Loco-regional treatment of HCC: current status

Clinical Radiology xxx (2017) e1ee10

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Review

Loco-regional treatment of HCC: current status L. Crocetti*, I. Bargellini, R. Cioni Division of Interventional Radiology, Department of Diagnostic and Interventional Radiology and Nuclear Medicine, Cisanello University Hospital, Pisa, Italy

art icl e i nformat ion Article history: Received in revised form 18 January 2017

Hepatocellular carcinoma (HCC) represents one of the few cancers for which locoregional treatments are recognised as being able to cure and/or prolong survival and are included in international guidelines. This is due to the unique nature of HCC, in most cases occurring in patients with underlying virus- or alcohol-related cirrhosis. The treatment choice in patients with HCC is therefore driven not only by tumour staging, as in the great majority of cancers, but also by careful evaluation of liver function and physical status. Another specific feature of HCC is that it is the only tumour that can be cured by organ transplantation, with the aim of treating both the cancer and underlying liver disease. These characteristics configure a complex scenario and prompt the need for close cooperation among interventional oncologists, surgeons, hepatologists, and anaesthesiologists. In patients with limited hepatic disease, preserved hepatic function and good performance status, categorised as very early and early-stage HCC according to the Barcelona Clinic Liver Cancer (BCLC) classification, image-guided tumour ablation is included among the curative treatments. More than half of patients with HCC are, however, diagnosed late, despite the widespread implementation of surveillance programmes, when curative treatments cannot be applied. For patients presenting with multinodular HCC and relatively preserved liver function, absence of cancer-related symptoms, and no evidence of vascular invasion or extrahepatic spread transcatheter arterial chemoembolisation (TACE) is the current standard of care. Although anti-tumour activity and promising survival results has been reported in cohorts of patients with advanced HCC treated with radio-embolisation, systemic treatment with the multi-kinase inhibitor, sorafenib, is still recommended for patients at this stage. In this article, current treatment strategies for HCC according to tumour stage are discussed, underlining the latest advances in the literature and technical developments. Ó 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Introduction Hepatocellular carcinoma (HCC) represents one of the few cancers for which locoregional treatments are * Guarantor and correspondent: L. Crocetti, Division of Interventional Radiology, Department of Diagnostic and Interventional Radiology and Nuclear Medicine, Cisanello University Hospital, Building No. 30A, Via Paradisa 2, IT-56124 Pisa, Italy. Tel.: þ39 050 995 551; fax: þ39 050 573 905. E-mail address: [email protected] (L. Crocetti).

recognised as being able to cure and/or prolong survival and are included in international guidelines.1e3 This is due to the unique nature of HCC, in most cases occurring in patients with underlying virus- or alcohol-related cirrhosis. The treatment choice in patients with HCC is therefore driven not only by tumour staging, as in the great majority of cancers, but also by careful evaluation of liver function and physical status. Another specific feature of HCC is that it is the only tumour that can be cured by organ

http://dx.doi.org/10.1016/j.crad.2017.01.013 0009-9260/Ó 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

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transplantation, with the aim of treating both cancer and underlying liver disease.1e3 These characteristics configure a complex scenario and prompt the need for close cooperation among interventional oncologists, surgeons, hepatologists, and anaesthesiologists. Decision making for treatment of HCC is supported by guidelines endorsed by different societies worldwide: European Association for the Study of the Liver (EASL) and the European Organization for Research and Treatment of Cancer (EORTC), American Association for the Study of Liver Diseases (AASLD), Asian Pacific Association for the Study of Liver (APASL), Korean Liver Cancer Study Group and the Japan Society of Hepatology.1e5 Differences in recommendations among guidelines mirror differences in cancer epidemiology, technique availability, and expertise in various countries. The Barcelona Clinic Liver Cancer (BCLC) classification has emerged during recent years as the standard classification that is used for clinical management of patients with HCC6,7 (Table 1). This classification links stage stratification with a recommended treatment strategy, and defines the standard of care for each tumour stage. It has been endorsed by EASL, EORTC and AASLD.1,2 According to the BCLC staging system, refined in 2016, image-guided tumour ablation is recommended in patients with very early and early-stage HCC.7 Despite the widespread implementation of surveillance programmes, more than half of the patients with HCC are diagnosed late, when curative treatments cannot be applied. In addition, in a high proportion of cases, the disease recurs after a curative therapy. For patients presenting with multinodular HCC and relatively preserved liver function, absence of cancer-related symptoms, and no evidence of vascular invasion or extrahepatic spread (i.e., those classified as intermediate stage according to the BCLC staging system), transcatheter arterial chemoembolisation (TACE) is the current standard of care. Although antitumour activity and promising survival results have been reported in cohorts of patients with advanced HCC treated with radio-embolisation, systemic treatment with the multi-kinase inhibitor, sorafenib, is still recommended for patients at this stage.1,2,7 In this article, current treatment strategies for HCC according to tumour stage are discussed, underlining the latest advances in the literature and technical developments. Table 1 The BCLC (Barcelona Clinic Liver Cancer) staging system.6,7 BCLC stage

ECOG PS

Liver function: ChildePugh

Tumour stage

Very early stage (0) Early stage (A)

0 0

A AeB

Intermediate stage (B) Advanced stage (C)

0 1e2

AeB AeB

Terminal stage (D)

3e4

C

Single, 2 cm Single, 3 nodules, 3 cm Multinodular Vascular invasion, extrahepatic spread Any

Stage 0, A, and B: all criteria should be fulfilled. Stage C and D: at least one criterion should be fulfilled. ECOG PS, Eastern Cooperative Oncology Group Performance Status.

Very early stage HCC In very early stage HCC, the presence of a solitary small nodule, <2 cm in diameter, in ChildePugh A patients, the absence of microvascular invasion and dissemination offers the highest likelihood of cure. According to the EASL-EORTC guidelines, these patients can be offered surgical resection if they have cirrhosis, but still have well-preserved liver function, normal bilirubin (<1 mg/dl; <17.1 mmol/l), and in the absence of clinically significant portal hypertension.1 Such patients will not decompensate after resection and may achieve a 5-year survival of 70%.8 In non-ideal patients with impaired liver function, although tumour removal would be technically feasible, resection may not be worth attempting as survival could be reduced. Despite the recent refinements in surgical techniques that result in a reduction of treatment-related mortality to 1e3%, in clinical practice the decision to resect HCC is based on individual patient components and local conditions that are not captured by guidelines. Most groups restrict the indication for anatomical resection to patients with very early HCCs that are in a suitable location for resection, to maximally preserve non-cancerous functional liver parenchyma.9 Nodules <2 cm, that are not subcapsular nor perivascular, are the ideal target for percutaneous ablation, with radiofrequency ablation (RFA) still considered the standard technique for liver tumour ablation at most institutions.10,11 In patients with very early HCC, the complete response rate approaches 97%, with 5year survival rates of 68%.12 Roayaie et al.13 reported a 15% mortality risk reduction in ablated patients compared to resected ones, thus endorsing the recommendation to give priority to ablation in patients with small tumours that can be effectively and safely ablated. Although there has been no robust trial data to compare the efficacy of surgery versus ablation, caseecontrol and modelling studies have shown ablation to be non-inferior and more cost-effective for patients with very early-stage HCCs.14e16 It has also been pointed out as individual characteristics belonging to each patient (e.g. whether the tumour is central or peripheral, close or distant form bile ducts, occurring in a patient who is lean or overweight, who presents with or without portal hypertension, who has a platelet count above or below 150,000/ml, etc.) influence the results of each treatment making it better or worse than average.14,15 As clinical experience suggests that treatment by ablation of HCC tumours in a subcapsular location or adjacent to the gallbladder is associated with an increased risk of major complications and incomplete ablation, such tumour locations are considered favourable for hepatic resection.17e21 Therefore, in patients with very early HCC, ablation can be offered as a firstline curative treatment when patients are not candidates for liver transplantation; however, a surgical approach is considered when individual variables, including tumour location, would make ablation unfeasible or unsafe.7 Among ablative modalities, RFA is considered the firstline ablation technique; its advantages and limitations being well understood as a result of the number of

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experimental animal studies and clinical trials.22,23 Microwave ablation (MWA) is becoming a competitor for RFA (Fig 1). Both techniques achieve the same effectiveness and survival in solitary HCC <2 cm24,25 with portal hypertension as the main determinant of patient outcome.7

Early-stage HCC Early-stage disease includes patients with preserved liver function (ChildePugh A and B) with solitary HCC or up to 3 nodules <3 cm in size. Resection and transplantation produce the best outcomes for well-selected candidates with HCC of BCLC stage A; 60e80% of patients survive for 5 years.1e7 Patients who are not suitable for surgery because of comorbidities should be considered for treatment with ablation. In a recent study describing the surgical management of HCC within the Bridge database, which collected information from a cohort of 8,656 patients of new incident cases worldwide, it was found that a total of 862 (10%) patients were classified as ideal resection candidates.13

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These results reflect the fact that associated conditions (advanced age, comorbidities) exclude a substantial proportion of patients from surgery. The relative roles of resection and ablation as first-line treatments have been debated, even among HCC patients who would meet AASLD/EASL criteria for surgery. Three randomised trials have provided conflicting results.26e28 In particular, limitations in study design reduce the clinical impact of the results. In fact the comparison between ablation and resection in nodules >3 cm in size is not conceptually correct, as it is well known that the RFA success rate drops dramatically for technical reasons while resection may offer a better outcome. The rate of failure of ablation also increases in the case of multinodular HCC and less compensated liver cirrhosis. In the prospective cohort analysis based on data from the nationwide follow-up survey by the Liver Cancer Study Group of Japan, including ChildePugh A and B HCC patients with up to three lesions 3 cm, the outcome of liver resection was superior to that of RFA (hazard ratio of liver resection to RFA for death was 0.84;

Figure 1 MWA of very early stage HCC in a 67-year-old male patient with hepatitis C virus (HCV)-related liver cirrhosis. Pre-treatment MRI shows the tumour as a small 15 mm hyperintense nodule (arrow, a) in the arterial phase, with hypointense appearance in the portal-venous phase (arrow, b). A 14 G MW antenna (AMICA, HS) is placed within the nodule under ultrasound guidance (c) and at the end of treatment (5 minutes, 60 W) a hyperechoic zone is visible in the site of the treated nodule together with the ablated track (d). On CT images obtained in the arterial (e) and the portal venous phase (f) 1 month after treatment, the tumour is replaced by a non-enhancing ablation zone that exceeds in size the diameter of the naive tumour. The findings are consistent with complete response. Please cite this article in press as: Crocetti L, et al., Loco-regional treatment of HCC: current status, Clinical Radiology (2017), http://dx.doi.org/ 10.1016/j.crad.2017.01.013

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95% confidence interval [CI], 0.74e0.95; p¼0.006).29 When RFA was applied in patients with single HCC <3 cm in ChildePugh class A cirrhosis, as in a multicentre retrospective comparison of resection and RFA conducted in 15 Italian centres, overall survival rates were similar (74.4% in the resection group and 66.2% in the RFA group; p¼0.353).30 The results of these studies seem to confirm that when ablation is performed in the appropriate patients, with compensated liver cirrhosis and small solitary HCCs, this approach can be offered as a first-line treatment option, as is the case for very early HCC.7,31 Recently, minimally invasive liver surgery (laparoscopic or robot-assisted) has emerged as a valuable treatment option for selected patients, causing less blood loss and fewer complications than open liver surgery.32 A caseecontrol study was undertaken to compare RFA with minimally invasive surgery for the management of patients with single 3-cm HCCs. This study suggested that minimally invasive surgery offers at least similar overall and disease-free survivals as percutaneous RFA in the management of selected patients (child A) with single 3-cm HCCs (median survivals in the surgical and ablated groups of 10010.8 and 7526.4 months, respectively, p¼0.147; disease-free survival 46.7% in the surgical group versus 56.7% in RFA group, p¼0.906).32 Complication rates were similar between both strategies. The authors were able to capture an important issue: that of different indications according to tumour location, often disregarded in clinical trials and guidelines. In fact, they concluded that minimally invasive surgery should be favoured in patients with peripheral HCCs in segments 2e6, while RFA should be preferred in centrally located tumours.32 To date, a single randomised controlled trial (RCT) showed equivalent therapeutic effects and complication rates between MWA and RFA in the treatment of HCC33; however, this study was undertaken during the initial development of MWA. Despite further evolution and improvement of the technique, comparisons of MWA and RFA have produced conflicting results in a number of observational studies.34e36 This lack of agreement may be related to differences in the generators/antennas used and it is still not clear whether the theoretical advantages of MWA are associated with clinical benefits. Two recent meta-analyses concluded that both RFA and MWA are equally effective and safe, but MWA may be more effective compared to RFA in preventing local tumour progression when treating larger tumours.37,38 Given the very similar profile of the two ablative modalities, is it difficult to foresee that a RCT will be soon designed and conducted with the aim of comparing differences in overall survival. There are some interesting features of MWA that could be analysed in comparison to RFA, such as the short time needed per procedure and the easy placement of one straight antenna to obtain the volume of ablation that would have needed several RFA electrodes or expandable electrodes. A non-chemical, non-thermal image-guided ablation technique that is currently undergoing clinical investigation in early-stage HCC is irreversible electroporation (IRE).39 IRE is a method to induce irreversible disruption of cell

membrane integrity, by changing the transmembrane potential, resulting in cell death without the need for additional pharmacological injury.40 Because IRE is a nonthermal technique, issues associated with perfusionmediated tissue cooling or heating (a significant challenge with thermal methods) are not relevant. So far the data published regarding the technique are mostly represented by case-series including lesions in difficult (perivascular or peribiliary) locations.41,42 When clinically significant portal hypertension and abnormal bilirubin contraindicate surgical treatment in patients with solitary HCC >3 and <5 cm, a combination of TACE followed by RFA has been used to minimise heat loss due to perfusion-mediated tissue cooling and increase the therapeutic effect of RFA.43 Recently, the results of a metaanalysis showed that RFA plus TACE significantly improved the overall survival rates at 1 and 3 years compared with RFA alone in patients with a single HCC >3 cm.44 TACE with drug-eluting beads has also been performed after an RFA procedure to increase tumour necrosis by exposing the peripheral part of the tumour to a high drug concentration, where only sub-lethal temperatures may be achieved in a standard RFA treatment.45 Further research to determine optimal methods of combining chemotherapeutic regimens (agent, route of administration, time interval between TACE and RFA or vice versa) with RFA is needed. It has been suggested that a single-step “combined” approach, with both procedures performed in the same session, makes it possible to obtain and amplify the synergistic effects of RFA and TACE.46 Moreover, initial reports seem to suggest that with the use of present MWA devices, percutaneous ablation of HCCs up to 5 cm can be achieved with high efficacy.47,48 Researchers and companies are also exploring new strategies for increasing the results of ablation. A phase III, randomised, double-blinded, placebo-controlled study investigating the efficacy and safety of lyso-thermosensitive liposomal doxorubicin in combination with RFA compared to RFA alone in the treatment of non-resectable HCC (HEAT trial) has been recently completed.49 When heated during a RFA procedure to 40 C, lyso-thermosensitive liposomal doxorubicin produces high drug concentrations in the surrounding margins of the ablation zone. RFA þ lysothermosensitive liposomal doxorubicin did not improve the efficacy of normal practice RFA; however, among the 285 patients with a solitary lesion who received at least 45minutes RFA dwell time, the hazard ratio for overall survival was 0.63 (95% CI: 0.41e0.96; p¼0.04).49 The OPTIMA study is currently ongoing to test the hypothesis that adding lysothermosensitive liposomal doxorubicin to a standardised RFA lasting 45 minutes increases survival compared with standardised RFA alone.50 Patients with solitary large tumours (>5 cm in size) deserve a special mention. Even though the tumours are not considered early-stage HCC and do not qualify for transplantation, there is no upper limit on size for surgical resection in the BCLC flowchart, and these patients should not be overlooked for surgical referral because their tumours are too large.14 It has been suggested that patients

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with large solitary tumours may benefit from surgery because surgical mortality has decreased and patients with operable solitary large tumours may be a self-selected group with low tendency for multifocal disease.14 Different ablative modalities are not currently providing sufficient volume of ablation to successfully treat these tumours, and when tumour size is >5 cm, the advantages of combination therapies seem negligible.51 Moreover, the results of TACE as a standalone therapy in tumours >5 cm, which are characterised by heterogeneous structure and vascularisation, are suboptimal, with a high rate of incomplete response and post-embolisation syndrome.52 In this setting, transarterial radio-embolisation, in which the main anti-cancer effect is given by radiation and the embolic effect of microparticles containing radionuclide (yttrium-90) is negligible, has been suggested as a treatment option.53

Intermediate-stage HCC Patients with intermediate-stage HCC, i.e., multinodular HCC, relatively preserved liver function (ChildePugh class A or B-7 points without ascites), absence of cancer-related symptoms, and no evidence of vascular invasion or extrahepatic spread are considered candidates for TACE.1,7 The recommendation for TACE as the standard-of-care for intermediate-stage HCC is based on the demonstration of improved survival compared with best supportive care or suboptimal therapies in a meta-analysis of six RCTs54; however, there was considerable heterogeneity between the individual study designs (including patient populations and TACE technique) as well as the study results. Furthermore, intermediate-stage HCC includes a heterogeneous population of patients varying widely in terms of tumour burden and liver function (ChildePugh A or B).55 It has therefore been suggested that although TACE improves survival for the intermediate-stage HCC class as a whole, not all patients with intermediate-stage HCC will derive similar benefit from TACE.56 Some absolute and relative contraindications exist, including tumour burden (size >10 cm) and impairment of liver function.56 From a technical point of view, although there is a general consensus about the fact that TACE should be as selective as possible, more standardisation of TACE protocols is still needed. The ideal TACE scheme should allow a maximum and sustained concentration of chemotherapeutic drug within the tumour with minimal systemic exposure combined with calibrated tumour vessel obstruction. The introduction of embolic microspheres that have the ability to actively sequester doxorubicin hydrochloride from solution and release it in a controlled and sustained fashion, has been shown to substantially diminish the amount of chemotherapy that reaches the systemic circulation compared with lipiodol-based regimens, thus significantly increasing the local concentration of the drug and the antitumoural efficacy57 (Fig 2). Survival after TACE performed with drug-eluting beads (DEB-TACE) is not different from that after conventional

Figure 2 Treatment of intermediate-stage HCC with TACE with drugeluting beads in a 75-year-old male patient with HCV-related liver cirrhosis. Pretreatment CT shows a two hypervascular HCC located at the dome of the liver (a) and in segment 5 (b), respectively 30 and 45 mm in size. After superselective catheterisation of tumour feeding vessels (c,d) treatment is performed with intra-arterial injection of 100e300 mm drug-eluting beads uploaded with 150 mg doxorubicin (DC Bead, BTG). CT obtained 1 month after the procedures shows complete response (e,f).

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lipiodol TACE (c-TACE), but the treatment is more reproducible and better tolerated. A randomised phase 2 trial showed a significant reduction in doxorubicin-related adverse events58; a later trial in Italy confirmed the better tolerance of patients to DEB-TACE.59 Cohort studies with an adequate selection of candidates60,61 have reported median survival beyond 40 months after DEB-TACE. The same survival figures are reported with c-TACE62 and rates of complications were the same with both techniques. An issue that has not been definitely solved is whether the addition of the chemotherapeutic agent to the embolic microspheres provides improved efficacy. In a RCT comparing beads uploaded with doxorubicin versus bland embolisation performed with an embolic microsphere with similar characteristics, the rate of tumour progression at 12 months was significantly lower in the drug-eluting bead arm than in the bland embolisation arm (46% versus 78%, p¼0.002). Time-to-progression increased from 36.2  9 to 42.4  9.5 weeks (p¼0.008).63 A recent RCT demonstrated that there was no apparent difference between DEB-TACE and embolisation with microspheres alone with similar results in term of tumour response (6% versus 5.9%, respectively), progression-free survival (2.8 versus 6.2 months, p¼0.11) and overall survival (20.8 versus 19.6 months, p¼0.64).64 The authors conclude that these results challenge the use of doxorubicin-eluting beads for chemoembolisation of HCC. Alternative strategies, including combination of systemic with intra-arterial therapies are being investigated to improve TACE-based regimens. Given that TACE causes local hypoxia resulting in angiogenic factors peak after the treatment, potentially stimulating residual tumour proliferation, combination of TACE with an anti-angiogenic therapy has been matter of investigation.65 Unfortunately, adjuvant treatment with sorafenib or brivanib has not improved outcomes.66,67 In patients in which the treated tumour shows no response after at least two sessions of TACE, when treatment fails to induce marked necrosis at sites that have progressed after initial response, when major progression (substantial liver involvement, vascular invasion, or extrahepatic spread) occurs after an initial response, and when retreatment is unsafe because of deterioration of liver function TACE treatment should be stopped.7 Radio-embolisation has recently emerged as a therapeutic option for intermediate-stage HCC. It has been suggested by a retrospective comparative effectiveness analysis that patients with intermediate HCC treated by conventional TACE or radio-embolisation may have similar survival times. Longer time-to-progression and less toxicity has been reported in patients treated with radio-embolisation.68,69 Similar results have been reported in two further studies, in which median survival rates of 15e18 months were recorded for patients with intermediate-stage HCC submitted to radio-embolisation.70,71 A recent retrospective study showed an overall survival advantage with radioembolisation: mean overall survival 39 months for radioembolisation versus 31 months for TACE (p¼0.014).72 RCTs would provide the highest level of evidence, but these are

not always available or realistically feasible. It has been estimated that a study such as this may require >1,000 patients to reveal an overall survival difference.68 Prospective comparator RCTs, such as Transarterial RAdioembolisation versus ChemoEmbolisation for the treatment of hepatocellular carcinoma (TRACE), are ongoing.73 Successful tumour downstaging attributable to radioembolisation has been demonstrated in some studies.74e77 In particular, radio-embolisation has been shown to downstage over half of patients outside of transplant criteria thus allowing them to undergo transplantation74; however, the recurrence-free survival and overall survival after transplant in the downstaged patients have yet to be compared with those of the patients who were already within transplant criteria. Intermediate-stage disease represents a heterogeneous group of patients and future research should be devoted to assessing the role TACE and radio-embolisation in different subgroups of patients. Endorsing the up-to-seven criteria introduced by Mazzaferro et al.77 for liver transplantation, a panel of experts suggested radio-embolisation as a preferred treatment if the tumour burden is really bulky (outside up-to seven) or uncountable nodules, if the probability of response to TACE is negligible, and the risk of decompensation or complications significant.53

Advanced-stage HCC Advanced-stage HCC includes patients who present with cancer symptoms and/or with vascular invasion or extrahepatic spread. Overall, these patients have a shorter life expectancy (50% survival at 1 year). According to the BCLC treatment strategy, systemic therapy with the multi-kinase inhibitor, sorafenib, is considered the therapy of choice for patients with advanced HCC.1,7 In two RCTs, this multikinase inhibitor with anti-angiogenic and antiproliferative properties, has been shown to prolong median overall survival and median time to radiological progression compared to placebo.78,79 Very recently, regorafenib has been approved as a second-line treatment after sorafenib failure.80 Many patients treated with locoregional therapies are actually classified as class C according to BCLC. In fact, selected categories of patients of advanced-stage HCC present with limited disease. These include patients with performance status 1 without extravascular or extrahepatic disease, patients who have a branch vein tumoural invasion or those who have a limited extrahepatic disease. It is debatable whether patients classified as advanced stage for a mildly impaired performance status, but with uninodular or multinodular disease without vascular invasion and extrahepatic spread, should be excluded from locoregional treatments. Similarly, when vascular invasion is limited to a venous branch, intra-arterial treatments, including TACE and radio-embolisation, are technically feasible and could represent a valuable option.81e83 In the presence of portal vein tumour thrombosis, however, TACE is theoretically contraindicated because of

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concerns that interruption to hepatic arterial blood supply could result in an enormous area of hepatic necrosis in patients whose blood supply is already compromised; however, TACE can be safely performed in the presence of adequate collateral circulation around the occluded portal

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vein. Two recent meta-analyses showed that patients who underwent a TACE procedure demonstrated a significantly higher survival rate in comparison with patients who received conservative treatment84,85; however, no advantages in overall survival rates were demonstrated in

Figure 3 Treatment of advanced-stage HCC with radio-embolisation in a 68-year-old male patient with HCV-related liver cirrhosis. Pretreatment CT shows an ill-defined hypervascular HCC located in segment 4 (arrow, a) infiltrating the left portal vein (arrow, b). During diagnostic work-up, the lesion appears to be fed mainly by the left artery branches. Small feeding vessels originating from the right hepatic artery are embolised with coils (arrow, c). PET/CT performed the day after 90Y injection (Therasphere, 1.6 GBq) demonstrates homogeneous radioactivity deposition within the tumour (d). CT obtained 4 months after the procedures show reduced hypervascularity of the liver tumour (e) and hypodensity of the portal vein thrombus (f). At 2-year follow-up CT, both the tumour and portal vein thrombus appear hypodense, with marked hypotrophy of the left hepatic lobe (g,h). Please cite this article in press as: Crocetti L, et al., Loco-regional treatment of HCC: current status, Clinical Radiology (2017), http://dx.doi.org/ 10.1016/j.crad.2017.01.013

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submitting a patient to TACE instead of, or combined with, sorafenib in the case of portal vein thrombosis.86 Hence, TACE cannot be consistently recommended for patients with advanced HCC. Many studies have been devoted to evaluating radioembolisation in advanced HCC, and in particular, in patients with portal vein invasion (Fig 3). Until now, there are no data on direct comparison of the efficacy and safety between TACE and radio-embolisation in such patients. Mazzaferro et al.71 demonstrated the safety and feasibility of radio-embolisation in the setting of portal vein thrombosis. Patients with portal vein thrombosis invading the right or left portal vein or its segmental branches had a median overall survival of 17 months after radioembolisation; patients with main portal vein thrombosis had a 9-month overall survival.71 Some studies have then suggested that radio-embolisation is more advantageous than sorafenib in portal vein thrombosis. Edeline et al. calculated a median overall survival of 26.2 versus 8.7 months in patients treated with radio-embolisation versus sorafenib, respectively (p¼0.054).87 Kulik et al.88 showed that radio-embolisation alone was just as effective as radioembolisation combined with sorafenib, although the latter group experienced more biliary complications necessitating a reduced sorafenib dose; however, although anti-tumour activity and promising survival results have been reported in cohorts of patients treated with radio-embolisation, guidelines still recommend further evaluation of its effect on overall survival in RCTs.1,7 SorAfenib versus Radioembolisation in Advanced Hepatocellular carcinoma (SARAH) is the first prospective head-to-head RCT of resin microspheres versus sorafenib and has been recently completed. The primary endpoint was overall survival. Secondary endpoints include adverse events rate, progression-free survival (PFS) at 6 months measured by imaging, tumour response rate, quality of life score, and cost of each strategy.89 More randomised studies are ongoing, evaluating radio-embolisation in comparison with sorafenib in the advanced setting, to better define the relative role of radio-embolisation in relation to sorafenib.90e93

Conclusion and further research Loco-regional treatments have a significant role in patients with HCC at all stages. Literature data support the use of image-guided ablation, primarily RFA, as the first-line treatment in patients with very early and early-stage HCC. Further studies should be devoted to evaluating if and when RFA should be substituted with MWA or a non-thermal technique such as IRE. Due to the similar profile of RFA and MWA, comparative RCTs of the two techniques with overall survival as the primary endpoint seem difficult to undertake. An approach aimed at evaluating the ease of execution, the time needed per procedure, and the effectiveness for tumours >3 cm in size would probably be useful in quantifying the advantages that MWA may offer. TACE is the treatment of choice, with improved survival, for patients with intermediate stage HCC. Similar overall

survival rates have been obtained with conventional Lipiodol TACE and DEB-TACE, the latter being better tolerated. An economic, cost-effectiveness approach would be helpful in assessing the respective role of these intra-arterial approaches. There are conditions (when TACE fails, when there is widespread nodular disease, when the risk of liver decompensation is high) in which radio-embolisation can be considered a valuable option for patients in the intermediate stage. Moreover, radio-embolisation has shown anti-tumoural activity and has had a positive impact on survival rates in the setting of advanced-stage HCC. Results of ongoing RCTs should help in defining the role of radioembolisation in selected intermediate- and advancedstage HCC patients.

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