Clin Mol Hepatol > Volume 26(4); 2019 > Article
Kim: How long should physicians follow up with patients after curative treatment for hepatocellular carcinoma?
Dear Editor,
We have read the article entitled “Substantial risk of recurrence even after 5 recurrence-free years in early-stage hepatocellular carcinoma patients” by Kim et al. [1] with great interest. The article describes the evaluation of the recurrence risk after 5 disease-free years in patients with hepatocellular carcinoma (HCC) undergoing curative treatment, such as surgical resection or radiofrequency ablation.
HCC is well-known for its high recurrence rate even after curative surgical resection [2]. Overall, the 5-year recurrence rate of HCC after curative resection is reported to be 60–70% [3], compared with 1–2% for early gastric cancer and about 30% for non-metastatic colorectal cancer [4,5]. Even for single nodular HCC sized less than 3 cm, the 5-year recurrence rate after surgical resection is 44% [6]. Typically, recurrence within 2 years after resection is classified as early recurrence, recurrence after 2 years is classified as late recurrence, and late recurrence of more than 2 years after resection is considered to be de novo HCC [7]. Tumor-related factors contribute to early recurrence. In contrast, underlying disease-related factors influence late recurrence [2,7,8]. Most patients with HCC have underlying chronic liver disease, which contributes to the de novo development of liver cancer, even though the patients have favorable tumor-related factors.
In this issue of Clinical and Molecular Hepatology, Kim et al. [1] highlight a high recurrence rate for HCC even after 5 recurrencefree years. The cumulative recurrence rates at 5 and 10 years were 60.3% and 71.0%, respectively, for 1,451 patients with HCC receiving radiofrequency ablation or surgical resection [1]. The next 5-year cumulative recurrence rate was 27.0% among 487 patients who had not experienced recurrence for at least 5 years after the initial diagnosis. This result is strikingly high compared with non-metastatic colon cancer for which recurrence rates are <1.5% per year after 5 years [5]. Due to this low recurrence rate, no further specified surveillance for non-metastatic colon cancer is recommended 5 years after the initial diagnosis [5].
For HCC, periodic surveillance is recommended for patients with risk factors such as hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, or liver cirrhosis [2]. In South Korea, biannual surveillance with ultrasonography and serum alpha-fetoprotein have been adopted as a national cancer screening program for patients aged 40 years or older with HBV, HCV, or cirrhosis. Even if patients have survived 5 years or more after curative surgical resection, patients with HBV, HCV, or cirrhosis should undergo biannual surveillance for HCC.
But what if patients do not have any established risk factors such as HBV, HCV, or cirrhosis? Recently, the number of HCC patients without established risk factors have been increasing, and the proportions of nonalcoholic fatty liver disease (NAFLD)-associated HCC have also been gradually growing [9-11]. NAFLD is a major risk factor for HCC in Western countries, and 10–20% of HCC cases are attributed to NAFLD in the USA [12]. Retrospective studies of the South Korean population have indicated that the proportions of NAFLD-associated HCC are 7–8% [9,10]. About 60–70% patients with NAFLD-associated HCC do not have underlying cirrhosis [10,11]. Kim et al. [1] also reported that only a minority of patients (6.9%) did not have HBV, HCV, or cirrhosis. Among 37 patients without HBV, HCV, or cirrhosis who did not develop recurrence for more than 5 years, six patients experienced recurrence 5.7 to 8.0 years after the initial diagnosis, with a 5-year cumulative recurrence rate of 20%. Although these patients previously have not been regarded as high-risk population for developing HCC, their recurrence rate was as high as those with established risk factors. Given that NAFLD-associated HCC patients have shown similar recurrence-free survival as other etiology-related HCC, it is conceivable that the recurrence rate is quite high [13,14].
If the recurrence rate is so high, how long and how often should we follow up on HCC patients without established risk factors? To date, there has been a lack of guidelines on the follow-up strategies for HCC cases from any etiology. The latest guideline by the American Association for the Study of Liver Disease recommends that patients should undergo surveillance after resection with imaging and alpha-fetoprotein at an interval of least every 3–6 months, without mentioning the follow-up period [15]. The latest National Comprehensive Cancer Network guideline for surveillance after curative treatment recommends imaging and alpha-fetoprotein every 3–6 months for 2 years, then every 6–12 months thereafter [16]. Given that the greatest risk of recurrence is observed during the first 2–3 years after curative treatment, intensive surveillance is required for the first 2–3 years [7]. Surveillance should be continued even after the first 2–3 years, and probably indefinitely. The surveillance interval may depend on the tumor doubling time, as in patients with high risk of developing HCC. Consequently, a 6-month interval seems to be reasonable. Another question of “Which imaging modalities would be better” remains a debatable issue. One consideration in this debate is that patients with NAFLD are more prone to obesity, which may hamper ultrasonography-based surveillance.
Since the results of the present study were based on a small number of patients in a retrospective study, we need to be very careful to avoid drawing a hasty conclusion. However, the results of this study still provide a glimpse as to whether physicians should follow up on HCC patients with or without established risk factors after 5 disease-free years. Further studies using detailed follow-up strategies are warranted.

Acknowledgments

This study was supported by a National Cancer Center Grant (NCC 2020162).

Footnotes

Conflicts of Interest: The author has participated in research sponsored by Ono-BMS and received honoraria from Abbvie.

Abbreviations

HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
NAFLD
nonalcoholic fatty liver disease

REFERENCES

1. Kim J, Kang W, Sinn DH, Gwak GY, Paik YH, Choi MS, et al. Substantial risk of recurrence even after 5 recurrence-free years in early-stage hepatocellular carcinoma patients. Clin Mol Hepatol 2020;26:516-528.

2. 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
3. Lee EC, Kim SH, Park H, Lee SD, Lee SA, Park SJ. Survival analysis after liver resection for hepatocellular carcinoma: a consecutive cohort of 1002 patients. J Gastroenterol Hepatol 2017;32:1055-1063.
crossref pmid
4. Youn HG, An JY, Choi MG, Noh JH, Sohn TS, Kim S. Recurrence after curative resection of early gastric cancer. Ann Surg Oncol 2010;17:448-454.
crossref pmid pdf
5. van der Stok EP, Spaander MCW, Grünhagen DJ, Verhoef C, Kuipers EJ. Surveillance after curative treatment for colorectal cancer. Nat Rev Clin Oncol 2017;14:297-315.
crossref pmid pdf
6. Yang HJ, Lee JH, Lee DH, Yu SJ, Kim YJ, Yoon JH, et al. Small single-nodule hepatocellular carcinoma: comparison of transarterial chemoembolization, radiofrequency ablation, and hepatic resection by using inverse probability weighting. Radiology 2014;271:909-918.
crossref pmid
7. 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
8. 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
9. Cho EJ, Kwack MS, Jang ES, You SJ, Lee JH, Kim YJ, et al. Relative etiological role of prior hepatitis B virus infection and nonalcoholic fatty liver disease in the development of non-B non-C hepatocellular carcinoma in a hepatitis B-endemic area. Digestion 2011;84 Suppl 1:17-22.
crossref pmid
10. Yoon CH, Jin YJ, Lee JW. Nonalcoholic fatty liver disease-associated hepatocellular carcinoma in a hepatitis B virus-endemic area. Eur J Gastroenterol Hepatol 2018;30:1090-1096.
crossref pmid
11. Pais R, Fartoux L, Goumard C, Scatton O, Wendum D, Rosmorduc O, et al. Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period. Aliment Pharmacol Ther 2017;46:856-863.
crossref pmid
12. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019;16:589-604.
crossref pmid pmc pdf
13. Yang T, Hu LY, Li ZL, Liu K, Wu H, Xing H, et al. Liver resection for hepatocellular carcinoma in non-alcoholic fatty liver disease: a multicenter propensity matching analysis with HBV-HCC. J Gastrointest Surg 2020;24:320-329.
crossref pmid pdf
14. Koh YX, Tan HJ, Liew YX, Syn N, Teo JY, Lee SY, et al. Liver resection for nonalcoholic fatty liver disease-associated hepatocellular carcinoma. J Am Coll Surg 2019;229:467-478 e1.
crossref pmid
15. Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2018;68:723-750.
crossref pmid
16. National Comprehensive Cancer Network (NCCN). Hepatobiliary Cancers. NCCN web site, <https://www.nccn.org/patients/guidelines/cancers.aspx>. Accessed 27 Jul 2020.

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