to BCLC stage.
      Liver failure or intrahepatic tumor growth are the cause of nearly 90% of deaths among HCC patients with extrahepatic disease [
      • Uka K.
      • Aikata H.
      • Takaki S.
      • Shirakawa H.
      • Jeong S.C.
      • Yamashina K.
      • et al.
      Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma.
      ]. For that reason, one may think that locoregional therapies could have a role in the treatment of patients with a limited burden of disease outside the liver. However, the available evidence shows that extrahepatic disease has a negative impact on prognosis after radioembolization. Median survival was 7.4 months (95% CI 4.3–13.1) in the European series [
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after (90) Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: a European evaluation.
      ] and 5.4 months (95% CI 2.7–7.5) in the US series [
      • Salem R.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Riaz A.
      • Ryu R.K.
      • Ibrahim S.
      • et al.
      Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
      ] which is not far from the median time to response of 6.6 months [
      • Salem R.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Riaz A.
      • Ryu R.K.
      • Ibrahim S.
      • et al.
      Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.
      ]. Yet, the combination of radioembolization and sorafenib is worth investigating in this subgroup of patients with a grim prognosis.

      Intermediate and early stages

      Those guidelines that endorse the BCLC staging system recommend TACE as first-line therapy for asymptomatic patients with multinodular unresectable tumors whose liver function is not severely compromised. The scientific evidence supporting this recommendation is based on the results from two positive randomized controlled trials [
      • Llovet J.M.
      • Real M.I.
      • Montana X.
      • Planas R.
      • Coll S.
      • Aponte J.
      • et al.
      Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.
      ,
      • Lo C.M.
      • Ngan H.
      • Tso W.K.
      • Liu C.L.
      • Lam C.M.
      • Poon R.T.
      • et al.
      Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.
      ] and two further metanalyses of patients treated with TACE or bland embolization [
      • Camma C.
      • Schepis F.
      • Orlando A.
      • Albanese M.
      • Shahied L.
      • Trevisani F.
      • et al.
      Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials.
      ,
      • Llovet J.M.
      • Bruix J.
      Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival.
      ]. The population recruited in these positive trials, nevertheless, includes a substantial proportion of patients in the early stage (single tumors), and most patients in the intermediate stage had single-lobe involvement that could be selectively embolized. Accordingly, the indication for tumor embolization sits astride the early and intermediate stages. Moreover, TACE is performed with very different indications and procedures worldwide, and this heterogeneity may help explain the wide differences in 2-year survival rates observed in prospective randomized trials (24–63%) as well as in retrospective series (11–47%) [
      • Sangro B.
      • D’Avola D.
      • Inarrairaegui M.
      • Prieto J.
      Transarterial therapies for hepatocellular carcinoma.
      ].
      Most patients in the intermediate stage that have received radioembolization as first-line therapy are those generally considered to be poor candidates for TACE. Poor candidates are usually those with bulky disease confined to the liver that still have a normal performance status and usually have a single large nodule or more than 5 nodules affecting both lobes [
      • Raoul J.L.
      • Sangro B.
      • Forner A.
      • Mazzaferro V.
      • Piscaglia F.
      • Bolondi L.
      • et al.
      Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization.
      ]. Although there is very scarce information on the results in this individual subgroup of patients, an encouraging median survival of 15.4–16.6 months has been reported for BCLC B patients with bilobar disease or more than 5 nodules, respectively [
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after (90) Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: a European evaluation.
      ]. In fact, it does not differ much from the median survival of 15.6–17.4 months observed in the very few series that describe the survival of patients treated by TACE according to BCLC stage [
      • Chen C.H.
      • Hu F.C.
      • Huang G.T.
      • Lee P.H.
      • Tsang Y.M.
      • Cheng A.L.
      • et al.
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      ,
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Kulik L.M.
      • Riaz A.
      • Ryu R.K.
      • Baker T.B.
      • et al.
      Chemoembolization for hepatocellular carcinoma: comprehensive imaging and survival analysis in a 172-patient cohort.
      ,
      • Wang J.H.
      • Changchien C.S.
      • Hu T.H.
      • Lee C.M.
      • Kee K.M.
      • Lin C.Y.
      • et al.
      The efficacy of treatment schedules according to Barcelona Clinic Liver Cancer staging for hepatocellular carcinoma – Survival analysis of 3892 patients.
      ] (Fig. 5). Survival is even better for those patients that are ideal candidates to TACE, with median overall survival of 22.8 (95% CI 13.6–36.0) for patients with 1–5 nodules and 23.2 months (95% CI 13.6–not reached) for tumors affecting a single lobe [
      • Sangro B.
      • Carpanese L.
      • Cianni R.
      • Golfieri R.
      • Gasparini D.
      • Ezziddin S.
      • et al.
      Survival after (90) Y resin microsphere radioembolization of hepatocellular carcinoma across BCLC stages: a European evaluation.
      ].
      In this setting, very recently, Salem et al. [
      • Salem R.
      • Lewandowski R.J.
      • Kulik L.
      • Wang E.
      • Riaz A.
      • Ryu R.K.
      • et al.
      Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma.
      ] have reported the retrospectively compared outcomes of patients treated exclusively by TACE or radioembolization in their institution that lacked portal vein thrombosis or extrahepatic disease. This series includes mainly patients with intermediate (53%) or early (35%) tumors treated in the same period (2001–2010), in which treatment allocation was decided by a multidisciplinary team. Median overall survival for TACE- and radioembolization-treated patients in the whole cohort was not significantly different (17.4 months for TACE vs. 20.5 months for radioembolization). When patients in the intermediate stage were evaluated separately, the hazard ratio for death in the radioembolization cohort was 0.86 (p = 0.579) in the multivariate analysis (the actual median overall survival for this population being 17.2 months (95% CI 13.5–29.6) in a previous report on the same group for patients). These comparable results in early- and intermediate-stage patients treated by radioembolization or TACE are consistent with other studies reporting that the survival of patients with early or intermediate tumors treated by locoregional therapies is very similar [
      • D’Avola D.
      • Inarrairaegui M.
      • Pardo F.
      • Rotellar F.
      • Marti P.
      • Bilbao J.I.
      • et al.
      Prognosis of hepatocellular carcinoma in relation to treatment across BCLC stages.
      ]. Two other recent series [
      • Carr B.I.
      • Kondragunta V.
      • Buch S.C.
      • Branch R.A.
      Therapeutic equivalence in survival for hepatic arterial chemoembolization and yttrium 90 microsphere treatments in unresectable hepatocellular carcinoma: a two-cohort study.
      ,
      • Kooby D.A.
      • Egnatashvili V.
      • Srinivasan S.
      • Chamsuddin A.
      • Delman K.A.
      • Kauh J.
      • et al.
      Comparison of yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma.
      ] have reported a similar survival in TACE- and radioembolization-treated patients, but they included at least 30–50% of patients with portal vein thrombosis.
      Patients in the early stage have been treated by 90Y most usually as a bridge to liver transplantation or as a palliative therapy for unresectable, unablatable tumors. In a preliminary study by Riaz et al. [
      • Riaz A.
      • Kulik L.
      • Lewandowski R.J.
      • Ryu R.K.
      • Giakoumis Spear G.
      • Mulcahy M.F.
      • et al.
      Radiologic–pathologic correlation of hepatocellular carcinoma treated with internal radiation using yttrium-90 microspheres.
      ], none of 15 patients at UNOS T2 stage progressed to T3 stage prior to transplantation, while 8 out of 10 patients were down-staged from T3 to T2 stage. Although these are encouraging results, we lack information about the rate of therapeutic success among those patients that are treated to avoid drop-out due to tumor progression after inclusion in the waiting list. When the explanted livers were studied, 100% tumor necrosis was observed in 89% of lesions smaller than 3 cm and 65% of lesions 3–5 cm in size [
      • Riaz A.
      • Kulik L.
      • Lewandowski R.J.
      • Ryu R.K.
      • Giakoumis Spear G.
      • Mulcahy M.F.
      • et al.
      Radiologic–pathologic correlation of hepatocellular carcinoma treated with internal radiation using yttrium-90 microspheres.
      ]. These numbers compare well with those 35–57% and 17–42% observed after TACE, respectively [
      • Golfieri R.
      • Cappelli A.
      • Cucchetti A.
      • Piscaglia F.
      • Carpenzano M.
      • Peri E.
      • et al.
      Efficacy of selective transarterial chemoembolization in inducing tumor necrosis in small (<5 cm) hepatocellular carcinomas.
      ,
      • Riaz A.
      • Lewandowski R.J.
      • Kulik L.
      • Ryu R.K.
      • Mulcahy M.F.
      • Baker T.
      • et al.
      Radiologic-pathologic correlation of hepatocellular carcinoma treated with chemoembolization.
      ]. However, tumor necrosis after neoadjuvant treatment in the transplant setting is a highly controversial issue with some series reporting minimal incidence of complete necrosis for any intra-arterial or percutaneous therapy [
      • Marin H.L.
      • Furth E.E.
      • Olthoff K.
      • Shaked A.
      • Soulen M.C.
      Histopathologic outcome of neoadjuvant image-guided therapy of hepatocellular carcinoma.
      ,
      • Mazzaferro V.
      • Battiston C.
      • Perrone S.
      • Pulvirenti A.
      • Regalia E.
      • Romito R.
      • et al.
      Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study.
      ].
      There is substantial evidence that in the vast majority of cases, radioembolization is followed by a reduction in the size of targeted lesions [
      • Sangro B.
      • Bilbao J.I.
      • Boan J.
      • Martinez-Cuesta A.
      • Benito A.
      • Rodriguez J.
      • et al.
      Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma.
      ,
      • Riaz A.
      • Kulik L.
      • Lewandowski R.J.
      • Ryu R.K.
      • Giakoumis Spear G.
      • Mulcahy M.F.
      • et al.
      Radiologic–pathologic correlation of hepatocellular carcinoma treated with internal radiation using yttrium-90 microspheres.
      ]. Moreover, it has been reported that lobar radioembolization can induce hypertrophy of the remnant segments of the liver [
      • Gaba R.C.
      • Lewandowski R.J.
      • Kulik L.M.
      • Riaz A.
      • Ibrahim S.M.
      • Mulcahy M.F.
      • et al.
      Radiation lobectomy: preliminary findings of hepatic volumetric response to lobar yttrium-90 radioembolization.
      ]. These two facts may make it possible to undertake a radical therapy that was not deemed indicated upfront by performing percutaneous ablation, surgical resection or even liver transplantation. Application of radical therapies after successful response to radioembolization has been described in different settings [
      • Lau W.Y.
      • Leung W.T.
      • Ho S.
      • Leung N.W.
      • Chan M.
      • Lin J.
      • et al.
      Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study.
      ,
      • Ettorre G.M.
      • Santoro R.
      • Puoti C.
      • Sciuto R.
      • Carpanese L.
      • Antonini M.
      • et al.
      Short-term follow-up of radioembolization with yttrium-90 microspheres before liver transplantation: new perspectives in advanced hepatocellular carcinoma.
      ,
      • Kulik L.M.
      • Mulcahy M.F.
      • Hunter R.D.
      • Nemcek Jr., A.A.
      • Abecassis M.M.
      • Salem R.
      Use of yttrium-90 microspheres (TheraSphere) in a patient with unresectable hepatocellular carcinoma leading to liver transplantation: a case report.
      ]. Among patients in the UNOS T3 stage, downstaging into radical therapies was reported in as many as two thirds of patients [
      • Kulik L.M.
      • Atassi B.
      • van Holsbeeck L.
      • Souman T.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • et al.
      Yttrium-90 microspheres (TheraSphere) treatment of unresectable hepatocellular carcinoma: downstaging to resection, RFA and bridge to transplantation.
      ]. This same group reported that downstaging of HCC from UNOS T3 to T2 stage was achieved more frequently with radioembolization than with TACE (58% vs. 31%, p = 0.023) [
      • Lewandowski R.J.
      • Kulik L.M.
      • Riaz A.
      • Senthilnathan S.
      • Mulcahy M.F.
      • Ryu R.K.
      • et al.
      A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization.
      ]. Since down-staging is influential only if it translates into a better outcome, we have analyzed the outcomes of those UNOS T3 patients that were treated radically after radioembolization. Noteworthy, their 5-year survival rate of 71% is quite comparable to what can be expected from radical therapies applied as first-line treatment (personal data).

      Inclusion in the treatment paradigm and future prospects

      Once again, it should be taken into account that the use of radioembolization in HCC is only supported by level II-2 evidence (obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group) and II-3 evidence [

      Force UPST. Guide to clinical preventive services: report of the US Preventive Services Task Force. In: Publishing D, editor; 1998. p. 24.

      ]. Yet, with very consistent results in large series coming from different institutions worldwide, radioembolization sits in between TACE and sorafenib waiting to be positioned in treatment algorithms for the treatment of unresectable HCC.
      Due to the high dose of radiation that can be safely delivered to partial liver volumes [
      • Riaz A.
      • Gates V.L.
      • Atassi B.
      • Lewandowski R.J.
      • Mulcahy M.F.
      • Ryu R.K.
      • et al.
      Radiation segmentectomy: a novel approach to increase safety and efficacy of radioembolization.
      ], radioembolization is a valuable alternative to TACE for those tumors in the earliest stages that are not amenable to percutaneous ablation because of location in the dome, the surface of the liver or the vicinity of large bile ducts or blood vessels. A prospective randomized trial is currently studying the role of sorafenib as an adjunct to radioembolization in the treatment of HCC patients in the waiting list for liver transplantation (NCT00846131). Furthermore, the US large scale randomized PREMIERE trial is comparing radioembolization with radiofrequency ablation, TACE or its combination for patients with unresectable HCC and a preserved liver function (NCT00956930) with response rate at 6 months and time to progression being the main endpoints in patients with ablatable and non-ablatable disease, respectively. For the typical TACE candidate, radioembolization is not likely to offer any significant advantage in survival. It has been calculated that more than 1000 patients would be needed to power a head-to-head equivalence trial against TACE with overall survival as the main endpoint [
      • Lewandowski R.J.
      • Kulik L.M.
      • Riaz A.
      • Senthilnathan S.
      • Mulcahy M.F.
      • Ryu R.K.
      • et al.
      A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization.
      ]. However, radioembolization seems to be better tolerated than TACE with statistically significant differences in terms of abdominal pain [
      • Lewandowski R.J.
      • Kulik L.M.
      • Riaz A.
      • Senthilnathan S.
      • Mulcahy M.F.
      • Ryu R.K.
      • et al.
      A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization.
      ], length of hospital stay [
      • Kooby D.A.
      • Egnatashvili V.
      • Srinivasan S.
      • Chamsuddin A.
      • Delman K.A.
      • Kauh J.
      • et al.
      Comparison of yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma.
      ] and post-embolization symptoms [
      • Goin J.E.
      • Dancey J.E.
      • Roberts C.A.
      • Sickles C.J.
      • Leung D.A.
      • Soulen M.C.
      Comparison of post-embolization syndrome in the treatment of patients with hepatocellular carcinoma: trans-catheter arterial chemo-embolization versus yttrium-90 glass microspheres.
      ]. Quality of life has been prospectively explored in two studies, a non-randomized US trial including patients with primary and secondary liver tumors (NCT00739167) and SIRTACE (NCT00867750), a European randomized clinical trial in which quality of life after TACE and radioembolization was compared. Both trials have finished recruitment and the results will very soon help answer this question. Certainly, radioembolization is an appealing alternative for those unresectable patients that are poor candidates to TACE because of numerous or large tumors. In this setting, the combination with systemically-acting sorafenib merits investigation in future clinical trials.
      With similar survival rates across different subgroups of patients, the good toxicity profile of radioembolization may make it an appealing alternative to, or what is more, a charming companion for sorafenib. Two different investigator-initiated international, large-scale randomized controlled trials with overall survival as major endpoint are exploring these possibilities. In the Asia–Pacific SIRveNIB trial, radioembolization and sorafenib are compared head-to-head for patients without extrahepatic disease (NCT01135056). In the European SORAMIC trial, the combination of radioembolization and sorafenib is being compared to sorafenib alone among patients not suitable for TACE, even in the presence of extrahepatic disease other than lung metastases (NCT01126645). Until the results of these trials become available, radioembolization could certainly be considered an option as good as sorafenib for those patients in the advanced stage that have a fairly preserved liver function and single lesions invading a segmental or lobar portal vein branch.
      As for any other therapy, effectiveness of radioembolization has to balance cost and availability. Radioembolization is a sophisticated therapy that requires the formation of a network of different specialists in Interventional Radiology, Nuclear Medicine or Radiotherapy, and Hepatology, Medical Oncology or Surgery. All the same, it is not an inexpensive therapy. The high cost of radioactive microspheres should, however, be weighed against the need to perform more sessions in a typical TACE treatment [
      • Kooby D.A.
      • Egnatashvili V.
      • Srinivasan S.
      • Chamsuddin A.
      • Delman K.A.
      • Kauh J.
      • et al.
      Comparison of yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma.
      ], particularly if the also costly drug-eluting beads are used, and against the increasing costs of biological therapies for cancer. Prospective evaluations are really needed in this respect and should be promoted by collaborative groups.
      Figure thumbnail fx4

      Conflict of interest

      B.S. received lecture fees from Sirtex Medical Europe GmBH.

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