European Radiology

, Volume 25, Issue 2, pp 380–390 | Cite as

Volumetric assessment of tumour response using functional MR imaging in patients with hepatocellular carcinoma treated with a combination of doxorubicin-eluting beads and sorafenib

  • Celia Pamela Corona-Villalobos
  • Vivek Gowdra Halappa
  • Jean-Francois H. Geschwind
  • Susanne Bonekamp
  • Diane Reyes
  • David Cosgrove
  • Timothy M Pawlik
  • Ihab R KamelEmail author



To prospectively assess treatment response using volumetric functional magnetic resonance imaging (MRI) metrics in patients with hepatocellular carcinoma (HCC) treated with the combination of doxorubicin-eluting bead–transarterial chemoembolization (DEB TACE) and sorafenib.


A single center study enrolled 41 patients treated with systemic sorafenib, 400 mg twice a day, combined with DEB TACE. All patients had a pre-treatment and 3–4 week post-treatment MRI. Anatomic response criteria (RECIST, mRECIST and EASL) and volumetric functional response (ADC, enhancement) were assessed. Statistical analyses included paired Student’s t-test, Kaplan-Meier curves, Cohen’s Kappa, and multivariate cox proportional hazard model.


Median tumour size by RECIST remained unchanged post-treatment (8.3 ± 4.1 cm vs. 8.1 ± 4.3 cm, p = 0.44). There was no significant survival difference for early response by RECIST (p = 0.93). EASL and mRECIST could not be analyzed in 12 patients. Volumetric ADC increased significantly (1.32 × 10−3 mm2/sec to 1.60 × 10−3 mm2/sec, p < 0.001), and volumetric enhancement decreased significantly in HAP (38.2 % to 17.6 %, p < 0.001) and PVP (76.6 % to 41.2 %, p < 0.005). Patients who demonstrated ≥ 65 % decrease PVP enhancement had significantly improved overall survival compared to non-responders (p < 0.005).


Volumetric PVP enhancement was demonstrated to be significantly correlated with survival in the combination of DEB TACE and sorafenib for patients with HCC, enabling precise stratification of responders and non-responders.

Key Points

PVP enhancement is significantly correlated with survival in responders (p < 0.005).

There was no significant survival difference for early response using RECIST (p = 0.93).

mRECIST or EASL could not assess tumour response in 29 % of patients.


Volumetric functional MRI DEB-TACE Sorafenib Diffusion-weighted MRI Treatment response 



Hepatocellular carcinoma


Intra-arterial therapies


Doxorubicin-eluting bead–transarterial chemoembolization


Response evaluation criteria in solid tumours


Modified RECIST


European association for study of liver disease


Apparent diffusion coefficient


Diffusion weighted imaging


Magnetic resonance imaging


Contrast enhanced MRI


Hepatic arterial phase


Portal venous phase


Complete response


Partial response


Stable disease


Progressive disease


Kaplan Meier


Alpha fetoprotein


Barcelona clinic liver cancer


Eastern cooperative oncology group



The scientific guarantor of this publication is Dr. Ihab R. Kamel. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. The authors state that this work has not received any funding. No complex statistical methods were necessary for this paper. Institutional Review Board approval was obtained. Written informed consent was obtained from all subjects (patients) in this study. Approval from the institutional animal care committee was not required because we did not study animal subjects. No study subjects or cohorts have been previously reported. This is a prospective study, a randomized controlled trial performed at one institution.


  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2001) Estimating the world cancer burden: Globocan 2000. Int J Cancer 94:153–156PubMedCrossRefGoogle Scholar
  2. 2.
    Befeler AS, Di Bisceglie AM (2002) Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 122:1609–1619PubMedCrossRefGoogle Scholar
  3. 3.
    Bruix J, Llovet JM (2002) Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 35:519–524PubMedCrossRefGoogle Scholar
  4. 4.
    Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390PubMedCrossRefGoogle Scholar
  5. 5.
    Camma C, Schepis F, Orlando A et al (2002) Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 224:47–54PubMedCrossRefGoogle Scholar
  6. 6.
    Llovet JM, Bruix J (2003) Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37:429–442PubMedCrossRefGoogle Scholar
  7. 7.
    Reyes DK, Vossen JA, Kamel IR et al (2009) Single-center phase II trial of transarterial chemoembolization with drug-eluting beads for patients with unresectable hepatocellular carcinoma: initial experience in the United States. Cancer J 15:526–532PubMedCrossRefGoogle Scholar
  8. 8.
    Wilhelm SM, Carter C, Tang L et al (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109PubMedCrossRefGoogle Scholar
  9. 9.
    Wang B, Xu H, Gao ZQ, Ning HF, Sun YQ, Cao GW (2008) Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol 49:523–529PubMedCrossRefGoogle Scholar
  10. 10.
    Li X, Feng GS, Zheng CS, Zhuo CK, Liu X (2004) Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 10:2878–2882PubMedGoogle Scholar
  11. 11.
    Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF (2011) Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma. J Clin Oncol 29:3960–3967PubMedCrossRefGoogle Scholar
  12. 12.
    Lencioni R, de Baere T, Burrel M et al (2012) Transcatheter treatment of hepatocellular carcinoma with doxorubicin-loaded DC bead (DEBDOX): technical recommendations. Cardiovasc Intervent Radiol 35:980–985PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Kamel IR, Liapi E, Reyes DK, Zahurak M, Bluemke DA, Geschwind JF (2009) Unresectable hepatocellular carcinoma: serial early vascular and cellular changes after transarterial chemoembolization as detected with MR imaging. Radiology 250:466–473PubMedCrossRefGoogle Scholar
  14. 14.
    Kamel IR, Bluemke DA, Eng J et al (2006) The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma. J Vasc Interv Radiol 17:505–512PubMedCrossRefGoogle Scholar
  15. 15.
    Lencioni R, Llovet JM (2010) Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 30:52–60PubMedCrossRefGoogle Scholar
  16. 16.
    Halappa VG, Bonekamp S, Corona-Villalobos CP et al (2012) Intrahepatic cholangiocarcinoma treated with local-regional therapy: quantitative volumetric apparent diffusion coefficient maps for assessment of tumor response. Radiology 264:285–294PubMedCrossRefGoogle Scholar
  17. 17.
    Gowdra Halappa V, Corona-Villalobos CP, Bonekamp S et al (2013) Neuroendocrine liver metastasis treated by using intraarterial therapy: Volumetric functional imaging biomarkers of early tumor response and survival. Radiology 266:502–513PubMedCrossRefGoogle Scholar
  18. 18.
    Bonekamp S, Jolepalem P, Lazo M, Gulsun MA, Kiraly AP, Kamel IR (2011) Hepatocellular carcinoma: response to TACE assessed with semiautomated volumetric and functional analysis of diffusion-weighted and contrast-enhanced MR imaging data. Radiology 260:752–761PubMedCrossRefGoogle Scholar
  19. 19.
    Bonekamp S, Halappa VG, Geschwind JF et al (2013) Unresectable hepatocellular carcinoma: MR imaging after intraarterial therapy. part II. response stratification using volumetric functional criteria after intraarterial therapy. Radiology. doi: 10.1148/radiol.13121637 Google Scholar
  20. 20.
    Galizia MS, Tore HG, Chalian H, McCarthy R, Salem R, Yaghmai V (2012) MDCT necrosis quantification in the assessment of hepatocellular carcinoma response to yttrium 90 radioembolization therapy: comparison of two-dimensional and volumetric techniques. Acad Radiol 19:48–54PubMedCrossRefGoogle Scholar
  21. 21.
    Liapi E, Geschwind JF (2011) Transcatheter arterial chemoembolization for liver cancer: is it time to distinguish conventional from drug-eluting chemoembolization? Cardiovasc Intervent Radiol 34:37–49PubMedCrossRefGoogle Scholar
  22. 22.
    Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247PubMedCrossRefGoogle Scholar
  23. 23.
    Bruix J, Sherman M, Llovet JM et al (2001) Clinical management of hepatocellular carcinoma. Conclusions of the barcelona-2000 EASL conference. European association for the study of the liver. J Hepatol 35:421–430PubMedCrossRefGoogle Scholar
  24. 24.
    Grady L (2006) Random walks for image segmentation. IEEE Trans Pattern Anal Mach Intell 28:1768–1783PubMedCrossRefGoogle Scholar
  25. 25.
    Bonekamp S, Li Z, Geschwind JF et al (2013) Unresectable hepatocellular carcinoma: MR imaging after intraarterial therapy. Part I. identification and validation of volumetric functional response criteria. Radiology. doi: 10.1148/radiol.13122307 Google Scholar
  26. 26.
    Lewin M, Fartoux L, Vignaud A, Arrive L, Menu Y, Rosmorduc O (2011) The diffusion-weighted imaging perfusion fraction f is a potential marker of sorafenib treatment in advanced hepatocellular carcinoma: a pilot study. Eur Radiol 21:281–290PubMedCrossRefGoogle Scholar
  27. 27.
    Schraml C, Schwenzer NF, Martirosian P et al (2009) Diffusion-weighted MRI of advanced hepatocellular carcinoma during sorafenib treatment: initial results. AJR Am J Roentgenol 193:W301-7. doi: 10.2214/AJR.08.2289
  28. 28.
    Takayasu K, Arii S, Matsuo N et al (2000) Comparison of CT findings with resected specimens after chemoembolization with iodized oil for hepatocellular carcinoma. AJR Am J Roentgenol 175:699–704PubMedCrossRefGoogle Scholar
  29. 29.
    Li Z, Bonekamp S, Halappa VG et al (2012) Islet cell liver metastases: assessment of volumetric early response with functional MR imaging after transarterial chemoembolization. Radiology 264:97–109PubMedCrossRefGoogle Scholar
  30. 30.
    European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer (2012) EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 56:908–943Google Scholar
  31. 31.
    Georgiades C, Geschwind JF, Harrison N et al (2012) Lack of response after initial chemoembolization for hepatocellular carcinoma: does it predict failure of subsequent treatment? Radiology 265:115–123PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Bonekamp D, Bonekamp S, Halappa VG et al (2013) Interobserver agreement of semi-automated and manual measurements of functional MRI metrics of treatment response in hepatocellular carcinoma. Eur J Radiol. doi: 10.1016/j.ejrad.2013.11.016 PubMedGoogle Scholar
  33. 33.
    Riaz A, Miller FH, Kulik LM et al (2010) Imaging response in the primary index lesion and clinical outcomes following transarterial locoregional therapy for hepatocellular carcinoma. JAMA 303:1062–1069PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© European Society of Radiology 2014

Authors and Affiliations

  • Celia Pamela Corona-Villalobos
    • 1
  • Vivek Gowdra Halappa
    • 2
  • Jean-Francois H. Geschwind
    • 3
  • Susanne Bonekamp
    • 2
  • Diane Reyes
    • 3
  • David Cosgrove
    • 4
  • Timothy M Pawlik
    • 5
  • Ihab R Kamel
    • 2
    Email author
  1. 1.The Russell H. Morgan Department of Radiology and Radiological SciencesJohns Hopkins University, School of MedicineBaltimoreUSA
  2. 2.The Russell H. Morgan Department of Radiology and Radiological Sciences, School of MedicineJohns Hopkins UniversityBaltimoreUSA
  3. 3.Department of Vascular and Interventional Radiology, School of MedicineJohns Hopkins UniversityBaltimoreUSA
  4. 4.Department of OncologyJohns Hopkins University, School of MedicineBaltimoreUSA
  5. 5.Department of Surgical OncologyJohns Hopkins University, School of MedicineBaltimoreUSA

Personalised recommendations