Do EASL and mRECIST responses have independent effects on survival in hepatocellular carcinoma patients treated with transarterial embolization?
Authors: Weijuan Wang, Yan Zhao, Guohong Han, Daiming Fan
Journal: Journal of Hepatology (2012)

EASL and mRECIST responses are independent prognostic factors for survival in hepatocellular cancer patients treated with transarterial embolizationJournal of HepatologyVol. 55Issue 6PreviewStandard RECIST criteria may not be the optimal method to assess response to loco-regional therapy for hepatocellular cancer (HCC). EASL and mRECIST, which measure changes in arterialized tumor, have been proposed. Here we compare the three criteria and their associations with survival. Full-Text PDF Reply to: “Do EASL and mRECIST responses have independent effects on survival in hepatocellular carcinoma patients treated with transarterial embolization?”Journal of HepatologyVol. 57Issue 1PreviewWe thank Wang and colleagues for their critical appraisal of our paper which explores the prognostic importance of early response assessment in patients with hepatocellular cancer (HCC) undergoing transarterial embolisation [1]. Wang et al. correctly point out that the prognosis for HCC patients is determined by many factors, including liver function, and are concerned that Child–Pugh score may have been a confounding factor in our analysis. Of the 83 patients included in the study, 69 had Child–Pugh A liver scores and only 13 had Child–Pugh B. Full-Text PDF Open Access We read with interest the paper by Gillmore et al. [[1]Gillmore R. Stuart S. Kirkwood A. Hameeduddin A. Woodward N. Burroughs A.K. et al.EASL and mRECIST responses are independent prognostic factors for survival in hepatocellular cancer patients treated with transarterial embolisation.J Hepatol. 2011; 55: 1309-1316Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar] regarding the impact of the European Association for the Study of the Liver (EASL) and modified Response Evaluation Criteria In Solid Tumors (mRECIST) on survival in hepatocellular carcinoma (HCC) patients treated with transarterial embolization. The authors compared RECIST1.1, EASL and mRECIST criteria and found that overall responses to EASL and mRECIST at 2–3 months after therapy were associated with survival. We consider this conclusion to be very important in clinical practice. Riaz et al. [[2]Riaz A. Miller F.H. Kulik L.M. Nikolaidis P. Yaghmai V. Lewandowski R.J. et al.Imaging response in the primary index lesion and clinical outcomes following transarterial locoregional therapy for hepatocellular carcinoma.JAMA. 2010; 303: 1062-1069Crossref PubMed Scopus (157) Google Scholar] evaluated the response in the primary index lesion after loco-regional therapy in HCC patients and found that the median time to the RECIST response was 7.7 months; this value was only 1.6 months when EASL criteria were used. We can attribute this result to the fact that, in contrast to the EASL criteria, the RECIST criteria do not address measures of antitumor activity other than tumor shrinkage, whereas loco-regional treatments such as transarterial chemoembolization (TACE) often cause acute tumor necrosis, which may not always be accompanied by a change in tumor size [[3]Llovet J.M. DiBisceglie A.M. Bruix J. Kramer B.S. Lencioni R. Zhu A.X. et al.Design and endpoints of clinical trials in hepatocellular carcinoma.J Natl Cancer Inst. 2008; 100: 698-711Crossref PubMed Scopus (1448) Google Scholar]. Based on the above considerations, RECIST is not applicable during the early postoperative period. Nevertheless, as it was a retrospective non-controlled study, some aspects of the investigation may preclude the possibility of drawing definitive conclusions. According to this study, patients defined as responders obtained a longer overall survival compared to non-responders, then, we wonder whether the liver function between the two groups was comparable. As is well known, the determination of a prognosis is much more complex in HCC patients than in patients with other solid neoplasms because of the degree of liver dysfunction, which is related to the underlying chronic liver disease as well as the related treatment. For this reason, liver function should be assessed for the reliable establishment of prognosis [[4]Piscaglia F. Bolondi L. et al.The intermediate hepatocellular carcinoma stage: should treatment be expanded?.Dig Liver Dis. 2010; 42S: S258-S263Abstract Full Text PDF Scopus (52) Google Scholar]. In the current study, 13 patients classified as Child-Pugh class B were included; we suspect that the different survival between responders and non-responders may not only represent different response, but also be affected by different liver functions. The study by Sala et al. [[5]Sala M. Llovet J.M. Vilana R. Bianchi L. Sole M. Ayuso C. et al.Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma.Hepatology. 2004; 40: 1352-1360Crossref PubMed Scopus (393) Google Scholar] showed that Child-Pugh class and initial response to percutaneous ablation were independent predictors of survival for HCC patients. Child-Pugh class A patients who displayed an initial complete response could even achieve 42% survival at 5 years. Riaz et al. [[2]Riaz A. Miller F.H. Kulik L.M. Nikolaidis P. Yaghmai V. Lewandowski R.J. et al.Imaging response in the primary index lesion and clinical outcomes following transarterial locoregional therapy for hepatocellular carcinoma.JAMA. 2010; 303: 1062-1069Crossref PubMed Scopus (157) Google Scholar] and Memon et al. [[6]Memon K. Kulik L. Lewandowski R.J. Wang E. Riaz A. Ryu R.K. et al.Radiographic response to locoregional therapy in hepatocellular carcinoma predicts patient survival times.Gastroenterology. 2011; 141: 526-535Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar] also demonstrated that, except for tumor response, liver function is another important factor significantly related to outcome by statistical analysis. We hold the opinion that, on the one hand, to assess the association between response and survival, it is imperative to eliminate the influence of confounding factors such as liver function. Therefore, the differences in outcomes represent differences in the tumor response. While on the other hand, to predict survival, we should take into account liver function even if it is not significantly related to survival by statistical analysis, since it is necessary but not sufficient to make a good prognostic variable only to analyse an association between variables and survival statistically by ‘information criterion’ or ‘measure of gradient’ [[7]Tournoux-Facon C. Paoletti X. Barbare J.-C. Bouche O. Rougier P. Dahan L. et al.Development and validation of a new prognostic score of death for patients with hepatocellular carcinoma in palliative setting.J Hepatol. 2011; 54: 108-114Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. Particularly, liver function at the time of the evaluation should be attached importance to. As for some of our cases, patients with well-preserved liver function at baseline underwent successful transarterial therapy and obtained tumor responses but died of liver failure after a short while (Fig. 1A–C ). It is therefore not possible to rule out changes in liver function after treatment. Another question relates to whether a single assessment was sufficient to estimate the patient responses. Response is a time-dependent variable, which is determined by two observations performed not less than 4 weeks apart [[8]Bruix J. Sherman M. Llovet J.M. Beaugrand M. Lencioni R. Burroughs A.K. et al.Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference.J Hepatol. 2001; 35: 421-430Abstract Full Text Full Text PDF PubMed Scopus (3799) Google Scholar]. The duration of the response is a critical issue. A total reduction in tumor bulk is meaningless if the duration is short-lived because of tumor recurrence or the appearance of new lesions as well as extrahepatic metastasis or vascular invasion [[9]Gwyther S.J. Schwartz L.H. et al.How to assess anti-tumour efficacy by imaging techniques.Eur J Cancer. 2008; 44: 39-45Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. For a response to be confirmed, it should be demonstrated on a second examination at a certain time after its initial evaluation. It may therefore be inappropriate to assess the response only once. Although they are convenient and practical in assessing tumor response and predicting survival, the EASL and mRECIST criteria using computed tomography (CT) may overestimate the extent of necrosis owing to the use of lipiodol uptake and retention as surrogates for necrosis [[10]Bruix J. Reig M. Rimola J. Forner A. Burrel M. Vilana R. et al.Clinical decision making and research in hepatocellular carcinoma: pivotal role of imaging techniques.Hepatology. 2011; https://doi.org/10.1002/hep. 24670Crossref Google Scholar]. Patients classified as CR may have residual disease at the time of the explant. It has been verified that the presence of extensive necrosis induced by chemoembolization correlates with outcome [[10]Bruix J. Reig M. Rimola J. Forner A. Burrel M. Vilana R. et al.Clinical decision making and research in hepatocellular carcinoma: pivotal role of imaging techniques.Hepatology. 2011; https://doi.org/10.1002/hep. 24670Crossref Google Scholar]. Then better imaging modality should be explored to make radiologic necrosis more precisely represent pathologic necrosis so as to provide a validation for the accurate use of mRECIST and EASL. In conclusion, further study is needed for more reasonable and comprehensive predictions of outcome. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.