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

Authors

  • Riad Salem,

    Corresponding author
    1. Department of Radiology, Section of Interventional Radiology and Division of Interventional Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL
    • Address reprint requests to: Riad Salem, M.D., M.B.A., Division of Interventional Oncology, Department of Radiology, Northwestern University, 676 North St. Clair, Suite 800, Chicago, IL 60611. E-mail: r-salem@northwestern.edu; fax: 312-695-0654.

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    • All authors contributed equally to this review.

  • Vincenzo Mazzaferro,

    1. Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Istituto Nazionale Tumori IRCCS, Milan, Italy
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    • All authors contributed equally to this review.

  • Bruno Sangro

    1. Liver Unit, Clinica Universidad de Navarra, and Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Pamplona, Spain
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    • All authors contributed equally to this review.


  • R.S. is funded in part by the National Institutes of Health (grant no.: CA126809). V.M. is funded by the Italian Association for Cancer Research.

  • Potential conflict of interest: Dr. Sangro consults and is on the speakers' bureau for Sirtex Medical. Dr. Mazzaferro is on the speakers' bureau for and received grants from Bayer and Nordion. Dr. Salem consults, advises, and is on the speakers' bureau for Nordion. He consults for and advises Bayer and Sirtex Medical.

Abbreviations
AFP

alpha-fetaprotein

BCLC

Barcelona Clinic Liver Cancer

CI

95% confidence interval

CPN

complete pathologic necrosis

DCR

disease control rate

ECs

endothelial cells

FDA

U.S. Food and Drug Administration

GI

gastrointestinal

HCC

hepatocellular carcinoma

IA

intra-arterial

LT

liver transplantation

PREMIERE

Prospective Randomized Trial of Radioembolization and Chemoembolization in Hepatocellular Carcinoma

OS

overall survival

PVE

portal vein embolization

PVT

portal venous thrombosis

RCTs

randomized, controlled trials

REILD

radioembolization-induced liver disease

SARAH

sorafenib versus radioembolization in advanced hepatocellular carcinoma

SIRveNIB

Phase III Multicenter Open-label Randomized Trial of Selective Internal Radiation Therapy versus Sorafenib in Locally Advanced Hepatocellular Carcinoma

SORAMIC

evaluation of sorafenib in combination with local micro-therapy guided by Gd-EOB-DTPA enhanced MRI in patients with inoperable hepatocellular carcinoma

SPECT

single-photon emission computed tomography

STOP-HCC

Phase III Clinical Trial of Intra-arterial TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma

TACE

transarterial chemoembolization

Tc-MAA

technetium-99m-labeled macroaggregated albumin

TTP

time to progression

UCSF

University of California San Francisco

UNOS

United Network for Organ Sharing

90Y

yttrium-90 radioembolization

YES-p

a prospective randomized clinical trial of 90Y radioembolization versus sorafenib for the treatment of advanced HCC with portal vein thrombosis

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.

Biological Rationale

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.

Review of Seminal Data and Comparative Effectiveness

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).

Table 1. Summary of Large Series Reporting On Long-Term Outcome After 90Y Radioembolization
  Intermediate StageBranch PVTMain PVTBranch or Main PVT
ReferenceChild-PughNOSa (95% CI)NOS (95% CI)NOS (95% CI)NOS (95% CI)
  1. 95% CI, 95% confidence interval; NC, not calculable.

  2. a

    Months.

  3. b

    Unpublished data for branch and main PVT cohorts provided by authors.

Hilgard et al.[27] (N = 108)A/B5116.4 (12.1-NC)  3310 (6-NC)
Salem et al.[3] (N = 291)A4817.3 (13.7-32.5)1916.6 (8.8-24)167.7 (3.3-13.2)3510.4 (7.2-16.6)
B3513.5 (6.4-25.4)276.5 (5-8.5)304.5 (2.9-6.6)575.6 (4.5-6.7)
Sangro et al.[7] (N = 325) bA8218.4 (13.6-23.2)4410.7 (8.3-17.1)329.7 (4.8-11.8)7610.2 (7.7-11.8)
B53.6 (2.4-10.8)
Mazzaferro et al.[33] (N = 51)A1518 (13-38)2317 (13-21)59 (4-NC)  
B268 (5-10)15  

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 patient stage.[3] Most important, this study was the first to outline, in a structured manner, expected response rate, TTP, and survival by Child-Pugh, UNOS, and BCLC. This granularity of detail in phase II has permitted hypothesis generation and statistical powering of 90Y studies.

In the last few years, European studies have also confirmed the safety and efficacy of 90Y. Hilgard et al. analyzed 90Y in 108 consecutive patients with advanced HCC.[27] They observed complete and partial response by necrosis criteria in 3% and 37%, respectively, with stable disease in 53%. TTP was 10.0 months, with OS of 16.4 months. This was the first study validating the technical reproducibility of outcomes, when compared to the 291-patient cohort. Also, clinical outcomes were similar, suggesting the consistent outcomes less dependent on local expertise, as previously considered. Finally, these findings provided a more compelling case for randomized, controlled trials (RCTs) with or without systemic agents in advanced HCC.[37]

The largest study of 90Y in HCC was published by Sangro et al. in 2011.[7] This was a multicenter, retrospective cohort review of 325 patients. Median OS was 12.8 months (BCLC A: 24.4 months; BCLC B: 16.9 months; BCLC C: 10.0 months). Independent prognostic factors on multivariate analysis included performance status, tumor burden, international normalized ratio >1.2, and extrahepatic disease. Important observations were gained from this study. Despite its retrospective nature, this was the first study with a significant number of participating groups with reproducible data between centers (>8), validating multicenter feasibility in technically involved procedures. Also, data were very comparable to glass microspheres, confirming that radiation appears to be the dominant mechanism of action. Finally, outcomes data were displayed stratified by BCLC, critical for the design of clinical trials using this staging strategy.[38, 39]

BCLC guidelines suggest that TACE is the standard of care for patients with intermediate disease. Although this is universally recognized by clinicians caring for the HCC patient, investigators have challenged this notion, identifying possible subgroups within the intermediate stage and suggesting a role for 90Y in the same setting. Given the difficulties in performing randomized TACE versus 90Y studies, a large comparative effectiveness study was published in 2011.[2] This compared 122 TACE and 123 90Y patients (toxicity, response, TTP, and survival). The groups were well balanced by Child-Pugh, UNOS, and BCLC, with older age in the 90Y cohort (P < 0.001). Findings included fewer transaminase elevations, a strong trend for better response (90Y: 49%; TACE: 36%; P = 0.052) and longer TTP with 90Y (90Y: 13.3 months; TACE: 8.4 months; P = 0.046). However, no survival difference could be identified (90Y: 20.5 months; TACE: 17.4 months; P = 0.232). Several important conclusions were drawn from this analysis. First, although there was no survival difference, radioembolization (outpatient procedure) was able to provide better disease control (longer TTP) with less toxicity than TACE (inpatient procedure). Second, although TTP has been suggested as a potential surrogate of survival, this study did not seem to provide compelling evidence in support of this contention. Finally, given the similarity of long-term survival outcomes, the findings brought into question the feasibility of a head-to-head comparative study between 90Y and TACE, requiring a 1,000-patient sample to demonstrate equivalence. Given the advent of sorafenib as the standard of care for patients progressing beyond intermediate disease, the feasibility of a statistically pure head-to-head (without crossover) comparison appears unlikely.[38] Hence, most investigators have begun to recognize 90Y for more advanced BCLC B/early BCLC C disease, because the secondary benefits of 90Y, including clinical toxicities, quality of life, days hospitalized, and cost-effectiveness, have been explored through feasibility studies.

Most recently, in 2012, the Milan-INT group presented the first, prospective phase II study powered to investigate 90Y in 52 patients with intermediate or advanced HCC.[33] Findings included a TTP of 11 months and survival of 15 months. Some patients were downstaged to resection despite advanced stage. Furthermore, survival of PVT patients did not differ from intermediate (non-PVT) patients. This study further validated the reproducibility of 90Y under controlled investigations and reconfirmed survival outcomes in patients with well-preserved liver function and vascular invasion. Given the lack of compelling clinical evidence supporting the TACE plus sorafenib combination (SPACE study abstract, press release), recent interest in combining 90Y with sorafenib has been reconsidered and subsequently catalyzed the development of head-to-head and combination studies with sorafenib in patients with PVT.

90Y Level of Evidence and Ongoing Controversies

There continues to be growing clinical interest in 90Y as a treatment modality for HCC. However, one of the ongoing controversies has been challenging the level of evidence with 90Y (no RCTs) and a thorough discussion of what would be required for 90Y incorporation into treatment guidelines. Although the European Society of Medical Oncology and the National Comprehensive Cancer Networks have recognized 90Y as a treatment option, the American and European Associations for the Study of the Liver have not.[40-42] A recent discussion at the International Liver Cancer Association meeting in Berlin highlighted the challenges that have been encountered over several years when attempting to raise the level of evidence with 90Y to achieve the level necessary for hepatology-oriented guidelines. These are summarized herein.

It is acknowledged that for new therapies (including 90Y) to become widely accepted, controlled research investigations are necessary. Other important factors include reproducibility and multicenter implementation. Furthermore, the economic feasibility of new approaches is important as is the proper framing of previously collected experiences. Given this background, historical details of 90Y should be provided.

Over one decade ago (1999), the U.S. Food and Drug Administration (FDA) approved, under a humanitarian basis, the use of implantable, radioactive microspheres for patients with unresectable HCC. To put this in context, this was before the publication and adoption of BCLC guidelines, the completion of the seminal studies establishing that TACE provided a survival benefit (2002), and the approval of sorafenib (2008).[37, 43, 44] This regulatory mechanism was necessary because, at the time, there were no approved agents for HCC (no comparator). In 2002, European approval for 90Y in liver neoplasia was also obtained. However, despite regulatory approvals, it was recognized that more controlled, randomized studies would be necessary to gain worldwide acceptance. Hence, in 2006, an international, randomized phase III trial comparing 90Y with best supportive care in advanced HCC was initiated. During the protocol review and site selection phase, the positive findings of sorafenib study were announced. The HCC landscape changed, with sorafenib becoming the standard of care in advanced disease.[37] The study was subsequently put on hold. However, given the compelling phase II evidence and safety profile in patients with PVT, the FDA expanded the label for 90Y (2006) to include PVT.[34] Therefore, in the strictest sense, the agent first approved for the treatment of advanced HCC (PVT) was 90Y. This came 40 years after the first attempts in HCC using the same isotope.[45] Despite these setbacks stemming from the ever-increasing complexity and dynamic research landscape of HCC, the evidence for 90Y has continued to grow.

Besides resulting in similar (if not better) survival in this population, 90Y is devoid of the significant side effects of sorafenib. These toxicities lead to treatment discontinuation (44%) and dose reduction or withdrawal (64%) in postmarketing studies, denying patients the well-established benefit of sorafenib.[37, 46] Moreover, in the subset analysis of the pivotal phase III trial, median OS among 108 patients with PVT receiving sorafenib was 8.1 months and disease control rate (DCR) was 26.8%, whereas for patients with Child-Pugh A and PVT treated by 90Y (Table 1), median OS ranged between 10 and 17 months with DCRs of 40%-80%.[47] Given this historical background, the limitations of comparing studies, as well as the need for higher level of evidence, several international, randomized, phase III studies have now been implemented (Table 2). Evaluation of sorafenib in combination with local micro-therapy guided by Gd-EOB-DTPA enhanced MRI in patients with inoperable hepatocellular carcinoma (SORAMIC) and Phase III Clinical Trial of Intra-arterial TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma (STOP-HCC) both investigate 90Y when added to sorafenib. Phase III Multicenter Open-label Randomized Trial of Selective Internal Radiation Therapy versus Sorafenib in Locally Advanced Hepatocellular Carcinoma (SIRveNIB), sorafenib versus radioembolization in advanced hepatocellular carcinoma (SARAH), and a prospective randomized clinical trial of 90Y radioembolization versus sorafenib for the treatment of advanced HCC with portal vein thrombosis (YES-p) all compare sorafenib to 90Y. These trials further confirm the strong phase II signals resulting in advancement to phase III trials.

Table 2. Ongoing Large-Scale RCTs With 90Y Radioembolization in HCC
AcronymNCT IDPhaseCountriesNEndpointExperimental ArmComparatorEstimated Completion DateStatus
PREMIERE00956930IIUSA124TTP90YcTACEAugust 2018Recruiting
SIRveNIB01135056IIIAsia-Pacific360Survival90YSorafenibJuly 2015Recruiting
SARAH01482442IIIFrance400Survival90YSorafenibMarch 2015Recruiting
STOP-HCC01556490IIIUSA-Europe400Survival90Y+sorafenibSorafenibOctober 2016Recruiting
SORAMIC01126645IIIEurope375Survival90Y+sorafenibSorafenibFebruary 2014Recruiting
YES-pPendingIIIEurope, Asia, USA328Survival90YSorafenibInitiated

Clinical trials in BCLC B disease are more challenging given the long natural history of untreated disease, large sample sizes required to demonstrate survival differences, as well as the crossover that invariably occurs at progression.[2] In fact, some have suggested that survival is not an appropriate endpoint when effective subsequent therapies exist.[48] Difficulties with survival studies are further highlighted with the extremely long survival time (median, 48 months) noted in hyperselected intermediate patients treated with TACE.[49] These observations further suggest that BCLC B is a heterogeneous group that, with such prolonged survival times in select groups, limits the feasibility of randomized studies (TACE versus 90Y). This heterogeneity was recently highlighted by an expert review panel.[50] Despite this, Prospective Randomized Trial of Radioembolization and Chemoembolization in Hepatocellular Carcinoma (PREMIERE) is a randomized phase II trial comparing TACE and 90Y in intermediate disease (Table 2). Furthermore, through the use of clinical and molecular factors, comparable subgroups within the heterogeneous intermediate stage will be studied in prospective RCTs using 90Y as the experimental arm. These will target tumor presentations in which amelioration of TACE results have already inferred, such as Child-Pugh B7, candidacy for transplantation after downstaging (“up-to-7” concept, expanded University of California San Francisco [UCSF]), and preserved performance status.[51-53]

Clinical Paradigm Shift and Novel Applications With 90Y

One of the pervasive observations with 90Y is that as an embolotherapy, it represents a major paradigm shift, when compared with TACE. TACE often involves patient preparation with antibiotics, antiemetics, and narcotics. The patient is admitted for a period ranging from 1 to 5 days for postembolization syndrome resulting from chemotherapy or arterial occlusive effects. Patients usually require 1-2 weeks for overall recovery, depending on their baseline performance status. In contradistinction, whereas 90Y requires a planning angiogram to identify and delineate the vascular anatomy, 90Y treatment also involves same-day discharge (23 hours in Europe), often without the need for antibiotics or pain management. Hence, for two therapies (TACE and 90Y) that intuitively target the same population (intermediate disease), differences in technical, side-effect, and outpatient profiles create challenges in patient enrollment during the informed consent process. These challenges were confirmed in a prospective phase II study comparing TACE and 90Y using quality-of-life metrics. The study demonstrated that despite enrolling more-advanced patients (larger tumors, performance status 1-2) to 90Y, 90Y outperformed TACE (small tumors, segmental injections)[54] by validated quality-of-life measures.

As clinical experience has been gained with this technology, several investigators have consistently made novel observations with 90Y. Although these have not been tested in the multicenter setting, they are of clinical interest and worthy of brief description in this review article. The first novel concept relates to surgical intervention for HCC and is termed “radiation segmentectomy,” in reference to the ability of applying radiation doses to small sectors of liver tissue 1,000× greater than achieved using external beam.[18] Using this idea, small sectors of tumor-bearing liver, usually considered for ablation or resection, but contraindicated because of location, comorbidities, and insufficient liver reserve, can be obliterated using 90Y. The sector of liver resorbs with time and disappears on cross-sectional imaging (“segmentectomy”).

Expanding on segmentectomy, the second concept is termed “radiation lobectomy,” observed in patients with right-lobe disease potentially amenable to curative resection, but excluded because of small future liver remnant.[55] Although the traditional method of inducing hypertrophy is portal vein embolization (PVE), hypertrophy rates are suboptimal in cirrhosis. In this patient population, treating the right-lobe disease with 90Y (as opposed to PVE) potentially accomplishes three important clinical tasks: (1) The tumor is treated while hypertrophy is being induced (PVE does not treat the HCC); (2) as the right-lobe HCC regresses with concomitant right lobar atrophy, a more-controlled diversion of portal venous flow ensues, with hypertrophy rates of over 40% in radiation-naïve future left-lobe remnants; and (3) waiting 6-12 weeks for lobectomy to be manifest mandates a biologic test of time, identifying those patients that would best be served by resection.[56, 57] Although the predictability and extent of segmental-lobar atrophy induced by 90Y is still the subject of active research, it is a fact that 90Y may combine anticancer and ablative effects on the target liver territory. That will add efficacy endpoints to be tested in patients rescued to surgical approaches not only in HCC, but also in selected cases of liver metastases (Fig. 1).

Figure 1.

Right-lobe radiohepatectomy demonstrating simultaneous 90Y treatment to the HCC, lobar atrophy, and regeneration or hypertrophy of the remnant liver after one single session of 90Y. This is a 70-year-old male with hepatitis C virus–related cirrhosis and good liver function (Child-Pugh A6, Model for End-Stage Liver Disease 8) who presented with 2 right-lobe HCCs (11 and 3 cm) associated with segmental portal vein invasion and AFP serum level of 3,412 IU/mL. (A) Baseline computed tomography scan. Right hepatic lobe volume (segments 5, 6, 7, and 8) was 1,325 cm3, whereas the remnant left lobe (segments 1, 2, 3, and 4) had a calculated volume of 434 cm3. (B) Six months after 90Y glass microsphere treatment, there is no evidence of active tumor, AFP is 14.3 IU/mL, and there is near complete atrophy of the right lobe. Right-lobe volume is now 152 cm3, whereas the left has hypertrophied to 1,202 cm3. The patient was considered for resection, but was eventually maintained on strict imaging follow-up. He is recurrence free 2 years after 90Y radioembolization.

The third novel application involves the controversial (but routinely practiced) downstaging to liver transplantation (LT). To date, two studies have demonstrated the ability of 90Y to downstage patients from UNOS T3 to T2.10 The first 35-patient series demonstrated a 56% downstaging rate.[58] The second, a comparative effectiveness study in T3 patients, demonstrated better downstaging of 90Y, when compared with TACE (58% versus 31%; P < 0.05).[4] This is largely explained by the high antitumoral effect of 90Y (necrosis and size criteria). In another comparative effectiveness analysis, a strong trend of improved response rate, when compared with TACE, was reported (90Y: 49%; TACE: 36%; P = 0.052).[2] High response rates by necrosis and size criteria have consistently been reported, suggesting that 90Y represents another potential tool for downstaging (Fig. 2).[3, 7, 27, 33, 57]

Figure 2.

Salvage transplantation after 90Y downstaging. This is a 58-year-old patient with good performance status Child-Pugh B7 cirrhosis who received 90Y glass microspheres for a large infiltrating HCC with satellites and non-neoplastic PVT (i.e., beyond the up-to-7 and UCSF criteria and BCLC C). After 3 months, though there was near total tumor response with postradiation right liver lobe atrophy and dense fibrosis, progressive deterioration of liver function occurred. The patient underwent LT because of tumor-unrelated Child-Pugh stage migration. The patient is alive and well (no recurrence) 2 years after transplantation (30 months after 90Y).

Finally, 90Y could represent an option to maintain select intermediate-advanced tumors within transplant possibility (bridging) when sustained tumor response exceeding 6 months has been observed, supported by up-to-7 and UCSF expanded criteria. These options become feasible and transplant exceptions considered in light of competitive benefit with respect to more-conventional indications for transplantation (Fig. 2).[52, 53]

It is often stated that from a research perspective, 90Y is a technique that inherently competes with TACE in BCLC B, because both are transarterial and involve the delivery of particulate “embolic” agents. However, this is not universally agreed upon by HCC experts. Rather, 90Y versatility translates into a potential role in many BCLC stages.[59] 90Y in BCLC A is suggested, in part, by higher CPN, compared to TACE, and by the innovative concepts of segmentectomy and lobectomy (permitting resection) and downstaging (permitting transplantation).[18, 56, 57] For BCLC B, comparative studies are also complex, because inherent quality-of-life differences, long natural history, as well as complications of crossover at progression, result in unachievable 1,000-patient trial designs.[2, 48, 54] Finally, in BCLC C, the dramatic effect on PVT (not observed with TACE) provides strong rationale for (combinations with and comparisons) to sorafenib.[33, 34, 60] Table 3 lists 90Y indications and contraindications that are generally recommended by expert consensus.

Table 3. Radioembolization Indications and Contraindications by General Consensus
Indications
Conventional
(based on retrospective and prospective cohort studies and case-control studies)
Intermediate HCC
Single, multinodular (2-3 or tumor burden <20% of the liver parenchyma) Child-Pugh A, normal liver function, PS 0
Okuda II, multifocal (bilobar or tumor burden 20%-40% of the liver parenchyma), Child-Pugh B, PS 0, only if good liver function and bilirubin <2 mg/dL
Advanced HCC
No extrahepatic disease, branch or main portal vein invasion, with normal liver function, PS 0
Investigational
(based on case reports or single-center studies)
Radiation-induced segmentectomy, for patients unfit for ablation or embolization
Radiation-induced hepatectomy associated with tumor treatment, for patients unfit for surgery because of comorbidities, or insufficient remnant liver
Downstaging procedure before resection or transplantation in case of intermediate-advanced HCC (exceeding conventional criteria)
Contraindications
  1. PS, performance status.

Relative
Renal failure
Untreated varices at high risk of bleeding
Absolute
Technical contraindication to intra-arterial treatment
Decompensated cirrhosis (CPT ≥8, jaundice, encephalopathy, refractory ascites, or hepatorenal syndrome)
Massive tumor with both lobes involved (tumor burden >75% of liver parenchyma)
Lung or GI shunts that cannot been corrected

Radioembolization represents a promising treatment option challenging the current paradigm of HCC treatment. Multiple centers have provided compelling data that suggest (1) high antitumoral effect, (2) downstaging to transplantation, (3) clinical application in PVT, (4) TACE survival equivalence using an outpatient schedule or improved quality of life, and (5) conversion of surgically inoperable patients (small liver remnant) to potential cure with resection following hypertrophy of the future liver remnant. Although clinical development has been challenging, the next few years will yield important information as results from the randomized phase III trials further define the role of 90Y in treatment algorithms.

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