Radiofrequency ablation of liver metastasis: potential impact on immune checkpoint inhibitor therapy

  • Yasunori MinamiEmail author
  • Naoshi Nishida
  • Masatoshi Kudo


Percutaneous radiofrequency ablation (RFA), a generally accepted alternative therapy for patients with liver metastases, is a minimally invasive approach with a favorable safety profile and a lower rate of major complications. The use of RFA or combined RFA plus resection can produce total tumor clearance in patients with unresectable liver metastases. However, the relatively high rate of local tumor progression has prevented the widespread use of RFA. Furthermore, its efficacy is controversial because there have been no comparisons for its effect on overall survival compared with standard options such as systemic chemotherapy. Meanwhile, immunotherapy has become a major research focus for oncology based on the recent successes reported for immune checkpoint inhibitors for melanoma, non-small cell lung cancer, gastric cancer, and other cancers. Immune checkpoints negatively regulate T cell function, and inhibition prevents the blockade of the immune system by cancer cells to prevent their destruction. Unfortunately, only some patients (< 25%) respond to immuno-oncology drugs, whereas other patients acquire resistance. However, RFA can induce massive necrotic cell death which might activate immunity and the presentation of cryptic antigens to induce tumor-specific T cell response. Because RFA can induce the rapid release of large amounts of tumor antigens, it can potentially stimulate transient immune responses to much tumor antigens. Combination therapies have induced synergistic enhancement of anticancer immune response in preclinical studies, indicating great promise for the future of oncologic treatment.

Key Points

• Only some patients respond to immuno-oncology drugs.

• RFA causes the release of large amounts of cellular debris, a source of tumor antigens that elicit immune responses against tumors.

• Combination RFA for liver metastases and immune checkpoint inhibitor therapies might synergistically enhance antitumor immunity.


Ablation techniques Immunotherapy Liver Neoplasm metastases 



Antigen-presenting cells


Confidence interval


Cytotoxic T lymphocyte–associated protein 4


Dendritic cell


Food and Drug Administration


Hazard ratio






Major histocompatibility complex


Overall survival


Programmed cell death-1


Programmed cell death ligand-1


Radiofrequency ablation


Tumor-associated antigen


Effector T cell


Regulatory T cell



The authors state that this work has not received any funding.

Compliance with ethical standards


The scientific guarantor of this publication is Prof. Masatoshi Kudo.

Conflict of interest

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.

Statistics and biometry

No complex statistical methods were necessary for this paper.

Informed consent

Written informed consent was not required for this study because it is a review of literature.

Ethical approval

Approval from the institutional animal care committee was not required because it is a review of literature.


• Performed at one institution


  1. 1.
    Torzilli G, Adam R, Viganò L et al (2016) Surgery of colorectal liver metastases: pushing the limits. Liver Cancer 6(1):80–89CrossRefGoogle Scholar
  2. 2.
    Shady W, Petre EN, Gonen M et al (2016) Percutaneous radiofrequency ablation of colorectal cancer liver metastases: factors affecting outcomes--a 10-year experience at a single center. Radiology 278(2):601–611CrossRefGoogle Scholar
  3. 3.
    Solbiati L, Ahmed M, Cova L, Ierace T, Brioschi M, Goldberg SN (2012) Small liver colorectal metastases treated with percutaneous radiofrequency ablation: local response rate and long-term survival with up to 10-year follow-up. Radiology 265(3):958–968CrossRefGoogle Scholar
  4. 4.
    Wong SL, Mangu PB, Choti MA et al (2010) American Society of Clinical Oncology 2009 clinical evidence review on radiofrequency ablation of hepatic metastases from colorectal cancer. J Clin Oncol 28(3):493–508CrossRefGoogle Scholar
  5. 5.
    Gervais DA, Goldberg SN, Brown DB, Soulen MC, Millward SF, Rajan DK (2009) Society of Interventional Radiology position statement on percutaneous radiofrequency ablation for the treatment of liver tumors. J Vasc Interv Radiol 20(7 Suppl):S342–S347CrossRefGoogle Scholar
  6. 6.
    Crocetti L, de Baere T, Lencioni R (2010) Quality improvement guidelines for radiofrequency ablation of liver tumours. Cardiovasc Intervent Radiol 33(1):11–17CrossRefGoogle Scholar
  7. 7.
    Jones RP, Kokudo N, Folprecht G et al (2016) Colorectal liver metastases: a critical review of state of the art. Liver Cancer 6(1):66–71CrossRefGoogle Scholar
  8. 8.
    Minami Y, Kudo M (2013) Radiofrequency ablation of liver metastases from colorectal cancer: a literature review. Gut Liver 7(1):1–6CrossRefGoogle Scholar
  9. 9.
    Ahmed M, Solbiati L, Brace CL et al (2014) Image-guided tumor ablation: standardization of terminology and reporting criteria—a 10-year update. Radiology 273(1):241–260Google Scholar
  10. 10.
    Stang A, Fischbach R, Teichmann W, Bokemeyer C, Braumann D (2009) A systematic review on the clinical benefit and role of radiofrequency ablation as treatment of colorectal liver metastases. Eur J Cancer 45(10):1748–1756CrossRefGoogle Scholar
  11. 11.
    Kudo M (2016) Immune checkpoint blockade in hepatocellular carcinoma: 2017 update. Liver Cancer 6(1):1–12CrossRefGoogle Scholar
  12. 12.
    Okazaki T, Honjo T (2006) The PD-1-PD-L pathway in immunological tolerance. Trends Immunol 27(4):195–201CrossRefGoogle Scholar
  13. 13.
    Alsaab HO, Sau S, Alzhrani R et al (2017) PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol 23(8):561CrossRefGoogle Scholar
  14. 14.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264CrossRefGoogle Scholar
  15. 15.
    Dempke WCM, Fenchel K, Uciechowski P, Dale SP (2017) Second- and third-generation drugs for immuno-oncology treatment-the more the better? Eur J Cancer 74:55–72CrossRefGoogle Scholar
  16. 16.
    Lee JW, Choi MH, Lee YJ et al (2017) Radiofrequency ablation for liver metastases in patients with gastric cancer as an alternative to hepatic resection. BMC Cancer 17(1):185CrossRefGoogle Scholar
  17. 17.
    Shen S, Peng H, Wang Y et al (2018) Screening for immune-potentiating antigens from hepatocellular carcinoma patients after radiofrequency ablation by serum proteomic analysis. BMC Cancer 18(1):117CrossRefGoogle Scholar
  18. 18.
    Shi L, Chen L, Wu C et al (2016) PD-1 blockade boosts radiofrequency ablation-elicited adaptive immune responses against tumor. Clin Cancer Res 22(5):1173–1184CrossRefGoogle Scholar
  19. 19.
    Ruers T, Van Coevorden F, Punt CJ et al (2017) Local treatment of unresectable colorectal liver metastases: results of a randomized phase ii trial. J Natl Cancer Inst 109(9)Google Scholar
  20. 20.
    Fernández Moro C, Bozóky B, Gerling M (2018) Growth patterns of colorectal cancer liver metastases and their impact on prognosis: a systematic review. BMJ Open Gastroenterol 5(1):e000217. CrossRefGoogle Scholar
  21. 21.
    Chu KF, Dupuy DE (2014) Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat Rev Cancer 14(3):199–208CrossRefGoogle Scholar
  22. 22.
    Slovak R, Ludwig JM, Gettinger SN, Herbst RS, Kim HS (2017) Immuno-thermal ablations - boosting the anticancer immune response. J Immunother Cancer 5(1):78CrossRefGoogle Scholar
  23. 23.
    Zerbini A, Pilli M, Penna A et al (2006) Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer Res 66(2):1139–1146CrossRefGoogle Scholar
  24. 24.
    Ito F, Ku AW, Bucsek MJ et al (2015) Immune adjuvant activity of pre-resectional radiofrequency ablation protects against local and systemic recurrence in aggressive murine colorectal cancer. PLoS One 10(11)Google Scholar
  25. 25.
    Obara K, Matsumoto N, Okamoto M et al (2008) Insufficient radiofrequency ablation therapy may induce further malignant transformation of hepatocellular carcinoma. Hepatol Int 2(1):116–123CrossRefGoogle Scholar
  26. 26.
    Yoshida S, Kornek M, Ikenaga N et al (2013) Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma. Hepatology 58(5):1667–1680CrossRefGoogle Scholar
  27. 27.
    Yoshida N, Midorikawa Y, Kajiwara T et al (2013) Hepatocellular carcinoma with sarcomatoid change without anticancer therapies. Case Rep Gastroenterol 7(1):169–174CrossRefGoogle Scholar
  28. 28.
    Papaioannou NE, Beniata OV, Vitsos P, Tsitsilonis O, Samara P (2016) Harnessing the immune system to improve cancer therapy. Ann Transl Med 4(14):261CrossRefGoogle Scholar
  29. 29.
    Wang Y, Luo F, Yang J, Zhao C, Chu Y (2017) New chimeric antigen receptor design for solid tumors. Front Immunol 22(8):1934CrossRefGoogle Scholar
  30. 30.
    Buchbinder EI, Desai A (2016) CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol 39(1):98–106CrossRefGoogle Scholar
  31. 31.
    Ostrand-Rosenberg S, Horn LA, Haile ST (2014) The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity. J Immunol 193(8):3835–3841CrossRefGoogle Scholar
  32. 32.
    Kreamer KM (2014) Immune checkpoint blockade: a new paradigm in treating advanced cancer. J Adv Pract Oncol 5(6):418–431Google Scholar
  33. 33.
    Friedman D, Baird JR, Young KH et al (2017) Programmed cell death-1 blockade enhances response to stereotactic radiation in an orthotopic murine model of hepatocellular carcinoma. Hepatol Res 47(7):702–714CrossRefGoogle Scholar
  34. 34.
    Du Y, Jin Y, Sun W, Fang J, Zheng J, Tian J (2018) Advances in molecular imaging of immune checkpoint targets in malignancies: current and future prospect. Eur Radiol.
  35. 35.
    Jenkins RW, Barbie DA, Flaherty KT (2018) Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer 118(1):9–16CrossRefGoogle Scholar
  36. 36.
    Pitt JM, Vétizou M, Daillère R et al (2016) Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and –extrinsic factors. Immunity 44(6):1255–1269CrossRefGoogle Scholar
  37. 37.
    Widenmeyer M, Shebzukhov Y, Haen SP et al (2011) Analysis of tumor antigen-specific T cells and antibodies in cancer patients treated with radiofrequency ablation. Int J Cancer 128(11):2653–2662CrossRefGoogle Scholar
  38. 38.
    Patel SA, Minn AJ (2018) Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies. Immunity 48(3):417–433CrossRefGoogle Scholar
  39. 39.
    den Brok MH, Sutmuller RP, Nierkens S et al (2006) Efficient loading of dendritic cells following cryo and radiofrequency ablation in combination with immune modulation induces anti-tumour immunity. Br J Cancer 95(7):896–905CrossRefGoogle Scholar
  40. 40.
    Dovedi SJ, Adlard AL, Lipowska-Bhalla G et al (2014) Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 74(19):5458–5468CrossRefGoogle Scholar
  41. 41.
    Gettinger SN, Wurtz A, Goldberg SB et al (2018) Clinical features and management of acquired resistance to PD-1 axis inhibitors in 26 patients with advanced non-small cell lung cancer. J Thorac Oncol 13(6):831–839CrossRefGoogle Scholar

Copyright information

© European Society of Radiology 2019

Authors and Affiliations

  • Yasunori Minami
    • 1
    Email author
  • Naoshi Nishida
    • 1
  • Masatoshi Kudo
    • 1
  1. 1.Department of Gastroenterology and HepatologyKindai University Faculty of MedicineOsaka-SayamaJapan

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