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Transarterial chemoembolization and sorafenib in patients with intermediate-stage hepatocellular carcinoma: time to enter routine clinical practice? “...the combination of transarterial chemoembolization and sorafenib, if proved effective, will add a new therapeutic option to the therapeutic armamentarium of hepatocellular carcinoma.” Rodolfo Sacco*,1, Michela Antonucci2, Irene Bargellini3, Sara Marceglia4, Valeria Mismas1 & Giuseppe Cabibbo5 According to the guidelines of the European Association for the Study of the Liver (EASL), patients affected from hepatocellular carcinoma (HCC) can be classified according to the Barcelona Clínic Liver Cancer (BCLC) staging system. This classification system divides HCC patients in five stages (0, A, B, C and D) on the basis of a number of prognostic and treatment-related variables such as tumor status and liver function. A specific treatment approach is then proposed for each of the above-mentioned stages. Transarterial chemoembolization (TACE) is recommended as first-line therapy in the treatment of patients with intermediate-stage (BCLC-B class) HCC [1] . The efficacy of this procedure is supported by robust data [2,3] . Despite its efficacy, however, there is still a lack of standardization in treatment methodology, and TACE protocols are widely variable both in terms of dosages and schedule (on demand vs fixed interval administration) [4] . Moreover, the longterm outcomes of patients managed with TACE are not fully satisfactory, with up to 80% of patients eventually showing tumor
progression [5] and TACE can be associated with a number of contraindications [4] . Of note, patients with BCLC-B HCC present highly heterogenic features, and therefore the behavior of intermediate-stage HCC patients is difficult to anticipate [6,7] . This heterogeneity is due to a number of characteristics including performance status, Child-Pugh class and presence of portal vein thrombosis. Therefore, the development of an effective treatment strategy for all patients with BCLC-B HCC does not appear to be an easy task: a tailored approach to optimize the clinical outcomes in each single patient is needed [8] . Treatment options different from TACE, such as surgery, local ablation, radioembolization or systemic therapy, may be effective in patients with intermediate-stage HCC, and research in this filed appears quite active [8] . One of the most promising treatment options is the combination of different therapies [8,9] . Sorafenib, an oral multityrosine kinase inhibitor, is the only systemic therapy to be approved in patients with HCC [10] . Current guidelines and expert opinions recommend the use of sorafenib in patients
Department of Gastroenterology, Pisa University Hospital, Pisa, Italy Section of Radiology – Di.Bi.Me.F., University of Palermo, Palermo, Italy 3 Department of Radiology, Pisa University Hospital, Pisa, Italy 4 Department of Engineering, University of Trieste, Trieste, Italy 5 Section of Gastroenterology – Di.Bi.M.I.S., University of Palermo, Palermo, Italy *Author for correspondence:
[email protected]
KEYWORDS
• combination therapy • HCC • intermediate stage • sorafenib • TACE
“Transarterial chemoembolization
is recommended as first-line therapy in the treatment of patients with intermediate-stage ... hepatocellular carcinoma.”
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“In the next years, the scientific community will likely have to deal with new, more conclusive evidence on the combination of transarterial chemoembolization and sorafenib in hepatocellular carcinoma patients.”
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with intermediate-stage HCC with progressing tumors, who failed to respond or are not suitable for TACE [1] . The combination of TACE and sorafenib may be based on a strong mechanistic rationale. In fact, TACE determines hypoxia and necrosis of tumor tissue, increasing the concentration of many angiogenic growth factors such as VEGF and IGF2, which can contribute to promote disease progression [11] . It has been observed that the degree of hypoxia induced by TACE can vary according to the liver segment to which TACE is applied [8] . As an example, the hypoxia induced by TACE in the helatic hilus (S1) is more evident than the hypoxia generated in other areas, possibly inducing a more substantial expression of VEGF. The growth effects on the tumor induced by the angiogenic factors can be blocked by the administration of sorafenib, eventually improving clinical outcome for HCC patients [12] . Moreover, TACE treatment can lead to the progressive vascular destruction, especially when TACE is performed repeatedly [8] . In this way, the overall effect of repeated TACE may be diminished or even abolished. Recent evidence shows that sorafenib therapy would promote normalization of tumor vasculature, thus improving the effect of concomitant chemotherapy administered by TACE [8] . This synergistic effect could further support the combination of TACE and sorafenib. While these effects are very well grounded, we cannot exclude that sorafenib administration might potentially interfere with the penetration of embolic materials, and consequently, reduce the efficacy of TACE. The combination of TACE and sorafenib has been largely investigated in recent years [8] . Of note, prospective studies conducted to date have considered the addition of sorafenib to either conventional TACE (c-TACE) or drug-eluting beads TACE (see [8] for a complete review of such studies). The association of c-TACE and sorafenib was evaluated in intermediate-stage HCC patients also within a sequential strategy, in other words, with TACE sessions and sorafenib administration being carried out one after the other [8] . The combination (sequential or concomitant) of TACE and sorafenib treatment has also been investigated in ‘real-life’ clinical practice conditions, under the umbrella of the Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib (GIDEON), conducted on more than 3200 patients [13] .
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Overall, the results observed in the abovementioned studies seem to suggest that the combination of TACE and sorafenib may result in some clinical benefits in patients with intermediate-stage HCC. In fact, the majority of the studies – but not the randomized Phase III trial SPACE [14] – showed longer time to progression with the combination strategy than with TACE alone, without any further safety warning, while the impact on OS remains more uncertain [15] . However, almost all analyses conducted to date included heterogeneous populations with a remarkable proportion of patients with advanced HCC. Furthermore, most studies were not randomized, and some of them used historical cohorts as controls. According to the above-discussed evidence, at present we believe that there may be some evidence supporting the use of the combination of TACE and sorafenib in BCLC-B patients, but further studies do appear necessary to provide new insights on the use of the combination of TACE and sorafenib. In particular, we feel that future studies should further investigate the optimal timing of the embolization related to antiangiogenic therapy (concomitant vs sequential) and the ideal administration schedule in relation to different dosing regimens of sorafenib [16–18] . Another line of research is the use of TACE and sorafenib in advanced-stage (BCLC-C) HCC patients: to date, this approach led to somehow promising results, but a better clarification on the subjects who would benefit more from this treatment is warranted [8] . Research on this intriguing combination is particularly active. More than 20 studies are ongoing or have been completed [8] . Those studies enroll a number of patients ranging from 11 to about 1700, and have different designs; patients’ characteristics are also highly heterogeneous. In the next years, the scientific community will likely have to deal with new, more conclusive evidence on the combination of TACE and sorafenib in HCC patients. We feel that future studies in the comprehensive field of HCC will likely be focused on an improved evaluation of patients’ characteristics with the aim to optimize the response to treatment and propose new classification systems to stratify patients on the basis of their tumor status and their potential response to therapy. In this context, the combination of TACE and sorafenib, if proved effective, will add a new therapeutic option to the therapeutic armamentarium of HCC.
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Transarterial chemoembolization & sorafenib in patients with intermediate-stage hepatocellular carcinoma Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes
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