Transarterial Radioembolization for Hepatocellular Carcinoma: Who, When… and Y(90)?

Abstract

See “Y90 Radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma,” by Salem R, Gordon AC, Mouli S, et al, on page 1155. See “Y90 Radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma,” by Salem R, Gordon AC, Mouli S, et al, on page 1155. Our knowledge of regional and local ablative therapy for hepatocellular carcinoma (HCC) has evolved substantially over the past 2 decades. Randomized controlled trials comparing different local ablative treatments, local ablative therapy versus resection, and transarterial chemoembolization (TACE) vs best supportive care, have helped secure the place of these treatments in practice guidelines from major liver societies.1Bruix J. Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6606) Google Scholar, 2EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943Abstract Full Text Full Text PDF PubMed Scopus (4553) Google Scholar According to the widely used Barcelona Clinic Liver Cancer (BCLC) staging system,1Bruix J. Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6606) Google Scholar, 2EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943Abstract Full Text Full Text PDF PubMed Scopus (4553) Google Scholar, 3Llovet J.M. Bru C. Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification.Semin Liver Dis. 1999; 19: 329-338Crossref PubMed Scopus (2940) Google Scholar patients with early HCC stage (BCLC A) are candidates for liver transplantation (LT), resection, and ablation with intent of cure. For intermediate HCC stage (BCLC B), TACE is considered the standard of care. For most patients with advanced HCC (BCLC C), sorafenib is the recommended treatment. Patients with advanced HCC, severe liver dysfunction, and poor performance status (BCLC D) receive only the best supportive care. In recent years, there has been growing interest in treating HCC with selective internal radiation therapy or yttrium-90 (Y90) trans-arterial radioembolization, in which glass (TheraSphere; BTG International, London, UK) or resin (SIR-Spheres; Sirtex Medical, New South Wales, Australia) microspheres of Y90 from 20 to 60 μm in size are administered with profound radiation effect but little ischemic damage.4Salem R. Mazzaferro V. Sangro B. Yttrium 90 radioembolization for the treatment of hepatocellular carcinoma: biologic lessons, current challenges and clinical perspectives.Hepatology. 2013; 58: 2188-2197Crossref PubMed Scopus (139) Google Scholar A large, prospective 5-year cohort study from Northwestern5Salem R. Lewandowski R.J. Mulcahy M.F. et al.Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.Gastroenterology. 2010; 138: 52-64Abstract Full Text Full Text PDF PubMed Scopus (766) Google Scholar demonstrated high antitumor effects from Y90. BCLC B and C patients who responded to Y90 radiographically had a significantly better survival than those who failed to respond. Subsequent large series from Europe have reproduced similar results, with objective tumor response rates in the 40% to 60% range by European Association for the Study of the Liver (EASL) criteria, and a relatively long time to progression (TTP) of 8 to 11 months after Y90.5Salem R. Lewandowski R.J. Mulcahy M.F. et al.Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.Gastroenterology. 2010; 138: 52-64Abstract Full Text Full Text PDF PubMed Scopus (766) Google Scholar, 6Hilgard P. Hamami M. Fouly A.E. et al.Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.Hepatology. 2010; 52: 1741-1749Crossref PubMed Scopus (328) Google Scholar, 7Sangro B. Carpanese L. Cianni R. et al.Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona Clinic Liver Cancer stages: a European evaluation.Hepatology. 2011; 54: 868-878Crossref PubMed Scopus (480) Google Scholar, 8Mazzaferro V. Sposito C. Bhoori S. et al.Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study.Hepatology. 2013; 57: 1826-1837Crossref PubMed Scopus (338) Google Scholar Because Y90 may be effective even with high tumor burden or portal vein invasion,9Memon K. Kulik L. Lewandowski R.J. et al.Radioembolization for hepatocellular carcinoma with portal vein thrombosis: impact of liver function on systemic treatment options at disease progression.J Hepatol. 2013; 58: 73-80Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Y90 seems to be best suited for BCLC C. Owing to the lack of level 1 evidence to confirm a survival benefit with Y90, its place in the HCC treatment algorithm has not been well-defined.1Bruix J. Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022Crossref PubMed Scopus (6606) Google Scholar, 2EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943Abstract Full Text Full Text PDF PubMed Scopus (4553) Google Scholar A number of large phase III randomized trials comparing Y90 with sorafenib (alone or in combination) are currently underway4Salem R. Mazzaferro V. Sangro B. Yttrium 90 radioembolization for the treatment of hepatocellular carcinoma: biologic lessons, current challenges and clinical perspectives.Hepatology. 2013; 58: 2188-2197Crossref PubMed Scopus (139) Google Scholar (Table 1).Table 1Summary of Ongoing Phase III Randomized Clinical Trials with Y90 Radioembolization in Hepatocellular CarcinomaModified from.4Salem R. Mazzaferro V. Sangro B. Yttrium 90 radioembolization for the treatment of hepatocellular carcinoma: biologic lessons, current challenges and clinical perspectives.Hepatology. 2013; 58: 2188-2197Crossref PubMed Scopus (139) Google ScholarNCT IDCountriesNumber of patientsEndpointExperimental armComparatorSIRveNIB01135056Asia-Pacific360SurvivalY90SorafenibSARAH01482442France400SurvivalY90SorafenibSTOP01556490USA-Europe400SurvivalY90 + SorafenibSorafenibSORAMIC01126645Europe375SurvivalY90 + SorafenibSorafenibYES-p01887717Europe, Asia, USA328SurvivalY90Sorafenib Open table in a new tab Also of interest is the role of Y90 as primary treatment in patients with early or intermediate stage HCC (BCLC A and B) or as bridging treatment before LT. In practice, not all patients are eligible for the best available treatment within a given HCC stage for reasons including technical issues or coexisting comorbidity. This brings up the concept of treatment stage migration,10Reig M. Darnell A. Forner A. et al.Systemic therapy for hepatocellular carcinoma: the issue of treatment stage migration and registration of progression using the BCLC-refined RECIST.Semin Liver Dis. 2014; 34: 444-455Crossref PubMed Scopus (86) Google Scholar where these patients would then receive the recommended treatment for the next HCC stage. The conventional wisdom is to apply TACE to patients with early stage HCC (BCLC A) if they are not candidates for LT, resection, or ablation, and for those with intermediate stage HCC (BCLC B). TACE is also the most commonly used bridging therapy before LT. In a large study from Northwestern comparing Y90 with TACE in BCLC A and B patients,11Salem R. Lewandowski R.J. Kulik L. et al.Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma.Gastroenterology. 2011; 140: 497-507Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar the investigators observed a significantly longer TTP with Y90 (13 months vs 8 months with TACE), but the rates of EASL response and survival were not significantly different. A smaller study from Mayo Clinic, Rochester,12Moreno-Luna L.E. Yang J.D. Sanchez W. et al.Efficacy and safety of transarterial radioembolization versus chemoembolization in patients with hepatocellular carcinoma.Cardiovasc Intervent Radiol. 2013; 36: 714-723Crossref PubMed Scopus (102) Google Scholar demonstrated no difference in rates of radiographic response or survival. Because these comparative studies are not randomized trials, the place of TACE as the preferred treatment in these subgroups has not been challenged seriously. In this issue of Gastroenterology, Salem et al13Salem R. Gordon A.C. Mouli S. et al.Y90 Radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma.Gastroenterology. 2016; 151: 1155-1163Google Scholar from Northwestern reported the results of the PREMIERE trial, an investigator-initiated, single-center phase II, prospective, randomized study comparing conventional TACE with Y90 in HCC. Nonresection candidates with HCC were included if they were Child-Pugh class A or B and BCLC stage A or B with a total bilirubin of <2 mg/dL and no evidence of macrovascular invasion. Of the 179 patients who met enrollment criteria, 45 chose to be randomized (24 patients in the Y90 arm and 21 in the TACE arm). The primary endpoint was median TTP, which was significantly longer with Y90 at >26 months compared with 7 months with TACE. After a median follow-up of 17 months, 12 patients (27%) had tumor progression but only 2 were in the Y90 arm. Among those who did not undergo LT, only 1 of 11 (9%) in the Y90 group had tumor progression versus 9 of 14 (64%) who received TACE. The study observed no difference in EASL radiographic response (87% for Y90 vs 74% for TACE) and median survival (19 months for Y90 vs 18 months for TACE). Both treatments were well-tolerated. The authors should be commended for their extraordinary efforts in conducting a very difficult randomized trial in a single center. The rigorous study design from a radiologic perspective allowed only multiphase abdominal magnetic resonance imaging, and 2 radiologists who reviewed each scan were blinded to the treatment received. Third reader adjudication was performed when needed. Conventional TACE with lipiodol was used in all patients. Lipiodol is radiodense but magnetic resonance imaging cannot detect lipiodol, thus allowing for proper blinding during assessments of radiographic tumor response or progression. One might argue for using TACE with drug-eluting beads instead of conventional TACE in this trial, in light of a trend for better EASL response and less side effects with TACE with drug-eluting beads in the PRECISION trial.14Lammer J. Malagari K. Vogl T. et al.Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study.Cardiovasc Intervent Radiol. 2010; 33: 41-52Crossref PubMed Scopus (1161) Google Scholar Nevertheless, there is no consensus that TACE with drug-eluting beads is clearly better than conventional TACE. The statistical analysis was robust, using the competing risk method in the estimation of TTP, and inverse probability of censoring weighting analysis to consider potential imbalance between groups in censoring. After these adjustments, a significantly longer TTP was confirmed in the Y90 group when compared with the TACE group. The trial was conducted at a center with extensive experience in both treatment modalities. The majority in both arms required only a single treatment session. The PREMIERE trial used TTP rather than survival as the primary endpoint. Given the natural history and long-predicted survival of early to intermediate stage HCC, as well as the high antitumor activities of both TACE and Y90, it would require an extremely large sample size to detect a significant difference in survival between the 2 treatment arms. TTP is considered an acceptable primary endpoint in treatment trial design for HCC.15Llovet J.M. Di Bisceglie A.M. Bruix J. et al.Design and endpoints of clinical trials in hepatocellular carcinoma.J Natl Cancer Inst. 2008; 100: 698-711Crossref PubMed Scopus (1432) Google Scholar However, one caveat to the PREMIERE trial is that assessment of TTP is hampered by the need for censoring at LT. Furthermore, comparison of TTP between treatments was based on a very small number of patients being followed for a sufficient duration. As illustrated in Figure 2 of the manuscript, only 12 patients in the Y90 arm were followed at 5 months and only 7 were still followed at 10 months from randomization. Based on the results of this study suggesting a longer TTP with Y90 when compared with TACE, the authors reported a change in practice at their institution to use Y90 as the primary bridging treatment to LT. The rationale behind the change was that a lower rate of tumor progression with Y90 would result in a lower risk of waitlist dropout when compared with TACE, and yet no information on actual waitlist dropout was provided to support this message. Furthermore, waitlist dropout is dictated by the center’s waiting time and tumor characteristics, and influenced perhaps to a lesser degree by the type of bridging therapy.16Mehta N. Dodge J.L. Goel A. et al.Identification of liver transplant candidates with hepatocellular carcinoma and a very low dropout risk: implications for the current organ allocation policy.Liver Transpl. 2013; 19: 1343-1353Crossref PubMed Scopus (106) Google Scholar The study population was heterogeneous. Only 56% of patients were ever listed for LT and 22% had initial tumors exceeding the Milan criteria17Mazzaferro V. Regalia E. Doci R. et al.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med. 1996; 334: 693-699Crossref PubMed Scopus (5647) Google Scholar requiring down-staging, and some seemed to be non-LT candidates receiving TACE or Y90 as primary treatments. Because radiographic tumor progression while on the waiting list before LT was suggested to be a risk factor for HCC recurrence after LT,18Lai Q. Avolio A.W. Graziadei I. et al.Alpha-fetoprotein and modified response evaluation criteria in solid tumors progression after locoregional therapy as predictors of hepatocellular cancer recurrence and death after transplantation.Liver Transpl. 2013; 19: 1108-1118Crossref PubMed Scopus (12) Google Scholar and given that TTP was significantly longer with Y90 than TACE, it would be useful to compare the 2 groups in terms of the risks for HCC recurrence based on proposed scoring systems,19Mehta N, Heimbach J, Harnois D, et al. A multi-center study to develop and validate a novel prediction index (RETREAT) for hepatocellular carcinoma recurrence after liver transplant. JAMA Oncology (in press).Google Scholar as well as actual post-LT HCC recurrence and survival. Although efficacy and safety are the main deciding factors for the choice between TACE and Y90, there are also logistical and economic considerations. TACE is associated with a postembolization syndrome requiring at least an overnight hospital stay for observation after the procedure, whereas a significant advantage of Y90 is that it is an outpatient procedure. A prophylactic antibiotic is given after most TACE cases, but not required after Y90. In contrast, there are no special preparations needed before TACE. Before Y90, however, a planning celiac and hepatic angiogram is necessary to define the vascular anatomy, and collateral arteries supplying the gallbladder, stomach, or intestine are embolized to avoid secondary complications. Additionally, scintigraphy with technetium-99m macroaggregated albumin is performed to estimate fraction of lung shunting. With respect to cost, a recent Monte Carlo simulation estimated that each Y90 treatment (unilobar) costs about twice as much as each TACE treatment.20Rostambeigi N. Dekarske A.S. Austin E.E. et al.Cost effectiveness of radioembolization compared with conventional transarterial chemoembolization for treatment of hepatocellular carcinoma.J Vasc Interv Radiol. 2014; 25: 1075-1084Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Undoubtedly, there is a learning curve for Y-90, a technology that is relatively new, technically more challenging, and center dependent in terms of success. As the field gains more experience with Y90, it may become more of a standardized routine procedure. The PREMIERE trial raises the level of evidence with Y90, and is an important first step in defining the place for Y90 in the HCC treatment algorithm. What we have also learned about Y90 is its versatility, as bridging or down-staging treatment for early stage HCC before LT, and as primary treatment for intermediate and advanced HCC, including those with portal vein thrombosis. Results of randomized trials comparing sorafenib with Y90 will be available within a few years to better define the role of Y90 in advanced HCC. For early to intermediate stage HCC, whether Y90 is the overall better choice than TACE will continue to be a matter of debate. The challenge after the PREMIERE trial is to establish reproducibility of a longer TTP or improved survival with Y90 compared with TACE in the primary treatment of intermediate stage HCC in a multicenter randomized trial, before we will see a change in the treatment landscape favoring Y90 over TACE. Y90 Radioembolization Significantly Prolongs Time to Progression Compared With Chemoembolization in Patients With Hepatocellular CarcinomaGastroenterologyVol. 151Issue 6PreviewConventional transarterial chemoembolization (cTACE) is used to treat patients with hepatocellular carcinoma (HCC). Radioembolization is a minimally invasive procedure that involves implantation of radioactive micron-sized particles loaded with yttrium-90 (Y90) inside the blood vessels that supply a tumor. We performed a randomized, phase 2 study to compare the effects of cTACE and Y90 radioembolization in patients with HCC. Full-Text PDF