Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality and has an increasing incidence worldwide. Locoregional therapies, defined as imaging-guided liver tumour-directed procedures, play a leading part in the management of 50–60% of HCCs. Radiofrequency is the mainstay for local ablation at early stages and transarterial chemoembolization (TACE) remains the standard treatment for intermediate-stage HCC. Other local ablative techniques (microwave ablation, cryoablation and irreversible electroporation) or locoregional therapies (for example, radioembolization and sterotactic body radiation therapy) have been explored, but have not yet modified the standard therapies established decades ago. This understanding is currently changing, and several drugs have been approved for the management of advanced HCC. Molecular therapies dominate the adjuvant trials after curative therapies and combination strategies with TACE for intermediate stages. The rationale for these combinations is sound. Local therapies induce antigen and proinflammatory cytokine release, whereas VEGF inhibitors and tyrosine kinase inhibitors boost immunity and prime tumours for checkpoint inhibition. In this Review, we analyse data from randomized and uncontrolled studies reported with ablative and locoregional techniques and examine the expected effects of combinations with systemic treatments. We also discuss trial design and benchmarks to be used as a reference for future investigations in the dawn of a promising new era for HCC treatment.

Key points

  • Locoregional treatments for hepatocellular carcinoma (HCC) are aimed at eliminating or reducing tumoural viability, delaying progression and ultimately extending overall survival; options include local ablative techniques and intra-arterial techniques.

  • Radiofrequency ablation is considered the standard treatment option among local ablative techniques for very early stage tumours (<2 cm) and for tumours at early stages not suitable for surgical therapies.

  • Transarterial chemoembolization is established as the standard of care for intermediate-stage lesions (multinodular liver-only disease in asymptomatic patients with compensated liver function) leading to median survivals of 25–30 months.

  • The role of radioembolization and stereotactic body radiotherapy is still to be defined, and further trials are required to delineate a patient subset deriving benefit from these treatments.

  • No systemic therapy tyrosine kinase inhibitor has been able to improve survival when tested in combination with locoregional treatment but there is rationale for combination therapies with immunotherapy in HCC.

  • Single-agent and combination therapies are being investigated in randomized controlled trials both in an adjuvant setting and combined with intra-arterial therapies, and results are expected to change HCC management within the next 5 years.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Percutaneous local ablative techniques for the treatment of HCC.
Fig. 2: Devices for intra-arterial therapy.
Fig. 3: Outcomes of randomized controlled trials assessing TACE.
Fig. 4: Rationale for combining locoregional therapies with immune therapies.
Fig. 5: Rationale for combining TKIs with immune therapies.
Fig. 6: Rationale for combining VEGF inhibitors with immune therapies.

References

  1. 1.

    Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 2, 16018 (2016).

    PubMed  Google Scholar 

  2. 2.

    Kulik, L. & El-Serag, H. B. Epidemiology and management of hepatocellular carcinoma. Gastroenterology 156, 477–491.e471 (2019).

    PubMed  Google Scholar 

  3. 3.

    Galle, P. R. et al. EASL clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 69, 182–236 (2018).

    Google Scholar 

  4. 4.

    Marrero, J. A. et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 68, 723–750 (2018).

    Google Scholar 

  5. 5.

    Llovet, J. M., Montal, R., Sia, D. & Finn, R. S. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 15, 599–616 (2018).

    PubMed  Google Scholar 

  6. 6.

    Greten, T. F., Lai, C. W., Li, G. & Staveley-O’Carroll, K. F. Targeted and immune-based therapies for hepatocellular carcinoma. Gastroenterology 156, 510–524 (2019).

    PubMed  Google Scholar 

  7. 7.

    Nault, J.-C., Cheng, A.-L., Sangro, B. & Llovet, J. M. Milestones in the pathogenesis and management of primary liver cancer. J. Hepatol. 72, 209–214 (2020).

    PubMed  Google Scholar 

  8. 8.

    Park, J. W. et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study. Liver Int. 35, 2155–2166 (2015).

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Livraghi, T. et al. Hepatocellular carcinoma: radio-frequency ablation of medium and large lesions. Radiology 214, 761–768 (2000).

    CAS  PubMed  Google Scholar 

  10. 10.

    Nault, J. C., Sutter, O., Nahon, P., Ganne-Carrie, N. & Seror, O. Percutaneous treatment of hepatocellular carcinoma: state of the art and innovations. J. Hepatol. 68, 783–797 (2018).

    PubMed  Google Scholar 

  11. 11.

    Llovet, J. M. et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359, 1734–1739 (2002).

    PubMed  Google Scholar 

  12. 12.

    Llovet, J. M. & Bruix, J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37, 429–442 (2003).

    CAS  PubMed  Google Scholar 

  13. 13.

    Lencioni, R., de Baere, T., Soulen, M. C., Rilling, W. S. & Geschwind, J. F. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: a systematic review of efficacy and safety data. Hepatology 64, 106–116 (2016).

    CAS  PubMed  Google Scholar 

  14. 14.

    Han, G. et al. Prediction of survival among patients receiving transarterial chemoembolization for hepatocellular carcinoma: a response-based approach. Hepatology 72, 198–212 (2019).

    Google Scholar 

  15. 15.

    Palmer, D. H., Malagari, K. & Kulik, L. M. Role of locoregional therapies in the wake of systemic therapy. J. Hepatol. 72, 277–287 (2020).

    CAS  PubMed  Google Scholar 

  16. 16.

    Salem, R., Mazzaferro, V. & Sangro, B. Yttrium 90 radioembolization for the treatment of hepatocellular carcinoma: biological lessons, current challenges, and clinical perspectives. Hepatology 58, 2188–2197 (2013).

    CAS  PubMed  Google Scholar 

  17. 17.

    Llovet, J. M. et al. Trial design and endpoints in hepatocellular carcinoma: AASLD consensus conference. Hepatology https://doi.org/10.1002/hep.31327 (2020).

    Article  PubMed  Google Scholar 

  18. 18.

    Raoul, J. L. et al. Updated use of TACE for hepatocellular carcinoma treatment: how and when to use it based on clinical evidence. Cancer Treat. Rev. 72, 28–36 (2019).

    CAS  PubMed  Google Scholar 

  19. 19.

    Kadalayil, L. et al. A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer. Ann. Oncol. 24, 2565–2570 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Attallah, A. M. et al. HCC-ART score, a simple, highly sensitive and specific test for early diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Br. J. Cancer 109, 1657–1665 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Meyer, T. et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol. Hepatol. 2, 565–575 (2017).

    PubMed  Google Scholar 

  22. 22.

    Lencioni, R. et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J. Hepatol. 64, 1090–1098 (2016).

    CAS  PubMed  Google Scholar 

  23. 23.

    Kudo, M. et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial. Hepatology 60, 1697–1707 (2014).

    CAS  PubMed  Google Scholar 

  24. 24.

    Vogel, A. et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29, iv238–iv255 (2018).

    CAS  PubMed  Google Scholar 

  25. 25.

    Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).

    CAS  PubMed  Google Scholar 

  26. 26.

    Finn, R. S. et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J. Clin. Oncol. 38, 2960–2970 (2020).

    PubMed  Google Scholar 

  27. 27.

    Yau, T. et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 6, e204564 (2020).

    PubMed Central  Google Scholar 

  28. 28.

    Ohri, N. et al. Radiotherapy for hepatocellular carcinoma: new indications and directions for future study. J. Natl Cancer Inst. 108, djw133 (2016).

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Vibert, E., Schwartz, M. & Olthoff, K. M. Advances in resection and transplantation for hepatocellular carcinoma. J. Hepatol. 72, 262–276 (2020).

    CAS  PubMed  Google Scholar 

  30. 30.

    Lencioni, R. A. et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228, 235–240 (2003).

    PubMed  Google Scholar 

  31. 31.

    Lin, S.-M., Lin, C.-J., Lin, C.-C., Hsu, C.-W. & Chen, Y.-C. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or =4 cm. Gastroenterology 127, 1714–1723 (2004).

    PubMed  Google Scholar 

  32. 32.

    Lin, S. M., Lin, C. J., Lin, C. C., Hsu, C. W. & Chen, Y. C. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut 54, 1151–1156 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Shiina, S. et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 129, 122–130 (2005).

    PubMed  Google Scholar 

  34. 34.

    Cho, Y. K., Kim, J. K., Kim, M. Y., Rhim, H. & Han, J. K. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology 49, 453–459 (2009).

    PubMed  Google Scholar 

  35. 35.

    Germani, G. et al. Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocelullar carcinoma: a meta-analysis. J. Hepatol. 52, 380–388 (2010).

    CAS  PubMed  Google Scholar 

  36. 36.

    Orlando, A., Leandro, G., Olivo, M., Andriulli, A. & Cottone, M. Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials. Am. J. Gastroenterol. 104, 514–524 (2009).

    PubMed  Google Scholar 

  37. 37.

    Omata, M. et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol. Int. 11, 317–370 (2017).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Breen, D. J. & Lencioni, R. Image-guided ablation of primary liver and renal tumours. Nat. Rev. Clin. Oncol. 12, 175–186 (2015).

    PubMed  Google Scholar 

  39. 39.

    Livraghi, T., Lazzaroni, S., Meloni, F. & Solbiati, L. Risk of tumour seeding after percutaneous radiofrequency ablation for hepatocellular carcinoma. Br. J. Surg. 92, 856–858 (2005).

    CAS  PubMed  Google Scholar 

  40. 40.

    Sasaki, A. et al. Microsatellite distribution and indication for locoregional therapy in small hepatocellular carcinoma. Cancer 103, 299–306 (2005).

    PubMed  Google Scholar 

  41. 41.

    Liao, M. et al. Radiofrequency ablation using a 10-mm target margin for small hepatocellular carcinoma in patients with liver cirrhosis: a prospective randomized trial. J. Surg. Oncol. 115, 971–979 (2017).

    PubMed  Google Scholar 

  42. 42.

    Minami, Y. & Kudo, M. Radiofrequency ablation of hepatocellular carcinoma: a literature review. Int. J. Hepatol. 2011, 104685 (2011).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Poggi, G., Tosoratti, N., Montagna, B. & Picchi, C. Microwave ablation of hepatocellular carcinoma. World J. Hepatol. 7, 2578–2589 (2015).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Lam, V. W. et al. Risk factors and prognostic factors of local recurrence after radiofrequency ablation of hepatocellular carcinoma. J. Am. Coll. Surg. 207, 20–29 (2008).

    PubMed  Google Scholar 

  45. 45.

    Lee, D. H. et al. Radiofrequency ablation of hepatocellular carcinoma as first-line treatment: long-term results and prognostic factors in 162 patients with cirrhosis. Radiology 270, 900–909 (2014).

    PubMed  Google Scholar 

  46. 46.

    Lencioni, R. et al. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology 234, 961–967 (2005).

    PubMed  Google Scholar 

  47. 47.

    N’Kontchou, G. et al. Radiofrequency ablation of hepatocellular carcinoma: long-term results and prognostic factors in 235 Western patients with cirrhosis. Hepatology 50, 1475–1483 (2009).

    PubMed  Google Scholar 

  48. 48.

    Sala, M. et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology 40, 1352–1360 (2004).

    PubMed  Google Scholar 

  49. 49.

    Livraghi, T. et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice? Hepatology 47, 82–89 (2008).

    Google Scholar 

  50. 50.

    Bale, R. et al. Stereotactic radiofrequency ablation of hepatocellular carcinoma: a histopathological study in explanted livers. Hepatology 70, 840–850 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Rossi, S. et al. Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular carcinomas: a long-term cohort study. Hepatology 53, 136–147 (2011).

    PubMed  Google Scholar 

  52. 52.

    Brunello, F. et al. Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: a randomized controlled trial. Scand. J. Gastroenterol. 43, 727–735 (2008).

    PubMed  Google Scholar 

  53. 53.

    Shiina, S. et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am. J. Gastroenterol. 107, 569–577; quiz 578 (2012).

    CAS  PubMed  Google Scholar 

  54. 54.

    Casadei Gardini, A. et al. Radiofrequency ablation of hepatocellular carcinoma: a meta-analysis of overall survival and recurrence-free survival. Onco Targets Ther. 11, 6555–6567 (2018).

    PubMed  Google Scholar 

  55. 55.

    Doyle, A. et al. Outcomes of radiofrequency ablation as first-line therapy for hepatocellular carcinoma less than 3cm in potentially transplantable patients. J. Hepatol. 70, 866–873 (2019).

    PubMed  Google Scholar 

  56. 56.

    Hermida, M. et al. Multimodal percutaneous thermal ablation of small hepatocellular carcinoma: predictive factors of recurrence and survival in western patients. Cancers 12, 313 (2020).

    CAS  PubMed Central  Google Scholar 

  57. 57.

    Chen, M. S. et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann. Surg. 243, 321–328 (2006).

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Feng, K. et al. A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J. Hepatol. 57, 794–802 (2012).

    PubMed  Google Scholar 

  59. 59.

    Huang, J. et al. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann. Surg. 252, 903–912 (2010).

    PubMed  Google Scholar 

  60. 60.

    Ng, K. K. C. et al. Randomized clinical trial of hepatic resection versus radiofrequency ablation for early-stage hepatocellular carcinoma. Br. J. Surg. 104, 1775–1784 (2017).

    CAS  PubMed  Google Scholar 

  61. 61.

    Izumi, N. et al. A multicenter randomized controlled trial to evaluate the efficacy of surgery vs. radiofrequency ablation for small hepatocellular carcinoma (SURF trial). J. Clin. Oncol. 37, 4002–4002 (2019).

    Google Scholar 

  62. 62.

    Yu, J. et al. Percutaneous cooled-probe microwave versus radiofrequency ablation in early-stage hepatocellular carcinoma: a phase III randomised controlled trial. Gut 66, 1172 (2017).

    PubMed  Google Scholar 

  63. 63.

    Giorgio, A. et al. Percutaneous radiofrequency ablation of hepatocellular carcinoma compared to percutaneous ethanol injection in treatment of cirrhotic patients: an Italian randomized controlled trial. Anticancer. Res. 31, 2291–2295 (2011).

    CAS  PubMed  Google Scholar 

  64. 64.

    Wang, C. et al. Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma. Hepatology 61, 1579–1590 (2015).

    PubMed  Google Scholar 

  65. 65.

    Peng, Z. W. et al. Radiofrequency ablation with or without transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a prospective randomized trial. J. Clin. Oncol. 31, 426–432 (2013).

    PubMed  Google Scholar 

  66. 66.

    Chen, K. et al. Increased survival in hepatocellular carcinoma with iodine-125 implantation plus radiofrequency ablation: a prospective randomized controlled trial. J. Hepatol. 61, 1304–1311 (2014).

    PubMed  Google Scholar 

  67. 67.

    Tak, W. Y. et al. Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions. Clin. Cancer Res. 24, 73–83 (2018).

    CAS  PubMed  Google Scholar 

  68. 68.

    Xia, Y. et al. Long-term effects of repeat hepatectomy vs percutaneous radiofrequency ablation among patients with recurrent hepatocellular carcinoma: a randomized clinical trial. JAMA Oncol. 6, 255–263 (2019).

    PubMed Central  Google Scholar 

  69. 69.

    Majumdar, A. et al. Management of people with early- or very early-stage hepatocellular carcinoma: an attempted network meta-analysis. Cochrane Database Syst. Rev. 3, Cd011650 (2017).

    PubMed  Google Scholar 

  70. 70.

    Cho, Y. K., Kim, J. K., Kim, W. T. & Chung, J. W. Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma: a Markov model analysis. Hepatology 51, 1284–1290 (2010).

    PubMed  Google Scholar 

  71. 71.

    Cucchetti, A. et al. Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma. J. Hepatol. 59, 300–307 (2013).

    PubMed  Google Scholar 

  72. 72.

    Poon, R. T. et al. High serum vascular endothelial growth factor levels predict poor prognosis after radiofrequency ablation of hepatocellular carcinoma: importance of tumor biomarker in ablative therapies. Ann. Surg. Oncol. 14, 1835–1845 (2007).

    PubMed  Google Scholar 

  73. 73.

    Liu, Y. et al. Effects of various interventions on the occurrence of macrovascular invasion of hepatocellular carcinoma after the baseline serum γ-glutamyltransferase stratification. Onco Targets Ther. 12, 1671–1679 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Tsuchiya, K. et al. Expression of keratin 19 is related to high recurrence of hepatocellular carcinoma after radiofrequency ablation. Oncology 80, 278–288 (2011).

    CAS  PubMed  Google Scholar 

  75. 75.

    Hoshida, Y. et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N. Engl. J. Med. 359, 1995–2004 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Kang, T. W. et al. Long-term therapeutic outcomes of radiofrequency ablation for subcapsular versus nonsubcapsular hepatocellular carcinoma: a propensity score matched study. Radiology 280, 300–312 (2016).

    PubMed  Google Scholar 

  77. 77.

    Hakime, A. et al. Clinical evaluation of spatial accuracy of a fusion imaging technique combining previously acquired computed tomography and real-time ultrasound for imaging of liver metastases. Cardiovas. Intervent. Radiol. 34, 338–344 (2011).

    Google Scholar 

  78. 78.

    Harari, C. M. et al. Microwave ablation: comparison of simultaneous and sequential activation of multiple antennas in liver model systems. Radiology 278, 95–103 (2016).

    PubMed  Google Scholar 

  79. 79.

    Vietti Violi, N. et al. Efficacy of microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma in patients with chronic liver disease: a randomised controlled phase 2 trial. Lancet Gastroenterol. Hepatol. 3, 317–325 (2018).

    PubMed  Google Scholar 

  80. 80.

    Shibata, T. et al. Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave coagulation therapy. Radiology 223, 331–337 (2002).

    PubMed  Google Scholar 

  81. 81.

    Abdelaziz, A. et al. Efficacy and survival analysis of percutaneous radiofrequency versus microwave ablation for hepatocellular carcinoma: an Egyptian multidisciplinary clinic experience. Surg. Endosc. 28, 3429–3434 (2014).

    PubMed  Google Scholar 

  82. 82.

    Xu, Y. et al. Microwave ablation is as effective as radiofrequency ablation for very-early-stage hepatocellular carcinoma. Chin. J. Cancer 36, 14 (2017).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Tan, W., Deng, Q., Lin, S., Wang, Y. & Xu, G. Comparison of microwave ablation and radiofrequency ablation for hepatocellular carcinoma: a systematic review and meta-analysis. Int. J. Hyperthermia 36, 264–272 (2019).

    PubMed  Google Scholar 

  84. 84.

    Glassberg, M. B. et al. Microwave ablation compared with radiofrequency ablation for treatment of hepatocellular carcinoma and liver metastases: a systematic review and meta-analysis. Onco Targets Ther. 12, 6407–6438 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Facciorusso, A., Di Maso, M. & Muscatiello, N. Microwave ablation versus radiofrequency ablation for the treatment of hepatocellular carcinoma: a systematic review and meta-analysis. Int. J. Hyperthermia 32, 339–344 (2016).

    CAS  PubMed  Google Scholar 

  86. 86.

    Loriaud, A. et al. Hepatocellular carcinoma abutting large vessels: comparison of four percutaneous ablation systems. Int. J. Hyperthermia 34, 1171–1178 (2018).

    PubMed  Google Scholar 

  87. 87.

    Lencioni, R., de Baere, T., Martin, R. C., Nutting, C. W. & Narayanan, G. Image-guided ablation of malignant liver tumors: recommendations for clinical validation of novel thermal and non-thermal technologies - a western perspective. Liver Cancer 4, 208–214 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Xu, J. et al. Radiofrequency ablation vs. cryoablation for localized hepatocellular carcinoma: a propensity-matched population study. Anticancer. Res. 38, 6381–6386 (2018).

    PubMed  Google Scholar 

  89. 89.

    Kim, R. et al. Percutaneous cryoablation for perivascular hepatocellular carcinoma: therapeutic efficacy and vascular complications. Eur. Radiol. 29, 654–662 (2019).

    PubMed  Google Scholar 

  90. 90.

    Cheng, R. G., Bhattacharya, R., Yeh, M. M. & Padia, S. A. Irreversible electroporation can effectively ablate hepatocellular carcinoma to complete pathologic necrosis. J. Vasc. Interv. Radiol. 26, 1184–1188 (2015).

    PubMed  Google Scholar 

  91. 91.

    Sutter, O. et al. Safety and efficacy of irreversible electroporation for the treatment of hepatocellular carcinoma not amenable to thermal ablation techniques: a retrospective single-center case series. Radiology 284, 877–886 (2017).

    PubMed  Google Scholar 

  92. 92.

    Di Costanzo, G. G. et al. Radiofrequency ablation versus laser ablation for the treatment of small hepatocellular carcinoma in cirrhosis: a randomized trial. J. Gastroenterol. Hepatol. 30, 559–565 (2015).

    PubMed  Google Scholar 

  93. 93.

    Bruix, J. et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 16, 1344–1354 (2015).

    CAS  PubMed  Google Scholar 

  94. 94.

    Kong, G. et al. Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release. Cancer Res. 60, 6950–6957 (2000).

    CAS  PubMed  Google Scholar 

  95. 95.

    Celik, H. et al. Radiofrequency ablation duration per tumor volume may correlate with overall survival in solitary hepatocellular carcinoma patients treated with radiofrequency ablation plus lyso-thermosensitive liposomal doxorubicin. J. Vasc. Interv. Radiol. 30, 1908–1914 (2019).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Lawrenceville, N. J., Celsion corporation receives recommendation from independent data monitoring committee to consider stopping the phase III optima study. News Release, 13 July 2020, https://bit.ly/2ZomTD5.

  97. 97.

    Duffy, A. G. et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J. Hepatol. 66, 545–551 (2017).

    CAS  PubMed  Google Scholar 

  98. 98.

    Sugimoto, K. et al. Irreversible electroporation versus radiofrequency ablation: comparison of systemic immune responses in patients with hepatocellular carcinoma. J. Vasc. Intervent. Radiol. 30, 845–853.e846 (2019).

    Google Scholar 

  99. 99.

    Partridge, B. R. et al. High-frequency irreversible electroporation for treatment of primary liver cancer: a proof-of-principle study in canine hepatocellular carcinoma. J. Vasc. Intervent. Radiol. 31, 482–491.e484 (2020).

    Google Scholar 

  100. 100.

    Greaney, S. K. et al. Intratumoral plasmid IL12 electroporation therapy in patients with advanced melanoma induces systemic and intratumoral T-cell responses. Cancer Immunol. Res. 8, 246 (2020).

    CAS  PubMed  Google Scholar 

  101. 101.

    Bertot, L. C., Sato, M., Tateishi, R., Yoshida, H. & Koike, K. Mortality and complication rates of percutaneous ablative techniques for the treatment of liver tumors: a systematic review. Eur. Radiol. 21, 2584–2596 (2011).

    PubMed  Google Scholar 

  102. 102.

    Kasugai, H., Osaki, Y., Oka, H., Kudo, M. & Seki, T. Severe complications of radiofrequency ablation therapy for hepatocellular carcinoma: an analysis of 3,891 ablations in 2,614 patients. Oncology 72 (Suppl. 1), 72–75 (2007).

    PubMed  Google Scholar 

  103. 103.

    Giorgio, A. et al. Percutaneous radiofrequency ablation of hepatocellular carcinoma in cirrhosis: analysis of complications in a single centre over 20 years. Br. J. Radiol. 90, 20160804 (2017).

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Park, M. J. et al. A comparison of US-guided percutaneous radiofrequency ablation of medium-sized hepatocellular carcinoma with a cluster electrode or a single electrode with a multiple overlapping ablation technique. J. Vasc. Intervent. Radiol. 22, 771–779 (2011).

    CAS  Google Scholar 

  105. 105.

    Woo, S. et al. Small- and medium-sized hepatocellular carcinomas: monopolar radiofrequency ablation with a multiple-electrode switching system — mid-term results. Radiology 268, 589–600 (2013).

    PubMed  Google Scholar 

  106. 106.

    Seror, O. et al. Hepatocellular carcinoma within milan criteria: no-touch multibipolar radiofrequency ablation for treatment-long-term results. Radiology 280, 611–621 (2016).

    PubMed  Google Scholar 

  107. 107.

    de Baère, T. et al. Adverse events during radiofrequency treatment of 582 hepatic tumors. Am. J. Roentgenol. 181, 695–700 (2003).

    Google Scholar 

  108. 108.

    Nakagomi, R. et al. Drastically reduced neoplastic seeding related to radiofrequency ablation for hepatocellular carcinoma. Am. J. Gastroenterol. 109, 774–776 (2014).

    PubMed  Google Scholar 

  109. 109.

    Yu, J. et al. Needle track seeding after percutaneous microwave ablation of malignant liver tumors under ultrasound guidance: analysis of 14-year experience with 1462 patients at a single center. Eur. J. Radiol. 81, 2495–2499 (2012).

    PubMed  Google Scholar 

  110. 110.

    Hakime, A., Tselikas, L., Otmezguine, Y., Deschamps, F. & de Baere, T. Artificial ascites for pain relief during microwave ablation of subcapsular liver tumors. Cardiovas. Interven. Radiol. 38, 1557–1562 (2015).

    Google Scholar 

  111. 111.

    Lee, S. et al. Percutaneous radiofrequency ablation of hepatocellular carcinomas: factors related to intraprocedural and postprocedural pain. Am. J. Roentgenol. 192, 1064–1070 (2009).

    Google Scholar 

  112. 112.

    Lo, C. M. et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35, 1164–1171 (2002).

    CAS  PubMed  Google Scholar 

  113. 113.

    Llovet, J. M., Bru, C. & Bruix, J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin. Liver Dis. 19, 329–338 (1999).

    CAS  PubMed  Google Scholar 

  114. 114.

    de Baere, T. et al. Treatment of liver tumors with lipiodol TACE: technical recommendations from experts opinion. Cardiovas. Interv. Radiol. 39, 334–343 (2016).

    Google Scholar 

  115. 115.

    Okusaka, T. et al. Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial. J. Hepatol. 51, 1030–1036 (2009).

    CAS  PubMed  Google Scholar 

  116. 116.

    Kudo, M. et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur. J. Cancer 47, 2117–2127 (2011).

    CAS  PubMed  Google Scholar 

  117. 117.

    Yu, S. C. et al. Unresectable hepatocellular carcinoma: randomized controlled trial of transarterial ethanol ablation versus transcatheter arterial chemoembolization. Radiology 270, 607–620 (2014).

    PubMed  Google Scholar 

  118. 118.

    Golfieri, R. et al. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br. J. Cancer 111, 255–264 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Kudo, M. et al. Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Lancet Gastroenterol. Hepatol. 3, 37–46 (2018).

    PubMed  Google Scholar 

  120. 120.

    Ikeda, M. et al. Transarterial chemoembolization with miriplatin vs. epirubicin for unresectable hepatocellular carcinoma: a phase III randomized trial. J. Gastroenterol. 53, 281–290 (2018).

    CAS  PubMed  Google Scholar 

  121. 121.

    Kudo, M. et al. Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial. Gut 69, 1492–1501 (2019).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Park, J. W. et al. Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: the phase III STAH trial. J. Hepatol. 70, 684–691 (2019).

    CAS  PubMed  Google Scholar 

  123. 123.

    Vilgrain, V. et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 18, 1624–1636 (2017).

    CAS  PubMed  Google Scholar 

  124. 124.

    Chow, P. K. H. et al. SIRveNIB: selective internal radiation therapy versus sorafenib in asia-pacific patients with hepatocellular carcinoma. J. Clin. Oncol. 36, 1913–1921 (2018).

    CAS  PubMed  Google Scholar 

  125. 125.

    Ricke, J. et al. Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J. Hepatol. 71, 1164–1174 (2019).

    CAS  PubMed  Google Scholar 

  126. 126.

    Kudo, M. et al. Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial. Lancet Gastroenterol. Hepatol. 3, 424–432 (2018).

    PubMed  Google Scholar 

  127. 127.

    Salem, R. et al. Y90 radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 151, 1155–1163.e1152 (2016).

    PubMed  PubMed Central  Google Scholar 

  128. 128.

    Lammer, J. et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovas. Interv. Radiol. 33, 41–52 (2010).

    Google Scholar 

  129. 129.

    Meyer, T. et al. A randomised phase II/III trial of 3-weekly cisplatin-based sequential transarterial chemoembolisation vs embolisation alone for hepatocellular carcinoma. Br. J. Cancer 108, 1252–1259 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Lencioni, R. et al. Transcatheter treatment of hepatocellular carcinoma with doxorubicin-loaded DC Bead (DEBDOX): technical recommendations. Cardiov. Interv. Radiol. 35, 980–985 (2012).

    Google Scholar 

  131. 131.

    Bolondi, L. et al. Heterogeneity of patients with intermediate (BCLC B) hepatocellular carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin. Liver Dis. 32, 348–359 (2012).

    CAS  PubMed  Google Scholar 

  132. 132.

    Kudo, M. et al. Subclassification of BCLC B stage hepatocellular carcinoma and treatment strategies: proposal of modified Bolondi’s subclassification (Kinki criteria). Dig. Dis. 33, 751–758 (2015).

    PubMed  Google Scholar 

  133. 133.

    Forner, A., Gilabert, M., Bruix, J. & Raoul, J. L. Treatment of intermediate-stage hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 11, 525–535 (2014).

    CAS  PubMed  Google Scholar 

  134. 134.

    Yin, L. et al. Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan criteria: a RCT. J. Hepatol. 61, 82–88 (2014).

    PubMed  Google Scholar 

  135. 135.

    Becker, G. et al. Combined TACE and PEI for palliative treatment of unresectable hepatocellular carcinoma. World J. Gastroenterol. 11, 6104–6109 (2005).

    PubMed  PubMed Central  Google Scholar 

  136. 136.

    Pitton, M. B. et al. Randomized comparison of selective internal radiotherapy (SIRT) versus drug-eluting bead transarterial chemoembolization (DEB-TACE) for the treatment of hepatocellular carcinoma. Cardiovas. Interv. Radiol. 38, 352–360 (2015).

    Google Scholar 

  137. 137.

    Johnson, P. J. et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J. Clin. Oncol. 33, 550–558 (2015).

    PubMed  Google Scholar 

  138. 138.

    Edeline, J. et al. A multicentre comparison between child pugh and albumin-bilirubin scores in patients treated with sorafenib for hepatocellular carcinoma. Liver Int. 36, 1821–1828 (2016).

    CAS  PubMed  Google Scholar 

  139. 139.

    Waked, I. et al. Transarterial chemo-embolisation of hepatocellular carcinoma: impact of liver function and vascular invasion. Br. J. Cancer 116, 448–454 (2017).

    PubMed  PubMed Central  Google Scholar 

  140. 140.

    Wang, Q. et al. Development of a prognostic score for recommended TACE candidates with hepatocellular carcinoma: a multicentre observational study. J. Hepatol. 70, 893–903 (2019).

    PubMed  Google Scholar 

  141. 141.

    Mazzaferro, V. et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet. Oncol. 10, 35–43 (2009).

    PubMed  Google Scholar 

  142. 142.

    Lencioni, R. & Llovet, J. M. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin. Liver Dis. 30, 52–60 (2010).

    CAS  PubMed  Google Scholar 

  143. 143.

    Llovet, J. M. & Lencioni, R. mRECIST for HCC: performance and novel refinements. J. Hepatol. 72, 288–306 (2020).

    PubMed  Google Scholar 

  144. 144.

    Vincenzi, B. et al. Prognostic relevance of objective response according to EASL criteria and mRECIST criteria in hepatocellular carcinoma patients treated with loco-regional therapies: a literature-based meta-analysis. PLoS ONE 10, e0133488 (2015).

    PubMed  PubMed Central  Google Scholar 

  145. 145.

    Hilgard, P. et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology 52, 1741–1749 (2010).

    CAS  PubMed  Google Scholar 

  146. 146.

    Lewandowski, R. J. et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am. J. Transplant. 9, 1920–1928 (2009).

    CAS  PubMed  Google Scholar 

  147. 147.

    Mazzaferro, V. et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study. Hepatology 57, 1826–1837 (2013).

    CAS  PubMed  Google Scholar 

  148. 148.

    Salem, R. et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 138, 52–64 (2010).

    CAS  PubMed  Google Scholar 

  149. 149.

    Sangro, B. et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 54, 868–878 (2011).

    PubMed  Google Scholar 

  150. 150.

    Kolligs, F. T. et al. Pilot randomized trial of selective internal radiation therapy vs. chemoembolization in unresectable hepatocellular carcinoma. Liver Int. 35, 1715–1721 (2015).

    PubMed  Google Scholar 

  151. 151.

    Mazzaferro, V. et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N. Engl. J. Med. 334, 693–699 (1996).

    CAS  PubMed  Google Scholar 

  152. 152.

    OPTN/UNOS Policy Notice Changes to HCC Criteria for Auto Approval. https://optn.transplant.hrsa.gov/media/2027/liver_policynotice_201612.pdf (2016).

  153. 153.

    Llovet, J. M. & Finn, R. S. Negative phase 3 study of (90)Y microspheres versus sorafenib in HCC. Lancet. Oncol. 19, e69 (2018).

    PubMed  Google Scholar 

  154. 154.

    Sposito, C. & Mazzaferro, V. The SIRveNIB and SARAH trials, radioembolization vs. sorafenib in advanced HCC patients: reasons for a failure, and perspectives for the future. Hepatobiliary Surg. Nutr. 7, 487–489 (2018).

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    Salem, R. et al. Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience. Hepatology 68, 1429–1440 (2018).

    PubMed  Google Scholar 

  156. 156.

    Biederman, D. M. et al. Outcomes of radioembolization in the treatment of hepatocellular carcinoma with portal vein invasion: resin versus glass microspheres. J. Vasc. Interv. Radiol. 27, 812–821.e812 (2016).

    PubMed  Google Scholar 

  157. 157.

    Garin, E. et al. Boosted selective internal radiation therapy with 90Y-loaded glass microspheres (B-SIRT) for hepatocellular carcinoma patients: a new personalized promising concept. Eur. J. Nucl. Med. Mol. Imaging 40, 1057–1068 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Garin, E. et al. Major impact of personalized dosimetry using 90Y loaded glass microspheres SIRT in HCC: Final overall survival analysis of a multicenter randomized phase II study (DOSISPHERE-01). J. Clin. Oncol. 38, 516–516 (2020).

    Google Scholar 

  159. 159.

    Spreafico, C. et al. Development of a prognostic score to predict response to yttrium-90 radioembolization for hepatocellular carcinoma with portal vein invasion. J. Hepatol. 68, 724–732 (2018).

    PubMed  Google Scholar 

  160. 160.

    Mosconi, C., Cucchetti, A., Pettinato, C., Golfieri, R. & Cappelli, A. Validation of response to yttrium-90 radioembolization for hepatocellular carcinoma with portal vein invasion. J. Hepatol. 69, 259–260 (2018).

    PubMed  Google Scholar 

  161. 161.

    Lee, J., Shin, I. S., Yoon, W. S., Koom, W. S. & Rim, C. H. Comparisons between radiofrequency ablation and stereotactic body radiotherapy for liver malignancies: meta-analyses and a systematic review. Radiother. Oncol. 145, 63–70 (2020).

    PubMed  Google Scholar 

  162. 162.

    Meyer, T. Stereotactic body radiotherapy for hepatocellular carcinoma – still searching for a role. J. Hepatol. 73, 15–16 (2020).

    PubMed  Google Scholar 

  163. 163.

    Bang, A. & Dawson, L. A. Radiotherapy for HCC: ready for prime time? JHEP Rep. 1, 131–137 (2019).

    PubMed  PubMed Central  Google Scholar 

  164. 164.

    Shen, P. C. et al. Comparison of stereotactic body radiation therapy and transarterial chemoembolization for unresectable medium-sized hepatocellular carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 105, 307–318 (2019).

    PubMed  Google Scholar 

  165. 165.

    Sapir, E. et al. Stereotactic body radiation therapy as an alternative to transarterial chemoembolization for hepatocellular carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 100, 122–130 (2018).

    PubMed  Google Scholar 

  166. 166.

    Ashamalla, H., Manzerova, J., Soni, V., Kodiyan, J. & Guirguis, A. Patterns of care and effectiveness of stereotactic body radiation therapy and yttrium-90 radioembolization in unresected hepatocellular carcinoma: an NCDB analysis. Int. J. Radiat. Oncol. Biol. Phys. 102, e63 (2018).

    Google Scholar 

  167. 167.

    Yoon, S. M. et al. Efficacy and safety of transarterial chemoembolization plus external beam radiotherapy vs sorafenib in hepatocellular carcinoma with macroscopic vascular invasion: a randomized clinical trial. JAMA Oncol. 4, 661–669 (2018).

    PubMed  PubMed Central  Google Scholar 

  168. 168.

    Duan, J. et al. Use of immunotherapy with programmed cell death 1 vs programmed cell death ligand 1 inhibitors in patients with cancer: a systematic review and meta-analysis. JAMA Oncol. 6, 375–384 (2020).

    PubMed  Google Scholar 

  169. 169.

    Greten, T. F., Duffy, A. G. & Korangy, F. Hepatocellular carcinoma from an immunologic perspective. Clin. Cancer Res. 19, 6678–6685 (2013).

    CAS  PubMed  Google Scholar 

  170. 170.

    Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 20, 1239–1251 (2019).

    CAS  PubMed  Google Scholar 

  171. 171.

    Topalian, S. L. et al. Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab. JAMA Oncol. 5, 1411–1420 (2019).

    PubMed Central  Google Scholar 

  172. 172.

    Sutherland, L. M. et al. Radiofrequency ablation of liver tumors: a systematic review. Arch. Surg. 141, 181–190 (2006).

    PubMed  Google Scholar 

  173. 173.

    Kaseb, A. O. et al. Immunologic correlates of pathologic complete response to preoperative immunotherapy in hepatocellular carcinoma. Cancer Immunol. Res. 7, 1390–1395 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Ayaru, L. et al. Unmasking of alpha-fetoprotein-specific CD4+ T cell responses in hepatocellular carcinoma patients undergoing embolization. J. Immunol. 178, 1914–1922 (2007).

    CAS  PubMed  Google Scholar 

  175. 175.

    Hiroishi, K. et al. Strong CD8+ T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma. J. Gastroenterol. 45, 451–458 (2010).

    CAS  PubMed  Google Scholar 

  176. 176.

    Mizukoshi, E. et al. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology 57, 1448–1457 (2013).

    CAS  Google Scholar 

  177. 177.

    Nobuoka, D. et al. Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes. Int. J. Oncol. 40, 63–70 (2012).

    CAS  PubMed  Google Scholar 

  178. 178.

    Zerbini, A. et al. Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer Res. 66, 1139–1146 (2006).

    CAS  PubMed  Google Scholar 

  179. 179.

    Zerbini, A. et al. Radiofrequency thermal ablation for hepatocellular carcinoma stimulates autologous NK-cell response. Gastroenterology 138, 1931–1942 (2010).

    CAS  PubMed  Google Scholar 

  180. 180.

    Chu, K. F. & Dupuy, D. E. Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat. Rev. Cancer 14, 199–208 (2014).

    CAS  PubMed  Google Scholar 

  181. 181.

    Haen, S. P. et al. Elevated serum levels of heat shock protein 70 can be detected after radiofrequency ablation. Cell Stress Chaperones 16, 495–504 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Ahmed, M. et al. Radiofrequency ablation (RFA)-induced systemic tumor growth can be reduced by suppression of resultant heat shock proteins. Int. J. Hyperthermia 34, 934–942 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Kalbasi, A. & Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 20, 25–39 (2020).

    CAS  PubMed  Google Scholar 

  184. 184.

    Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    CAS  PubMed  Google Scholar 

  185. 185.

    Guan, Q. et al. Correlation between vascular endothelial growth factor levels and prognosis of hepatocellular carcinoma patients receiving radiofrequency ablation. Biotechnol. Biotechnol. Equip. 29, 119–123 (2015).

    CAS  PubMed  Google Scholar 

  186. 186.

    Petrillo, M. et al. Hypoxia and tumor angiogenesis in the era of hepatocellular carcinoma transarterial loco-regional treatments. Future Oncol. 14, 2957–2967 (2018).

    CAS  PubMed  Google Scholar 

  187. 187.

    Yang, J., Yan, J. & Liu, B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front. Immunol. 9, 978 (2018).

    PubMed  PubMed Central  Google Scholar 

  188. 188.

    Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G. & Jain, R. K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15, 325–340 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Khan, K. A. & Kerbel, R. S. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat. Rev. Clin. Oncol. 15, 310–324 (2018).

    CAS  PubMed  Google Scholar 

  190. 190.

    Rahma, O. E. & Hodi, F. S. The Intersection between tumor angiogenesis and immune suppression. Clin. Cancer Res. 25, 5449–5457 (2019).

    CAS  PubMed  Google Scholar 

  191. 191.

    Missiaen, R., Mazzone, M. & Bergers, G. The reciprocal function and regulation of tumor vessels and immune cells offers new therapeutic opportunities in cancer. Semin. Cancer Biol. 52, 107–116 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193.

    Shi, L. et al. Inflammation induced by incomplete radiofrequency ablation accelerates tumor progression and hinders PD-1 immunotherapy. Nat. Commun. 10, 5421 (2019).

    PubMed  PubMed Central  Google Scholar 

  194. 194.

    Marelli, L. et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc. Intervent. Radiol. 30, 6–25 (2007).

    PubMed  Google Scholar 

  195. 195.

    Llovet, J. M., Montal, R. & Villanueva, A. Randomized trials and endpoints in advanced HCC: role of PFS as a surrogate of survival. J. Hepatol. 70, 1262–1277 (2019).

    PubMed  Google Scholar 

  196. 196.

    Kudo, M. et al. Response evaluation criteria in cancer of the liver (RECICL) proposed by the Liver Cancer Study Group of Japan (2009 revised version). Hepatol. Res. 40, 686–692 (2010).

    PubMed  Google Scholar 

  197. 197.

    Therasse, P. 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. 92, 205–216 (2000).

    CAS  PubMed  Google Scholar 

  198. 198.

    Forner, A. et al. Evaluation of tumor response after locoregional therapies in hepatocellular carcinoma: are response evaluation criteria in solid tumors reliable? Cancer 115, 616–623 (2009).

    PubMed  Google Scholar 

  199. 199.

    Llovet, J. M. et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J. Natl Cancer Inst. 100, 698–711 (2008).

    PubMed  Google Scholar 

  200. 200.

    Georgiades, C. et al. Lack of response after initial chemoembolization for hepatocellular carcinoma: does it predict failure of subsequent treatment? Radiology 265, 115–123 (2012).

    PubMed  PubMed Central  Google Scholar 

  201. 201.

    Bruix, J. et al. Clinical decision making and research in hepatocellular carcinoma: pivotal role of imaging techniques. Hepatology 54, 2238–2244 (2011).

    PubMed  Google Scholar 

  202. 202.

    Lencioni, R. New data supporting modified RECIST (mRECIST) for hepatocellular carcinoma. Clin. Cancer Res. 19, 1312–1314 (2013).

    PubMed  Google Scholar 

  203. 203.

    Seyal, A. R. et al. Reproducibility of mRECIST in assessing response to transarterial radioembolization therapy in hepatocellular carcinoma. Hepatology 62, 1111–1121 (2015).

    CAS  PubMed  Google Scholar 

  204. 204.

    Salem, R. & Lewandowski, R. J. Chemoembolization and radioembolization for hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 11, 604–e44 (2013).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

J.M.L is supported by European Commission (EC)/Horizon 2020 Program (HEPCAR, Ref. 667273-2), EIT Health (CRISH2, Ref. 18053), Accelerator Award (CRUCK, AEEC, AIRC) (HUNTER, Ref. C9380/A26813), National Cancer Institute (P30-CA196521), U.S. Department of Defense (CA150272P3), Samuel Waxman Cancer Research Foundation, Spanish National Health Institute (SAF2016-76390) and the Generalitat de Catalunya/AGAUR (SGR-1358). P.K.H. is supported by the fellowship grant of the German Research Foundation (DFG HA 8754/1-1). T.F.G. is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. T.M. is supported by the NIHR UCLH Biomedical Research Centre.

Author information

Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Josep M. Llovet.

Ethics declarations

Competing interests

J.M.L. receives research support from Bayer HealthCare Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb, Eisai Inc. and Ipsen. He has also received consulting fees from AstraZeneca, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Can-Fite, Celsion Corporation, Eisai Inc., Eli Lilly, Glycotest, Ipsen, Merck, Nucleix, Roche and Sirtex. T.D.B. has received research support from Boston-Scientific Galil, and Terumo, and advisory board fees from AstraZeneca, Boston-Scientific, Esai, Guerbet and Terumo. L.K. receives consulting fees from Bayer, Eisai, Exelixis, Gilead and Merck, and research funding from Glycotest and TARGET-HCC. T.M. has received advisory board fees from AstraZeneca, BTG, Eisai, Ipsen, Roche and Tarveda. The remaining co-authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks E. Kim and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

U.S. National Library of Medicine Clinical Trials.gov: https://clinicaltrials.gov/

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Llovet, J.M., De Baere, T., Kulik, L. et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 18, 293–313 (2021). https://doi.org/10.1038/s41575-020-00395-0

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing