Radioembolization for hepatocellular carcinoma: The time has come
Authors: Beau Toskich, Tushar Patel
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Toskich advises for BTG plc and NeuWave. He owns stock in Advanced Medical Isotope Corporation. See Article On Page 873 Locoregional therapies, such as transarterial chemoembolization (TACE), are widely used for hepatocellular carcinoma (HCC) in the United States, Europe, and Asia. The final analysis of the GIDEON investigation revealed that locoregional therapies account for the majority of interventions for HCC worldwide, with procedural numbers that exceed resection and transplantation. Under the current Barcelona Clinic Liver Cancer (BCLC) staging system, ablation has been sanctioned as a first‐line treatment for patients with very‐early‐stage HCC who are not transplant candidates. This will likely further increase nonoperative interventions in the years to come. As such, HCC has become an entity wherein the majority of patients are diagnosed, treated, and surveilled almost solely with image‐guided medicine and visual surrogates for histology. Although many patients may never achieve a cure, locoregional treatments offer proficient disease control with well‐tolerated, low‐morbidity, outpatient procedures. New locoregional therapies have developed alongside the discipline of interventional oncology, but more questions have been generated in their wake—particularly on the survival benefit of in situ therapy. However, the treatment of HCC involves an increasingly complex landscape that necessitates management of near innumerable clinical permutations. Among others, these include a kaleidoscope of variable underlying liver disease substrates, tumor biology, effects of multiple interventions and systemic therapy, and the managing a field defect with insufficient data. Superimposed on this are issues associated with organ allocation, evolving HCC risk factors, and other medical, financial, and psychosocial factors that can impact treatment approaches. As such, evaluating the merit of locoregional therapies remains a formidable task given that this confounding interplay obscures true therapeutic efficacy. Transarterial radioembolization (TARE) has progressively evolved from experimental utilization in the 1960s, last‐line palliative therapy in the former decade, and now to a distinctive treatment option for HCC that is both competitive and complementary to other approaches. Currently, TARE is used as definitive radiotherapy for small lesions, a bridge to transplantation, palliation for locally advanced disease with or without vascular invasion, and as a neoadjuvant to resection (Fig. 1). Expanded indications for TARE can be attributed to a matured understanding of optimal approaches for the treatment of liver cancer with vascular conduit microbrachytherapy, coupled with an improved knowledge of dosimetry, microsphere delivery, and toxicity. Consequently, many centers have begun to embrace TARE as a first‐line treatment for HCC.1Figure 1: Potential indications for TARE and treatment trajectory.In this month's issue, Riaz et al.2 distilled outcomes from their large procedural experience with TARE to address the ubiquitous tumor board question—does imaging response convey survival benefit? Their results show that imaging response after TARE for HCC may indeed predict survival and provide a robust basis for future studies and the use of TARE. This engages a critical issue for patients with limited‐stage disease who are ineligible for transplant, resection, or ablation; not an uncommonly encountered problem. Their large cohort allows for a succinct response by excluding several variables that have confounded previous studies. This study arrives at an opportune moment given that applications of TARE are only becoming more complex and repeating this experience may prove challenging. The versatility of TARE is made possible through several physical properties, which are exclusive to radioembolization. Yttrium 90 (Y90) delivers energy through beta particles that limit collateral damage to nontarget structures and a short half‐life that permits safe surgical instrumentation within 30 days posttreatment. Similar to TACE, Y90 microspheres follow an intrinsic vascular dose preferential that favors tumor deposition. This attribute enables safe, whole‐liver cytoreduction while similarly providing well tolerated, segmental and lobar ablative radiation doses; some of the highest achieved in medicine. These characteristics have allowed for large strides in radiation therapy against traditionally radioresistant tumors such as HCC in a highly radiosensitive organ. Despite TARE being traditionally reserved as a salvage instrument for locally advanced HCC, both large‐cohort retrospective and prospective randomized data suggest that TARE may potentially be superior to TACE as a means to bridge transplant candidates.3 This is a crucial advantage in the setting of current United Network for Organ Sharing implemented waiting periods for tumor exception points and transplant candidacy that indirectly associate time to progression (TTP) with survival. Although the recent SARAH and SIRveNIB trials did not accomplish their primary endpoints of survival utilizing lower radiation doses with resin microspheres, the superior quality of life provided by TARE over sorafenib cannot be ignored. Perhaps the most impactful use of Y90 will be as ablative radiotherapy in precisely targeted, small volumes of liver. The benefit to this approach is reduced toxicity while safely achieving radiation doses in anatomic locations that may otherwise be unamenable to other ablation modalities, including stereotactic body radiation therapy. Early results with this approach show complete pathological responses in over 50% of tumors and retrospective outcomes that approximate those observed with combination TACE and microwave ablation.5 Further investigation is certainly warranted. Repeat treatments are not limited by cumulative whole‐organ dose as Y90 microspheres may be readministered within the same treatment volume of perfused liver, or hepatic angiosome. Moreover, the procedure is performed as an outpatient and can be condensed to a single session in certain cases. Although resection and transplant remain gold standards for cure, the majority of patients with HCC are not suitable candidates for these surgical interventions. In addition, the present limitations in reliably staging tumor and assessing its biology may undermine the benefits of a microscopically margin‐negative resection or transplant in the event of early recurrence. Surgical candidacy may be limited by cirrhosis and portal hypertension, staging future remnant liver remnant (FLR), uncertain tumor biology, vascular invasion, inadequate FLR volume, and the challenges of extrahepatic comorbidities. Although portal vein embolization (PVE) and operative liver partitioning are well‐implemented techniques to generate FLR, they offer a limited period of hypertrophy challenged by inadvertent tumor growth and morbidity, respectively. Lobar ablative TARE as a neoadjuvant to hepatectomy may be utilized in both primary and metastatic liver cancer as a means of safely devitalizing the future resection site while concurrently treating tumor with safe, high local dose radiation.7 This eventually generates FLR hypertrophy comparable to PVE while exclusively allowing for tumor control, with complete pathological responses reported, permitting a valuable biological test of time in high‐risk patients. Surgical resection should be performed by a team familiar with postradioembolization operative considerations. Looking forward, the use of radiological response to predict survival will create the potential for more regimented uses of locoregional therapies. Encouraging developments in imaging may predict tumors with aggressive biology and better manage stage migration.10 Treatment allocation could be determined as much by a tumor's radiological phenotype as its size. Radioembolization practices will likely evolve with improvements in particle simulation to better predict dose and the use of adjuvants to increase tumor access and radiosensitivity. The current trials that combine TARE with emerging immunotherapies also offer promise for an in situ tumor vaccine. The increasing roles for TARE as a complement to comprehensive HCC care make its incorporation within current management guidelines challenging given that it could justifiably be used within several BCLC stages (Fig. 1). While future randomized studies are always necessary, the ability to adequately prognosticate the impact of TARE with radiological response will enhance its potential as a first‐line option for the treatment for HCC in select patients.