Chemoembolization and radioembolization

Best Practice & Research Clinical Gastroenterology 28 (2014) 909e919

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Best Practice & Research Clinical Gastroenterology

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Chemoembolization and radioembolization Bruno Sangro, MD, PhD, Director, Liver Unit *
n Biom
Clinica Universidad de Navarra, and Centro de Investigacio edica en Red de Enfermedades
ticas y Digestivas (CIBEREHD), Avda, Pio XII 36, 31008 Pamplona, Spain Hepa

a b s t r a c t Keywords: Transarterial chemoembolization, TACE Drug-eluting beads, DEB Radioembolization, RE Yttrium Selective Internal Radiation Therapy, SIRT

Chemoembolization and radioembolization are at the core of the treatment of patients with hepatocellular carcinoma who cannot receive potentially curative therapies such as transplantation, resection or percutaneous ablation. They differ in the mechanism of action (ischaemia and increase cytotoxic drug exposure for chemoembolization, internal irradiation for radioembolization) and may target different patient populations. Chemoembolization with cytotoxic drug-eluting beads is a more standardized although not necessarily more effective way of performing chemoembolization. Cytoreduction is achieved in most patients but complete tumor ablation may be achieved and lead to extended survival. Grade 1 level of evidence support the use of chemoembolization for the treatment of patients in the early and intermediate stages while grade 2 evidence supports the use of radioembolization for the treatment of patients in intermediate to advanced stages. Selecting the best candidates for both techniques is still a work in progress that ongoing clinical trials are trying to address. © 2014 Elsevier Ltd. All rights reserved.

Introduction Most patients with hepatocellular carcinoma (HCC) are diagnosed at late stages, when curative surgical treatments cannot be applied [1]. According to guidelines from the European and American Association for the Study of the Liver [2,3], the BCLC classification with its five tumor stages should be

* Tel.: þ34 948 255 400; fax: þ34 948 296 500. E-mail address: [email protected].

http://dx.doi.org/10.1016/j.bpg.2014.08.009 1521-6918/© 2014 Elsevier Ltd. All rights reserved.

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used for tumor staging. Surgery by means of resection or transplantation and percutaneous ablation are restricted to the very early or early tumors (stage 0 and A) while intraarterial and systemic therapies are recommended for intermediate and advanced tumors, respectively (stages B and C) [4]. However, up to 50% of patients cannot receive the recommended treatment modality because of availability, technical issues, age or comorbidities [5] and guidelines are evidence-based flexible frameworks on which individual therapeutic strategies can be built upon by multidisciplinary teams [2]. The most common intraarterial techniques used in HCC treatment are transarterial chemoembolization (TACE) with or without drug-eluting beads (DEB) and radioembolization (RE). They differ in mechanism of action, technique and typical patient population, which translates into differences in patient monitoring, complications and outcomes. And they are all widely accepted for treating appropriately selected HCC patients.

Chemoembolization Conventional procedures TACE comprises different procedures intended to increase the exposure of tumor cells to cytotoxic agents, and to induce ischemic necrosis. In conventional TACE this is accomplished by the sequential intra-arterial injection of chemotherapeutic agents mixed with Lipiodol and embolizing particles. The wide variety of drug vehicles, cytotoxic agents and embolizing particles available has introduced numerous variations worldwide. Emulsification in Lipiodol is believed to increase intratumoral retention of the cytotoxic agents although all drugs used (doxorubicin, mitomycin C, doxorubicin and cisplatin) are highly hydrophilic. This is followed by embolization of the target vessels with gelfoam, which is very heterogeneous in size, or the more recently calibrated polyvinyl alcohol or acrylic copolymer gelatin particles. The use of calibrated particles is increasing worldwide since they can be chosen by size according to the target vessel [6]. The place where the tip of the catheter is placed and the degree of blood flow stasis achieved determine the volume of non-tumoral liver that is involved and the degree of dearterialization, and thereby influence the final outcome. Superselective catheterization and complete stasis are recommended to maximize the benefit. Complete responses are rarely seen after a single session of conventional TACE and repeated sessions can be scheduled at fixed pre-planned intervals or depending on the observed response. This ‘on demand’ approach to repeated TACE is recommended nowadays because of its more favourable safety profile [7]. Patients are thus evaluated every 6e8 weeks and additional TACE sessions are performed only if contrast-enhanced areas revealing tumor activity are observed in cross-sectional imaging. Conventional TACE is largely a safe procedure frequently followed by side effects that can be occasionally severe. The most common (>40% of patients) is the post-embolization syndrome, consisting of mild and transient nausea, abdominal pain and fever. A transient decline in liver function is common but acute liver decompensation (ascites, encephalopathy or jaundice) is reported in only 0.1e3% of procedures [8,9]. Biliary and gastrointestinal complications have been reported in 2e10% [10] and 1e5% [11] of patients, respectively. Other complications include liver abscesses in patients with incompetent ampulla [12], vascular injury from repeated intraarterial chemotherapy [13], and tumor rupture [12]. Mortality rates range widely from 0.003 to 10% in the different series [14,15] but when the appropriate patients and procedures are selected, conventional TACE is a highly safe technique. The evidence that supports the use of conventional TACE for unresectable HCC is two randomized controlled trials in selected patients with preserved liver function [16,17]. Three meta-analyses [14,18,19] have afterwards confirmed that conventional TACE improves survival of unresectable HCC patients. According to Western guidelines, TACE is indicated in HCC patients in the intermediate stage, i.e., those with multinodular HCC, relatively preserved liver function, absence of cancer-related symptoms, and no evidence of vascular invasion or extrahepatic spread [3]. However, around half of the patients recruited in the two positive trials were likely patients in the early stage in which ablation was deemed unfeasible. In fact, the range of patients treated by TACE in clinical practice largely exceeds the boundaries of the intermediate stage (Table 1) and reported survivals widely range from 8 to 26% at five years [15,20e24].

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Table 1 Summary of recent series of HCC patients receiving chemoembolization or radioembolization. Ref

[20] [85] [33] [37] [41] [57] [59] [48] [44]

Treatment

cTACE cTACE cTACE DEB-TACE DEB-TACE RE RE RE RE

N

172 44 107 173 104 291 52 108 325

Staging

Tumor burden

Response rate

Response duration

Survival

BCLC (A/B/C/D)

Single tumors

EASL criteria

TTP (months)

Median (months)

36/42/20/2 27/44/29/0 11/89/0/0 nr 39/61/0/0 17/28/52/3 0/33/67/0 2745/51/0 16/27/56/1

43% 34% 26% 64% nr 27% 3% nr 24%

64 67 mRECIST

57 EASL 40 EASL 40 EASL

18.6a 16.3 16.2 48.7 mean 48.6

7.9 7.5

7.9 11 10

15 16.4 12.8

cTACE: conventional TACE. DEB-TACE: TACE with drug-eluting beads. RE: radioembolization with Y90 microspheres. EASL: European Association for the Study of the Liver. a For patients without extrahepatic metastases.

Among 4966 Japanese patients without vascular invasion, extrahepatic metastases or prior treatment that received superselective conventional TACE, median survival was 3.3 years [25]. However, when median survival is reported by tumor stage, it ranges from 16 to 45 months in the early stage, from 15.6 to 18.2 months in intermediate stage, and from 6.8 to 13.6 in the advanced stage (Table 2). Table 2 Long-term outcomes in recent series of HCC patients receiving chemoembolization or radioembolization according to stage. Ref, year Stage A [86], 2008 [20], 2010 [87], 2012 [88], 2009 [89], 2013 [41], 2012 [57], 2010 (no EHD) [44], 2011 [89], 2013 Stage B [86], 2008 [20], 2010 [88], 2009 [89], 2013 [41], 2012 [57], 2010 (no EHD) [44], 2011 [48], 2010 [59], 2013 [89], 2013 Stage C [20], 2010 [86], 2008 [88], 2009 [11], 2011 [90], 2011 [89], 2013 [76], 2010 [44], 2011 [59], 2013 [57], 2010 (no EHD) [48], 2010 [89], 2013

Treatment

N

Median overall survival (months)

cTACE cTACE cTACE cTACE cTACE DEB-TACE RE RE RE

453 62 73 80 23 41 48 52 12

35.4 40 37.9 29.9 18.6 40.6 26.9 24.4 23.9

cTACE cTACE cTACE cTACE DEB-TACE RE RE RE RE RE

741 73 163 13 63 83 87 51 17 34

18.2 17.4 16.8 13 42.8 17.2 16.9 16.4 18 16.8

cTACE cTACE cTACE cTACE cTACE cTACE RE RE RE RE RE RE

23 200 48 44/40 83 19 25 183 35 107

6.6 6.8 13.6 5.3 main/10.2 branch 5.6 10.1 10 10 13 7.3

14

8.4

cTACE: conventional TACE. DEB-TACE: TACE with drug-eluting beads. RE: radioembolization with Y90 microspheres. EHD: extrahepatic disease.

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Liver functional reserve is key to an optimal selection of candidates. Conventional TACE should be contraindicated in patients with decompensated cirrhosis. A recent consensus from a panel of experts has recommended a series of absolute and relative contraindications for TACE [7] that include comorbidities, hepatic encephalopathy, altered performance status, reduced or absent portal vein flow, biliary obstruction and large/massive tumors. TACE is also generally contraindicated in patients with branch or main portal vein thrombosis (PVT), since occlusion of arterial blood flow by may induce liver failure. Although superselective TACE may not be harmful in selected patients with segmental PVT [11,26], a clinical benefit has not been specifically demonstrated in this population. Tumor response after conventional or DEB-TACE should be evaluated using EASL [27] or modified RECIST [28] criteria that take into account tumor shrinkage as well as tumor necrosis. Patients that show no tumor response shortly after TACE is completed have a significantly worse prognosis [29e31]. If complete tumor necrosis is not achieved after the first session of TACE, a second attempt is warranted because feeding arteries may have been missed [32]. However, patients that do not respond to two consecutive sessions of TACE should be considered for alternative therapies including RE or the systemic agent Sorafenib [7]. Decision algorithms based on scores that take into account changes in liver function, levels of transaminases and tumor response [33] should be validated prospectively before they can be recommended for clinical use. TACE using drug-eluting beads (DEB-TACE) The concept of DEB-TACE is to load embolizing particles with various types of chemotherapeutic agents and to deliver them intraarterially in a manner similar to that of conventional TACE. Once injected near the tumor and besides its ischemic effect, a slow and controlled release of the drug into the tumor environment may enhance the anti-tumoral activity. Two particles are commercially available i.e. DC-Beads® (Biocompatibles, UK) and HepaSphere® (BioSphere Medical, Inc., USA) thar can be loaded with doxorubicin for the treatment of HCC. DEB-TACE is generally well tolerated too and not surprisingly the spectrum of adverse events is similar to conventional TACE. Major complications including liver abscesses and liver failure occur in 4e10% of patients [34e38]. Irreversible liver failure and treatment-related death have been reported in 1.6% and 0.96% of patients in prospective clinical trials [37,38]. It has a more favourable pharmacokinetic profile than conventional TACE [38] that translates into less systemic adverse events [39] due to a reduced systemic exposure to doxorubicin. Interestingly, more advanced patients seem to tolerate DEB-TACE better than conventional TACE although this information deserves a restrained interpretation since patients with poor liver function are at high risk of complications irrespective of the modality of TACE that is used. The patient profile is similar for conventional and DEB-TACE but an incremental survival benefit has not been shown for DEB-TACE (Tables 1 and 2). In a large randomized trial, the primary endpoints (superiority of DEB-TACE in achieving objective tumor response at six months and in producing fewer treatment-related serious adverse events in the first 30 days) were not met [39]. However, response rate was slightly higher (52% vs. 44%) and time to progression slightly longer (7.1 vs. 6.4 months) for DEB-TACE using DC-Beads® compared to conventional TACE. In a prospective randomized comparison of DEB-TACE and bland embolization, objective response rate at nine months according to EASL criteria was higher in the DEB-TACE group (55% vs. 31%) but survival at 12 months was similar (85.3% vs. 86%) [40]. Despite this lack of comparative effectiveness, DEB-TACE has provided a way of performing TACE in a more standardized way and has shown that when the optimal patients are selected, the beneficial effect of TACE can indeed challenge that of percutaneous ablation. Recent reports on nearly 300 patients in the early and intermediate stages from two experienced centres show 3-year and 5-year survival rates of 62e66% and 22e38%, respectively [37,41]. Radioembolization Those procedures in which intra-arterially injected radioactive microspheres are used for selective internal radiation treatment (SIRT) are also named radioembolization (RE). The most important difference between RE and TACE is the mechanism of action, i.e. irradiation vs. ischemia/chemotherapy. In

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RE, radioactive isotopes are deployed inside the tumor vasculature carried in microparticles [42]. Yttrium-90 (90Y) is the most commonly used isotope. As a pure beta emitter it has a short tissue penetration (mean 2.5 mm). Two types of microspheres are commercially available i.e. SIR-Spheres® (Sirtex Medical Limited, Australia) made of resin and TheraSphere® (Biocompatibles, UK) made of glass. In contrast with the larger than 100 microns particles used in TACE to occlude tumor feeding vessels, much smaller particles (25e35 microns) are used in RE to reach the tumor microvasculature. After implantation, a low dose-rate brachytherapy is applied to the tumor during the radioactive decay process (90Y half-life is 64.2 h). Due to the lack of macroembolic effect [43] and of the need of isolation for radiation protection, RE can be performed even as an outpatient procedure. However, because of the small size of the particles that allows them to bypass the tumor filter if there are large arteriovenous connections, and the high sensitivity of the gastrointestinal tract to radiation, a simulation of the actual treatment has to be performed 1e2 weeks prior to RE. Patients can only be considered for RE provided the degree of arterio-venous shunting to the lung is limited (usually less than 20%) and there is no possibility that microspheres may reach the gastrointestinal tract. Also based on the lack of relevant ischemic effect, segmental, lobar and even whole-liver treatments may be performed safely [44]. And finally, as opposed to the pre-planned schedule of repeated procedures (fixed or on demand) of TACE, patients typically receive one RE procedure. RE is well tolerated although mild fatigue may appear particularly among advanced HCC patients [44]. Rare but potentially severe complications result from the irradiation of non-tumoral tissues include pneumonitis [45], cholecystitis [46] gastrointestinal ulcerations [47] and liver damage. Liver toxicity is the most challenging adverse event. A variable incidence of liver decompensation including ascites (0e18%) or encephalopathy (0e4%) has been reported [46,48e52]. Radioembolization-induced liver disease or REILD is a distinct form of liver decompensation consisting in jaundice and ascites appearing 4e8 weeks after RE. The incidence of REILD in cirrhotic patients was 9.3% in the largest reported series [53]. To avoid REILD, patients should only be considered for RE in the presence of a preserved liver function, i.e. no recent history of ascites or hepatic encephalopathy and a total bilirubin level 2 mg/dL [54]. And the amount of irradiation delivered to the non-tumoral liver parenchyma should be limited according to different algorithms [53,55]. Tumor shrinkage is observed almost universally after RE although it may take months to occur [56] with median time to response of about six months [57]. By mixed (size and necrosis) response criteria, tumor response rates vary between 40 and 90%, with disease control rates in targeted lesions of 80e100%. Time to response taking into account vascular enhancement occurs earlier, around 2 months from the time of RE [57]. As in TACE, tumor responders have a significantly prolonged overall survival [58]. No randomized controlled trial comparing RE with other therapies has been published yet but good level two evidence can be compiled from large, well characterized cohort series (Tables 1 and 2) [44,48,57,59]. Intermediate stage patients treated by RE reach a median survival of 16e18 months [44,57,59]. Broadly equivalent survivals after TACE and RE have been reported in retrospective analyses of single institutions. In the largest comparative study, all-type adverse events, response rate and time to progression were better in RE than in conventional TACE but overall survival was no different [60]. Quality of life has been reported as better after RE in comparison with TACE basically because of the lack of post-embolization syndrome [61] although this observation has been challenged by recent yet unpublished results from our group. For patients that are good candidates for TACE (i.e. those with a few liver nodules that can be treated superselectively), RE is unlikely to improve long-term outcomes like overall survival and potential advantages such as less intensive follow-up or better tolerance are unlikely to justify large scale comparative trials. However, other potential indications that are still considered investigational [62] aim at this subgroup of patients. The first one is complete tumor ablation for nodules that are not candidates to percutaneous ablation. A very high dose of irradiation can be delivered by superselective RE [63] with complete pathological necrosis being achieved in 90% of tumors <3 cm and 33% of tumors >5 cm [64]. These rates compare favourably with those obtained after TACE [65,66]. The second is bridging therapy in an attempt to avoid dropping from the waiting list of liver transplantation because very long median time to progression of 25.1 months (95% CI 8e27 months) has been reported after RE [60]. And the third is using RE as a downstaging therapy. Tumor shrinkage following RE may allow large

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tumors to reach the size where ablation is more effective (3 cm) and may make patients beyond Milan criteria for liver transplantation meet this endpoint. Furthermore, through a sustained liberation of pro-regenerative factors [67], lobar RE may induce contralateral lobe hypertrophy that contributes to resectability [68]. Out of 35 patients at UNOS T3 stage treated by RE, 66% were downstaged to a T2 stage where resection, RFA, or transplant could be indicated [69]. Compared with TACE, downstaging from UNOS T3 to T2 stage was achieved more frequently with RE (58% vs. 31%) and overall survival favoured RE [70]. In a more recent series in which 29% of 21 UNOS T3 stage patients later underwent resection or transplantation, 3-year survival rate was 75% [71]. These three potential indications cover areas of therapeutic uncertainty since there is a lack of strong scientific evidence supporting the conventionally used TACE. Most patients currently treated by RE are poor candidates to TACE because of a high tumor burden, presence of vascular invasion or lack of response to previous TACE or DEB-TACE. The other therapeutic alternative for these patients is the systemic agent Sorafenib on the basis of a randomized controlled trial that proved that Sorafenib prolonged survival of HCC patients [72]. As microspheres used in RE have no ischemic effect [73], they can be safely applied to patients with PVT without the risk of ischemic hepatitis [49,74], and can offer a median survival in the range of 6e13 months [44,48,57,59], very similar to those 6.5e10.7 months reported for Sorafenib in the same group in the pivotal trials [72,75]. Furthermore, in patients with only branch or segmental PVT, survival extends to 10e14 months [49,59,76]. Survival after RE was 15.4 months in patients failing TACE [44] which compares well with the 11.9 and 9.9 months for the Sorafenib and placebo-treatment arms survival in patients failing TACE in the SHARP trial [77]. An important marginal survival benefit can be expected in those patients with advanced HCC in which an objective tumor response is obtained since reported 3-year survival rate is 25% [59]. On the basis of these outcomes and the better tolerance of RE in comparison with Sorafenib, the indications described above have been adopted as standard in many referral centres. A recent expert opinion consensus accredited that RE could be first-line therapy for the subgroup of intermediate stage patients that have well-preserved liver function (Child A) and high tumor burden (beyond the up-to-7 rule) [78]. TACE and RE in combination with systemic agents Tumor hypoxia intentionally caused by TACE can induce upregulation of circulating vascular endothelial growth factor (VEGF), which is essential for HCC growth, invasion, and metastasis. Recent studies have reported a significant association between VEGF upregulation after TACE and poor prognosis [79,80]. Therefore, adjuvant or concurrent use of an anti-angiogenic agent may be helpful for HCC patients who are treated with TACE [81] and several clinical trials are currently evaluating this combined effect on the outcome of patients with unresectable HCC. The results already available are disappointing. Among patients with >25% tumor necrosis or shrinkage at 1e3 months following one or two TACE sessions, time to progression was not better in those that received Sorafenib than in those that received placebo (5.4 months vs. 3.7 months, respectively; p ¼ 0.25) [82]. When continuous Sorafenib or placebo was given concurrently with DEB-TACE, and the hazard ratio for time to progression was 0.797 in favour of Sorafenib (95% CI 0.588e1.080; p ¼ 0.072) but overall survival was comparable [83]. Cooperative groups are also carrying out similar studies to further investigate the role of Sorafenib in HCC patients undergoing embolization. On the other hand, the potential of RE to induce VEGF production has not been well characterized. A recent study including mainly patients with liver metastases has reported an increase in serum VEGF after RE [84]. The addition of RE to Sorafenib for intermediate and advanced stage patients is being explored in randomized controlled trials. Supportively, safety seems not an issue in the combination of Sorafenib with either TACE or RE. Summary The intraarterial therapies TACE and RE are the mainstay of the treatment of HCC patients who cannot receive curative approaches. Good tumor responses are generally observed when a reduced number of not very large tumors are embolized in a selective fashion (ideally through a distinct feeding vessel). Based on three meta-analyses, conventional TACE is the standard of care for HCC patients in the

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intermediate stage. DEB-TACE has become recently a more standardized way of performing TACE with similar outcomes and less systemic effects. RE is a form of brachytherapy for liver tumors in which the source of radiation has to access the tumor vascular network. In contrast with conventional TACE, evidence supporting the use of RE in the treatment of HCC patients comes from consistent, large cohort series involving patients with more advanced HCC, not suitable for other locoregional therapies or who have failed to TACE. TACE and RE should not be considered competing therapies but rather complementary tools. For those patients with small to medium-sized tumors that can be treated selectively, TACE can be provided in most centres. RE could be an alternative to repeated TACE for patients that fail to respond to initial TACE, and a first option in those who are poor candidates to TACE, mainly because of bulky disease and PVT, but still have a good liver function. The combination of TACE and RE with systemic agents is being explored in large randomized studies. With these and other studies, the clinical indications and specific patients ideally suited for these palliative interventions will continue to be refined.

Practice points  TACE is the standard of care for HCC patients in the intermediate stage and for those in the early stage that are not suitable for surgical or percutaneous ablation.  DEB-TACE has not proved to perform better than conventional TACE or bland embolization but is preferred in many centres because of the higher standardization of the procedure.  Radioembolization is not considered a standard of care for HCC patients but is nevertheless used in many experienced centres to treat patients that are not good candidates or have progressed to TACE and for those in the advanced stage because of portal vein invasion.  Appropriate patient selection, particularly regarding good liver function and limited tumor burden, is key to the success of TACE and radioembolization since both procedures can induce liver decompensation in cirrhotic patients when performed in a non-selective fashion.

Research agenda  The best way of performing TACE in terms of devices, vascular endpoint and schedule has not been defined.  The ideal candidates for TACE and radioembolization are still to be defined.  Controlled studies are necessary to define the comparative efficacy of TACE and radioembolization in different scenarios including bridging therapy to liver transplantation, downstaging to curative therapies, or achieving complete ablation of tumors that cannot be ablated surgically or percutaneously.  Ongoing clinical trials are exploring the role of Sorafenib in combination with TACE and radioembolization.  Ongoing trials will also answer the question of whether radioembolization is any better than sorafenib in prolonging the survival of poor TACE candidates.

Conflict of interest statement Bruno Sangro has received lecture and consulting fees from Sirtex Medical and Bayer Healthcare. Acknowledgements CIBEREHD is funded by Instituto de Salud Carlos III, Spain.

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