Worldwide, hepatocellular carcinoma

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1 Vascular and Interventional Radiology Review Fidelman and Kerlan TACE and 90 Y Radioembolization to Treat HCC Vascular and Interventional Radiology Review FOCUS ON: Nicholas Fidelman 1 Robert K. Kerlan, Jr. Fidelman N, Kerlan RK Jr Keywords: 90 Y radioembolization, hepatocellular carcinoma, transarterial chemoembolization DOI: /AJR Received March 31, 2015; accepted without revision April 11, Both authors: Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Ave, Rm M-361, San Francisco, CA Address correspondence to N. Fidelman (nicholas.fidelman@ucsf.edu). AJR 2015; 205: X/15/ American Roentgen Ray Society Transarterial Chemoembolization and 90 Y Radioembolization for Hepatocellular Carcinoma: Review of Current Applications Beyond Intermediate-Stage Disease OBJECTIVE. The practice guideline of the American Association for the Study of Liver Diseases currently recommends transarterial chemoembolization (TACE) for the treatment of intermediate-stage hepatocellular carcinoma (HCC). The use of transarterial radioembolization (TARE) using 90 Y microspheres is not formally recommended. This article discusses the current clinical applications of TACE and TARE and compares the clinical utility of these techniques for various subpopulations of patients with HCC. CONCLUSION. For most clinical scenarios, the efficacy and safety of TACE and TARE are probably equivalent. However, TARE appears to have an advantage over TACE in the facilitation of surgical resection by resulting in compensatory hypertrophy of the future liver remnant and possibly in the treatment of patients with portal vein tumor thrombus. On the contrary, TACE is the transarterial treatment of choice for patients with marginal hepatic reserve (i.e., hyperbilirubinemia, ascites) who may be candidates for transplant. Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer in men [1], the seventh most common in women [1], and overall the third leading cause of cancer-related deaths [2]. In part because of the hepatitis C epidemic, the incidence of HCC in the United States has nearly tripled over the past 2 decades [1]. As outlined in the American Association for the Study of Liver Diseases (AASLD) practice guideline for HCC, treatment options depend on tumor burden, the severity of underlying liver disease, and a patient s functional status [3, 4]. The Barcelona Clinic Liver Cancer HCC staging system [4] (Fig. 1) takes into account these clinical parameters and is widely used in clinical practice. Potentially curative treatments include liver transplant (LT), resection, and thermal ablation. Transarterial therapies are considered palliative. The only form of arterial therapy for HCC that is recommended in the AASLD practice guideline is transarterial chemoembolization (TACE), which is indicated for the treatment of intermediate-stage HCC [4]. Transarterial radioembolization (TARE) with 90 Y microspheres is mentioned in passing as possibly indicated for patients with portal vein throm- bosis, whereas bland transarterial embolization is not recommended at all [4]. However, TACE and TARE may result in complete or near-complete tumor necrosis at pathology [5, 6] and are commonly used to treat disease that is not in the intermediate-stage disease category [7]. The purpose of this article is to outline the applications of TACE and TARE in contemporary clinical practice and to compare their utility for various subpopulations of patients with HCC. Tools of the Trade TACE Agents TACE involves transarterial delivery of chemotherapy via a hepatic artery supplying the tumor followed by the administration of an embolic agent. No standardized protocol exists with regard to the choice of chemotherapeutic drug or drugs, dosage, dilution, or rate of injection [8]. A number of chemotherapy drugs are currently in use including anthracyclines (daunorubicin, doxorubicin, epirubicin), platinum-based agents (cisplatin, lobaplatin, miriplatin), mitomycin C, and 5-fluorouracil. Conventional TACE involves the delivery of a mixture of aqueous chemotherapy solution and ethiodized oil in the form of an emulsion followed by the ad- 742 AJR:205, October 2015

2 TACE and 90 Y Radioembolization to Treat HCC ministration of embolic particles. Multiple studies have evaluated different drug dosages and combinations but have not found one regimen that is superior to others [7]. Centers in the United States that offer conventional TACE use varying doses of doxorubicin and mitomycin C. Cisplatin was commonly used until 2011 when production of the powder form of the drug was permanently discontinued. More recently, interest in the use of drugeluting beads (DEBs), mainly doxorubicin, has been growing. Positively charged drug molecules are bound to negatively charged microspheres, which allows sustained release of the drug from the microspheres over the course of days. Although the toxicity profile of TACE with DEBs has been found to be superior to that of conventional TACE, a recent prospective randomized controlled trial (RCT) did not show an improvement in efficacy of TACE with DEBs in comparison with conventional TACE [9]. Furthermore, the efficacy of DEB TACE has been compared with bland embolization in RCTs, and the results have been conflicting [10, 11]. It is noteworthy that the individual microsphere products and drugs have been approved for clinical use by the U.S. Food and Drug Administration (FDA), but the use of drug-loaded microspheres has not been approved by the FDA. Stage 0: PS 0; Child-Pugh A Very early stage (stage 0): 1 lesion < 2 cm; PS 0 Early stage (stage A): 1 lesion < 5 cm or 2 or 3 lesions each < 3 cm; PS 0 1 Lesion 2 or 3 Lesions Portal pressure or bilirubin level Normal Increased No Comorbidities Yes HCC Stages A C: PS 0 2; Child-Pugh A or B Intermediate stage (stage B): multinodular; PS 0 TARE Agents TARE involves the regional administration of 20- to 60-μm particles labeled with 90 Y into the hepatic artery branches that are supplying the tumor. Embolization is not a desired procedure endpoint. On the contrary, oxygen supply to the tumor tissue is required for the radiation-induced production of free radicals that results in double-strand DNA breaks, which ultimately lead to irreversible tumor cell damage. Yttrium-90 undergoes beta decay to 90 Zr with a half-life of 64 hours and decay energy of 2.28 MeV. Two 90 Y microsphere agents are available on the market: glass and resin microspheres. During the manufacture process of glass microspheres (TheraSphere, BTG International), the 90 Y precursor 90 Sr is embedded within the microspheres, whereas it is ionically bound to the resin microspheres (SIR-Sphere, Sirtex Medical). The glass microspheres have been approved by the FDA for the treatment of HCC under a Humanitarian Device Exemption. The resin microspheres have been approved by the FDA for the treatment of colorectal metastases to the liver. Their use for treatment of other malignancies, including HCC, is considered off-label. Treatment dosimetry for glass and resin microspheres is quite different. Although standard dosing of glass microspheres typically results in an absorbed liver radiation dose of Gy, the typical absorbed liver dose after the administration of resin microspheres is approximately Gy [12]. The safety and efficacy of the two 90 Y microsphere agents have not been compared prospectively to date. A recent meta-analysis [13] was based on retrospective studies and found a modest efficacy advantage for resin microspheres. However, a more recent large single-arm series from Europe [14], Asia [15, 16], and Australia [17] using resin microspheres and from Europe [18] and the United States using glass microspheres [19] reported similar efficacy results for the treatment of patients with unresectable HCC. Review of Clinical Applications As outlined in the AASLD practice guideline [3, 4], the treatment of patients with HCC calls for a multidisciplinary team that includes hepatologists, medical oncologists, transplant and oncologic surgeons, and interventional radiologists. Treatment recommendations are based on a patient s performance status, the disease burden, and the severity of the underlying liver disease. In the subsequent sections, the contemporary role of TACE and TARE will be explored for patients with potentially resectable, transplantable, and ablatable disease and for patients with unresectable and advanced HCC. Advanced stage (stage C): vein invasion; M1; N1; PS 0 2 Stage D: PS > 2; Child-Pugh C Terminal stage (stage D) Resection Transplant RFA TACE Sorafenib or trial Symptomatic treatment Curative treatments Palliative treatments Fig. 1 Flowchart shows adaptation of Barcelona Clinic Liver Cancer staging system for hepatocellular carcinoma (HCC). PS = performance status, RFA = radiofrequency ablation, TACE = transarterial chemoembolization. (Adapted with permission from updated practice guideline of American Association for the Study of Liver Diseases [4]) AJR:205, October

3 Fidelman and Kerlan Treating Potentially Resectable Hepatocellular Carcinoma Patients with HCC who are referred for surgical resection usually have an excellent performance status, normal or near-normal liver function (Child-Pugh class A or better), and either a solitary lesion or two or three lesions confined to one liver lobe. The recurrence-free survival rate after major hepatectomy is approximately 50% at 2 years and 25% at 5 years [20]. Neoadjuvant arterial therapy TACE has been evaluated as neoadjuvant therapy before major hepatic resection. The goals of preoperative TACE are to reduce tumor mass, thus making surgery easier, to destroy microscopic tumor foci, and to reduce the vascularity of the tumors. Arguments against the use of neoadjuvant TACE include TACE-related liver function impairment; a delay in performing definitive surgery during which some resectable tumors might become unresectable; and the relative ineffectiveness of TACE against poorly differentiated cell populations, which may result in more aggressive residual tumors [21]. A recent meta-analysis of several RCTs [22] has shown that preoperative TACE did not result in an improvement in disease-free survival or overall survival (OS) when compared with major hepatectomy alone. Furthermore, there was no improvement in postoperative tumor recurrence or OS for patients with tumors larger than 5 cm [22], a group of patients that could have potentially benefited the most from neoadjuvant TACE. There are no prospective data on the neoadjuvant use of 90 Y radioembolization. However, retrospective studies have reported the ability to downsize large lesions to resection. The numbers of patients who were able to undergo resection after TARE have been small [23, 24]. Nevertheless, patients with large lesions (> 5 cm) that span the right and left liver lobes or that are located in close proximity to the middle hepatic vein (an anatomic landmark for lobectomy) are sometimes referred for neoadjuvant TACE or TARE. Additional prospective studies in this area are warranted. Future liver remnant challenge One significant challenge to patient access to major hepatectomy is the inadequate size of the future liver remnant (FLR). An FLR of 40% of the preoperative liver volume has been recommended for patients with chronic hepatitis or cirrhosis [25 27], whereas an FLR of > 50% is considered safer for patients at a higher risk for liver decompensation [25, 28]. Right hepatectomy or trisegmentectomy often leads to an FLR volume below the established 40% threshold. A standard procedure performed to increase the FLR is portal vein embolization (PVE), which typically results in an approximately 30% increase of the FLR and may result in an increase as high as 50% if the segment IV portal vein is also embolized [29]. The biologic mechanism for an FLR increase is the atrophy-hypertrophy complex, which refers to the liver s response to hepatocellular loss by controlled restoration of liver parenchyma. Regardless of the cause of cellular loss in the liver, hypertrophy is relatively constant when there is a minimum amount of functional liver remaining. Occlusion of the portal vein leads to hepatic tissue ischemia and reperfusion injury, which ultimately lead to atrophy. A volume increase in the nonembolized liver is due to the release of growth factors and cytokines triggered by increased portal flow [30]. Hemodynamic modulation of PVE may also cause a compensatory increase in the arterial flow to the tumor, which may result in an increase in tumor size [31, 32]. Therefore, it may be reasonable to combine arterial antitumor therapy with PVE. A combination of TACE and PVE has been reported to result in extensive necrosis (70 83% necrosis) in the majority of patients treated using TACE followed by PVE [33, 34]. The atrophy-hypertrophy complex is also the mechanism for treated liver lobe atrophy and untreated lobe hypertrophy after 90 Y radiation lobectomy. The concept of radiation lobectomy was first introduced by Gaba et al. [35] in 2009; they reported a 52% reduction in the treated liver lobe volume and a compensatory 40% increase in the volume of the untreated liver lobe [35]. These results were confirmed in a subsequent larger series [24]. Another group reported a 23% decrease in the treated liver lobe and a 42% increase in the treated liver lobe [36]. Despite these promising results, only a minority of patients were able to undergo resection or transplant, and only limited data are available on pathologic correlation with respect to tumor response. Bridging and Downstaging to Liver Transplant Patients with good performance status (0 2), impaired liver function, and liver-limited HCC without vascular invasion may be candidates for LT [4]. Long-term survival for patients with early-stage HCC (one lesion < 5 cm or two or three lesions < 3 cm [i.e., within the Milan criteria]) has been shown to be similar to that of LT recipients without HCC [37]. More recently, it has been shown that patients with tumors outside the Milan criteria (one lesion > 5 cm and 8 cm; two or three lesions with at least one lesion > 3 cm and 5 cm with a total diameter of 8 cm; or four or five lesions, each 3 cm, with a total diameter of 8 cm) that were successfully downstaged to within the Milan criteria have a long-term survival and HCC recurrence rate similar to patients with disease meeting the Milan criteria without downstaging [38]. Liver-directed transarterial or ablative therapy is commonly used to bridge patients to transplant or to downstage tumors to Milan criteria. Bridging to transplant The rationale behind bridging therapy, which is now the standard of care in most transplant centers with a waiting time of more than 6 months, is to prevent dropout from the waiting list due to tumor progression [39]. The most commonly used liver-directed modalities for bridging to transplant are TACE and radiofrequency ablation (RFA) [40]. Recent studies evaluating the extent of tumor necrosis for patients who have undergone TACE monotherapy before transplant have reported that 38 57% of lesions showed complete necrosis after TACE [5, 41]. Studies evaluating histopathologic response to 90 Y radioembolization have reported that 36 70% of the lesions showed complete necrosis at histopathology [42 44]. A promising variation to the conventional radioembolization technique that may prove helpful in bridging to transplant is radiation segmentectomy. This technique involves delivery of the entire calculated lobar 90 Y dose to one or two liver segments. Vouche et al. [6] reported the results of a recent multicenter study of radiologic-pathologic correlation after radiation segmentectomy: In the 33 of 102 patients who underwent LT, 52% of the lesions showed complete necrosis at histopathology and the remaining lesions showed partial (50 99%) necrosis. Downstaging to transplant The goal of downstaging intermediate-stage HCC in transplant candidates is to achieve posttransplant outcomes comparable to those of non-hcc patients [39]. A common strategy aimed at achieving downstaging involves both arterial therapy and ablative approaches (thermal, chemical, or both). The choice of liver-directed therapy is based on lesion size and location; the relationship of the lesion to the major vessels, ducts, gallbladder, abdominal wall, and bowel; and the patient s 744 AJR:205, October 2015

4 TACE and 90 Y Radioembolization to Treat HCC underlying liver function. Most groups who have reported on successful downstaging to Milan criteria and University of California, San Francisco, criteria [38, 45 49] have chosen TACE for endovascular therapy. Radioembolization-based downstaging strategies are not commonplace [42 44, 50]. Lewandowski et al. [51] performed a retrospective study to compare TACE- and TARE-based downstaging strategies in 86 patients (43 patients in each group); the median lesion size was 5.7 cm in the TACE group and 5.6 cm in the TARE group. Downstaging to the Milan criteria was achieved in 31% of TACE patients and 58% of TARE patients. These findings are provocative and warrant verification in a prospective RCT. Bridging and downstaging for patients with Child-Pugh C cirrhosis The AASLD practice guidelines [3, 4] recommend that patients with Child-Pugh C cirrhosis should be offered only supportive care measures regardless of the tumor burden in the liver. However, patients with Child-Pugh C and early-stage HCC and even some patients with intermediate-stage HCC who are in good health otherwise and who may qualify for transplant after downstaging are offered liver-directed therapy while on the transplant list or before listing. These patients are generally not candidates for radioembolization because of the excessively high risk of liver decompensation and liver disease related mortality [52, 53]. However, patients in this group can be safely treated with TACE [54] and with other liver-directed treatment modalities, particularly RFA and percutaneous ethanol injection (PEI) [38]. Downsizing to Thermal Ablation and Planned Combination Therapy Improved local tumor control can be achieved in patients with Child-Pugh A and B cirrhosis who are not candidates for transplant by a combination of transarterial and ablative liver-directed therapy. Downsizing to thermal ablation Several retrospective studies have evaluated the outcomes of TACE for patients with large (> 5 cm) and very large (> 10 cm) HCC without macrovascular invasion [55 57]. These studies have shown that TACE could be safely performed in patients with large lesions and that patients who underwent thermal ablation after several sessions of TACE had significantly longer OS than patients who were treated with TACE alone [55 57]. Thus, the median OS was nearly doubled for patients who received thermal ablation after TACE (range of median OS, months) compared with patients treated with TACE alone (range of median OS, 6 13 months) [56, 57]. To date, data regarding downstaging to thermal ablation after radioembolization have been limited to a few patients included in large cohorts of patients with unresectable HCC [6, 24]. However, because the ability to induce tumor necrosis of TACE and TARE is known to be comparable [5, 6, 41], either form of transarterial therapy could probably be used to downsize HCC before thermal ablation. Downsizing to planned combination therapy Several RCTs have evaluated the safety and efficacy of a combination of TACE and thermal ablation compared with ablation alone [58 64] or with TACE alone [62, 63]. A recent meta-analysis of RCTs evaluating TACE versus TACE plus RFA combination therapy [65] showed significant improvements in 1-, 3-, and 5-year OS for patients with lesions > 3 cm who underwent combination therapy without an associated increase in major complications in the combination therapy group. However, no advantage to combination therapy was seen for patients with lesions < 3 cm in diameter. In another recent meta-analysis of RCTs that evaluated a combination of TACE and any form of ablative therapy versus any form of monotherapy [66], the authors included a subanalysis of studies of TACE with RFA or TACE with PEI versus TACE monotherapy. Significant improvements in 1-, 3-, and 5-year OS were shown for TACE plus RFA compared with TACE alone. Similarly, there were significant improvements in 1- and 5-year OS for TACE plus RFA compared with TACE alone [66]. Prospective randomized trials on combination therapy involving radioembolization and ablation have not yet been performed. However, the reported high rates of near-complete tumor necrosis at pathology after TARE (especially after radiation segmentectomy) make this treatment modality an attractive choice for planned combination therapy with thermal ablation, particularly for lesions > 5 cm in diameter. TACE Versus TARE for Treating Unresectable Hepatocellular Carcinoma TACE has an established survival benefit over best supportive care for patients with unresectable HCC [67, 68] who have good performance status and preserved liver function (Child-Pugh B or better). TARE has been evaluated in prospective single-arm studies in a similar patient population: These studies have determined that the median OS after radioembolization is months [14, 15, 69]. As expected, OS tends to be significantly longer for patients with Child-Pugh A cirrhosis than for those with Child-Pugh B cirrhosis (22 vs 15 months, respectively) and for patients without portal vein tumor thrombus (PVTT) after controlling for severity of the underlying cirrhosis [19]. Several multicenter RCTs are under way that aim to establish whether there is a survival benefit for radioembolization when compared with sorafenib for patients with unresectable HCC (NCT identifiers , , on ClinicalTrials.gov). Although there are several ongoing prospective multicenter RCTs designed to compare the safety and efficacy of TACE and TARE for unresectable HCC (NCT identifiers , , , on ClinicalTrials.gov), most of the available data directly comparing these two transarterial therapies are from retrospective studies (Table 1). The largest retrospective study to date has been by Salem et al. [70]: In that study, they included 245 patients with unresectable HCC without portal vein thrombosis. TACE was performed with doxorubicin, mitomycin C, cisplatin, ethiodized oil, and permanent particles, whereas glass microspheres were used for TARE. The study showed a significantly longer time to disease progression after TARE (mean, 13.3 months) compared with TACE (8.4 months) and a nonsignificant trend toward improvement in median OS (20.5 months for TARE vs 17.4 months for TACE). Postembolization syndrome symptoms (i.e., abdominal pain and fever) were significantly more common after TACE, but the rates of severe adverse events for TACE and TARE were similar. Other retrospective studies that compared TACE and TARE have generally reported statistically similar median OS (6 18 months for TACE vs months for TARE) and a similar prevalence of adverse events [71 74]. Carr et al. [75] found a significantly longer median OS after radioembolization compared with TACE; however, patients in the TACE group had significantly worse hyperbilirubinemia at baseline than patients in the TARE group [75]. Kolligs et al. [76] recently reported the results of a pilot multicenter RCT that included 28 patients with unresectable HCC and a Child-Pugh-Turcotte score of up to 7. The inclusion requirements were a performance AJR:205, October

5 Fidelman and Kerlan TABLE 1: Data From Retrospective Studies Comparing the Safety and Efficacy of Transarterial Chemoembolization (TACE) and Transarterial Radioembolization (TARE) for the Treatment of Patients With Unresectable Hepatocellular Carcinoma Therapy (No. of Patients) Regimen Median OS (mo) First Author [Reference No.] Year Study Was Published status of 2 or better, up to five liver lesions with a composite maximum diameter 20 cm, and macrovascular invasion or extrahepatic disease. Patients were randomized to receive TACE with epirubicin (50 mg/m 2 ), ethiodized oil, and either 150- or 300-μm or 300- to 500-μm tris-acryl gelatin microspheres at 6-week intervals until all tumorrelated enhancement was no longer observed on MRI (n = 15) or to receive a single TARE treatment with resin microspheres (n = 13) with a median activity of 1.6 GBq to the whole liver (n = 7), a single lobe (n = 5), or one segment (n = 1). The primary endpoint was health-related quality of life (HRQOL), which was assessed using a standard instrument (Functional Assessment of Cancer Therapy Hepatobiliary Cancer [FACT- Hep] questionnaire). Secondary endpoints included adverse events, radiographic response (Response Evaluation Criteria in Solid Tumors [RECIST], version 1.0), progression-free survival (PFS), and OS calculated from the day of the first procedure. Because of missing baseline data, the HRQOL outcomes could be evaluated for only 18 patients (64%), and patients randomized to TARE had significantly lower baseline FACT-Hep scores, which remained lower than those for the TACE group for the first 12 weeks after the commencement of treatment. However, after 12 weeks, the FACT-Hep scores for the two groups became similar. Radiologic responses for TACE and TARE were not significantly different (partial response [PR], 13.3% vs 30.8% of patients, respectively; disease control rate, 73.3% vs 76.9%) and median PFS values were similar as well (3.6 and 3.7 months). The frequency of adverse events was 92.3% for the TARE group and 66.7% for TACE group (not a statistically significant difference), but there were more TACE TARE Drugs Used for Conventional TACE gastrointestinal adverse events in the TARE group than in the TACE group (six patients vs one patient, respectively; p = 0.029). Salem et al. [77] performed a prospective nonrandomized study focused on quality-oflife assessment of 29 patients who underwent TARE and 27 patients who underwent TACE for unresectable HCC. The FACT-Hep survey instrument was used. Patients in the TACE group had significantly lower hepatic tumor burden, allowing injection of the segmental arteries. Quality-of-life measures at baseline were similar for the two groups. Despite the more advanced disease of patients who received radioembolization, they had a significantly better quality of life based on social wellbeing, functional well-being, and embolotherapy-specific scores. There was also a trend toward better overall quality of life in the TARE group than in the TACE group. The studies published to date suggest that TARE might result in improved time to progression and improved safety profile compared with TACE; however, OS is unlikely to be affected by the choice of transarterial therapy. Ongoing prospective randomized trials will help supply comparative data for these two therapeutic modalities. Treating Advanced-Stage Hepatocellular Carcinoma The current AASLD practice guideline [4] recommends that patients with advanced HCC (defined as the presence of macrovascular invasion into the portal or hepatic vein or both veins, extracapsular tumor extension, and metastatic disease) who have good performance status and preserved liver function (Child-Pugh B or better) should be treated systemically with an FDA-approved tyrosine kinase inhibitor sorafenib or enrolled in a clinical trial of 90 Y Microspheres Used for TARE TACE TARE p Carr [75] C Glass Kooby [74] D, C, M Resin Lance [72] D, C Glass or resin Salem [70] D, C, M Glass Moreno-Luna [71] D, M Glass El Fouly [73] D Glass NS Note C = cisplatin, D = doxorubicin, M = mitomycin C, OS = overall survival. other systemic agents. Sorafenib is a tumorstatic agent, so it is unlikely to have a cytoreductive effect [78]. Therefore, there has been considerable interest in potentially cytoreductive transarterial liver-directed therapy for patients with locally advanced HCC and even for select patients with limited extrahepatic metastatic disease. Macrovascular invasion Several studies have reported the results of TACE [79 84] or TARE [85 88] for patients with PVTT. In this patient population, perfusion to the affected liver lobe is predominantly via the hepatic artery. Therefore, TARE should, in theory, be safer than TACE because, unlike TACE, TARE is nonembolic and therefore may not lead to the same extent of hepatic parenchymal ischemia. To date, there have not been any retrospective or prospective studies that directly compare TACE and TARE for the treatment of HCC with macrovascular invasion. A recent meta-analysis [89] summarized data from five of the studies that compared TACE with supportive care for patients with PVTT. The authors found that patients who received TACE had a significantly higher 1-year survival than patients who received supportive care (odds ratio, 3.1; 95% CI, ). Patients included in this meta-analysis did not receive sorafenib. The results of the individual studies describing the role of TACE for patients with PVTT are summarized in Table 2. The median OS was months and was significantly longer for TACE responders than for nonresponders [79 81, 83, 84]. Several patients were successfully downstaged to resection or ablation [81]. The most common adverse events were related to postembolization syndrome. However, hepatic decompensation (albeit transient) was reported in 35% of patients in one of the studies [81]. 746 AJR:205, October 2015

6 TACE and 90 Y Radioembolization to Treat HCC TABLE 2: Recently Published Studies on Transarterial Chemoembolization (TACE) for Patients With Portal Vein Tumor Thrombus (PVTT) First Author [Reference No.] Table 3 summarizes the results of recent studies that included patients with PVTT treated with 90 Y radioembolization. The median OS ranged from 3.2 to 13 months and was significantly longer for patients with underlying Child-Pugh A than Child-Pugh B liver disease. A minority of the patients experienced partial regression of intrahepatic and intraportal lesions. Retrospective studies probably underreported the prevalence of severe adverse events [86 88]. Mazzaferro et al. [18] have provided detailed information regarding 35 patients with PVTT as a part of a prospective phase 2 study. Although the prevalence of most severe adverse events was less than 10%, hyperbilirubinemia was reported in 30% of patients and clinical liver decompensation occurred in 37%. The survival advantage of either TACE or TARE compared with standard-of-care sorafenib is unknown. A prospective multicenter RCT evaluating TARE versus sorafenib in patients with PVTT is currently recruiting patients (NCT identifier on Clinicaltrials.gov). To date, no studies have directly compared TACE and TARE for the treatment of TABLE 3: Recently Published Studies on Transarterial Radioembolization (TARE) with 90 Y Microspheres for Patients With Portal Vein Tumor Thrombus First Author [Reference No.] Year Study Was Published Year Study Was Published No. of Patients No. of Patients Drugs Administered for Conventional TACE 90 Y Microspheres Used for TARE Median OS (mo) Median OS (mo) Mazzaferro [18] Glass Child-Pugh A, 16; Child-Pugh B, 6; overall, 13 Memon [85] Glass Child-Pugh A, 13.8; Child-Pugh B, 6.5 Radiologic Response (% of Patients) Grade 3 or 4 Adverse Event (% of Patients) WHO criteria: ORR a, 37; DCR b, 74 WHO criteria: ORR a, 38; DCR b, 87 Sangro [14] Resin Overall, 10.2 NR NR Tsai [86] Glass or resin Child-Pugh A, 7.7; Child-Pugh B, 2.7; overall, 7.0 RECIST version 1.1: ORR a, 8; DCR b, 58 Iñarrairaegui [87] Resin Overall, 10 RECIST version 1.1: ORR a, 4; DCR b, 67 Radiologic Response Based on RECIST (% of Patients) Liu [79] C, D, E, M a 6.1 NR NR Chern [84] C, D, M Responders, 10.5; nonresponders, 5.5; all patients, 6.2 DCR b, 42 None Tawada [83] C, E, Mi a Responders, 14.5; nonresponders, 5.8 ORR c (parenchyma), 60; ORR c (PVTT), 39 Niu [80] C, E 8.7 NR NR Luo [81] E, L, M 7.1 Complete response, 0; partial response, 20; stable disease, 43; progressive disease, 37 d Woodall [88] Glass Overall, 3.2 NR None Grade 3 or 4 Adverse Event (% of Patients) Abnormal AST value, 70; abnormal ALT value, 55; hyponatremia, 6; thrombocytopenia, 6; hyperbilirubinemia, 3; leukopenia, 3; anemia, 3 Liver decompensation, transient, 35; cholecystitis, 2 Note OS = overall survival, RECIST = Response Evaluation Criteria in Solid Tumors, C = cisplatin, D = doxorubicin, E = epirubicin, M = mitomycin C, NR = not reported, Mi = miriplatin, AST = aspartate aminotransferase, ALT = alanine aminotransferase, L = lobaplatin. a Multiple different TACE regimens were used. b DCR (disease control rate) is defined as follows: (complete response + partial response + stable disease). c ORR (overall response rate) is defined as follows: (complete response + partial response). d In addition, disease was downstaged in nine patients: six underwent surgery, one underwent radiofrequency ablation (RFA), and two underwent RFA and percutaneous ethanol injection. Fatigue, 9; abdominal pain, 6; nausea, 9; anorexia, 14; fever, 3; ascites, 6; variceal hemorrhage, 6; cholecystitis, 3; bile duct stenosis, 9; hyperbilirubinemia, 30; hypoalbuminemia, 17; leukopenia, 17; liver decompensation, 37 NR Ascites, 13; encephalopathy, 13; fatigue, 9; abdominal pain, 9; liver failure, 13; elevated AST, 13; hyperbilirubinemia, 13 Encephalopathy, 12; ascites, 12; hyperbilirubinemia, 12 Note OS = overall survival, WHO = World Health Organization, NR = not reported, RECIST = Response Evaluation Criteria in Solid Tumors, AST = aspartate aminotransferase. a ORR (overall response rate) is defined as follows: (complete response + partial response). b DCR (disease control rate) is defined as follows: (complete response + partial response + stable disease). AJR:205, October

7 Fidelman and Kerlan HCC Stage 0: PS 0; Child-Pugh A Stages A C: PS 0 2; Child-Pugh A or B Stage D: Child-Pugh C Very early stage (stage 0): 1 lesion < 2 cm; PS 0 1 Early stage (stage A): 1 lesion < 5 cm or 2 or 3 lesions each < 3 cm; PS 0 2 patients with PVTT. Although the severity of laboratory liver function test abnormalities and postembolization syndrome is probably lower for patients treated with TARE because of the minimally embolic nature of the procedure, available single-arm studies report similar median OS values and comparable prevalence rates of clinical liver decompensation ( 35% for TACE and 37% for TARE) [15, 81]. Infiltrative disease In contrast to nodular-type HCC, infiltrative HCC is not recognized as a focal tumor but instead permeates throughout the liver. Radiologically, infiltrative HCC has indistinct borders, lacks the typical enhancement pattern seen in nodular HCC, and is often diagnosed together with macrovascular invasion. Its permeative appearance often blends into the background of a cirrhotic liver, causing difficulties in visualization on both ultrasound and crosssectional imaging [90, 91]. A diagnosis of infiltrative HCC portends a poor prognosis, with a median OS of 4 months [92]. Although no prospective studies evaluating liver-directed therapy versus best supportive care for patients with infiltrative HCC have been performed to date, retrospective Intermediate stage (stage B): 1 lesion > 5 cm or multinodular; PS Lesion 2 or 3 Lesions Multinodular Enlarge FLR PVE with or without TACE or TARE studies that have included a cohort receiving supportive care have reported that patients who underwent TACE tended to have significantly longer median OS than patients who received only supportive care (median OS, 6 7 months vs 3 4 months, respectively) [92, 93]. Information regarding radiologic response 1 month after TACE was described in a study by Han et al. [94] that included 52 patients with infiltrative HCC. According to the European Association for the Study of the Liver (EASL) criteria, none of the patients experienced a complete response (CR), 18% of patients had a partial response (PR), and 47% had stable disease (SD). Severe adverse events, including hepatic decompensation, renal failure, and variceal bleeding, were reported in 12 17% of patients [94, 95]. The clinical use of 90 Y radioembolization for patients with infiltrative HCC has been limited in large part because of observations made by Goin et al. [52, 53] that patients with infiltrative HCC had a significantly higher 3-month mortality than patients with HCC showing a nodular growth pattern after treatment with glass microspheres. There is a black box warning in the glass microsphere Advanced stage (stage C): vein invasion; M1; N1; PS 0 2 Terminal stage (stage D) Downsize Bridge or Downstage PS 0 1 PS > 2 TACE or TARE TACE RFA PEI TARE TACE or TARE RFA PEI TACE or TARE Resection RFA Transplant Sorafenib or trial Symptomatic treatment Curative treatments Palliative treatments Fig. 2 Flowchart shows overview of utilization of transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) with 90 Y microspheres in current clinical practice for treatment of patients with hepatocellular carcinoma (HCC). Note that there is insufficient evidence to support use of TARE for patients with impaired hepatic function (serum bilirubin > 2.0 mg/dl). PS = performance status, FLR = future liver remnant, PVE = portal vein embolization, RFA = radiofrequency ablation, PEI = percutaneous ethanol ablation. package insert against treating patients with infiltrative HCC. Nevertheless, both glass and resin microspheres are used to treat infiltrative HCC off-label. Kokabi et al. [96] described the use of TARE in 18 patients with infiltrative HCC. Radiologic responses according to the modified RECIST criteria 3 months after therapy showed CR in 11% of patients, PR in 61%, SD in 11%, and progressive disease in 17%. Safety data were not included in that study. The median OS was 13 months and was significantly longer for responders than for nonresponders (14 vs 5.5 months, respectively). Although the results of retrospective studies suggest that TACE may confer a survival benefit over supportive care for patients with infiltrative HCC, this observation may have been subject to selection bias because it is likely that patients in overall better health were more likely to be offered TACE. The limited available data regarding the use of TARE for patients with infiltrative HCC also appear to be promising. However, before widespread adoption of TACE and TARE for the treatment of infiltrative HCC, prospective studies comparing transarterial therapies with sorafenib are needed. 748 AJR:205, October 2015

8 TACE and 90 Y Radioembolization to Treat HCC TABLE 4: Relative Advantages of Transarterial Chemoembolization (TACE) and Transarterial Radioembolization (TARE) in the Treatment of Hepatocellular Carcinoma (HCC) Clinical Application (Characteristics of Eligible Patients a ) TACE vs TARE Notes Downsize tumor before major hepatectomy (Child-Pugh A or better; performance status 0 or 1) FLR enlargement (Child-Pugh A or better; performance status 0 or 1) Bridge and downstage to LT (Child-Pugh B or better) Conclusion The current AASLD practice guideline [4] recommends TACE for the treatment of patients with intermediate-stage HCC who have good performance status and preserved liver function (Child-Pugh B or better). TARE is not included in the treatment algorithm. However, as summarized in this article, both TACE and TARE are currently being used for the treatment of most subpopulations of patients with HCC, and their clinical uses extend beyond the treatment of intermediate-stage HCC. These uses include downsizing to surgical resection or thermal ablation, bridging or downstaging to transplant, treatment of patients with PVTT, and treatment of patients with infiltrative HCC. Figure 2 summarizes the extended uses of TACE and TARE beyond those listed in the AASLD practice guideline. The relative advantages of TACE and TARE based on the data summarized in this article are summarized in Table 4. For most clinical scenarios, the efficacy and safety of TACE and TARE are probably equivalent. However, TARE appears to have an advantage over TACE in the facilitation of surgical resection by resulting in compensatory hypertrophy of the FLR and possibly in the treatment of patients with PVTT. On the contrary, TACE is the transarterial treatment of choice for patients with marginal hepatic reserve (i.e., hyperbilirubinemia, ascites) who may be candidates for transplant. In the next few years, the results of the ongoing multicenter RCTs comparing TACE with TARE Probably equivalent TARE preferred Probably equivalent No improvement in disease-free survival or OS for neoadjuvant TACE; limited data for TARE TARE likely to increase FLR size even after failure to respond to PVE; TACE has no effect on FLR size and may be used as adjunct to PVE to maximize tumor necrosis before surgery Most available data support use of TACE; however, TARE (especially radiation segmentectomy) may lead to extensive tumor necrosis Bridge and downstage to LT (Child-Pugh C) TACE preferred TACE can be used for patients with marginal hepatic reserve Downsize to thermal ablation Probably equivalent Limited data for both techniques, especially TARE Unresectable HCC Probably equivalent TARE might be better tolerated than TACE; randomized trials comparing TACE with TARE and TARE with sorafenib are ongoing Macrovascular invasion Probably equivalent TARE may cause less hepatocellular tissue damage, but efficacy and SAE profiles are similar; randomized trial comparing TARE with sorafenib is ongoing Infiltrative growth pattern Probably equivalent Limited data for both techniques, especially TARE Note OS = overall survival, FLR = future liver remnant, PVE = portal vein embolization, LT = liver transplant, SAE = severe adverse effect. a Performance status of 0 2 and underlying liver function of Child-Pugh B or better unless specified otherwise. and TARE with standard-of-care sorafenib will be published and can be used to help guide clinical decision making. 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Treatment of unresectable hepatocellular carcinoma with in- tive liver failure after major hepatic resection for outcome following down-staging of hepatocel- trahepatic yttrium 90 microspheres: a risk-strat- hepatocellular carcinoma in the modern era with lular carcinoma prior to liver transplantation: an ification analysis. J Vasc Interv Radiol 2005; special reference to remnant liver volume. J Am intention-to-treat analysis. Hepatology 2008; 16: Coll Surg 1999; 188: : Goin JE, Salem R, Carr BI, et al. Treatment of 750 AJR:205, October 2015