Advertisement

Established and novel imaging biomarkers for assessing response to therapy in hepatocellular carcinoma

  • Tao Jiang
    Affiliations
    Division of Abdominal Imaging and Intervention, Harvard Medical School and Massachusetts General Hospital, 55 Fruit Street, White 270, Boston, MA 02114, USA

    Department of Radiology, ChangZheng Hospital Affiliated to Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China
    Search for articles by this author
  • Andrew X. Zhu
    Correspondence
    Corresponding authors. Tel.: +1 617 643 3415; fax: +1 617 724 3166 (A.X. Zhu), tel.: +1 617 726 3937; fax: +1 617 726 4891 (D.V. Sahani).
    Affiliations
    Massachusetts General Hospital Cancer Center, 55 Fruit Street, LH/POB 232, Boston, MA 02114, USA
    Search for articles by this author
  • Dushyant V. Sahani
    Correspondence
    Corresponding authors. Tel.: +1 617 643 3415; fax: +1 617 724 3166 (A.X. Zhu), tel.: +1 617 726 3937; fax: +1 617 726 4891 (D.V. Sahani).
    Affiliations
    Division of Abdominal Imaging and Intervention, Harvard Medical School and Massachusetts General Hospital, 55 Fruit Street, White 270, Boston, MA 02114, USA
    Search for articles by this author
Published:September 03, 2012DOI:https://doi.org/10.1016/j.jhep.2012.08.022

      Summary

      The management of hepatocellular carcinoma (HCC) is evolving because of recently introduced novel therapeutic approaches. There is growing recognition that optimal outcome requires choosing treatment tailored to suit each individual patient, necessitating an early and accurate assessment of tumor response to therapy. The established and adapted image biomarkers based on size for tumor burden measurement continues to be applied to HCC as size measurement can easily be used in any clinical practice. However, in the setting of novel targeted therapies and liver directed treatments, simple tumor anatomical changes can be less informative and usually appear later than biological changes. Therefore the importance of image biomarkers such as tumor viability measurement, functional perfusion and diffusion imaging for response assessment is increasingly being recognized. Although promising, these imaging biomarkers have not gone through all the required steps of standardization and validation. In this review, we discuss various established, evolving and emerging imaging biomarkers and the criteria of response evaluation and their challenges in HCC.

      Introduction

      Hepatocellular carcinoma (HCC) is a highly prevalent disease worldwide. Most HCC patients present with advanced disease at the time of diagnosis and have poor prognosis [
      • Thomas M.B.
      • Zhu A.X.
      Hepatocellular carcinoma: the need for progress.
      ]. HCC is the third most common cause of cancer-related death in the world, causing more than 500,000 deaths every year and representing a major health challenge with significant and increasing global impact [
      • Jemal A.
      • Siegel R.
      • Xu J.
      • Ward E.
      Cancer statistics, 2010.
      ]. Although surgical resection and liver transplantation are curative therapeutic options, they are indicated only in fewer than 20% patients due to advanced disease staging, poor hepatic function and limited organ availability [
      • Alsina A.E.
      Liver transplantation for hepatocellular carcinoma.
      ]. Liver directed therapies (non-surgical locoregional treatment directed to HCC) are increasingly used as alternative options to surgery, especially in patients with unresectable disease. Although many novel targeted chemotherapy agents have been developed for clinical trials owing to significant progress in the understanding of the molecular pathogenesis of HCC over the past several years [
      • Lencioni R.
      Loco-regional treatment of hepatocellular carcinoma in the era of molecular targeted therapies.
      ,
      • Finn R.S.
      Development of molecularly targeted therapies in hepatocellular carcinoma: where do we go now?.
      ], the underlying mechanism of action of these new approaches is vastly different from the conventional chemotherapy and the expectations are unique for assessing the success of these therapies. In addition, given the high cost, toxicity as well as choices of treatment options, an early assessment of tumor response to treatment in advanced HCC is crucial to any individualize treatment paradigm.
      Traditionally, therapeutic response has been assessed by serial tumor burden measurements according to Response Evaluation Criteria in Solid Tumors (RECIST), World Health Organization (WHO) criteria, or European Association for the Study of the Liver (EASL) criteria [
      • Miller A.B.
      • Hoogstraten B.
      • Staquet M.
      • Winkler A.
      Reporting results of cancer treatment.
      ,
      • Rosen M.A.
      Use of modified RECIST criteria to improve response assessment in targeted therapies: challenges and opportunities.
      ,
      • Therasse P.
      • Arbuck S.G.
      • Eisenhauer E.A.
      • Wanders J.
      • Kaplan R.S.
      • Rubinstein L.
      • et al.
      New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
      ,
      • 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. European Association for the Study of the Liver.
      ]. Current imaging modalities, such as computed tomography (CT) and magnetic resonance (MR) imaging, provide reliable and reproducible anatomical data in order to demonstrate tumor burden changes. However, with the introduction of novel targeted agents, there has been a growing interest to monitor the therapeutic response at an early phase of treatment by measuring tumor viability and/or perfusion. Other advances in MR imaging such as diffusion weighted imaging (DWI) are also emerging as biomarkers of cellular integrity [
      • Koh D.M.
      • Collins D.J.
      Diffusion-weighted MRI in the body: applications and challenges in oncology.
      ]. In addition, positron emission tomography (PET) can be used to investigate tumor metabolism [
      • Shields A.F.
      Positron emission tomography measurement of tumor metabolism and growth: its expanding role in oncology.
      ]. With the availability of so many imaging techniques, it is challenging to determine the most appropriate image biomarker to serve as a surrogate end point of treatment response.
      Figure thumbnail fx4

      Tumor burden measurement

      Although improvement of clinical symptoms and survival are considered the ultimate proof of the effectiveness of therapy in HCC, surrogate end points, such as objective response or time to progression in phase II trials according to radiological tumor burden measurement, are increasingly used [
      • 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.
      ]. The tumor burden measurement to assess the in vivo effectiveness of an oncologic drug was initially performed using WHO criteria and subsequently RECIST was introduced and approved for clinical use in 2000 [
      • Therasse P.
      • Arbuck S.G.
      • Eisenhauer E.A.
      • Wanders J.
      • Kaplan R.S.
      • Rubinstein L.
      • et al.
      New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
      ]. RECIST was primarily conceived to provide specific guidelines for tumor burden measurement. After extensive experience and validation in several chemotherapeutic trials in solid tumors including HCC (Table 1), it was revised in 2009 with the introduction of RECIST 1.1 [
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • Schwartz L.H.
      • Sargent D.
      • Ford R.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      ,
      • Faivre S.
      • Raymond E.
      • Boucher E.
      • Douillard J.
      • Lim H.Y.
      • Kim J.S.
      • et al.
      Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study.
      ,
      • Zhu A.X.
      • Holalkere N.S.
      • Muzikansky A.
      • Horgan K.
      • Sahani D.V.
      Early antiangiogenic activity of bevacizumab evaluated by computed tomography perfusion scan in patients with advanced hepatocellular carcinoma.
      ,
      • Zhu A.X.
      • Stuart K.
      • Blaszkowsky L.S.
      • Muzikansky A.
      • Reitberg D.P.
      • Clark J.W.
      • et al.
      Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma.
      ,
      • Zhu A.X.
      • Sahani D.V.
      • Duda D.G.
      • di Tomaso E.
      • Ancukiewicz M.
      • Catalano O.A.
      • et al.
      Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.
      ,
      • Thomas M.B.
      • Chadha R.
      • Glover K.
      • Wang X.
      • Morris J.
      • Brown T.
      • et al.
      Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma.
      ,
      • Sanoff H.K.
      • Bernard S.
      • Goldberg R.M.
      • Morse M.A.
      • Garcia R.
      • Woods L.
      • et al.
      Phase II study of capecitabine, oxaliplatin, and cetuximab for advanced hepatocellular carcinoma.
      ,
      • Hsu C.H.
      • Yang T.S.
      • Hsu C.
      • Toh H.C.
      • Epstein R.J.
      • Hsiao L.T.
      • et al.
      Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma.
      ,
      • Hilgard P.
      • Hamami M.
      • Fouly A.E.
      • Scherag A.
      • Muller S.
      • Ertle J.
      • et al.
      Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.
      ,
      • Asnacios A.
      • Fartoux L.
      • Romano O.
      • Tesmoingt C.
      • Louafi S.S.
      • Mansoubakht T.
      • et al.
      Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: results of a multicenter phase 2 study.
      ,
      • Llovet J.
      • Ricci S.
      • Mazzaferro V.
      • et al.
      SHARP Investigators. Sorafenib in advanced hepatocellular carcinoma.
      ,
      • Muller C.
      • Schoniger-Hekele M.
      • Schernthaner R.
      • Renner B.
      • Peck-Radosavljevic M.
      • Brichta A.
      • et al.
      Percutaneous ethanol instillation therapy for hepatocellular carcinoma – a randomized controlled trial.
      ,
      • Molinari M.
      • Kachura J.R.
      • Dixon E.
      • Rajan D.K.
      • Hayeems E.B.
      • Asch M.R.
      • et al.
      Transarterial chemoembolisation for advanced hepatocellular carcinoma: results from a North American cancer centre.
      ].
      Table 1Response in hepatocellular carcinoma and image biomarkers.
      HCC, hepatocellular carcinoma; TACE, transcatheter arterial chemoembolization; RFA, radiofrequency ablation; PEI, percutaneous ethanol injection; CR, complete response; PR, partial response; SD, stable disease; VEGFR, vascular endothelial growth factor receptor; VEGF, vascular endothelial cell growth factor; EGFR/HER1, epidermal growth factor receptor/human epidermal growth factor receptor 1; EGFR, epidermal growth factor receptor; mRECIST, modified response evaluation criteria in solid tumors; 3D, three dimensional tumor volumetric measurement; EASL, European Association for the Study of the Liver; DWI, diffusion weighted imaging.
      RECIST was adapted for HCC and as per its guidelines, a target lesion should meet all the following criteria: the lesion can be classified as measurable lesion (i.e., the longest diameter ⩾1 cm); is suitable for repeat measurement; shows intratumoral enhancement on contrast-enhanced CT or MRI; and the lesion has not been previously treated with local–regional therapy. It is mandated that only lesions with discernible margins and those showing arterial enhancement are selected as target lesions.
      The tumor measurements as defined by RECIST are indeed quantitative, reproducible and simpler to apply and therefore meet the FDA’s expectations for using imaging as a surrogate end point. However, over time the limitations of anatomic measurements in HCC became more evident [
      • Llovet J.M.
      • Ricci S.
      • Mazzaferro V.
      • Hilgard P.
      • Gane E.
      • Blanc J.F.
      • et al.
      Sorafenib in advanced hepatocellular carcinoma.
      ,
      • Cheng A.L.
      • Kang Y.K.
      • Chen Z.
      • Tsao C.J.
      • Qin S.
      • Kim J.S.
      • et al.
      Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
      ]. Therefore expert groups convened by the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD) introduced the concept of including bidimensional measure (as described by the WHO criteria) of tumor enhancement in arterial phase of contrast-enhanced imaging studies to assess only viable target tumors [
      • 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. European Association for the Study of the Liver.
      ]. The tumor viability measurement guidelines have recently been amended to include the measurement of only the longest diameter of the enhancing tumors to formally amend RECIST to modified RECIST (mRECIST) [
      • Lencioni R.
      • Llovet J.M.
      Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.
      ].
      It has often been questioned whether the unidimensional measurements in RECIST accurately reflect total tumor burden. Moreover, for irregular and poorly defined target HCC lesions, considerable intra- and interobserver variability of unidimensional measurements has been found, which may lead to substantial differences in response assessment [
      • Monsky W.L.
      • Kim I.
      • Loh S.
      • Li C.S.
      • Greasby T.A.
      • Deutsch L.S.
      • et al.
      Semiautomated segmentation for volumetric analysis of intratumoral ethiodol uptake and subsequent tumor necrosis after chemoembolization.
      ]. With the introduction of three-dimensional (3D) software tools on modern CT and MRI equipment, the reproducibility of volumetric measurements in response evaluation for HCC was investigated [
      • Monsky W.L.
      • Kim I.
      • Loh S.
      • Li C.S.
      • Greasby T.A.
      • Deutsch L.S.
      • et al.
      Semiautomated segmentation for volumetric analysis of intratumoral ethiodol uptake and subsequent tumor necrosis after chemoembolization.
      ]. Monsky et al. confirmed that the tumor volumetry measurement is reproducible and superior to RECIST to predict long-term outcome [
      • Monsky W.L.
      • Kim I.
      • Loh S.
      • Li C.S.
      • Greasby T.A.
      • Deutsch L.S.
      • et al.
      Semiautomated segmentation for volumetric analysis of intratumoral ethiodol uptake and subsequent tumor necrosis after chemoembolization.
      ]. The consistency of volume measurement was also confirmed in phantom experiments with a reported error of 1–5% [
      • Sohaib S.A.
      • Turner B.
      • Hanson J.A.
      • Farquharson M.
      • Oliver R.T.
      • Reznek R.H.
      CT assessment of tumour response to treatment: comparison of linear, cross-sectional and volumetric measures of tumour size.
      ].
      However, the practical clinical value of tumor volume measurements remains controversial. Moreover, we do not know whether the recommended volume equivalents (73% tumor growth and 65% size diminution) converted from diameter thresholds (20% and 30%, respectively) can be effectively applied without sacrificing either reproducibility or sensitivity to tumor progression or partial response.

      HCC viability measurement

      Current targeted systemic agents and several directed therapies present particular challenges to response monitoring in clinical research. In a recent study on HCC treated with transarterial chemoembolization (TACE) or percutaneous ablation, RECIST-based tumor measurement has underestimated the extent of partial tumor response because of therapy-induced tumor necrosis [
      • Forner A.
      • Ayuso C.
      • Varela M.
      • Rimola J.
      • Hessheimer A.J.
      • de Lope C.R.
      • et al.
      Evaluation of tumor response after locoregional therapies in hepatocellular carcinoma: are response evaluation criteria in solid tumors reliable?.
      ]. As discussed earlier, EASL and AASLD have recommended bidimensional measurement of tumor viability (tumor enhancement in the arterial phase) and they subsequently adopted the modification in the RECIST criteria (mRECIST) [
      • 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. European Association for the Study of the Liver.
      ,
      • Llovet J.M.
      • Di Bisceglie A.M.
      • Bruix J.
      • Kramer B.S.
      • Lencioni R.
      • Zhu A.X.
      • et al.
      Design and endpoints of clinical trials in hepatocellular carcinoma.
      ,
      • 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.
      ]. Memon et al. reported that following chemoembolization, the EASL method was a more effective surrogate than the WHO approach in predicting clinical outcome and survival [
      • 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.
      ,
      • 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.
      ].
      The mRECIST follows the cut-off percentages for response assessment similar to those laid down in RECIST to defines four response categories as: complete response (CR) (100% decrease in amount of enhancing tissue in target lesions), partial response (PR) (>30% decrease in the sum of diameters of viable target lesions, taking as reference the baseline sum of the diameters of enhancing tissue in target lesions), progressive disease (PD) (>20% in the sum of the diameters of viable target lesions, taking as reference the smallest sum of the diameters of viable target lesions recorded since treatment started) and SD (neither PR nor PD) [
      • Lencioni R.
      • Llovet J.M.
      Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.
      ]. The mRECIST has gained increased recognition as a potential new response assessment instrument in HCC clinical trials (Fig. 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 embolization.
      ]. In the phase II study of brivanib in advanced HCC, mRECIST was able to demonstrate a higher response and disease control rate and longer time to tumor progression that the conventional WHO criteria [
      • Park J.W.
      • Finn R.S.
      • Kim J.S.
      • Karwal M.
      • Li R.K.
      • Ismail F.
      • et al.
      Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma.
      ]. In a recent retrospective study of 53 patients who received sorafenib for advanced HCC, mRECIST was found to capture a higher objective response rate compared with RECIST [
      • Edeline 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.
      ]. Additionally, patients who achieved an objective response according to mRECIST had a longer overall survival than non-responding patients [
      • Edeline 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.
      ].
      Figure thumbnail gr1
      Fig. 1Serial contrast enhanced CT images. The images were obtained (A) before, (B) at 2 months and (C) after 4 months of sorafenib treatment in a 56-year-old woman with multifocal HCC. A gradual decrease in tumor viability (increased necrosis) of the dominant mass can be observed. At 4 months, >50% of the tumor is non-viable while the tumor burden measurement by RECIST and WHO has increased.
      However, subjectivity in lesion assessment and the need of a consistent imaging protocol for all the image time points are inherent limitations with mRECIST. It is recommended that triphasic scan protocols should be performed for HCC detection and staging and the measurement is computed in the contrast enhanced phase that optimally displays the tumor margins [
      • Jiang T.
      • Kambadakone A.
      • Kulkarni N.M.
      • Zhu A.X.
      • Sahani D.V.
      Monitoring response to antiangiogenic treatment and predicting outcomes in advanced hepatocellular carcinoma using image biomarkers, CT perfusion, tumor density, and tumor size (RECIST).
      ]. Heterogeneity in the liver parenchyma and vascular shunting or altered perfusion in the vicinity of HCC are frequently encountered in patients with advanced HCC, especially in those with angioinvasive disease [
      • Quiroga S.
      • Sebastia C.
      • Pallisa E.
      • Castella E.
      • Perez-Lafuente M.
      • Alvarez-Castells A.
      Improved diagnosis of hepatic perfusion disorders: value of hepatic arterial phase imaging during helical CT.
      ]. Therefore, in advanced HCC, portal venous phase or delayed phase images can be used to clearly delineate the tumor margin for measuring tumor burden. However, arterial phase images should be reviewed to ensure the correct lesion is being measured and to identify new lesions. Moreover, in the arterial phase, it is easier to detect the size and extent of tumor thrombus in the portal venous phase [
      • Sniderman K.W.
      Hepatocellular carcinoma with portal vein tumor thrombus.
      ].
      The tumor viability measurement based on the diameter of the viable tumor may be challenging in lesions showing partial internal necrosis. In addition, tissue necrosis estimation based on the quantitative change in Hounsfield Units (HU) on CT can be flawed in those receiving antiangiogenic drugs or liver directed therapies. MRI is generally a more sensitive technique for necrosis detection due to its superior tissue contrast and the non-viable tissue appears as high signal areas on the T2 weighted images. In a comparative study, MRI has been shown to be more sensitive than MDCT for detecting viable residual tumors after TACE [
      • Kloeckner R.
      • Otto G.
      • Biesterfeld S.
      • Oberholzer K.
      • Dueber C.
      • Pitton M.B.
      MDCT versus MRI assessment of tumor response after transarterial chemoembolization for the treatment of hepatocellular carcinoma.
      ]. Due to these limitations in the image-based methods, support is increasing to consider a multiparametric analysis approach by combining morphological response with physiologic/functional changes [
      • 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.
      ,
      • 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.
      ]. Riaz et al. observed that a combination of tumor size (WHO) and necrosis (EASL) was a more sensitive surrogate end point than the individual guidelines (WHO and EASL) for assessing treatment effectiveness after loco-regional therapies [
      • 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.
      ,
      • 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.
      ].
      Similarly, the tumor density measurement in HU on contrast enhanced CT (CECT) can serve as an additional method for response assessment in solid tumors [
      • Choi H.
      • Charnsangavej C.
      • Faria S.C.
      • Macapinlac H.A.
      • Burgess M.A.
      • Patel S.R.
      • et al.
      Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria.
      ]. In gastrointestinal stromal tumors (GISTs) treated with imatinib mesylate, reduced tumor density on the portal venous phase CT has correlated with the underlying tumor necrosis or cystic or myxoid degeneration, following therapy without substantial changes in tumor size [
      • Choi H.
      • Charnsangavej C.
      • Faria S.C.
      • Macapinlac H.A.
      • Burgess M.A.
      • Patel S.R.
      • et al.
      Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria.
      ]. The tumor density (HU) is measured by drawing a region of interest circumscribing the margin of the tumor in the portal venous phase [
      • Choi H.
      • Charnsangavej C.
      • De Castro Faria S.
      • Tamm E.P.
      • Benjamin R.S.
      • Johnson M.M.
      • et al.
      CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: a quantitative analysis correlated with FDG PET findings.
      ]. A decrease in tumor HU of ⩾15% correlated better with progression free survival than the tumor burden measurement [
      • Benjamin R.S.
      • Choi H.
      • Macapinlac H.A.
      • Burgess M.A.
      • Patel S.R.
      • Chen L.L.
      • et al.
      We should desist using RECIST, at least in GIST.
      ]. The tumor density measurement was developed for GIST, treated with imatinib mesylate but it might serve the same purpose in other solid tumors being treated with targeted drugs that can induce devascularization or necrosis.
      Density measurement has been validated for portal phase images only and therefore it remains unclear whether the criteria will prove applicable to arterial phase images. In two recent studies in HCC, tumor density measurements on the portal venous phase CT images were found to be more sensitive than RECIST in detecting early and late changes following treatment with bevacizumab and sunitinib. Therefore there may be some value in using this approach in HCC [
      • Jiang T.
      • Kambadakone A.
      • Kulkarni N.M.
      • Zhu A.X.
      • Sahani D.V.
      Monitoring response to antiangiogenic treatment and predicting outcomes in advanced hepatocellular carcinoma using image biomarkers, CT perfusion, tumor density, and tumor size (RECIST).
      ,
      • Faivre 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.
      ].
      However, several unresolved questions remain with regards to the tumor density/viability assessment. First, there is no consensus on the instrument selection and scanning technique. Second, there are only limited reports in the application of this method in clinical trials and most studies were conducted retrospectively. Third, tumor necrosis or density changes may be restricted to certain classes of targeted agents, i.e., antiangiogenic agents. Triphasic CT technique is highly recommended to improve tumor conspicuity and to provide insight into tumor enhancement characteristics, for more accurate assessment of treatment effects. Therefore, it is prudent to compare unenhanced and enhanced CT images before and after treatment using a similar scanning and contrast media injection protocol. These novel tumor assessment approaches will require prospective validation in large clinical trials.

      Perfusion imaging

      It is now evident that in many cases molecular targeted agents initially suppress tumor growth by downregulating angiogenesis but without causing substantial regression in tumor measurements. Therefore, the measurement of size will not detect these changes. Indeed, imaging techniques that can detect changes in the tumor microenvironment are more suited to monitor effects of these newer therapies (Fig. 2, Fig. 3). Since the therapeutic effects on the tumor microvascular environment alter tissue perfusion, therapy induces tissue enhancement kinetic changes on dynamic contrast enhanced (DCE) imaging studies [
      • Kudo M.
      Imaging blood flow characteristics of hepatocellular carcinoma.
      ]. Technologic advancements in CT and MRI and availability of commercial software have enabled perfusion imaging with CT and MRI. The fundamental principle of perfusion imaging is based on DCE imaging techniques that compute the temporal changes in tissue enhancement after intravenous administration of contrast media. Tissue enhancement can be divided into two phases involving intra and extravascular compartment. By obtaining a series of CT or MR images in quick succession in the region of interest during these two phases and applying appropriate mathematical modeling, the tissue perfusion can be quantified. A variety of imaging protocols have been proposed for perfusion imaging and the protocol selection should be made on the availability of the scanner technology and the pertinent physiologic parameter of interest. Since their introduction over a decade ago, perfusion imaging techniques have evolved. Most scanners now come equipped with sophisticated hardware platforms coupled with powerful and user-friendly software packages for enabling image postprocessing and analysis. However, the computed perfusion parameters are dependent on the scan protocol and the mathematical model/software for image processing [
      • Miles K.A.
      • Hayball M.P.
      • Dixon A.K.
      Functional images of hepatic perfusion obtained with dynamic CT.
      ,
      • Kambadakone A.R.
      • Sahani D.V.
      Body perfusion CT: technique, clinical applications, and advances.
      ]. The commonly described perfusion CT parameters include blood flow (BF), blood volume (BV), permeability surface area (PS), time to peak enhancement (TTP) and transfer constant (Ktrans). Similarly for perfusion MR, transfer constant (Ktrans) is the most accepted quantitative surrogate end point from compartment models [
      • Morgan B.
      • Thomas A.L.
      • Drevs J.
      • Hennig J.
      • Buchert M.
      • Jivan A.
      • et al.
      Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies.
      ,
      • van Laarhoven H.W.
      • Rijpkema M.
      • Punt C.J.
      • Ruers T.J.
      • Hendriks J.C.
      • Barentsz J.O.
      • et al.
      Method for quantitation of dynamic MRI contrast agent uptake in colorectal liver metastases.
      ].
      Figure thumbnail gr2
      Fig. 2Transverse CT grey scale images after enhancement and corresponding functional perfusion CT maps for the estimated blood flow (BF) at pre- and 2 weeks post-treatment with bevacizumab antiangiogenic therapy in a 59-year-old man with HCC. There was an obvious decrease in the enhancement and perfusion of HCC.
      Figure thumbnail gr3
      Fig. 3Functional transfer constant (Ktrans) maps from MR perfusion for early response monitoring in sunitinib antiangiogenic therapy. Ktrans is one of the hemodynamic parameters in dynamic MRI for vessel permeability measurements. After 2 weeks of treatment with sunitinib, HCC showed a 96% drop of Ktrans in the 47-year-old man with positive tumor response, which presented a conspicuity of permeability change in HCC.
      The perfusion imaging techniques have been studied extensively in a variety of solid tumors and have also found applications in HCC (Table 2) [
      • Zhu A.X.
      • Holalkere N.S.
      • Muzikansky A.
      • Horgan K.
      • Sahani D.V.
      Early antiangiogenic activity of bevacizumab evaluated by computed tomography perfusion scan in patients with advanced hepatocellular carcinoma.
      ,
      • Zhu A.X.
      • Sahani D.V.
      • Duda D.G.
      • di Tomaso E.
      • Ancukiewicz M.
      • Catalano O.A.
      • et al.
      Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.
      ,
      • Chen G.
      • Ma D.Q.
      • He W.
      • Zhang B.F.
      • Zhao L.Q.
      Computed tomography perfusion in evaluating the therapeutic effect of transarterial chemoembolization for hepatocellular carcinoma.
      ]. On perfusion CT, HCC has been reported to show substantially higher perfusion (high BF, BV, and PS with low MTT) compared to normal liver tissue [
      • Zhu A.X.
      • Holalkere N.S.
      • Muzikansky A.
      • Horgan K.
      • Sahani D.V.
      Early antiangiogenic activity of bevacizumab evaluated by computed tomography perfusion scan in patients with advanced hepatocellular carcinoma.
      ]. After antiangiogenic drugs or HCC directed therapies, decrease in tumor perfusion parameters has been shown within days of initiation of treatment [
      • Zhu A.X.
      • Holalkere N.S.
      • Muzikansky A.
      • Horgan K.
      • Sahani D.V.
      Early antiangiogenic activity of bevacizumab evaluated by computed tomography perfusion scan in patients with advanced hepatocellular carcinoma.
      ,
      • Cheng A.L.
      • Kang Y.K.
      • Chen Z.
      • Tsao C.J.
      • Qin S.
      • Kim J.S.
      • et al.
      Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
      ]. In selected studies, drop in CT perfusion parameters predicted favorable therapeutic response at treatment completion (Fig. 2). Similarly, Zhu et al. have shown that HCC nodules showing more substantial reduction in tumor permeability (Ktrans) on perfusion MR soon after sunitinib, had better long-term outcome [
      • Zhu A.X.
      • Holalkere N.S.
      • Muzikansky A.
      • Horgan K.
      • Sahani D.V.
      Early antiangiogenic activity of bevacizumab evaluated by computed tomography perfusion scan in patients with advanced hepatocellular carcinoma.
      ] (Fig. 3).
      Table 2Reported results of new imaging modalities according to scheduled treatments in hepatocellular carcinoma.
      TACE, transcatheter arterial chemoembolization; RFA, radiofrequency ablation; TAIC, transcatheter arterial infusion chemotherapy; SC, systemic chemotherapy; DCE-US, dynamic contrast-enhanced ultrasonography; DWI, diffusion weighted imaging; PET, positron emission tomography; FDG, 2-fluoro-2-deoxy-d-glucose; HAP, hepatic artery perfusion; HAF, hepatic arterial fracture; HBV, hepatic blood volume; PR, partial response; BF, blood flow; BV, blood volume; PS, permeability surface; MTT, mean transit time; HPI, hepatic perfusion index; Ktrans, volume transfer constant; ADC, apparent diffusion coefficients; SUV, standardized uptake value.
      With CT, relatively high radiation dose and limited coverage of the anatomy are two major drawbacks of perfusion technique. Several efforts are being made with low dose scanning approaches [
      • Kambadakone A.R.
      • Sahani D.V.
      Body perfusion CT: technique, clinical applications, and advances.
      ]. Likewise, there is no consensus on a scanning protocol or a mathematical model specific for HCC. Since the liver has a dual arterial and portal venous perfusion, the scan protocols should ideally include dual inputs to estimate quantitative perfusion parameters for hepatic tumors. However, due to larger tumor burden in advanced HCC and frequent occurrence of angioinvasion into the portal venous system (tumor thrombosis), single arterial input is often applied as a simplifying assumption [
      • Sahani D.V.
      • Holalkere N.S.
      • Mueller P.R.
      • Zhu A.X.
      Advanced hepatocellular carcinoma: CT perfusion of liver and tumor tissue – initial experience.
      ]. In addition, the dominant arterial perfusion in advanced HCC also supports using single arterial input function but it remains unknown whether the same will hold true in small or intermediate HCC. Also a single most discriminated perfusion parameter remains elusive. For example, although MTT changes predicted stable or partial response, BF, BV or PS remains the most commonly reported variables [
      • Faivre S.
      • Raymond E.
      • Boucher E.
      • Douillard J.
      • Lim H.Y.
      • Kim J.S.
      • et al.
      Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study.
      ,
      • Lencioni R.
      • Llovet J.M.
      Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.
      ]. It has been reported that MTT varies during HCC progression, depending on pressure and degree of surrounding tumor compression [
      • Jiang H.J.
      • Lu H.B.
      • Zhang Z.R.
      • Wang Y.M.
      • Huang Q.
      • Huang Y.H.
      • et al.
      Experimental study on angiogenesis in a rabbit VX2 early liver tumour by perfusion computed tomography.
      ]. This assertion challenges the notion that MTT represents the most accurate computed perfusion marker.
      Perfusion MR, on the other hand, lacks ionizing radiation, has superior contrast resolution and provides more coverage, therefore enabling repeated examination and continuous sampling [
      • Hsu C.Y.
      • Shen Y.C.
      • Yu C.W.
      • Hsu C.
      • Hu F.C.
      • Hsu C.H.
      • et al.
      Dynamic contrast-enhanced magnetic resonance imaging biomarkers predict survival and response in hepatocellular carcinoma patients treated with sorafenib and metronomic tegafur/uracil.
      ]. Additional challenges confronting perfusion MR and CT include lack of accepted standards of image acquisition and analysis, variable reproducibility (especially with MR) and no established response evaluation criteria (Table 3).
      Table 3Advantages and disadvantages of imaging methods for monitoring response in HCC.
      3D, three dimensional tumor volumetric measurement; mRECIST, modified RECIST; HU, housefield unit for tumor density measurement; DCE, dynamic contrast-enhanced imaging; DWI, diffusion weighted imaging; MR, MR spectroscopy; PET, positron emission tomography.

      Dynamic contrast-enhanced ultrasonography (DCE-US)

      Ultrasound imaging is an inexpensive and widely available technique, and frequent serial examinations may be performed at short intervals. However, the RECIST’s criteria do not apply to ultrasound because of its subjective nature with reproducibility inferior to CT and MRI.
      At present, DCE-US has been used in various clinical trials for assessing response to treatments of HCC, mainly in liver directed therapies (Table 2) [
      • Choi D.
      • Lim H.K.
      • Lee W.J.
      • Kim S.H.
      • Kim Y.H.
      • Lim J.H.
      Early assessment of the therapeutic response to radio frequency ablation for hepatocellular carcinoma: utility of gray scale harmonic ultrasonography with a microbubble contrast agent.
      ,
      • Salvaggio G.
      • Campisi A.
      • Lo Greco V.
      • Cannella I.
      • Meloni M.F.
      • Caruso G.
      Evaluation of posttreatment response of hepatocellular carcinoma: comparison of ultrasonography with second-generation ultrasound contrast agent and multidetector CT.
      ]. It should be pointed out that DCE-US has the potential to play an important role to monitor response to antiangiogenic treatment. For example, DCE-US can be used to quantify dynamic changes in tumor vascularity as early as 3 days after bevacizumab administration in patients with HCC [
      • 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.
      ]. DCE-US processing also allows real time assessment of blood flow in arterioles as small as 15 μm [
      • Ferrara K.W.
      • Merritt C.R.
      • Burns P.N.
      • Foster F.S.
      • Mattrey R.F.
      • Wickline S.A.
      Evaluation of tumor angiogenesis with US: imaging, Doppler, and contrast agents.
      ]. Moreover, DCE-US can assess hemodynamic imaging biomarkers in HCC, such as blood volume and flow, time to peak intensity, area under the curve, slope coefficient of wash-in, by detecting the signal originating from low concentration microbubble contrast agents.
      However, DCE-US studies present some inherent limitations. In a minority of cases, DCE-US will yield unacceptable images of the entire liver, especially in large or uncooperative patients. It can investigate only one lesion (or potentially only one plane of a lesion) and has in the past been unable to provide the full volumetric coverage routinely achieved with CT and MR imaging. Multiple boluses of US contrast are often necessary to visualize multiple HCC. In the minority of cases, DCE-US will yield unacceptable images of the entire HCC, especially in large or uncooperative patients. With the advancements of 3D/4D acquisition with the potential of volumetric assessment of contrast enhancement and targeted contrast agents, DCE-US is potentially more applied to the field of early treatment assessment [
      • Kodama T.
      • Tomita N.
      • Yagishita Y.
      • Horie S.
      • Funamoto K.
      • Hayase T.
      • et al.
      Volumetric and angiogenic evaluation of antitumor effects with acoustic liposome and high-frequency ultrasound.
      ] (Table 3).

      MR diffusion weighted imaging (DWI)

      DWI uses phase-defocusing and phase-refocusing gradients that allow evaluation of the rate of microscopic water diffusion. Apparent diffusion coefficient (ADC) measurement can be quantified by acquiring images with a different gradient duration and amplitude (b-values). Following treatment, the biophysiologic changes in HCC can alter its diffusion properties as revealed on DWI-MRI.
      Monitoring effectiveness of treatment is often challenging, especially following liver directed therapy. Evidence is now emerging in support of DWI-MRI as a biomarker for assessing early treatment effects of liver directed and targeted therapies (Fig. 4) (Table 2) [
      • Goshima S.
      • Kanematsu M.
      • Kondo H.
      • Yokoyama R.
      • Tsuge Y.
      • Shiratori Y.
      • et al.
      Evaluating local hepatocellular carcinoma recurrence post-transcatheter arterial chemoembolization: is diffusion-weighted MRI reliable as an indicator?.
      ,
      • Kamel I.R.
      • Bluemke D.A.
      • Eng J.
      • Liapi E.
      • Messersmith W.
      • Reyes D.K.
      • et al.
      The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma.
      ,
      • Rhee T.K.
      • Naik N.K.
      • Deng J.
      • Atassi B.
      • Mulcahy M.F.
      • Kulik L.M.
      • et al.
      Tumor response after yttrium-90 radioembolization for hepatocellular carcinoma: comparison of diffusion-weighted functional MR imaging with anatomic MR imaging.
      ,
      • Schraml C.
      • Schwenzer N.F.
      • Martirosian P.
      • Bitzer M.
      • Lauer U.
      • Claussen C.D.
      • et al.
      Diffusion-weighted MRI of advanced hepatocellular carcinoma during sorafenib treatment: initial results.
      ,
      • Yuan Z.
      • Ye X.D.
      • Dong S.
      • Xu L.C.
      • Xu X.Y.
      • Liu S.Y.
      • et al.
      Role of magnetic resonance diffusion-weighted imaging in evaluating response after chemoembolization of hepatocellular carcinoma.
      ,
      • Kubota K.
      • Yamanishi T.
      • Itoh S.
      • Murata Y.
      • Miyatake K.
      • Yasunami H.
      • et al.
      Role of diffusion-weighted imaging in evaluating therapeutic efficacy after transcatheter arterial chemoembolization for hepatocellular carcinoma.
      ]. An increase in tumor ADC values after TACE correlated with favorable response and tumor necrosis whereas the recurrence or viable tumor presented a low ADC [
      • Kubota K.
      • Yamanishi T.
      • Itoh S.
      • Murata Y.
      • Miyatake K.
      • Yasunami H.
      • et al.
      Role of diffusion-weighted imaging in evaluating therapeutic efficacy after transcatheter arterial chemoembolization for hepatocellular carcinoma.
      ]. Similarly, after yttrium-90 radioembolization, ADC values on DWI at 1 month preceded anatomic tumor size change at 3 months [
      • Rhee T.K.
      • Naik N.K.
      • Deng J.
      • Atassi B.
      • Mulcahy M.F.
      • Kulik L.M.
      • et al.
      Tumor response after yttrium-90 radioembolization for hepatocellular carcinoma: comparison of diffusion-weighted functional MR imaging with anatomic MR imaging.
      ].
      Figure thumbnail gr4
      Fig. 4Transverse arterial phase CE-MRI image and a corresponding ADC map from DW-MRI performed before and 4 weeks after TACE are shown. There is complete devascularization in the HCC (arrow) evident as reduced tumor enhancement on the follow-up CE-MRI (A and B). Similarly, there is an obvious increase in the tumor ADC (arrow) from baseline, confirming the treatment effectiveness (C and D).
      The changes in HCC following treatment are believed to be due to a complex process but the loss of cell membrane integrity and necrosis are the two most likely explanations. The intact cell membranes in viable tumor limit the mobility of water molecules that is reflected as a low ADC, however, the necrosis enhances membrane permeability which allows for increased motion of water molecules and results in a rise in tumor ADC. Moreover, with the use of recommended multiple b-values; it is possible to differentiate true diffusion from perfusion-related diffusion on DWI-MR [
      • Kudo M.
      Imaging blood flow characteristics of hepatocellular carcinoma.
      ].
      DWI-MR is gaining acceptance in clinical practice as the image acquisition is relatively easier and can be performed on scanners from all the equipment manufacturers. The technique is reasonably reproducible, the ADC values can be easily quantified without use of any advanced software and contrast material administration is not required for DWI-MRI. However, this technology is evolving with no accepted protocols and quantified standards. Despite these concerns, the National Cancer Institute (NCI) has recognized the potential of this technique and has proposed consensus guidelines for DWI to meet minimum standards for its use as an effective image biomarker [
      • Padhani A.R.
      • Liu G.
      • Koh D.M.
      • Chenevert T.L.
      • Thoeny H.C.
      • Takahara T.
      • et al.
      Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations.
      ] (Table 3).

      Positron emission tomography (PET)

      PET is a quantitative imaging modality and 18F-fluorodeoxyglucose (18F-FDG), a glucose analog, is the most commonly used PET tracer in clinical practice. Typically, malignant tumors show increased FDG tumor uptake due to the increased number of glucose transport molecules and the increased activity of hexokinase isoenzymes. However, 18F-FDG accumulations in HCC depend on the underlying tumor biology and FDG-6-phosphatase activity. Overall, the FDG-PET sensitivity in detecting HCC is lower (50–70%) than other liver tumors and the tumor FDG uptake is influenced by cellular differentiation with the lowest performance in well-differentiated HCC [
      • Talbot J.N.
      • Fartoux L.
      • Balogova S.
      • Nataf V.
      • Kerrou K.
      • Gutman F.
      • et al.
      Detection of hepatocellular carcinoma with PET/CT: a prospective comparison of 18F-fluorocholine and 18F-FDG in patients with cirrhosis or chronic liver disease.
      ]. Given the limitations of FDG in HCC, other tracers with different molecules including choline-based tracers are being investigated [
      • Kuang Y.
      • Salem N.
      • Tian H.
      • Kolthammer J.A.
      • Corn D.J.
      • Wu C.
      • et al.
      Imaging lipid synthesis in hepatocellular carcinoma with [methyl-11c]choline: correlation with in vivo metabolic studies.
      ]. Unlike FDG, the 18-fluoro choline tracer has higher sensitivity for differentiated HCC while its performance is lower for more aggressive, poorly differentiated tumors [
      • Yamamoto Y.
      • Nishiyama Y.
      • Kameyama R.
      • Okano K.
      • Kashiwagi H.
      • Deguchi A.
      • et al.
      Detection of hepatocellular carcinoma using 11C-choline PET: comparison with 18F-FDG PET.
      ].
      Standardized uptake value (SUV) is the accepted semi-quantitative biomarker of tracer uptake in PET. There is growing evidence that in PET-positive HCC, early metabolic response may reflect molecular changes and predict long-term outcome after completion of therapy (Table 2) [
      • Torizuka T.
      • Tamaki N.
      • Inokuma T.
      • Magata Y.
      • Yonekura Y.
      • Tanaka A.
      • et al.
      Value of fluorine-18-FDG-PET to monitor hepatocellular carcinoma after interventional therapy.
      ,
      • Paudyal B.
      • Oriuchi N.
      • Paudyal P.
      • Tsushima Y.
      • Iida Y.
      • Higuchi T.
      • et al.
      Early diagnosis of recurrent hepatocellular carcinoma with 18F-FDG PET after radiofrequency ablation therapy.
      ,
      • Higashi T.
      • Hatano E.
      • Ikai I.
      • Nishii R.
      • Nakamoto Y.
      • Ishizu K.
      • et al.
      FDG PET as a prognostic predictor in the early post-therapeutic evaluation for unresectable hepatocellular carcinoma.
      ].
      Nevertheless, 18F-FDG is not a tumor-specific tracer and the reproducibility of SUV is influenced by the time of image acquisition from tracer injection. Therefore, the European Organization for Research and Treatment of Cancer (EORTC) has defined response assessment criteria for PET [
      • Young H.
      • Baum R.
      • Cremerius U.
      • Herholz K.
      • Hoekstra O.
      • Lammertsma A.A.
      • et al.
      Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group.
      ]. EORTC has also suggested that the initial region of interest for SUV measurements should contain only viable tumor and be used consistently on the subsequent scans. To overcome some of the limitations of the EORTC criteria, Wahl et al. had even proposed modified criteria with more stringent requirements for tumor response assessment with PET [
      • Wahl R.L.
      • Jacene H.
      • Kasamon Y.
      • Lodge M.A.
      From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors.
      ]. It is clear that further efforts are needed in HCC to validate whether SUV is a sensitive biomarker of response and correlates with long-term clinical outcome. High costs remain also a limiting factor for a widespread use of PET/PET-CT in the management of HCC (Table 3).

      Conclusions

      In the new era of HCC practice, there is growing recognition that for the treatment to be optimal, it should be tailored to suit the needs of each individual patient. This requires early and accurate assessment of tumor response to therapy. An ideal imaging biomarker should be able to detect an immediate response to any therapeutic regimen in one examination. Since liver directed therapies and newer targeted drugs induce biologic changes much earlier than size-based alterations in tumor burden, reliance on tumor viability for response assessment has increased. In addition, there has been a growing research interest to validate physiologic image biomarkers such as perfusion and diffusion imaging to monitor the early treatment effects of novel therapies in HCC. Although promising, some of these newer imaging biomarkers have not gone through all the required steps of standardization and validation. However, with the rapidly changing landscape to treat HCC, these newer imaging tools hold promise to optimize the assessment of early treatment response, and will likely play an increasingly important role in the management of HCC in the future.

      Conflicts of interest

      Tao Jiang, M.D. received partial financial support from the National Natural Science Foundation of China (No. 81101044), Shanghai Rising-Star Program, Special program of military medicine of second military medical university. The other authors declared no conflicts of interest.

      References

        • Thomas M.B.
        • Zhu A.X.
        Hepatocellular carcinoma: the need for progress.
        J Clin Oncol. 2005; 23: 2892-2899
        • Jemal A.
        • Siegel R.
        • Xu J.
        • Ward E.
        Cancer statistics, 2010.
        CA Cancer J Clin. 2010; 60: 277-300
        • Alsina A.E.
        Liver transplantation for hepatocellular carcinoma.
        Cancer Control. 2010; 17: 83-86
        • Lencioni R.
        Loco-regional treatment of hepatocellular carcinoma in the era of molecular targeted therapies.
        Oncology. 2010; 78: 107-112
        • Finn R.S.
        Development of molecularly targeted therapies in hepatocellular carcinoma: where do we go now?.
        Clin Cancer Res. 2010; 16: 390-397
        • Miller A.B.
        • Hoogstraten B.
        • Staquet M.
        • Winkler A.
        Reporting results of cancer treatment.
        Cancer. 1981; 47: 207-214
        • Rosen M.A.
        Use of modified RECIST criteria to improve response assessment in targeted therapies: challenges and opportunities.
        Cancer Biol Ther. 2010; 9: 20-22
        • Therasse P.
        • Arbuck S.G.
        • Eisenhauer E.A.
        • Wanders J.
        • Kaplan R.S.
        • Rubinstein L.
        • et al.
        New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
        J Natl Cancer Inst. 2000; 92: 205-216
        • 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. European Association for the Study of the Liver.
        J Hepatol. 2001; 35: 421-430
        • Koh D.M.
        • Collins D.J.
        Diffusion-weighted MRI in the body: applications and challenges in oncology.
        AJR Am J Roentgenol. 2007; 188: 1622-1635
        • Shields A.F.
        Positron emission tomography measurement of tumor metabolism and growth: its expanding role in oncology.
        Mol Imaging Biol. 2006; 8: 141-150
        • 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 (535, e521–522): 526-535
        • Eisenhauer E.A.
        • Therasse P.
        • Bogaerts J.
        • Schwartz L.H.
        • Sargent D.
        • Ford R.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247
        • Faivre S.
        • Raymond E.
        • Boucher E.
        • Douillard J.
        • Lim H.Y.
        • Kim J.S.
        • et al.
        Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study.
        Lancet Oncol. 2009; 10: 794-800
        • Zhu A.X.
        • Holalkere N.S.
        • Muzikansky A.
        • Horgan K.
        • Sahani D.V.
        Early antiangiogenic activity of bevacizumab evaluated by computed tomography perfusion scan in patients with advanced hepatocellular carcinoma.
        Oncologist. 2008; 13: 120-125
        • Zhu A.X.
        • Stuart K.
        • Blaszkowsky L.S.
        • Muzikansky A.
        • Reitberg D.P.
        • Clark J.W.
        • et al.
        Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma.
        Cancer. 2007; 110: 581-589
        • Zhu A.X.
        • Sahani D.V.
        • Duda D.G.
        • di Tomaso E.
        • Ancukiewicz M.
        • Catalano O.A.
        • et al.
        Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.
        J Clin Oncol. 2009; 27: 3027-3035
        • Thomas M.B.
        • Chadha R.
        • Glover K.
        • Wang X.
        • Morris J.
        • Brown T.
        • et al.
        Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma.
        Cancer. 2007; 110: 1059-1067
        • Sanoff H.K.
        • Bernard S.
        • Goldberg R.M.
        • Morse M.A.
        • Garcia R.
        • Woods L.
        • et al.
        Phase II study of capecitabine, oxaliplatin, and cetuximab for advanced hepatocellular carcinoma.
        Gastrointest Cancer Res. 2011; 4: 78-83
        • Hsu C.H.
        • Yang T.S.
        • Hsu C.
        • Toh H.C.
        • Epstein R.J.
        • Hsiao L.T.
        • et al.
        Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma.
        Br J Cancer. 2010; 102: 981-986
        • Hilgard P.
        • Hamami M.
        • Fouly A.E.
        • Scherag A.
        • Muller S.
        • Ertle J.
        • et al.
        Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.
        Hepatology. 2010; 52: 1741-1749
        • Asnacios A.
        • Fartoux L.
        • Romano O.
        • Tesmoingt C.
        • Louafi S.S.
        • Mansoubakht T.
        • et al.
        Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: results of a multicenter phase 2 study.
        Cancer. 2008; 112: 2733-2739
        • Llovet J.
        • Ricci S.
        • Mazzaferro V.
        • et al.
        SHARP Investigators. Sorafenib in advanced hepatocellular carcinoma.
        N Engl J Med. 2008; 359: 378-390
        • Muller C.
        • Schoniger-Hekele M.
        • Schernthaner R.
        • Renner B.
        • Peck-Radosavljevic M.
        • Brichta A.
        • et al.
        Percutaneous ethanol instillation therapy for hepatocellular carcinoma – a randomized controlled trial.
        Wien Klin Wochenschr. 2008; 120: 608-618
        • Molinari M.
        • Kachura J.R.
        • Dixon E.
        • Rajan D.K.
        • Hayeems E.B.
        • Asch M.R.
        • et al.
        Transarterial chemoembolisation for advanced hepatocellular carcinoma: results from a North American cancer centre.
        Clin Oncol (R Coll Radiol). 2006; 18: 684-692
        • Llovet J.M.
        • Ricci S.
        • Mazzaferro V.
        • Hilgard P.
        • Gane E.
        • Blanc J.F.
        • et al.
        Sorafenib in advanced hepatocellular carcinoma.
        N Engl J Med. 2008; 359: 378-390
        • Cheng A.L.
        • Kang Y.K.
        • Chen Z.
        • Tsao C.J.
        • Qin S.
        • Kim J.S.
        • et al.
        Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
        Lancet Oncol. 2009; 10: 25-34
        • Lencioni R.
        • Llovet J.M.
        Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.
        Semin Liver Dis. 2010; 30: 52-60
        • Monsky W.L.
        • Kim I.
        • Loh S.
        • Li C.S.
        • Greasby T.A.
        • Deutsch L.S.
        • et al.
        Semiautomated segmentation for volumetric analysis of intratumoral ethiodol uptake and subsequent tumor necrosis after chemoembolization.
        AJR Am J Roentgenol. 2010; 195: 1220-1230
        • Sohaib S.A.
        • Turner B.
        • Hanson J.A.
        • Farquharson M.
        • Oliver R.T.
        • Reznek R.H.
        CT assessment of tumour response to treatment: comparison of linear, cross-sectional and volumetric measures of tumour size.
        Br J Radiol. 2000; 73: 1178-1184
        • Forner A.
        • Ayuso C.
        • Varela M.
        • Rimola J.
        • Hessheimer A.J.
        • de Lope C.R.
        • et al.
        Evaluation of tumor response after locoregional therapies in hepatocellular carcinoma: are response evaluation criteria in solid tumors reliable?.
        Cancer. 2009; 115: 616-623
        • Llovet J.M.
        • Di Bisceglie 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: 698-711
        • 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: 695-704
        • 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 embolization.
        J Hepatol. 2011; 55: 1309-1316
        • Park J.W.
        • Finn R.S.
        • Kim J.S.
        • Karwal M.
        • Li R.K.
        • Ismail F.
        • et al.
        Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma.
        Clin Cancer Res. 2011; 17: 1973-1983
        • Edeline 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: 147-156
        • Jiang T.
        • Kambadakone A.
        • Kulkarni N.M.
        • Zhu A.X.
        • Sahani D.V.
        Monitoring response to antiangiogenic treatment and predicting outcomes in advanced hepatocellular carcinoma using image biomarkers, CT perfusion, tumor density, and tumor size (RECIST).
        Invest Radiol. 2012; 47: 11-17
        • Quiroga S.
        • Sebastia C.
        • Pallisa E.
        • Castella E.
        • Perez-Lafuente M.
        • Alvarez-Castells A.
        Improved diagnosis of hepatic perfusion disorders: value of hepatic arterial phase imaging during helical CT.
        Radiographics. 2001; 21 (questionnaire 288–294): 65-81
        • Sniderman K.W.
        Hepatocellular carcinoma with portal vein tumor thrombus.
        Radiology. 1998; 207: 552-553
        • Kloeckner R.
        • Otto G.
        • Biesterfeld S.
        • Oberholzer K.
        • Dueber C.
        • Pitton M.B.
        MDCT versus MRI assessment of tumor response after transarterial chemoembolization for the treatment of hepatocellular carcinoma.
        Cardiovasc Intervent Radiol. 2010; 33: 532-540
        • Choi H.
        • Charnsangavej C.
        • Faria S.C.
        • Macapinlac H.A.
        • Burgess M.A.
        • Patel S.R.
        • et al.
        Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria.
        J Clin Oncol. 2007; 25: 1753-1759
        • Choi H.
        • Charnsangavej C.
        • De Castro Faria S.
        • Tamm E.P.
        • Benjamin R.S.
        • Johnson M.M.
        • et al.
        CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: a quantitative analysis correlated with FDG PET findings.
        AJR Am J Roentgenol. 2004; 183: 1619-1628
        • Benjamin R.S.
        • Choi H.
        • Macapinlac H.A.
        • Burgess M.A.
        • Patel S.R.
        • Chen L.L.
        • et al.
        We should desist using RECIST, at least in GIST.
        J Clin Oncol. 2007; 25: 1760-1764
        • Faivre 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: 4504-4512
        • Kudo M.
        Imaging blood flow characteristics of hepatocellular carcinoma.
        Oncology. 2002; 62: 48-56
        • Miles K.A.
        • Hayball M.P.
        • Dixon A.K.
        Functional images of hepatic perfusion obtained with dynamic CT.
        Radiology. 1993; 188: 405-411
        • Kambadakone A.R.
        • Sahani D.V.
        Body perfusion CT: technique, clinical applications, and advances.
        Radiol Clin North Am. 2009; 47: 161-178
        • Morgan B.
        • Thomas A.L.
        • Drevs J.
        • Hennig J.
        • Buchert M.
        • Jivan A.
        • et al.
        Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies.
        J Clin Oncol. 2003; 21: 3955-3964
        • van Laarhoven H.W.
        • Rijpkema M.
        • Punt C.J.
        • Ruers T.J.
        • Hendriks J.C.
        • Barentsz J.O.
        • et al.
        Method for quantitation of dynamic MRI contrast agent uptake in colorectal liver metastases.
        J Magn Reson Imaging. 2003; 18: 315-320
        • Chen G.
        • Ma D.Q.
        • He W.
        • Zhang B.F.
        • Zhao L.Q.
        Computed tomography perfusion in evaluating the therapeutic effect of transarterial chemoembolization for hepatocellular carcinoma.
        World J Gastroenterol. 2008; 14: 5738-5743
        • Sahani D.V.
        • Holalkere N.S.
        • Mueller P.R.
        • Zhu A.X.
        Advanced hepatocellular carcinoma: CT perfusion of liver and tumor tissue – initial experience.
        Radiology. 2007; 243: 736-743
        • Jiang H.J.
        • Lu H.B.
        • Zhang Z.R.
        • Wang Y.M.
        • Huang Q.
        • Huang Y.H.
        • et al.
        Experimental study on angiogenesis in a rabbit VX2 early liver tumour by perfusion computed tomography.
        J Int Med Res. 2010; 38: 929-939
        • Hsu C.Y.
        • Shen Y.C.
        • Yu C.W.
        • Hsu C.
        • Hu F.C.
        • Hsu C.H.
        • et al.
        Dynamic contrast-enhanced magnetic resonance imaging biomarkers predict survival and response in hepatocellular carcinoma patients treated with sorafenib and metronomic tegafur/uracil.
        J Hepatol. 2011; 55: 858-865
        • Choi D.
        • Lim H.K.
        • Lee W.J.
        • Kim S.H.
        • Kim Y.H.
        • Lim J.H.
        Early assessment of the therapeutic response to radio frequency ablation for hepatocellular carcinoma: utility of gray scale harmonic ultrasonography with a microbubble contrast agent.
        J Ultrasound Med. 2003; 22: 1163-1172
        • Salvaggio G.
        • Campisi A.
        • Lo Greco V.
        • Cannella I.
        • Meloni M.F.
        • Caruso G.
        Evaluation of posttreatment response of hepatocellular carcinoma: comparison of ultrasonography with second-generation ultrasound contrast agent and multidetector CT.
        Abdom Imaging. 2010; 35: 447-453
        • 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: 291-300
        • Ferrara K.W.
        • Merritt C.R.
        • Burns P.N.
        • Foster F.S.
        • Mattrey R.F.
        • Wickline S.A.
        Evaluation of tumor angiogenesis with US: imaging, Doppler, and contrast agents.
        Acad Radiol. 2000; 7: 824-839
        • Kodama T.
        • Tomita N.
        • Yagishita Y.
        • Horie S.
        • Funamoto K.
        • Hayase T.
        • et al.
        Volumetric and angiogenic evaluation of antitumor effects with acoustic liposome and high-frequency ultrasound.
        Cancer Res. 2011; 71: 6957-6964
        • Goshima S.
        • Kanematsu M.
        • Kondo H.
        • Yokoyama R.
        • Tsuge Y.
        • Shiratori Y.
        • et al.
        Evaluating local hepatocellular carcinoma recurrence post-transcatheter arterial chemoembolization: is diffusion-weighted MRI reliable as an indicator?.
        J Magn Reson Imaging. 2008; 27: 834-839
        • Kamel I.R.
        • Bluemke D.A.
        • Eng J.
        • Liapi E.
        • Messersmith W.
        • Reyes D.K.
        • et al.
        The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma.
        J Vasc Interv Radiol. 2006; 17: 505-512
        • Rhee T.K.
        • Naik N.K.
        • Deng J.
        • Atassi B.
        • Mulcahy M.F.
        • Kulik L.M.
        • et al.
        Tumor response after yttrium-90 radioembolization for hepatocellular carcinoma: comparison of diffusion-weighted functional MR imaging with anatomic MR imaging.
        J Vasc Interv Radiol. 2008; 19: 1180-1186
        • Schraml C.
        • Schwenzer N.F.
        • Martirosian P.
        • Bitzer M.
        • Lauer U.
        • Claussen C.D.
        • et al.
        Diffusion-weighted MRI of advanced hepatocellular carcinoma during sorafenib treatment: initial results.
        AJR Am J Roentgenol. 2009; 193: W301-W307
        • Yuan Z.
        • Ye X.D.
        • Dong S.
        • Xu L.C.
        • Xu X.Y.
        • Liu S.Y.
        • et al.
        Role of magnetic resonance diffusion-weighted imaging in evaluating response after chemoembolization of hepatocellular carcinoma.
        Eur J Radiol. 2010; 75: e9-e14
        • Kubota K.
        • Yamanishi T.
        • Itoh S.
        • Murata Y.
        • Miyatake K.
        • Yasunami H.
        • et al.
        Role of diffusion-weighted imaging in evaluating therapeutic efficacy after transcatheter arterial chemoembolization for hepatocellular carcinoma.
        Oncol Rep. 2010; 24: 727-732
        • Padhani A.R.
        • Liu G.
        • Koh D.M.
        • Chenevert T.L.
        • Thoeny H.C.
        • Takahara T.
        • et al.
        Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations.
        Neoplasia. 2009; 11: 102-125
        • Talbot J.N.
        • Fartoux L.
        • Balogova S.
        • Nataf V.
        • Kerrou K.
        • Gutman F.
        • et al.
        Detection of hepatocellular carcinoma with PET/CT: a prospective comparison of 18F-fluorocholine and 18F-FDG in patients with cirrhosis or chronic liver disease.
        J Nucl Med. 2010; 51: 1699-1706
        • Kuang Y.
        • Salem N.
        • Tian H.
        • Kolthammer J.A.
        • Corn D.J.
        • Wu C.
        • et al.
        Imaging lipid synthesis in hepatocellular carcinoma with [methyl-11c]choline: correlation with in vivo metabolic studies.
        J Nucl Med. 2011; 52: 98-106
        • Yamamoto Y.
        • Nishiyama Y.
        • Kameyama R.
        • Okano K.
        • Kashiwagi H.
        • Deguchi A.
        • et al.
        Detection of hepatocellular carcinoma using 11C-choline PET: comparison with 18F-FDG PET.
        J Nucl Med. 2008; 49: 1245-1248
        • Torizuka T.
        • Tamaki N.
        • Inokuma T.
        • Magata Y.
        • Yonekura Y.
        • Tanaka A.
        • et al.
        Value of fluorine-18-FDG-PET to monitor hepatocellular carcinoma after interventional therapy.
        J Nucl Med. 1994; 35: 1965-1969
        • Paudyal B.
        • Oriuchi N.
        • Paudyal P.
        • Tsushima Y.
        • Iida Y.
        • Higuchi T.
        • et al.
        Early diagnosis of recurrent hepatocellular carcinoma with 18F-FDG PET after radiofrequency ablation therapy.
        Oncol Rep. 2007; 18: 1469-1473
        • Higashi T.
        • Hatano E.
        • Ikai I.
        • Nishii R.
        • Nakamoto Y.
        • Ishizu K.
        • et al.
        FDG PET as a prognostic predictor in the early post-therapeutic evaluation for unresectable hepatocellular carcinoma.
        Eur J Nucl Med Mol Imaging. 2010; 37: 468-482
        • Young H.
        • Baum R.
        • Cremerius U.
        • Herholz K.
        • Hoekstra O.
        • Lammertsma A.A.
        • et al.
        Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group.
        Eur J Cancer. 1999; 35: 1773-1782
        • Wahl R.L.
        • Jacene H.
        • Kasamon Y.
        • Lodge M.A.
        From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors.
        J Nucl Med. 2009; 50: 122S-150S