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Annals of Oncology 24 (Supplement 2): ii24–ii29, 2013 Intermediate hepatocellular carcinoma: currenttreatments and future perspectives J.-F. Dufour1,2*, I. Bargellini3, N. De Maria4, P. De Simone4, I. Goulis5 & R. T. Marinho61Hepatology, Department of Clinical Research, University of Berne, Berne; 2University Clinic for Visceral Surgery and Medicine, Inselspital, University of Berne, Berne,Switzerland; 3Department of Diagnostic and Interventional Radiology, University of Pisa, Pisa; 4Gastroenterology, Department of Internal Medicine, University Hospital of Modena, Modena, Italy; 54th Department of Internal Medicine, Aristotelian University of Thessaloniki, Greece; 6Liver Unit, Department of Gastroenterology and Hepatology, Hospital de Santa Maria, Medical School of Lisbon, Lisboa, Portugal Current guidelines recommend transarterial chemoembolization (TACE) as the standard treatment of Barcelona-Clinic Liver Cancer (BCLC)-B patients. However, the long-term survival outcomes of patients managed with this technique do not appear fully satisfactory; in addition, intermediate-stage hepatocellular carcinoma (HCC) includes a heterogeneous population of patients with varying tumour burdens, liver function and disease aetiology. Therefore, not all patients with intermediate-stage HCC may derive similar benefit from TACE, and some patients may benefit from other treatmentoptions, which are currently approved or being explored. These include different TACE modalities, such as selective TACE or drug-eluting beads TACE and radioembolization. The introduction of sorafenib in the therapeutic armamentarium for HCC has provided a new therapeutic option for the treatment of BCLC-B patients who are unsuitable to TACE or in whom TACE resulted in unacceptable toxicity. In addition, clinical trials aimed at investigating the potential role of this molecule in the treatment of patients with intermediate-stage HCC within combination therapeutic regimens are ongoing. This narrative review will present and discuss the most recent evidence on the locoregional or medical treatment with sorafenib in patients with intermediate-stage HCC.
Key words: adverse events, chemoembolization, locoregional, SIRT, sorafenib, systemic targeted therapy, TACE with still well-preserved liver function (Child-Pugh A5 due toalbumin 4.8 g/dl, total bilirubin 0.9 mg/dl, INR 0.99) and only The recent guidelines issued by the European Association for two nodules <3 cm and a patient with persistent ascites and the Study of Liver (EASL) endorse the Barcelona-Clinic Liver jaundice (Child-Pugh B) with multifocal large tumours will be Cancer (BCLC) classification for the staging of hepatocellular classified as affected by intermediate-stage HCC.
carcinoma (HCC) []. This classification divides HCC Therefore, not all patients with intermediate-stage HCC will patients into five stages (0, A, B, C and D) according to derive similar benefit from TACE, and some patients may different prognostic variables and allocates therapies according benefit from other treatment options, which are currently approved or being explored (Figure ) These include About 20% of HCC patients are classified as affected by different TACE modalities, such as selective TACE or drug- BCLC-B, or intermediate-stage HCC, and present a 2-year eluting beads (DB)-TACE, and radioembolization or survival of ∼50% []. The management of these patients, like combination approaches [–For instance, the combination that of other HCC subjects, should be based on themultidisciplinary interaction among different specialists ].
of TACE and radiofrequency ablation gave promising results in Current guidelines recommend transarterial chemoembolization (TACE) as the standard treatment of The introduction of sorafenib in the therapeutic BCLC-B patients ]. However, despite several recent armamentarium for HCC has provided a new therapeutic advances and technical refinements, the long-term survival option for the treatment of BCLC-B patients who are outcomes of patients managed with this technique do not unsuitable to TACE or in whom TACE resulted in appear fully satisfactory [in addition, intermediate-stage unacceptable toxicity. In addition, clinical trials aimed at HCC includes a heterogeneous population of patients with investigating the potential role of this molecule in the varying tumour burdens, liver function and disease aetiology treatment of patients with intermediate-stage HCC within []. As reported by Piscaglia and Bolondi both a patient combination therapeutic regimens are ongoing.
This review will present and discuss the most recent evidence on the locoregional or medical treatment withsorafenib in patients with intermediate-stage HCC. Surgical *Correspondence to: Prof. Jean-Francois Dufour, Hepatology, Department of Clinical procedures, including resection or transplantation, can be Research, University of Berne, Murtenstrasse 35, 3010 Bern, Switzerland; Tel: +41-31-632-31-91; Fax: +41-31-632-49-97; E-mail: considered in selected patients, as reviewed in Zhang et al. The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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the imaging modalities for locoregional treatments is beyondthe scopes of this review.
TACE is considered as the standard treatment of patients withcompensated liver function (Child B up to 8 points), with largesingle nodule or multifocal HCC (<5 cm) not occluding theportal venous vessels and without extrahepatic spreadSurvival benefits determined by TACE were reportedin two randomized, controlled trials (RCTs): Llovet et al. [ Figure 1. Locoregional (LR) or medical treatment of patients with showed a significant survival advantage in favour of TACE over intermediate-stage HCC, either approved or under investigation. Asterisk transarterial embolization [hazard ratio (HR) for death: 0.47; 95% confidence interval (CI), 0.25–0.91; P = 0.025], and Lo et al. [showed a 50% reduction in the relative risk of deathwith TACE versus symptomatic treatment (95% CI, 0.31–0.81; Resection may be a valid option in selected patients ]. More P = 0.005). In addition, the efficacy of TACE has been in detail, radical resection can be considered in: (i) patients evaluated in other RCTs, and two of these did not show a with single HCC and large tumour nodule, swelling outward, prolonged survival time with respect to controls clear border or pseudocapsule and <30% hepatic tissue Despite this, the results of a meta-analysis published in 2003 destroyed or >50% compensatory hepatic hypertrophy and (ii) indicated that treatment with transarterial embolization/TACE patients with multiple HCC with ≤3 nodules localized in one is associated with a significantly higher 2-year survival rate lobe or segment of the liver []. Other patients may be eligible than in the control group (odds ratio, 0.53; 95% CI, 0.32–0.89; for palliative resection (see Zhang et al. ] for a deeper P = 0.017) []. These findings are in agreement with those discussion on indication for palliative resection). Due to the reported in another meta-analysis of 18 RCTs, which shows shortage of available organs, it is currently recommended that that TACE improves the overall survival (OS) at 2 years only those HCC patients with an estimated high probability of compared with non-active treatment; however, the magnitude post-transplant survival benefit may be selected for liver of this benefit is relatively small [].
transplantation. The Milan criteria (1 lesion ≤5 cm or 2–3 TACE-associated adverse events (AEs), although usually lesions ≤3 cm), proposed in 1996, still represent the basis for transient and manageable, occur in a significant proportion the selection of the best candidates for liver transplant [– (35–100%) of patients: they include post-embolization ]. However, the adoption of expanded and/or down-staging syndrome (comprising fever, abdominal pain and a moderate criteria for liver transplant has been proposed and is currently degree of ileus), relevant liver function deterioration, ascites under clinical investigation ]. For instance, a study by and gastrointestinal bleeding In addition, TACE does Mazzaferro—the leading investigator of the team who have some contra-indications, both absolute and relative identified the same Milan criteria —conducted on 1556 patients has suggested that more HCC patients could be Collectively, these findings indicated that treatment with eligible for transplantation if the Milan criteria were replaced TACE may be associated with some benefits in terms of OS, by a more precise estimation of survival based on individual although the level of benefit varies and considerable AEs may tumour characteristics and up-to-seven criteria ].
occur: therefore, a careful selection of patients appears crucial These findings are confirmed by a study on more than 6000 before the initiation of TACE therapy ].
patients included in the US Scientific Registry of Transplant In the future, additional trials should be conducted to Recipients database: this analysis shows that the Milan criteria investigate some ‘grey areas’ still present in the current are too restrictive, and patients with larger total tumour knowledge of TACE, such as the use and type of the volume can enjoy satisfactory post-transplant survivals [].
chemotherapeutic agent, as well as the best type of embolizing Moreover, a composite patient selection score combining total medium Of note, recent evidence supports the use of the tumour volume and alpha fetoprotein can be considered the EASL criteria or the mRECIST criteria, rather than the most effective of all tested staging criteria for the prediction of standard RECIST criteria, in the evaluation of clinical response the survival of transplanted patients [].
after TACE ]. Gilmore et al. reported a significantassociation between survival and overall EASL and mRECIST responses: response was associated with a 44% risk reduction and mRECIST with a 42% reduction. Conversely, there was nosignificant association between survival and RECIST 1.1 The most widely used locoregional therapies for the treatment responses These data are corroborated by those reported of intermediate-stage HCC are TACE, selective TACE, DB- by Shim et al. who show that the HRs for time to progression (TTP) and OS in responders were 0.15 (95% CI: interventions are image-guided and therefore a careful 0.10–0.21) and 0.18 (95% CI: 0.13–0.26), respectively, when the imaging, also before and after treatment, represents an essential mRECIST definition of an objective response was used and prerequisite for their success A detailed description of 0.16 (95% CI: 0.11–0.22) and 0.23 (95% CI: 0.16–0.33), Table 1. Absolute and relative contraindications for TACE (reproducedfrom Raoul et al. with permission) • Decompensated cirrhosis (Child-Pugh B ≥8) including: – Jaundice– Clinical encephalopathy– Refractory ascites– Hepatorenal syndrome • Extensive tumour with massive replacement of both entire lobes • Severely reduced portal vein flow (e.g. non-tumoural portal vein • Technical contraindications to hepatic intra-arterial treatment, • Renal insufficiency (creatinine ≥2 mg/dl or creatinine clearance Figure 2. Complete response, objective response and disease control rate [cumulative number (%) of patients] at 6 months in the PRECISION V trial (reproduced from Lammer et al. [], with permission).
• Co-morbidities involving compromised organ function: The randomized, controlled PRECISION V trial has compared DB-TACE with the standard TACE for the treatment of 212 cirrhotic patients with HCC ]. At 6 months, the DB- • Untreated varices at high risk of bleeding TACE group showed higher rates of complete response, • Bile-duct occlusion or incompetent papilla due to stent or surgery objective response and disease control compared with thecTACE group (Figure ) []. Although the predefinedhypothesis of superiority was not met in the overall population, respectively, with the EASL response criteria. In a recent paper, patients with Child-Pugh B, Eastern Cooperative Oncology Kim et al. reached the same conclusions, further supporting Group 1, bilobar disease and recurrent disease presented a the significant association between TACE response and OS significant increase in objective response (P = 0.038). In addition, DB-TACE was associated with a reduction in serious Selectivity in positioning the catheter may enhance the liver toxicity and a lower rate of doxorubicin-related side-effects efficacy of TACE. Selective TACE indeed comprises the when compared with the standard TACE.
injection of chemotherapeutic agents into the segmental or These findings are overall in line with those reported in subsegmental branches feeding the tumours [Golfieri et al.
another RCT by Malagari et al. ], which compared DB- [] compared the effectiveness of selective/superselective TACE with doxorubicin (n = 41) and bland embolization TACE versus standard TACE in determining tumour necrosis, (n = 43). At 6 months, a complete response, assessed with the in a prospective database of 67 consecutive patients (122 EASL criteria, was seen in 11 patients (26.8%) in the DB-TACE nodules, all <5 cm). The mean histological necrosis level was group versus 6 patients (14%) in the bland embolization group, 64.7%; complete tumour necrosis was obtained in 42.6% of the whereas a partial response was achieved in 19 patients (46.3%) nodules. When compared with the standard TACE, selective/ and 18 (41.9%) patients, respectively. An advantage for DB- superselective TACE was associated with higher mean levels of TACE has been also reported in terms of rate of recurrences necrosis (75.1 versus 52.8%; P = 0.002) and a higher rate of and TTP (42.4 ± 9.5 versus 36.2 ± 9.0 weeks; P = 0.008).
complete necrosis (53.8 versus 29.8%, P = 0.013). A direct The overall favourable efficacy of DB-TACE is further relationship was reported between the tumour diameter and corroborated by a recent international, long-term (5 years of the mean tumour necrosis level (59.6% for lesions <2 cm, follow-up) study In total, 173 HCC patients not suitable 68.4% for lesions 2.1–3 cm and 76.2% for lesions >3 cm).
for curative treatments were enrolled; 41% were classified as These findings suggest that selective/superselective TACE may Child-Pugh B. The OS at 5 years was 22.5%, with higher rates determine a higher rate of tumour necrosis than the standard achieved in Child-Pugh class A compared with Child-Pugh TACE; however, very small nodules (<2 cm) may not respond class B patients (29.4 versus 12.8%). The mean OS was 43.8 months. Multivariate analysis identified some significant andindependent determinants of 5-year survival: these were thenumber of lesions, lesion vascularity, initially achieved complete response and objective response.
DB-TACE uses doxorubicin-loaded beads rather than the In a recent observational study by Burrel et al. [] (n = 104; conventional doxorubicin Lipiodol® (Guerbet, Genoa, Italy) 63 patients were BCLC-B), DB-TACE was associated with the emulsion It has been suggested that this approach could median survival of 48.6 months, and only 10 patients reported result in an overall favourable toxicity profile and antitumor major complications associated with this intervention. This activity (response rates ranging from 13.3 to 80.7%) study confirmed the safety of DB-TACE in patients with HCC and defined the survival gain that can be obtained, providing key evidence to decide among controversial indications and TACE [However, these data might not be directly extendedto clinical practice, since they were collected in a single, highly Sorafenib is currently the only drug approved for the treatment specialized centre. In addition, included patients had to meet of patients with advanced HCC (BCLC-C stage); however, the very stringent selection criteria ( preserved liver function, use of this molecule in the treatment of intermediate patients is absence of symptoms, extrahepatic spread or vascular approved in patients with BCLC-B HCC who are unsuitable to TACE or in whom TACE resulted in unacceptable toxicityAccording to available evidence, sorafenib has arole in patients who fail or are not eligible to TACE, as recently suggested by a Panel of Experts []. We propose here a Radioembolization is an investigational technique which slightly modified version of the same algorithm (Figure ).
has given some promising results in preliminary experiences Bruix et al. [] carried out a subanalysis of the landmark ]. It is defined as the infusion of radioactive substances SHARP study to compare the efficacy and safety of sorafenib (such as Iodine-131-labelled lipiodol or microspheres alone in patients with BCLC-B (sorafenib, n = 54; placebo, containing Yttrium-90) into the hepatic artery ]. Given the n = 51) versus BCLC-C (sorafenib, n = 245; placebo, n = 252) hypervascularity of HCC, microspheres will be preferentially stage of HCC. Overall, the benefit determined by sorafenib, delivered to the tumour area and selectively emit high-energy, expressed in terms of OS and TTP, was similar in BCLC-B low-penetration radiation to the tumour Salem et al. ] (median OS: 14.5 months, +39% versus placebo; median TTP: have reported the results of a feasibility study which included 6.9 months, +113% versus placebo, P = 0.0016) and BCLC-C 291 patients with HCC, who received a total of 526 treatments (median OS: 9.7 months, +43% versus placebo, P = 0.018; with radioembolization. The response rate according to the median TTP: 4.9 months, +69% versus placebo, P = 0.00003) EASL criteria was 57%; the overall TTP was 7.9 months.
subgroups and was consistent with that reported in the overall Survival times were longer in patients with Child-Pugh A (17.2 population The incidence of grade 3/4 drug-related AEs months) than in those with Child-Pugh B disease (7.7 months; was not different in the two subgroups and was similar to that P = 0.002). Reported toxic effects included fatigue (57%), pain reported for the overall SHARP study population. The authors (23%) and nausea/vomiting (20%); 19% exhibited grade 3/4 concluded that these findings confirm a retained efficacy of bilirubin toxicity. The 30-day mortality rate was 3%.
sorafenib even in the intermediate-stage HCC [].
However, the relevant costs associated with In an observational setting, a subanalysis of the global phase radioembolization may limit a wide use of this technique [].
IV GIDEON study documented an OS of 12.6 months for Moreover, the recent EASL Guidelines stressed that, due to the BCLC-B patients, as assessed in a cohort of 311 Child-Pugh A lack of RCTs comparing radioembolization with and B patients []. In the smaller Italian SOFIA study, the OS chemoembolization or sorafenib in patients with intermediate- of the 74 BCLC-B patients treated with sorafenib was longer or advanced-stage HCC, further research is needed to establish than that reported in the 222 BCLC-C patients evaluated (20.6 a competitive efficacy role in these populations [ versus 8.4 months; P < 0.0001) []. Taken together, these Figure 3. Proposed algorithm for the treatment of patients with intermediate-stage HCC. Response is defined according to mRECIST criteria.
preliminary results lend some support to the potential use of multidisciplinary perspective. Lastly, sorafenib, the only sorafenib monotherapy in patients with BCLC-B stage of HCC.
systemic treatment currently approved for the treatment of It is widely accepted that TACE promotes the synthesis of HCC, has a role in the treatment of patients with BCLC-B proangiogenic factors via a hypoxia-driven mechanism stage of HCC who are unsuitable to TACE or in whom TACE Therefore, there may be a rationale for the combination of sorafenib with TACE, since sorafenib inhibits the action of Another intriguing arena is represented by the combination or the sequential use of locoregional approaches and sorafenib.
Preliminary evidence, collected in a phase I trial, shows that Moreover, preliminary evidence suggests that sorafenib may be the combination of sorafenib and TACE is not associated with used in patients who fail or are not eligible to TACE, in a major AEs and, therefore, could deserve further investigations sequential manner. The potential combination of TACE (either []. Moreover, given the overall more favourable efficacy/ standard TACE or DB-TACE) and systemic targeted therapy safety profile of DB-TACE compared with the standard TACE, also represents a promising treatment strategy, currently being the combination of sorafenib with DB-TACE appears explored in different phase III trials.
promising. Clinical trials investigating this therapeuticapproach (namely the START, SOCRATES and TACTIS) are ongoing and will likely provide new evidence on the efficacyand safety of a combination of TACE and sorafenib in the Editorial assistance was provided by Luca Giacomelli, PhD, on treatment of intermediate-stage HCC patients. The results of behalf of inScience Communication, Springer Healthcare; this the global phase II SPACE trial have been recently published in assistance was funded by Bayer Italy.
an abstract form []. In total, 307 patients with BCLC-B stageof HCC were randomized to sorafenib (n = 154) or placebo(n = 153) in combination with TACE with doxorubicin-eluting beads (DEBDOX). Even if this study met its primary end point JFD participated in advisory boards for BMS, Bayer, Gilead, from a statistical point of view (P = 0.072 for TTP), the actual Novartis, Roche. IG participated in advisory boards for BMS, improvement of the median TTP was not clinically relevant Gilead, Novartis, Roche, MSD. Other authors declare no (from 166 to 169 days). The results of other ongoing studies conflict of interest directly relevant to this study.
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Rapid Trabecular Bone Loss After Cardiac Transplantation Using FK506 (Tacrolimus)-Based Immunosuppression H.U. Stempfle, C. Werner, S. Echtler, T. Assum, B. Meiser, C.E. Angermann, K. Theisen, and R. Ga¨rtnerTHE MACROLIDE lactone tacrolimus (FK506) is a P Ͻ .01). No fracture was documented. There were nonew immunosuppressive drug that has demonstratedsignificant differences in biochemi

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