Yttrium 90 radioembolization for the treatment of hepatocellular carcinoma: Biological lessons, current challenges, and clinical perspectives

Hepatocellular carcinoma (HCC) is the sixth-most common malignancy diagnosed worldwide.1 Late-stage presentation, comorbidities, and limited donor availability enables only 10% of patients to receive curative therapies. Hence, there exists a critical need for novel treatments addressing HCC at all stages. During the last decade, several transarterial locoregional therapies have been developed. One of these, yttrium-90 (90Y) radioembolization, has matured into a recognized treatment option, with a demonstration of a clear palliative role by inducing necrosis and delaying progression.2-8 This overview will describe the biological rationale for 90Y, highlight seminal data, propose research questions, and discuss the future role of 90Y in HCC. HCC is a tumor that arises almost exclusively in cirrhosis caused by viruses, alcohol, or non-alcohol-related steatohepatitis, insulin-resistant metabolism, autoimmunity, and others. Therefore, survival of HCC patients is related to the tumor and underlying liver condition. In fact, genomic data coded in nontumoral cirrhotic tissue have shown the ability to determine risk of tumor recurrence after resection or ablation; this explains the tendency of HCC to recur and develop de novo tumor foci usually confined within the liver during the history of the disease.9 The observation that HCC is mostly a liver-limited cancer has allowed the development of a wide range of therapeutic strategies aimed at locoregional approaches and organ replacement by means of transplantation.10 Experience gained in recent years indicates that HCC is truly a radiosensitive tumor. External irradiation (electrons, protons, and carbon) produces significant tumor responses in patients with HCC.11 Limitations to its clinical applicability are determined by the coexisting intense radiosensitivity of normal liver tissue, precluding the irradiation of large liver volumes with doses >35-40 Gy.12 Intra-arterial (IA) radiation therapies were developed in an attempt to capitalize on the arterial perfusion of HCC, with the aim of delivering tumoricidal doses to liver tumors irrespective of number, size, and location (sparing normal parenchyma). Radioembolization is a term proposed by a panel of experts to define those procedures in which radioactive microspheres are injected IA for internal radiation purposes.13 It is the artery in which microspheres are injected that defines the volume of liver tissue exposed to radiation (intravascular brachytherapy). Contrary to transarterial chemoembolization (TACE), in which a combination of drug and ischemia are likely to drive the antitumor effect, 90Y effects are predominantly caused by the radiation effect, with a minor contribution from microembolization.14 Given this mechanism of action, patients with macrovascular invasion may be treated. The commercially available microspheres include resin (SIR-Spheres; SIRTeX Medical, Lane Cove, NSW, Australia) or glass (TheraSphere; Nordion, Ottawa, Ontario, Canada); both are loaded with 90Y, a pure beta emitter (i.e., no isolation or radioprotection). 90Y is a high-energy radiation source with a short half-life (2.67 days) and a short tissue penetration (2.5 mm). Within 2 weeks after injection, >95% of the radiation has been deposited. Glass and resin microspheres differ in several characteristics (specific activity and number of spheres). Despite these differences, clinical outcomes appear equivalent.15 The biological effects of radiotherapy are mediated by the absorbed dose (energy absorbed/unit mass). With 90Y, absorbed dose may be heterogeneous, depending on hemodynamics and variable intratumoral vessel density within each liver tumor.16 Despite this heterogeneity, most injected microspheres are preferentially absorbed into the tumor microvasculature in a 3:1 to 20:1 ratio, compared to the normal liver, with a preferential deposition in the periphery of nodules (dose, >500 Gy).17, 18 Exposure to radiation then produces irreversible cell damage in tumor epithelial, stromal, and endothelial cells (ECs) that ultimately leads to compromised tumor growth. In mouse models, radiation preferentially damages ECs of the gut microvasculature, suggesting that ECs may represent the principal targets for radiation and that the death of epithelial stem cells may be a secondary event in gastrointestinal (GI) toxicity.19 Similarly, it has been proposed that tumor cell death in response to radiotherapy may represent a secondary event after the death of ECs.20 High doses to hyperperfused tissue suggest that vessel damage may be key to the antitumoral effect of 90Y. Heterogeneous deposition of microspheres results in a variability of dosimetric considerations. In radioembolization, millions of 90Y sources are infused into the arterial vasculature. To predict ultimate 90Y deposition, a simulation angiogram is performed 1-2 weeks before treatment using 20-100 micron-sized technetium-99m-labeled macroaggregated albumin (Tc-MAA) particles. Planar and single-photon emission computed tomography (SPECT) gamma-camera imaging are then used to measure hepatopulmonary shunting to determine the average radiation dose that will be delivered to tumor and nontumor areas. There is variability in correlating between Tc-MAA and actual microsphere deposition (Spearman's correlation: 0.45-0.82).21 Furthermore, the resulting estimates reflect the average dose for a certain volume and not the actual dose, as calculated for external or interstitial radiotherapy. Historically, activity measured with intraoperative probes did correlate with the actual dose of radiation delivered and with Tc-MAA planar scintigraphy.22 Although the threshold absorbed dose resulting in objective tumor response remains a point of debate and depends on tumor type, vascularity, previous systemic agents, and use of radiosensitizers, tumor responses have been reported with doses as low as 40 Gy.23 These limitations in dosimetry do not impede the clinical use of 90Y. Tumor shrinkage occurs almost invariably after 90Y using the current methods for activity calculation.8, 13 Research concepts based on tumor and nontumor dosimetry methods applied to Tc-MAA planar and/or SPECT imaging have been proposed and await external validation.24, 25 As is well known with radiotherapy, it may take 3-6 months for the optimal response (i.e., size reduction) to manifest; consequently, median time to response is 6.6 (size) and 1.2 months (necrosis).3, 8, 26 Progression is often the result of new lesions (intra- or extrahepatic) or within the treated area, because microscopic nests of tumor cells are unlikely to have been affected by 90Y given their lack or arterialization.8 Reported median time to progression (TTP) ranges from 7.9 to 10.0 months (entire cohort) and from 11.8 to 15.5 months for patients with absent portal vein invasion.3, 27 However, given unpredictable tumor biology, early progression may be anticipated by baseline tumor characteristics (e.g., multinodularity, bilobar disease, vascular invasion, or elevated alpha-fetoprotein [AFP]).28 Identifying early progressors is important, because the role of systemic agents may be essential in improving long-term outcomes. Coexistence of HCC and cirrhosis affects 90Y outcomes in a manner similar to other treatments. Although vascular changes in the cirrhotic liver (arterioportal or venous shunts) may result in higher chances of technical contraindications, reduced functional reserve (increasing the risk of liver failure) after radiation mandates the adoption of technical methods maximizing parenchymal sparing.29 Imprecise dosimetry models that plague most arterial treatments hinder dose-tolerance analyses. In a three-dimensional liver model, absorbed dose was higher around the portal area than the central venules, potentially explaining the higher 90Y tolerance, compared to external beam irradiation.30 These models assume that microspheres are lodged in the distal arterial branches and uniformly scattered throughout the entire liver parenchyma without clustering. In contrast, microspheres can be found in portal and hepatic veins in normal liver and in fibrotic septa of cirrhotic livers, where they may form clusters and distribute heterogeneously. Hence, given these limitations, a precise dose-event relationship in liver tolerance remains elusive. Despite this, there is general agreement to limit the parenchymal dose to <50 Gy.7 Aside from isolated benign changes in liver function, a form of sinusoidal obstruction syndrome appearing 4-8 weeks after 90Y manifest as jaundice and mild ascites, and a moderate increase in gamma-glutamyl transpeptidase/alkaline phosphatase has been described in patients without cirrhosis as radioembolization-induced liver disease (REILD).31 This syndrome may also appear in 0%-33% of patients with cirrhosis treated in a whole-liver fashion and in 8%-15% of those in which only a partial volume is targeted.32 In the largest series published, grade 3 or higher bilirubin levels were observed within 3 months after therapy in 6%-14%.3, 7 Although a causal relationship could only be confirmed in controlled clinical trials, it is very likely that the increased bilirubin levels reflect some kind of REILD. This is further supported by the fact thcat increased bilirubin is not associated with changes in synthetic liver function (i.e., decreased albumin and prothrombin activity).7 Nonetheless, these findings underscore the acceptable safety profile of 90Y in HCC. Furthermore, other more-comprehensive definitions of liver decompensation in patients receiving 90Y may be considered. For instance, extending the recording of adverse events as potentially related to 6 months will provide a conservative estimate.33 Although such an extended definition of toxicity may inform prospective clinical trials on 90Y, it also gives rise to overestimations of REILD, because deterioration of liver function and performance status may occur in intermediate-advanced HCC, independently from any anticancer treatment. Over the last 10 years, there has been significant scientific advancement in the field of 90Y. Standardization of the practice and assessment of indications has transformed radioembolization from a procedure relying on local expertise to a routine procedure yielding predictable results in properly trained centers. Early series were limited by sample size, with a 43- and 24-patient series describing outcomes in small cohorts.6, 8, 28 Since then, seven well-controlled investigations establishing the safety and antitumoral effect of 90Y have been published; these will be presented temporally (Table 1). One of the common indications for 90Y that has emerged is HCC with portal venous thrombosis (PVT). Because 90Y is a microembolic procedure causing minimal occlusion of hepatic arteries, it may be safely used in the setting of PVT.34 This is a relevant clinical scenario, because PVT significantly increases the chances of extrahepatic spread.9 Given this interest, the first large-series analysis was a phase II study by Kulik et al. analyzing 90Y in 108 HCC patients with (34%) and without PVT (66%). Partial response rates of 42.2% (size) and 70% (necrosis) were reported.34 Survival varied by location of PVT and presence of cirrhosis. This study was important given its multicenter nature, challenging preconceived notions that embolotherapy could not be applied in the setting of PVT (ischemic hepatitis). Because 90Y is microembolic, this study reintroduced the idea of embolotherapy in the context of vascular invasion.14 Recently, mature long-term outcomes for PVT patients treated with 90Y in the sorafenib era were updated.35 It is unknown whether treating patients with PVT has any effect on metastatic dissemination, regardless of the response in the tumor thrombus. In 2010, a detailed review of the pathologic findings subsequent to 90Y treatment was presented by Riaz et al. in patients bridged or downstaged to transplantation.26 The intent was to examine the antitumoral effect of 90Y, a pathological proof of concept. This analysis demonstrated a very high rate (89%) of complete pathologic necrosis (CPN) in smaller lesions (1-3 cm) and a promising rate of CPN in larger lesions (65%; 3-5 cm) (independent pathology review). These data were compared to the CPN achieved in an identical pathology review of HCC after conventional TACE,36 confirming that 90Y could achieve better antitumoral effect (pathology), when compared with the standard of care (TACE), thereby introducing a new tool to the armamentarium of downstaging strategies. In 2010, the seminal experience from Northwestern University confirmed the positive outcomes of 291 patients with HCC treated with 90Y. This was a prospective, 5-year cohort study not only investigating long-term outcomes, but also presenting imaging follow-up, response rate (size and necrosis), TTP, and survival stratified by Child-Pugh, United Network for Organ Sharing (UNOS), and Barcelona Clinic Liver Cancer (BCLC). Child-Pugh A (with or without PVT) and Child-Pugh B (without PVT) potentially benefitted from treatment. TTP was longer for Child-Pugh A and B without PVT (15.5 and 13 months, respectively), when compared with those with PVT (5.6 and 5.9 months, respectively). As expected, survival was negatively affected by liver function (Child-Pugh A: 17.2 months; Child-Pugh B: 7.7 months; P = 0.002). TTP and overall survival (OS) varied by important, this study was the first to in a response TTP, and survival by Child-Pugh, and This of in phase II has and of 90Y In the last years, have also confirmed the safety and of 90Y. et al. 90Y in 108 patients with observed complete and partial response by necrosis in and with disease in TTP was 10.0 months, with of This was the first study the technical of outcomes, when compared to the clinical outcomes were suggesting the outcomes on local as considered. these findings a for controlled trials with or without systemic agents in The largest study of 90Y in HCC was by et al. in This was a cohort review of was months A: months; B: months; 10.0 on analysis performance tumor and extrahepatic were gained from this Despite its nature, this was the first study with a significant number of with data between multicenter in data were very to glass confirming that radiation to be the mechanism of outcomes data were stratified by critical for the of clinical trials using this suggest that is the standard of care for patients with Although this is recognized by for the HCC have this within the and suggesting a role for 90Y in the Given the in 90Y a large study was in This compared and 90Y patients TTP, and The were well by Child-Pugh, and with in the 90Y cohort a for better response P = and longer TTP with 90Y months; months; P = However, no survival could be months; months; P = important were from this there was no survival radioembolization was to provide better disease with toxicity than TTP has been as a of this study did not to provide in of this given the of long-term survival outcomes, the findings into the of a study between 90Y and a sample to Given the of sorafenib as the standard of care for patients disease, the of a pure (without Hence, most have to 90Y for disease, because the secondary of 90Y, clinical of and have been in the presented the prospective phase II study to 90Y in patients with or a TTP of months and survival of patients were downstaged to resection Furthermore, survival of PVT patients did not differ from This study further the of 90Y controlled investigations and survival outcomes in patients with liver function and vascular Given the lack of clinical the sorafenib combination study recent in 90Y with sorafenib has been and the development of and combination with sorafenib in patients with There to be clinical in 90Y as a treatment for HCC. However, of the has been challenging the of with 90Y and a of be for 90Y into treatment Although the of and the Cancer have recognized 90Y as a treatment option, the and for the of the Liver have A recent at the Liver Cancer in the that have been several years when to the of with 90Y to achieve the for These are It is that for new therapies to controlled research investigations are important include and multicenter Furthermore, the of new approaches is important as is the of Given this of 90Y be Over the and a the use of radioactive microspheres for patients with HCC. To this in this was before the and adoption of the of the seminal establishing that a survival and the of sorafenib This mechanism was at the there were no agents for HCC In for 90Y in liver was also However, it was recognized that be to Hence, in an phase 90Y with care in HCC was During the review and the positive findings of sorafenib study were The HCC with sorafenib the standard of care in The study was on However, given the phase II and safety profile in patients with the the for 90Y to include PVT.34 Therefore, in the the first for the treatment of HCC was 90Y. This 40 years after the first in HCC using the Despite these from the and research of HCC, the for 90Y has to resulting in similar not survival in this 90Y is of the significant effects of These to treatment and dose or in patients the of in the analysis of the phase median 108 patients with PVT receiving sorafenib was months and disease rate was for patients with Child-Pugh A and PVT treated by 90Y (Table median between 10 and months with of Given this the limitations of as well as the need for higher of several phase have been (Table of sorafenib in combination with local by in patients with carcinoma and of Intra-arterial in the of with Hepatocellular both 90Y when to of in Hepatocellular sorafenib radioembolization in carcinoma and a prospective clinical of 90Y radioembolization sorafenib for the treatment of HCC with portal vein thrombosis all sorafenib to 90Y. These trials further the phase II resulting in advancement to phase trials in B disease are challenging given the history of disease, large sample to survival differences, as well as the that invariably occurs at In fact, some have that survival is not an when subsequent therapies with survival are further with the survival time in patients treated with These further suggest that B is a with such survival in the of This was by an review Despite this, of Radioembolization and in Hepatocellular is a phase II and 90Y in disease (Table Furthermore, the use of clinical and within the will be in prospective using 90Y as the These will tumor in which of results have such as Child-Pugh for after downstaging University of and performance One of the with 90Y is that as an it a when compared with often with and The is for a from to for syndrome resulting from or arterial usually 1-2 weeks for overall depending on their baseline performance In 90Y a angiogram to and the vascular 90Y treatment also in often without the need for or Hence, for therapies and that the in and in during the These were confirmed in a prospective phase II study and 90Y using The study demonstrated that patients performance status to 90Y, 90Y by As clinical experience has been gained with this several have novel with 90Y. Although these have not been in the multicenter they are of clinical and of in this review The first novel to for HCC and is in to the ability of radiation doses to small of liver tissue than achieved using external this small of liver, usually for or but because of comorbidities, and liver can be using 90Y. The of liver with time and on imaging on the is observed in patients with disease potentially to curative but because of small future liver Although the of inducing is portal vein rates are in cirrhosis. In this treating the disease with 90Y to potentially important clinical The tumor is treated is not the as the HCC with a of portal venous with rates of in future and weeks for to be manifest mandates a of those patients that be by Although the and of by 90Y is the of it is a fact that 90Y may anticancer and effects on the liver will to be in patients to approaches not only in HCC, but also in of liver 1). The novel the downstaging to liver To have demonstrated the ability of 90Y to patients from to The first series demonstrated a downstaging The a study in demonstrated better downstaging of 90Y, when compared with P This is by the high antitumoral effect of 90Y and size In a of response when compared with was reported P = High response rates by necrosis and size have been suggesting that 90Y tool for downstaging 90Y could represent an to intermediate-advanced tumors within when tumor response 6 months has been supported by and These and in of with to indications for It is often that from a research 90Y is a that with in because both are transarterial and the of However, this is not by HCC 90Y into a role in 90Y in A is in by higher compared to and by the concepts of and and downstaging For are also because differences, as well as of at result in in the effect on PVT observed with rationale for with and to 3 90Y indications and that are by Radioembolization a promising treatment challenging the current of HCC treatment. have data that suggest high antitumoral effect, downstaging to clinical in survival using an or of and of patients liver to with resection of the future liver Although clinical development has been the years will important as results from the phase trials further define the role of 90Y in treatment