TACE with or without systemic therapy?

Abstract

Hepatology, Department of Clinical Research, University of Bern, Switzerland;Department of Visceral Surgery and Medicine,Inselspital, University of Bern, SwitzerlandSee Article, pages 1336–1342Transarterial chemoembolisation (TACE) delivers a chemothera-peutic agent (usually doxorubicin) into the feeding vessels of ahepatocellular carcinoma(HCC) and blocks the subsequent perfu-sion of these vessels by the injection of a plugging material. Tworandomized controlled trials, conducted 10 years ago, reported asurvival advantage for patients with a preserved liver function[1,2]. Subsequent meta-analysis confirmed that TACE increasedthe survival of patients with HCC [3,4]. TACE is a particularlyattractive option for the management of patients with HCCbecause it is associated with few side effects and requires nomore than a 24-h hospitalization. Until recently, TACE was anotoriously heterogeneous procedure with variable outcomes.The demonstration that the delivery of small beads loaded withdoxorubicin was associated with fewer systemic side effects ledto a standardization of the TACE procedure [5]. TACE is offeredto patients in stage B of the Barcelona classification, which repre-sents the largest fraction of patients seeking treatment. There-fore, improvements of TACE therapy are a matter of urgency.TACE has two intrinsic limitations: it treats only the tumor tis-sue dependent on the embolized vessels and it elicits a reactionof growth factors. HCC sustains its growth by angiogenesis; spe-cifically by promoting the formation of blood vessels from sur-rounding arteries. Although TACE embolizes the principalfeeding arteries of the tumor, it leaves smaller vessels open,which explains why the procedure is palliative and not curative.Moreover, in cases of multifocal HCC with foci too small to beradiologically visible, TACE does not treat these additionallesions. In fact, it may even promote their growth [6]. Therefore,one improvement would be to prevent the recruitment of thesesecondary vessels. TACE induces a central anoxia with a periphe-ral hypoxia. This hypoxic stress provokes cells to release angio-genic growth factors. It is well documented that the circulatinglevels of VEGF increase after TACE [7,8]. Nowadays these limita-tions of TACE can be alleviated. Systemic antiangiogenic thera-pies have been developed, exemplified by sorafenib, which hasbeen approved for the systemic treatment of HCC. Althoughattractive in theory, the combination of sorafenib with TACEcould be associated with more side effects, such as abscesses. Aphase I study tested the safety and feasibility of combiningsorafenib with TACE, beginning the systemic treatment a weekbefore the first TACE and without stopping the drug during theTACE sessions [9]. This study was not associated with major sideeffects opening the field to phase II studies.In this issue of the Journal, Joong-Won Park and co-workersreport the results of a single-center phase II, open-label, single-arm study combining sorafenib with TACE in 50 patients [10].Ninety-four percent were Child–Pugh class A, 70% were treatedwith surgical or locoregional therapies before enrollment. Sixtypercent received the concurrent treatment as planned for24 weeks. The most common reasons for discontinuation ofsorafenib was HCC progression (17 patients), and for only 1patient, adverse event. The authors report an overall median timeto progression of 7.3 months for the 41 patients BCLC stage B andof 5.0 months for the 9 patients in BCLC stage C. The 6-monthprogression-free survival rate was 52%. The authors conclude thatthe increased survival is an improvement when compared withhistorical control patients treated only with TACE. Given the het-erogeneous characteristics of the patients included andof the his-torical control population, it remains impossible to infer that thecombined treatment from this trial is more efficacious. Moreover,this trial was designed such that the systemic therapy withsorafenib was withheld for the TACE sessions and reintroducedon day 3 after the procedure or delayed further in case of majorlaboratory abnormalities. This prudent scheme was selected toavoid an augmentation of post-TACE complications with sorafe-nib. Nevertheless, it might have been deleterious because oftumor rebound after sorafenib interruption, as has been observedin animal models [11]. Moreover, the concentration of VEGFpeaks on the day following TACE [7]. Therefore, in contrast to acontinuous scheme, this scheme denies sorafenib at the time itis the most needed [12].Additional studies have tested sorafenib in combination withTACE. Erhardt presented a trial with a similar, interrupted design,but enrolled 45 treatment naive patients and performed lipiodo-lization rather than embolization [13]. The overall survival was20 months. Unfortunately, the lack of a control group limits theinterpretation of the survival, which is not beyond the expectedrange for patients treated with TACE only. The clinical commu-nity awaits the results of the ECOG E1208 phase III trial, whichhas included a control group, to better appreciate the potentialand limitations of interrupted combination (NCT01004978).Journal of Hepatology 2012 vol. 56