Clin Mol Hepatol > Volume 28(2); 2022 > Article
Kim: Surgical resection versus ablation for early hepatocellular carcinoma: The debate is still open
Very early hepatocellular carcinoma (HCC) is usually regarded as a single tumor <2 cm in diameter without vascular invasion. Barcelona Clinic Liver Cancer (BCLC) stage 0 or modified Union for International Cancer Control (UICC) stage I falls into this category. Approximately, 5–10% of patients in the West and 15% of patients in Korea are diagnosed at this stage [1-4]. Very early or early HCC can be treated using ablation, surgical resection, or transplantation [5].
In this issue of Clinical and Molecular Hepatology, Lee et al. [6] evaluated the long-term outcomes of surgical resection and radiofrequency ablation (RFA) for single HCC ≤3 cm in patients with well-preserved liver function (Child-Pugh class A). This multicenter retrospective study of 391 patients compared the surgical resection with RFA for a sufficient follow-up time of more than 5 years. After adjusting for covariates, the estimated cumulative overall survival rate was slightly higher in patients who underwent RFA than in those who underwent surgical resection (97.0% vs. 95.8% at 2 years, 92.3% vs. 89.2% at 4 years, 85.3% vs. 79.7% at 6 years, and 80.9% vs. 73.8% at 8 years, respectively) without statistical significance. However, cumulative recurrence-free survival rate was significantly higher in patients who underwent surgical resection than in those who underwent RFA (78.5% vs. 66.3% at 2 years, 62.1% vs. 44.5% at 4 years, 53.3% vs. 34.4% at 6 years, and 48.6% vs. 29.4% at 8 years, respectively). A subgroup analysis suggested that the difference of recurrence-free survival rate between RFA and surgical resection was statistically significant in patients without cirrhosis, whereas recurrence-free survival was comparable between patients with cirrhosis who underwent surgical resection and those with cirrhosis treated with RFA.
The pattern of recurrence after RFA is usually categorized into intrahepatic local recurrence, intrahepatic distant recurrence, and extrahepatic distant metastasis. Incomplete ablation or tumor aggressiveness may lead to intrahepatic local recurrence [7]. Risk factors for intrahepatic local recurrence include larger tumor size (>3 cm), insufficient safety margin, and tumor location (adjacent to the major blood vessels) [7,8]. On the other hand, distant recurrence may result from a combination of tumor metastasis and de novo carcinogenesis [7]. Risk factors for intrahepatic distant metastasis also include larger tumor size, tumor multiplicity, and high serum alpha-fetoprotein level as well as portal hypertension [7,8].
In the present study, a plausible reason for the difference in the recurrence-free survival rates between RFA and surgical resection would be that local factors, such as insufficient safety margin, are more likely to contribute to the higher recurrence of RFA than host factors, such as the presence of cirrhosis. The insufficient ablative margin of less than 5 mm is associated with higher recurrence after RFA [9]. Tumor location is also one of the most critical factors to predict local recurrence for RFA [10]. Unfavorable location such as periportal or subphrenic location as well as tumor size ≥2.0 cm are closely associated with local tumor progression in RFA [10]. Non-subcapsular and non-perivascular tumors or tumors located in posterosuperior liver portions showed similar local tumor progression rates between RFA and laparoscopic surgical resection [11]. Although the present study did not investigate the association of the tumor location and the recurrence, the authors demonstrated that recurrence-free survival rate was comparable for HCC ≤2 cm. Surgical resection provides better recurrence-free survival and comparable overall survival; however, it is accompanied by higher postoperative morbidity and longer hospital stay [12]. Recently, laparoscopic liver resection showed better perioperative and survival outcome compared to open liver resection [13]. For small HCCs located in the anterolateral segments of the liver, laparoscopic liver resection was associated with similar complication and overall survival rates, and better recurrence-free survival rate compared with RFA [14].
Underlying chronic liver disease can contribute to the de novo development of liver cancer after surgical resection [15,16]. The mode of surgical resection may also affect the recurrence rate after curative resection. Anatomic resection involves the removal of a hepatic segment or subsegment, which includes tumor-bearing portal tributaries as major branches of the portal vein and hepatic artery [17]. Non-anatomic resection preserves non-tumor hepatic parenchyma and offers less extensive liver resection. Anatomic resection provides better tumor control than non-anatomical resection [17]. A retrospective study using propensity score matching methods compared RFA with non-anatomical surgical resection for HCC ≤3 cm without vascular invasion. The 5-year cumulative intrahepatic distant recurrence and disease-free survival rates did not differ between patients treated with RFA and those treated with non-anatomic surgical resection (47.0% vs. 40.2%, P=0.240; and 48.9% vs. 54.4%, P=0.201, respectively) [18]. Non-anatomic surgical resection might not be significantly better in effectiveness compared with RFA in terms of preventing recurrence.
To decrease the intrahepatic local recurrence after RFA, new ablative techniques may play a role by improving the efficacy and size of ablation [7]. Different ablation modes such as multi-bipolar ablation with no-touch technique or microwave ablation may lead to effective ablation and extend the indications of local ablation [7]. Different approaches also enable safe treatment of tumors present in difficult locations. To minimize recurrence, it is important to predict tumor aggressiveness. High tumor markers, arterial peritumor enhancement, or hepatobiliary peritumoral hypointensity on magnetic resonance imaging showed the association with microvascular invasion [19]. In case of HCC with a high probability of microvascular invasion, surgical resection offered better results in terms of recurrence when compared with RFA [19].
Recently, a multicenter, phase 3 clinical trial comparing surgical resection and RFA for HCC ≤3 cm and ≤3 nodules was conducted [20]. Interestingly, 150 patients in the surgery group and 152 patients in the RFA group were enrolled between 2009 and 2015 after confirming that all patients could be treated using either surgery or RFA. In both groups, 90% of the patients had solitary HCC. The 5-year overall survival rate was comparable between the two groups (surgery group, 74.6%; RFA group, 70.4%; P=0.828). The 5-year recurrence-free survival rates were 54.7% and 50.5% in the surgery and RFA groups, respectively (P=0.498). Although the final report has not been published yet, balances between the modes of each treatment (e.g., application of newer ablation techniques or anatomic resection), tumor biology, or location should also be incorporated into the interpretation of results.
Presence of solitary HCC ≤3 cm is one of the earlier stages of HCC and can even be regarded as the easiest stage. However, tumor biology (aggressiveness), location, and hepatic reserves are ascribed to the heterogeneity of this stage. Surgical resection generally offers a lower risk of recurrence at the cost of potential complications or a longer hospital stay. RFA shows a comparable recurrence rate or overall survival rate in case of some favorably located tumors, but high recurrence rates for other unfavorably located tumors [1,21,22]. For HCC ≥2 cm or located in the subphrenic or perivascular area, surgical resection would be the better option; while RFA could show similar outcomes with surgical resection for HCC <2 cm or non-subphrenic or non-perivascular HCC. Although substantial advances have been made in both surgical resection and local ablation, the risk of recurrence should still be weighed over the risk of potential complications.

FOOTNOTES

Conflicts of Interest
The author has no conflicts to disclose.

Abbreviations

BCLC
Barcelona Clinic Liver Cancer
HCC
hepatocellular carcinoma
RFA
radiofrequency ablation
UICC
Union for International Cancer Control

REFERENCES

1. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2018;69:182-236.
pmid
2. Yoon JS, Lee HA, Park JY, Kim BH, Lee IJ, Chon YE, et al. Hepatocellular carcinoma in Korea between 2008 and 2011: an analysis of Korean nationwide cancer registry. J Liver Cancer 2020;20:41-52.
crossref
3. Chon YE, Lee HA, Yoon JS, Park JY, Kim BH, Lee IJ, et al. Hepatocellular carcinoma in Korea between 2012 and 2014: an analysis of data from the Korean nationwide cancer registry. J Liver Cancer 2020;20:135-147.
crossref
4. Yoon JS, Lee HA, Kim HY, Sinn DH, Lee DH, Hong SK, et al. Hepatocellular carcinoma in Korea: an analysis of the 2015 Korean nationwide cancer registry. J Liver Cancer 2021;21:58-68.
crossref
5. Korean Liver Cancer Association; National Cancer Center. 2018 Korean Liver Cancer Association-National Cancer Center Korea practice guidelines for the management of hepatocellular carcinoma. Gut Liver 2019;13:227-299.
pmid pmc
6. Lee J, Jin YJ, Shin SK, Kwon JH, Kim SG, Suh YJ, et al. Surgery versus radiofrequency ablation in patients with Child-Pugh class-A/single small (≤3 cm) hepatocellular carcinoma. Clin Mol Hepatol 2022;28:207-218.
crossref
7. Nault JC, Sutter O, Nahon P, Ganne-Carrié N, Séror O. Percutaneous treatment of hepatocellular carcinoma: state of the art and innovations. J Hepatol 2018;68:783-797.
crossref pmid
8. Kim YS, Rhim H, Cho OK, Koh BH, Kim Y. Intrahepatic recurrence after percutaneous radiofrequency ablation of hepatocellular carcinoma: analysis of the pattern and risk factors. Eur J Radiol 2006;59:432-441.
crossref pmid
9. Teng W, Liu KW, Lin CC, Jeng WJ, Chen WT, Sheen IS, et al. Insufficient ablative margin determined by early computed tomography may predict the recurrence of hepatocellular carcinoma after radiofrequency ablation. Liver Cancer 2015;4:26-38.
crossref pmid pmc
10. Lee MW, Kang D, Lim HK, Cho J, Sinn DH, Kang TW, et al. Updated 10-year outcomes of percutaneous radiofrequency ablation as firstline therapy for single hepatocellular carcinoma <3 cm: emphasis on association of local tumor progression and overall survival. Eur Radiol 2020;30:2391-2400.
crossref pmid
11. Lee DH, Kim JW, Lee JM, Kim JM, Lee MW, Rhim H, et al. Laparoscopic liver resection versus percutaneous radiofrequency ablation for small single nodular hepatocellular carcinoma: comparison of treatment outcomes. Liver Cancer 2021;10:25-37.
crossref pmid pmc
12. Vitale A, Peck-Radosavljevic M, Giannini EG, Vibert E, Sieghart W, Van Poucke S, et al. Personalized treatment of patients with very early hepatocellular carcinoma. J Hepatol 2017;66:412-423.
crossref pmid
13. Kabir T, Tan ZZ, Syn NL, Wu E, Lin JD, Zhao JJ, et al. Laparoscopic versus open resection of hepatocellular carcinoma in patients with cirrhosis: meta-analysis. Br J Surg 2021;109:21-29.
crossref pmid
14. Kim S, Yoon CJ, Cho JY, Han HS, Yoon YS, Lee HW, et al. Comparative long-term outcomes of laparoscopic hepatectomy and radiofrequency ablation for hepatocellular carcinoma located in the anterolateral segments of the liver. J Hepatobiliary Pancreat Sci Sci 2022;29:349-358.
crossref
15. Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003;38:200-207.
crossref pmid
16. Wu JC, Huang YH, Chau GY, Su CW, Lai CR, Lee PC, et al. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol 2009;51:890-897.
crossref pmid
17. Moris D, Tsilimigras DI, Kostakis ID, Ntanasis-Stathopoulos I, Shah KN, Felekouras E, et al. Anatomic versus non-anatomic resection for hepatocellular carcinoma: a systematic review and meta-analysis. Eur J Surg Oncol 2018;44:927-938.
crossref pmid
18. Kang TW, Kim JM, Rhim H, Lee MW, Kim YS, Lim HK, et al. Small hepatocellular carcinoma: radiofrequency ablation versus nonanatomic resection--propensity score analyses of long-term outcomes. Radiology 2015;275:908-919.
crossref pmid
19. Lee S, Kang TW, Song KD, Lee MW, Rhim H, Lim HK, et al. Effect of microvascular invasion risk on early recurrence of hepatocellular carcinoma after surgery and radiofrequency ablation. Ann Surg 2021;273:564-571.
crossref pmid
20. Kudo M, Hasegawa K, Kawaguchi Y, Takayama T, Izumi N, Yamanaka N, et al. A multicenter randomized controlled trial to evaluate the efficacy of surgery versus radiofrequency ablation for small hepatocellular carcinoma (SURF trial): analysis of overall survival. J Clin Oncol 2021;39(15_suppl):4093.
crossref
21. Lee S, Kang TW, Cha DI, Song KD, Lee MW, Rhim H, et al. Radiofrequency ablation vs. surgery for perivascular hepatocellular carcinoma: propensity score analyses of long-term outcomes. J Hepatol 2018;69:70-78.
crossref pmid
22. Song KD, Lim HK, Rhim H, Lee MW, Kang TW, Paik YH, et al. Hepatic resection vs percutaneous radiofrequency ablation of hepatocellular carcinoma abutting right diaphragm. World J Gastrointest Oncol 2019;11:227-237.
crossref pmid pmc

Editorial Office
The Korean Association for the Study of the Liver
Room A1210, 53 Mapo-daero(MapoTrapalace, Dowha-dong), Mapo-gu, Seoul, 04158, Korea
TEL: +82-2-703-0051   FAX: +82-2-703-0071    E-mail: kasl@kams.or.kr
Copyright © The Korean Association for the Study of the Liver.         
COUNTER
TODAY : 480
TOTAL : 974764
Close layer