Jacob Abell

Background: Hepatocellular carcinoma (HCC) is the 6th most common cause of cancer worldwide with 700,000 new cases each year and the average survival rate is 19.6% in the United States.¹ The most common primary malignancy of the liver, HCC significant risk factors include chronic alcohol consumption, viral infections, obesity and type II diabetes.² These risk factors cause liver cirrhosis which leads to molecular failures including cell cycle deregulation, and DNA methylation alteration, ultimately causing HCC.² Liver transplantation is currently the best treatment, because it addresses the background cirrhosis found in 80% of patients.¹ However, there is currently a chronic liver donor shortage with increasing obesity prevalence and decreasing liver health.^{1, 3} Liver resection in cirrhotic patients can be associated with complications such as worsening ascites and liver failure.¹ These findings suggest new treatment techniques for HCC treatment may be necessary.

Objective: In this review, the effectiveness of chemotherapy use prior to radiofrequency ablation for hepatocellular carcinoma was explored.

Search Methods: An online search of Pubmed was performed with timeframe 2018-2023 and key terms: “hepatocellular carcinoma”, “chemotherapy”, “radiofrequency ablation”, “combination therapy”.

Results: One emerging systemic chemotherapy for HCC is Sorafenib, which inhibits tumor proliferation and angiogenesis.⁴ Studies show that sorafenib use prior to radiofrequency ablation (RFA) can decrease tumor volume and allow RFA to increase ablation area, making these treatments more effective together than either alone.⁴ However, when RFA is incomplete it can cause transformed survivor cells that are resistant to further treatment.⁵ This suggests that tumors less than 2cm in size will best benefit from chemotherapy and RFA, since tumors larger than this are more likely to only experience partial ablation from the RFA.⁵ Arsenic trioxide, a leukemia drug, can mitigate the effects of incomplete RFA by inhibiting HCC proliferation, posing a possible solution for larger tumors.⁶ Systemically, combined resiquimod and RFA have been shown to increase the CD8 T cells and NK cells allowing them to infiltrate both primary and distant tumors, further treating HCC.⁷ In clinical trials cisplatin before RFA did not significantly improve HCC recurrence free survival rate of early stage HCC, however, it may be effective in decreasing intrahepatic distant recurrence.⁸ When subgroups were analyzed, it was demonstrated that the therapy had beneficial effects when patients had a single nodule and Child-Pugh score 5, increasing their distant recurrence free survival rate.⁸   With increases of advanced liver cirrhosis as a result of obesity, it is more difficult to detect HCC with ultrasonography.⁸ The use of angiography to evaluate HCC before HAIC and RFA may increase the accuracy of treatments which could increase the efficacy of this combination treatment.⁸

Conclusions: Overall, chemotherapy and RFA combination therapy is promising in mice and culture studies but is not yet supported clinically. Few clinical trials have been conducted so far, so future combinations with drugs like sorafenib may yield more successful results. Additionally using angiography instead of ultrasonography to localize and detect HCC would allow for greater accuracy of chemotherapy and RFA treatments.

Works Cited:

1. Swaid F, Geller DA. Minimally Invasive Primary Liver Cancer Surgery. Surg Oncol Clin N Am. 2019;28(2):215-227. doi:10.1016/j.soc.2018.11.002
2. Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res. 2021;149:1-61. doi:10.1016/bs.acr.2020.10.001
3. Killackey MT. Transplantation in obese patient. Mt Sinai J Med. 2012;79(3):388-396. doi:10.1002/msj.21315
4. Tang Z, Kang M, Zhang B, et al. Advantage of sorafenib combined with radiofrequency ablation for treatment of hepatocellular carcinoma. Tumori. 2017;103(3):286-291. doi:10.5301/tj.5000585
5. Wang F, Xu C, Li G, Lv P, Gu J. Incomplete radiofrequency ablation induced chemoresistance by up-regulating heat shock protein 70 in hepatocellular carcinoma. Exp Cell Res. 2021;409(2):112910. doi:10.1016/j.yexcr.2021.112910
6. Dong S, Li Z, Kong J, Wu S, Gao J, Sun W. Arsenic trioxide inhibits angiogenesis of hepatocellular carcinoma after insufficient radiofrequency ablation via blocking paracrine angiopoietin-1 and angiopoietin-2. Int J Hyperthermia. 2022;39(1):888-896. doi:10.1080/02656736.2022.2093995
7. Tian Z, Hong B, Chen J, Tang Z. Combination of Radiofrequency Ablation With Resiquimod to Treat Hepatocellular Carcinoma Via Inflammation of Tumor Immune Microenvironment and Suppression of Angiogenesis. Front Oncol. 2022;12:891724. Published 2022 Jun 2. doi:10.3389/fonc.2022.891724
8. Oyama A, Nouso K, Yoshimura K, et al. Randomized controlled study to examine the efficacy of hepatic arterial infusion chemotherapy with cisplatin before radiofrequency ablation for hepatocellular carcinoma. Hepatol Res. 2021;51(6):694-701. doi:10.1111/hepr.13633