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.
• 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.
This is a preview of subscription content, log in to check access.
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.
Written informed consent was not required for this study because it is a review of literature.
Approval from the institutional animal care committee was not required because it is a review of literature.
• Performed at one institution
Torzilli G, Adam R, Viganò L et al (2016) Surgery of colorectal liver metastases: pushing the limits. Liver Cancer 6(1):80–89CrossRefGoogle Scholar
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
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
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
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
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
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
Minami Y, Kudo M (2013) Radiofrequency ablation of liver metastases from colorectal cancer: a literature review. Gut Liver 7(1):1–6CrossRefGoogle Scholar
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
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
Kudo M (2016) Immune checkpoint blockade in hepatocellular carcinoma: 2017 update. Liver Cancer 6(1):1–12CrossRefGoogle Scholar
Okazaki T, Honjo T (2006) The PD-1-PD-L pathway in immunological tolerance. Trends Immunol 27(4):195–201CrossRefGoogle Scholar
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
Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264CrossRefGoogle Scholar
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
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
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
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
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
Chu KF, Dupuy DE (2014) Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat Rev Cancer 14(3):199–208CrossRefGoogle Scholar
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
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
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
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
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
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
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
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
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
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
Kreamer KM (2014) Immune checkpoint blockade: a new paradigm in treating advanced cancer. J Adv Pract Oncol 5(6):418–431Google Scholar
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
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. https://doi.org/10.1007/s00330-018-5814-3
Jenkins RW, Barbie DA, Flaherty KT (2018) Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer 118(1):9–16CrossRefGoogle Scholar
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
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
Patel SA, Minn AJ (2018) Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies. Immunity 48(3):417–433CrossRefGoogle Scholar
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
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
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