To TACE or not to TACE? Lessons from a negative trial
Authors: Jean-Luc Raoul, Marine Gilabert, Xavier Adhoute
Journal: The Lancet. Gastroenterology & hepatology (2017)

In the Lancet Gastroenterology & Hepatology, Tim Meyer and colleagues1Meyer T Fox R Ma YT et al.Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial.Lancet Gastroenterol Hepatol. 2017; (published online June 22.)http://dx.doi.org/10.1016/S2468-1253(17)30156-5PubMed Google Scholar report the results of TACE 2, a placebo-controlled, double-blinded, phase 3 trial that assessed the use of sorafenib in combination with transarterial chemoembolisation (TACE) in patients with unresectable hepatocellular carcinoma. This negative trial is of major importance and provides important data concerning TACE. First, this study1Meyer T Fox R Ma YT et al.Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial.Lancet Gastroenterol Hepatol. 2017; (published online June 22.)http://dx.doi.org/10.1016/S2468-1253(17)30156-5PubMed Google Scholar highlights the lack of survival benefit in combining anti-angiogenic drugs with TACE. This is the third negative large randomised trial (two phase 3 trials2Kudo M Han G Finn RS et al.Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial.Hepatology. 2014; 60: 1697-1707Crossref PubMed Scopus (236) Google Scholar and one phase 2 trial3Lencioni R Llovet JM Han G et al.Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial.J Hepatol. 2016; 64: 1090-1098Summary Full Text Full Text PDF PubMed Scopus (436) Google Scholar have now been done) testing concurrent administration of TACE with an anti-angiogenic drug (sorafenib or brivanib) to inhibit or delay tumour progression. Only a faint positive signal was observed in the small Asian subgroup of the phase 2 SPACE trial;3Lencioni R Llovet JM Han G et al.Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial.J Hepatol. 2016; 64: 1090-1098Summary Full Text Full Text PDF PubMed Scopus (436) Google Scholar all other analyses were negative. The TACE 2 trial represents the second largest prospective series of European patients treated by TACE. The largest trial (PRECISION Italia4Golfieri R Giampalma E Renzulli M et al.Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma.Br J Cancer. 2014; 111: 255-264Crossref PubMed Scopus (373) Google Scholar) compared conventional TACE with doxorubicin-eluting beads, and was terminated prematurely for futility after inclusion of 177 patients. In both series (TACE 2, PRECISION Italia), patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease were included: patients with performance status of zero or one in both studies, and patients with portal vein thrombosis but not of the main portal vein, in TACE 2. Treatment had to be segmental or subsegmental in the PRECISION Italia study,4Golfieri R Giampalma E Renzulli M et al.Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma.Br J Cancer. 2014; 111: 255-264Crossref PubMed Scopus (373) Google Scholar which included fewer patients with severe disease (more patients with performance status of 0, more patients with only one lesion and smaller lesions, fewer patients with alcoholic disease), and TACE was repeated on demand in both trials. The objective response rate (as assessed by modified Response Evaluation Criteria in Solid Tumours; mRECIST) was 89% in the PRECISION Italia trial and 52% in the TACE 2 trial. Median time to progression was similar in both trials (9 months and 11 months), and median overall survival was 28–29 months in PRECISION Italia and 20–21 months in TACE 2. Notably, in the SPACE trial,3Lencioni R Llovet JM Han G et al.Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial.J Hepatol. 2016; 64: 1090-1098Summary Full Text Full Text PDF PubMed Scopus (436) Google Scholar median overall survival was less than 20 months among non-Asian patients (mostly from Europe), despite inclusion of only patients with a performance status of 0. The combined data from these studies, which together form a rather homogeneous series of European patients who represent the clinical situation relatively well, TACE on demand corresponded to a median of two sessions, resulted in objective tumour response in most cases, with a median time to progression of 9–11 months and median overall survival ranging from 20 to 29 months. Broader inclusion criteria appear to yield poorer results, particularly in cases of portal vein thrombosis. Additionally, in TACE 2 the use of the hepatoma arterial-embolisation prognostic (HAP) score, which is based5Kadalayil L Benini R Pallan L et al.A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer.Ann Oncol. 2013; 24: 2565-2570Crossref PubMed Scopus (222) Google Scholar on four parameters (albumin, bilirubin, α-fetoprotein [AFP], and tumour size), provided good prognostic value and seemed valuable in identifying patients who would not benefit from TACE. In trials that included western patients treated with sorafenib, the median overall survival for non-Asian patients ranges between 12 months6Johnson PJ Qin S Park JW et al.Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.J Clin Oncol. 2013; 31: 3517-3524Crossref PubMed Scopus (577) Google Scholar and 15 months7Cheng AL Kang YK Lin DY et al.Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.J Clin Oncol. 2013; 31: 4067-4075Crossref PubMed Scopus (572) Google Scholar and is longer among patients without extrahepatic metastases or portal vein thrombosis, and with access to second lines of treatment. It is sensible to conclude that TACE is suitable for patients who are expected by HAP score and other measures (eg, NIACE) to have a median overall survival of more than 15–16 months. In the TACE 2 trial, the median overall survival was around 31 months for patients with a HAP score of A, 21 months for B, 15 months for C, and 6 months for D. Clearly, patients with HAP score D are not candidates for TACE. Those with HAP scores A and B benefit from TACE; but for those with score C, a prospective trial comparing medical treatment with interventional radiology is needed to determine benefit. However, the use of HAP score has some drawbacks, because it does not take into account the performance status nor some other tumour parameters (number, aspect, portal vein thrombosis). In the PRECISION Italia trial, which excluded patients with portal vein thrombosis and infiltrative tumours, the multivariate survival analysis showed that a performance status of 1 and the presence of multiple tumours were independent prognostic factors. These factors (performance status and number of nodules) are components of the NIACE score,8Adhoute X Penaranda G Raoul JL et al.NIACE score for hepatocellular carcinoma patients treated by surgery or transarterial chemoembolization.Eur J Gastroenterol Hepatol. 2017; 29: 706-715Crossref PubMed Scopus (10) Google Scholar which distinguishes different prognostic groups among patients within each BCLC class. The NIACE score was established and retrospectively validated in patients with BCLC stage B treated by TACE. With a cutoff value of 3, this score allows for the differentiation of patients with low (13 months) and high (20 months) median overall survival. The presence of portal vein thrombosis was a poor prognostic factor in a study in 2017,9Waked I Berhane S Toyoda H et al.Transarterial chemo-embolisation of hepatocellular carcinoma: impact of liver function and vascular invasion.Br J Cancer. 2017; 116: 448-454Crossref PubMed Scopus (50) Google Scholar and has been part of the exclusion criteria (including segmental portal vein thrombosis) in other trials.10Lo CM Ngan H Tso WK et al.Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.Hepatology. 2002; 35: 1164-1171Crossref PubMed Scopus (2201) Google Scholar To confirm the need to exclude patients with portal vein thrombosis from TACE, the negative contribution of this parameter needs to be studied in the TACE 2 trial. In the future, it will also be important to do a prospective trial in patients who could technically receive TACE (BCLC stage B but with a performance status of 1) but have a poor prognosis (expected survival less than 15 months) based on HAP or NIACE score, comparing first-line TACE with systemic treatment. The data produced by this important trial not only show that the combination of TACE plus sorafenib is not of interest, but stimulate us to move to score-based trials to better define the population that will benefit from TACE. This strategy might be another way to personalise treatment for hepatocellular carcinoma. J-LR reports personal fees from Bayer, personal fees from Bristol-Myers Squibb, personal fees from BTG, and grants from Celgene, outside the submitted work. MG and XA declare no competing interests. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trialThe addition of sorafenib to DEB-TACE does not improve progression-free survival in European patients with hepatocellular carcinoma. Alternative systemic therapies need to be assessed in combination with TACE to improve patient outcomes. Full-Text PDF Open Access