Response assessment methodologies in hepatocellular carcinoma: Complexities in the era of local and systemic treatments
Authors: Riad Salem, Frank H. Miller, Vahid Yaghmai, Robert J. Lewandowski
Journal: Journal of Hepatology (2013)

Although the mainstay of hepatocellular carcinoma (HCC) treatment has been locoregional, new systemic agents have demonstrated significant improvement in time-to-progression (TTP) and survival, leading some to postulate TTP as a surrogate of survival. While there is some rationale supporting this concept in advanced disease, complexities in HCC imaging should temper expanding this enthusiasm to early/intermediate disease until more robust evidence is available. Several examples of this lack of correlation exist in the radiofrequency ablation (RFA), chemoembolization (TACE)/radioembolization, and systemic therapy literature. Although we agree with EASL-EORTC guidelines that mRECIST helps move the field forward, several imaging complexities remain unaddressed [1Lencioni R. Llovet J.M. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.Semin Liver Dis. 2010; 30: 52-60Crossref PubMed Scopus (2730) Google Scholar, 2EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943PubMed Google Scholar]. These were highlighted by our core imaging research group following a formal review of 463 HCC patients (1818 scans) treated with chemoembolization/radioembolization [3Salem R. Lewandowski R.J. Mulcahy M.F. Riaz A. Ryu R.K. Ibrahim S. et al.Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.Gastroenterology. 2010; 138: 52-64Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar, 4Lewandowski R.J. Mulcahy M.F. Kulik L.M. Riaz A. Ryu R.K. Baker T.B. et al.Chemoembolization for hepatocellular carcinoma: comprehensive imaging and survival analysis in a 172-patient cohort.Radiology. 2010; 255: 955-965Crossref PubMed Scopus (123) Google Scholar].The first imaging complexity relates to arterial embolic therapies. Since these are performed at staged intervals, imaging follow-up involves the simultaneous radiologic interpretation of treated/untreated disease. This creates difficulty in assessing response; should response only be measured in the treated lesion(s)? How should untreated targets be considered if they have sufficiently enlarged to meet progressive disease criteria? Should imaging only be assessed when all tumors have been treated and if so, how should patients never completing all treatments (toxicities/decompensation) be reported? [5Riaz 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 (the journal of the American Medical Association): 1062-1069Crossref PubMed Scopus (153) Google Scholar, 6Shim J.H. Lee H.C. Won H.J. Shin Y.M. Kim K.M. Lim Y.S. et al.Maximum number of target lesions required to measure responses to transarterial chemoembolization using the enhancement criteria in patients with intrahepatic hepatocellular carcinoma.J Hepatol. 2012; 56: 406-411Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. These methodological nuances are under-reported in locoregional therapy studies. Accurately assessing response/progression (or lack thereof) in the liver is critical since HCC progression is predominantly local [[7]Senthilnathan S. Memon K. Lewandowski R.J. Kulik L. Mulcahy M.F. Riaz A. et al.Extrahepatic metastases occur in a minority of hepatocellular carcinoma patients treated with locoregional therapies: analyzing patterns of progression in 285 patients.Hepatology. 2012; 55: 1432-1442Crossref PubMed Scopus (57) Google Scholar]. This is also of importance since it suggests that the clinical sequelae of progression may be dependent on the treatment received (see Clinical scenarios, Supplementary information). These concepts further suggest that new (automated) tools should focus on response and progression in the liver (as opposed to extrahepatic sites).The second issue relates to “confirmatory progression”. Evaluating cirrhotic livers for new lesions can be quite challenging. Hypervascularity/washout is not a perfect criterion. It is not uncommon for equivocal lesions to become suspicious of HCC, yet at follow-up, become less conspicuous. Hence, confirmatory progression (particularly of new nodules) in HCC should be considered. This approach will minimize premature discontinuation of treatment. We have observed this artifact where a “new nodule” in a patient on sorafenib is declared as progressive disease (PD) with treatment discontinuation. At follow-up, despite no treatment, the lesion has disappeared, suggesting sorafenib was prematurely discontinued (PD overcall).The third issue relates to retrospective adjudication. Guidelines suggest that an equivocal lesion, ultimately determined to represent an HCC, should be retrospectively adjudicated to the time it was first observed. It is therefore possible to exhibit a TTP of 0 if a baseline equivocal lesion was only later confirmed to be HCC. Although unlikely, we have observed this phenomenon in varying magnitudes. In this scenario, retrospective adjudication weakens any TTP/survival correlation.The fourth issue relates to the need to capture HCC-related portal vein thrombosis in response guidelines. Despite no change in index lesion size, HCC treatment may result in the retraction/disappearance of portal vein thrombosis (PVT). We acknowledge that mRECIST appropriately labels PVT as non-target with subjective response/progression assessment. Imaging tools that objectively/consistently quantify this relevant finding are needed.The fifth point involves the interobserver reproducibility of measuring the longest uni/bidimensional diameter of enhancing tissue. While RFA may result in clear zones of necrosis and viable tissue, this is not the case with embolotherapies. We have encountered challenges when multiple readers attempted to reliably define the same (or comparable) areas of enhancing tissue following embolotherapy. This is a critical issue needing further investigation, with solutions that may potentially require automated imaging tools.Finally, and potentially most importantly, the mechanism of action and the time-dependence of response are often ignored. Embolic therapies lead to reduced tumor enhancement because of vascular occlusion. Since this finding may be observed on a contrast scan immediately after embolization, this cannot simply be labeled as necrosis. Alternatively, non-embolic therapies (Yttrium-90/radiotherapy/systemic) require time for response to manifest and in fact, may not lead to pronounced “necrotic” features. The lack of reduction in enhancement does not necessarily suggest treatment failure. Rather, it may represent tissue in the process of undergoing cell death, with lack of enhancement observed at a later date. Furthermore, although systemic agents may lead to reduced enhancement, this finding of “necrosis” may not necessarily represent cell death. In fact, tumoral enhancement may quickly return once the systemic agent is discontinued, suggesting hypoenhancement may not necessarily represent “necrosis” as we understand it pathologically [8Edeline J. Boucher E. Rolland Y. Vauleon E. Pracht M. Perrin C. et al.Comparison of tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST in patients treated with sorafenib for hepatocellular carcinoma.Cancer. 2012; 118: 147-156Crossref PubMed Scopus (228) Google Scholar, 9Faivre S. Zappa M. Vilgrain V. Boucher E. Douillard J.Y. Lim H.Y. et al.Changes in tumor density in patients with advanced hepatocellular carcinoma treated with sunitinib.Clin Cancer Res. 2011; 17 (an official journal of the American Association for Cancer Research): 4504-4512Crossref PubMed Scopus (69) Google Scholar].We believe enhancement criteria are skewed towards therapies that mechanistically cause avascularity (RFA, TACE), ignoring those not dependent on arterial occlusion (Y90/radiotherapy/systemic). The enthusiasm for new imaging methodologies should be tempered until more controlled studies are completed, including radiology–pathology correlation; there is only one such study to date [[10]Riaz A. Memon K. Miller F.H. Nikolaidis P. Kulik L.M. Lewandowski R.J. et al.Role of the EASL, RECIST, and WHO response guidelines alone or in combination for hepatocellular carcinoma: radiologic–pathologic correlation.J Hepatol. 2011; 54: 695-704Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. The above mentioned methodological complexities/nuances, among others, need to be incorporated in future versions of guidelines as we believe this granularity of detail is essential when reporting response in HCC studies.When it comes to HCC and response assessment, there is still a lot of work to do including standardization, interobserver reproducibility, volume analysis, radiology–pathology correlation and imaging surrogates of survival. While automated software appears to be an attractive tool for response assessment, further research and validation are needed before being able to implement these in routine clinical care.Financial supportThere was no external funding for this study. RS is supported in part by NIH grant CA126809.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Although the mainstay of hepatocellular carcinoma (HCC) treatment has been locoregional, new systemic agents have demonstrated significant improvement in time-to-progression (TTP) and survival, leading some to postulate TTP as a surrogate of survival. While there is some rationale supporting this concept in advanced disease, complexities in HCC imaging should temper expanding this enthusiasm to early/intermediate disease until more robust evidence is available. Several examples of this lack of correlation exist in the radiofrequency ablation (RFA), chemoembolization (TACE)/radioembolization, and systemic therapy literature. Although we agree with EASL-EORTC guidelines that mRECIST helps move the field forward, several imaging complexities remain unaddressed [1Lencioni R. Llovet J.M. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.Semin Liver Dis. 2010; 30: 52-60Crossref PubMed Scopus (2730) Google Scholar, 2EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943PubMed Google Scholar]. These were highlighted by our core imaging research group following a formal review of 463 HCC patients (1818 scans) treated with chemoembolization/radioembolization [3Salem R. Lewandowski R.J. Mulcahy M.F. Riaz A. Ryu R.K. Ibrahim S. et al.Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes.Gastroenterology. 2010; 138: 52-64Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar, 4Lewandowski R.J. Mulcahy M.F. Kulik L.M. Riaz A. Ryu R.K. Baker T.B. et al.Chemoembolization for hepatocellular carcinoma: comprehensive imaging and survival analysis in a 172-patient cohort.Radiology. 2010; 255: 955-965Crossref PubMed Scopus (123) Google Scholar]. The first imaging complexity relates to arterial embolic therapies. Since these are performed at staged intervals, imaging follow-up involves the simultaneous radiologic interpretation of treated/untreated disease. This creates difficulty in assessing response; should response only be measured in the treated lesion(s)? How should untreated targets be considered if they have sufficiently enlarged to meet progressive disease criteria? Should imaging only be assessed when all tumors have been treated and if so, how should patients never completing all treatments (toxicities/decompensation) be reported? [5Riaz 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 (the journal of the American Medical Association): 1062-1069Crossref PubMed Scopus (153) Google Scholar, 6Shim J.H. Lee H.C. Won H.J. Shin Y.M. Kim K.M. Lim Y.S. et al.Maximum number of target lesions required to measure responses to transarterial chemoembolization using the enhancement criteria in patients with intrahepatic hepatocellular carcinoma.J Hepatol. 2012; 56: 406-411Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. These methodological nuances are under-reported in locoregional therapy studies. Accurately assessing response/progression (or lack thereof) in the liver is critical since HCC progression is predominantly local [[7]Senthilnathan S. Memon K. Lewandowski R.J. Kulik L. Mulcahy M.F. Riaz A. et al.Extrahepatic metastases occur in a minority of hepatocellular carcinoma patients treated with locoregional therapies: analyzing patterns of progression in 285 patients.Hepatology. 2012; 55: 1432-1442Crossref PubMed Scopus (57) Google Scholar]. This is also of importance since it suggests that the clinical sequelae of progression may be dependent on the treatment received (see Clinical scenarios, Supplementary information). These concepts further suggest that new (automated) tools should focus on response and progression in the liver (as opposed to extrahepatic sites). The second issue relates to “confirmatory progression”. Evaluating cirrhotic livers for new lesions can be quite challenging. Hypervascularity/washout is not a perfect criterion. It is not uncommon for equivocal lesions to become suspicious of HCC, yet at follow-up, become less conspicuous. Hence, confirmatory progression (particularly of new nodules) in HCC should be considered. This approach will minimize premature discontinuation of treatment. We have observed this artifact where a “new nodule” in a patient on sorafenib is declared as progressive disease (PD) with treatment discontinuation. At follow-up, despite no treatment, the lesion has disappeared, suggesting sorafenib was prematurely discontinued (PD overcall). The third issue relates to retrospective adjudication. Guidelines suggest that an equivocal lesion, ultimately determined to represent an HCC, should be retrospectively adjudicated to the time it was first observed. It is therefore possible to exhibit a TTP of 0 if a baseline equivocal lesion was only later confirmed to be HCC. Although unlikely, we have observed this phenomenon in varying magnitudes. In this scenario, retrospective adjudication weakens any TTP/survival correlation. The fourth issue relates to the need to capture HCC-related portal vein thrombosis in response guidelines. Despite no change in index lesion size, HCC treatment may result in the retraction/disappearance of portal vein thrombosis (PVT). We acknowledge that mRECIST appropriately labels PVT as non-target with subjective response/progression assessment. Imaging tools that objectively/consistently quantify this relevant finding are needed. The fifth point involves the interobserver reproducibility of measuring the longest uni/bidimensional diameter of enhancing tissue. While RFA may result in clear zones of necrosis and viable tissue, this is not the case with embolotherapies. We have encountered challenges when multiple readers attempted to reliably define the same (or comparable) areas of enhancing tissue following embolotherapy. This is a critical issue needing further investigation, with solutions that may potentially require automated imaging tools. Finally, and potentially most importantly, the mechanism of action and the time-dependence of response are often ignored. Embolic therapies lead to reduced tumor enhancement because of vascular occlusion. Since this finding may be observed on a contrast scan immediately after embolization, this cannot simply be labeled as necrosis. Alternatively, non-embolic therapies (Yttrium-90/radiotherapy/systemic) require time for response to manifest and in fact, may not lead to pronounced “necrotic” features. The lack of reduction in enhancement does not necessarily suggest treatment failure. Rather, it may represent tissue in the process of undergoing cell death, with lack of enhancement observed at a later date. Furthermore, although systemic agents may lead to reduced enhancement, this finding of “necrosis” may not necessarily represent cell death. In fact, tumoral enhancement may quickly return once the systemic agent is discontinued, suggesting hypoenhancement may not necessarily represent “necrosis” as we understand it pathologically [8Edeline J. Boucher E. Rolland Y. Vauleon E. Pracht M. Perrin C. et al.Comparison of tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST in patients treated with sorafenib for hepatocellular carcinoma.Cancer. 2012; 118: 147-156Crossref PubMed Scopus (228) Google Scholar, 9Faivre S. Zappa M. Vilgrain V. Boucher E. Douillard J.Y. Lim H.Y. et al.Changes in tumor density in patients with advanced hepatocellular carcinoma treated with sunitinib.Clin Cancer Res. 2011; 17 (an official journal of the American Association for Cancer Research): 4504-4512Crossref PubMed Scopus (69) Google Scholar]. We believe enhancement criteria are skewed towards therapies that mechanistically cause avascularity (RFA, TACE), ignoring those not dependent on arterial occlusion (Y90/radiotherapy/systemic). The enthusiasm for new imaging methodologies should be tempered until more controlled studies are completed, including radiology–pathology correlation; there is only one such study to date [[10]Riaz A. Memon K. Miller F.H. Nikolaidis P. Kulik L.M. Lewandowski R.J. et al.Role of the EASL, RECIST, and WHO response guidelines alone or in combination for hepatocellular carcinoma: radiologic–pathologic correlation.J Hepatol. 2011; 54: 695-704Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. The above mentioned methodological complexities/nuances, among others, need to be incorporated in future versions of guidelines as we believe this granularity of detail is essential when reporting response in HCC studies. When it comes to HCC and response assessment, there is still a lot of work to do including standardization, interobserver reproducibility, volume analysis, radiology–pathology correlation and imaging surrogates of survival. While automated software appears to be an attractive tool for response assessment, further research and validation are needed before being able to implement these in routine clinical care. Financial supportThere was no external funding for this study. RS is supported in part by NIH grant CA126809. There was no external funding for this study. RS is supported in part by NIH grant CA126809. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Supplementary data Download .docx (.01 MB) Help with docx files Supplementary Scenarios 1 and 2 and ReferenceThis doc contains Supplementary scenarios and Reference. Download .docx (.01 MB) Help with docx files Supplementary Scenarios 1 and 2 and ReferenceThis doc contains Supplementary scenarios and Reference.