Towards new tools for refined management of patients with advanced hepatocellular carcinoma under systemic therapy: Some enthusiasm with a word of caution
Authors: Fabio Piscaglia, Alessandro Cucchetti, Christoph F. Dietrich, Veronica Salvatore
Journal: Journal of Hepatology (2013)

Early prediction of response to sorafenib in patients with advanced hepatocellular carcinoma: The role of dynamic contrast enhanced ultrasoundJournal of HepatologyVol. 59Issue 5PreviewSorafenib has become the standard first-line treatment for patients with advanced HCC and acts by inducing alterations in tumor vascularity. We wanted to evaluate the feasibility of dynamic CEUS (D-CEUS) as a predictor of early tumor response to sorafenib and to correlate functional parameters with clinical efficacy end points. Full-Text PDF In the present issue of the Journal of Hepatology, Dr. Zocco and coworkers from Rome, Italy, showed original data on a much debated and burning issue: is it possible to early predict response to antiangiogenic treatment in hepatocellular carcinoma (HCC) prior to the first standard assessment at approximately two months [[1]Zocco M.A. Gargovich M. Lupascu A. Di Stasio E. Roccarina D. Annichiarico B.E. et al.Early prediction of response to sorafenib in patients with advanced hepatocellular carcinoma: the role of dynamic contrast enhanced ultrasound.J Hepatol. 2013; 56: 1014-1021Abstract Full Text Full Text PDF Scopus (69) Google Scholar]? Clearly this issue is important for any tumor. Indeed a molecular characterization prior to therapy commencement has already become part of clinical practice for some tumors, in order to tailor the pharmacological therapy to the aim of limiting the occurrence of non or poor responders. This is not yet in place for HCC, where the single standard agent for advanced cases or cases unsuitable for locoregional treatments is the antiangiogenic drug sorafenib. Nonetheless, even having one single agent, the question of whether it is possible to predict the response to sorafenib before its start is important. Unfortunately, this question has received a negative answer so far, since no marker has been identified yet [[2]Llovet J.M. Pena C.E. Lathia C.D. Shan M. Meinhardt G. Bruix J. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma.Clin Cancer Res. 2012; 18: 2290-2300Crossref PubMed Scopus (442) Google Scholar] and no patient is selected for treatment based on the expectations of response. The next question is, therefore, whether it would be at least possible to have an early on-treatment information about the outcome and most importantly about which patient is going to rapidly progress notwithstanding sorafenib. In fact, whoever will achieve stable disease or response will continue the systemic therapy, hence even an earlier information about a later beneficial outcome will not change the strategy, but may only add costs. Conversely, the possibility to identify at an early time point (within the first 15 days after treatment start) those patients who will subsequently show tumor progression already at the first imaging assessment (usually at 6–10 weeks after treatment start, corresponding to no benefit from systemic therapy) would be of crucial importance. Such information could theoretically anticipate the stop of treatment and accordingly could enable the enrolment in second line treatment trials, before the patient's general conditions or liver dysfunctions have deteriorated to a level no more matching the enrolment criteria. An early stop of ineffective treatment would also contribute to save money and avoid the persistence of possible side effects. Clearly any such decision, to anticipatedly stop treatment, is an important issue. Thus the tool for the decision should be specific enough to avoid false positive cases of inefficacy. The article by Zocco et al. [[1]Zocco M.A. Gargovich M. Lupascu A. Di Stasio E. Roccarina D. Annichiarico B.E. et al.Early prediction of response to sorafenib in patients with advanced hepatocellular carcinoma: the role of dynamic contrast enhanced ultrasound.J Hepatol. 2013; 56: 1014-1021Abstract Full Text Full Text PDF Scopus (69) Google Scholar] proposes the use of dynamic contrast enhanced ultrasound (CEUS) of tumor perfusion at two weeks after sorafenib start as a tool to identify those patients who will be categorized as progressors already at two months when assessed by the mRECIST criteria, as currently recommended [3European Association for the Study of the Liver European Organization for Research and Treatment of Cancer EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943Abstract Full Text Full Text PDF PubMed Scopus (4808) Google Scholar, 4Italian Association for the Study of the Liver (AISF) AISF Expert Panel Position paper of the Italian Association for the Study of the Liver (AISF): the multidisciplinary clinical approach to hepatocellular carcinoma.Dig Liver Dis. 2013; ([Epub ahead of print])https://doi.org/10.1016/j.dld.2013.01.012Abstract Full Text Full Text PDF Scopus (154) Google Scholar]. The use of CEUS to this aim is not new, as it has been studied in other tumors, and particularly in gastrointestinal stromal tumors (GIST), treated with antiangiogenics. In this setting, the use of CEUS to monitor treatment response to GIST has been already endorsed by the European Society of Medical Oncology [[5]ESMO/European Sarcoma Network Working Group Gastrointestinal stromal tumors: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2012; 23: vii49-vii55Crossref PubMed Scopus (238) Google Scholar] and was shown to provide useful information in other tumors treated with antiangiogenics, such as renal cell carcinoma [[6]Lassau N. Koscielny S. Albiges L. Chami L. Benatsou B. Chebil M. et al.Metastatic renal cell carcinoma treated with sunitinib: early evaluation of treatment response using dynamic contrast-enhanced ultrasonography.Clin Cancer Res. 2010; 16: 1216-1225Crossref PubMed Scopus (161) Google Scholar]. Some preliminary data were also reported for HCC, but either not under the standard of treatment [[7]Lassau N. Koscielny S. Chami L. Chebil M. Benatsou B. Roche A. et al.Advanced hepatocellular carcinoma: early evaluation of response to bevacizumab therapy at dynamic contrast-enhanced US with quantification–preliminary results.Radiology. 2011; 258: 291-300Crossref PubMed Scopus (182) Google Scholar] or with very limited number of patients [[8]Frampas E. Lassau N. Zappa M. Vullierme M.P. Koscielny S. Vilgrain V. Advanced hepatocellular carcinoma: early evaluation of response to targeted therapy and prognostic value of perfusion CT and dynamic contrast enhanced-ultrasound. Preliminary results.Eur J Radiol. 2013; 82: e205-e211Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar] or using different contrast parameters and assessment timing [[9]Knieling F. Waldner M.J. Goertz R.S. Zopf S. Wildner D. Neurath M.F. et al.Early response to anti-tumoral treatment in hepatocellular carcinoma–can quantitative contrast-enhanced ultrasound predict outcome?.Ultraschall Med. 2013; 34: 38-46PubMed Google Scholar]. CEUS is advantageous in this setting, thanks to its low cost and easy repeatability and is very well accepted by patients. The study by Zocco et al. [[1]Zocco M.A. Gargovich M. Lupascu A. Di Stasio E. Roccarina D. Annichiarico B.E. et al.Early prediction of response to sorafenib in patients with advanced hepatocellular carcinoma: the role of dynamic contrast enhanced ultrasound.J Hepatol. 2013; 56: 1014-1021Abstract Full Text Full Text PDF Scopus (69) Google Scholar] has some strong points. Patients were enrolled according to the usual clinical indications to start sorafenib, with not excessively restrictive criteria, even though the number of patients with no extravascular spread nor macrovascular invasion, but only with symptomatic tumor was relatively high, thus it will reflect the clinical practice. Only three patients (7%) could not be included due to unsuitable ultrasound target, thus there was not an additional reason for superselection. The timing at two weeks for reassessment is reasonable. Later time points, such as at one month, would not provide a significant advantage over standard reassessment, despite they were used by two preliminary studies [8Frampas E. Lassau N. Zappa M. Vullierme M.P. Koscielny S. Vilgrain V. Advanced hepatocellular carcinoma: early evaluation of response to targeted therapy and prognostic value of perfusion CT and dynamic contrast enhanced-ultrasound. Preliminary results.Eur J Radiol. 2013; 82: e205-e211Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 9Knieling F. Waldner M.J. Goertz R.S. Zopf S. Wildner D. Neurath M.F. et al.Early response to anti-tumoral treatment in hepatocellular carcinoma–can quantitative contrast-enhanced ultrasound predict outcome?.Ultraschall Med. 2013; 34: 38-46PubMed Google Scholar]. Conversely, earlier time points, not investigated herein, up to a few days after treatment start, could be of interest and deserve specific investigations. The authors correctly separated progressors (who are the target of the study) from non-progressors at the standard time of two months. Very interestingly, the CEUS parameters showing most reliable predictive value are two variables related to the blood volume in the investigated area [10Piscaglia F. Nolsoe C. Dietrich C.F. Cosgrove D.O. Gilja O.H. Bachmann Nielsen M. et al.On non-hepatic applications.Ultraschall Med. 2011; 2012: 33-59Google Scholar, 11Dietrich C.F. Averkiou M.A. Correas J.M. Lassau N. Leen E. Piscaglia F. An EFSUMB introduction into Dynamic Contrast-Enhanced Ultrasound (DCE-US) for quantification of tumour perfusion.Ultraschall Med. 2012; 33: 344-351Crossref PubMed Scopus (311) Google Scholar]. At variance, time-to-peak which is related to blood flow [10Piscaglia F. Nolsoe C. Dietrich C.F. Cosgrove D.O. Gilja O.H. Bachmann Nielsen M. et al.On non-hepatic applications.Ultraschall Med. 2011; 2012: 33-59Google Scholar, 11Dietrich C.F. Averkiou M.A. Correas J.M. Lassau N. Leen E. Piscaglia F. An EFSUMB introduction into Dynamic Contrast-Enhanced Ultrasound (DCE-US) for quantification of tumour perfusion.Ultraschall Med. 2012; 33: 344-351Crossref PubMed Scopus (311) Google Scholar] was not significantly associated with progression, as well as mean transit time. Such data tend to suggest that indeed CEUS is able to identify a decrease in tumor blood volume. The fact that the former two parameters appear to be reliable to the aim of predicting response is based on the finding that responders showed negative values up to the threshold of third interquartile (decrease in enhancement level) whereas progressors had positive values. According to the results of the study, however, progressors were considered those subjects showing an increase of such values by >10% at two weeks of treatment in comparison to baseline. Selecting higher threshold would theoretically make the identification of progressors more specific, but would decrease the overall accuracy, as reported by the authors, since some progressors would be considered as responders. However, in order to avoid stopping therapy in dubious responders, a suggestion could be to initially adopt a more conservative approach, selecting a higher threshold than the most accurate (change >10%). The fact that progressors were separated from non-progressor by such a narrow range (change >10%, corresponding to slightly more than the mean coefficients of variations) justifies the need for automated and computerized calculations of signal intensity [[11]Dietrich C.F. Averkiou M.A. Correas J.M. Lassau N. Leen E. Piscaglia F. An EFSUMB introduction into Dynamic Contrast-Enhanced Ultrasound (DCE-US) for quantification of tumour perfusion.Ultraschall Med. 2012; 33: 344-351Crossref PubMed Scopus (311) Google Scholar], preventing the possibility to adopt a strategy only based on visual impression. The limited coefficient of variations of CEUS quantification and the reliability of the results may have derived from the use of a methodology based on quantification of precompressed, raw signal data and not linearized video data [[12]Salvatore V. Borghi A. Sagrini E. Galassi M. Gianstefani A. Bolondi L. et al.Quantification of enhancement of focal liver lesions during contrast-enhanced ultrasound (CEUS). Analysis of ten selected frames is more simple but as reliable as the analysis of the entire loop for most parameters.Eur J Radiol. 2012; 81: 709-713Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. This is only speculative, but just mentioning that there are different methodologies for contrast quantification, based on different proprietaries softwares implies a word of caution in using the results directly in the clinical practice, especially when the technology is not identical to the one used in this article [[1]Zocco M.A. Gargovich M. Lupascu A. Di Stasio E. Roccarina D. Annichiarico B.E. et al.Early prediction of response to sorafenib in patients with advanced hepatocellular carcinoma: the role of dynamic contrast enhanced ultrasound.J Hepatol. 2013; 56: 1014-1021Abstract Full Text Full Text PDF Scopus (69) Google Scholar]. Another study on a more limited patient population, using a different equipment and quantification software, consistently showed the Area Under the Curve of enhancement to be the most useful parameter, which is reassuring, but the best cut-off was quite different [[8]Frampas E. Lassau N. Zappa M. Vullierme M.P. Koscielny S. Vilgrain V. Advanced hepatocellular carcinoma: early evaluation of response to targeted therapy and prognostic value of perfusion CT and dynamic contrast enhanced-ultrasound. Preliminary results.Eur J Radiol. 2013; 82: e205-e211Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar]. Very importantly, the operators need to be adequately trained in CEUS quantification (which involves a specific and reliable choice of the scanning plane and acquisition settings and contrast injection modality, so that subsequent scans over time could be reproduced) and the equipments or softwares should be preliminary tested and validated. Fabio Piscaglia has received fees from Bayer, Bracco, Esaote, GE, Siemens; Christoph F. Dietrich has received fees from Abbott (Abvie), Bracco, Essex, Falk, GE, Hitachi, Merck, Novartis, Sanofi-Aventis, Pentax, Roche, Shire, Siemens, Toshiba. The other authors have nothing to disclose.