Prevention of recurrence after resection of hepatocellular carcinoma: A daunting challenge

H epatocellular carcinoma (HCC) is a common cancer worldwide. It is frequently associated with hepatitis B or C viral infection and underlying cirrhosis. Advances in ablation therapies and liver transplantation have improved the chance of curative treatment for early HCC associated with severe cirrhosis. However, surgical resection is still the mainstay of curative treatment, especially for patients who present with large tumors associated with early cirrhosis. Recent improvement in surgical techniques and perioperative care has significantly reduced operative mortality and, to some extent, has improved the long-term survival of HCC patients after resection. Nonetheless, long-term prognosis after surgical resection of HCC remains unsatisfactory, compared with other common human cancers, because of a high recurrence rate and lack of effective adjuvant therapy. Most series in the literature reported a 5-year recurrence rate >70%, which is the main cause of longterm death, rather than the underlying cirrhosis. Over the past three decades, numerous studies have attempted to identify an effective strategy to prevent the recurrence of HCC. Adjuvant systemic chemotherapy is a common strategy to reduce tumor recurrence after resection of many solid organ cancers, but it has not been shown to be beneficial in HCC. The reasons for failure of systemic chemotherapy in HCC include chemoresistance of HCC cells and poor tolerance of cytotoxic drugs in cirrhotic patients. Randomized, controlled trials on locoregional chemotherapy or chemoembolization as adjuvant or neoadjuvant therapy also failed to show a significant effect on the reduction of recurrence after resection of HCC. Several approaches of adjuvant therapy, including transarterial radioactive iodine, adoptive immunotherapy, and use of retinoid after resection of HCC, have been reported to reduce recurrence rates in small-sample randomized trials conducted in the 1990s; however, their potential benefits have not been validated by subsequent trials. A recent large-scale phase II/III randomized trial involving 401 patients on the use of retinoid after resection of HCC failed to demonstrate a significant effect on recurrence-free survival. Evidence from meta-analyses of several recent randomized trials on interferon (IFN) showed that it may reduce recurrence after resection of hepatitis virus-related HCC. However, the data were pooled from trials that were each with a small sample size; hence, the overall evidence is still weak. Furthermore, IFN is associated with significant toxicity and high discontinuation rates, as demonstrated in one trial conducted in my institution. Prevention of recurrence after resection of HCC is a difficult challenge, compared with other cancers, because of its tumor biology. First, the intrinsic chemoresistance of HCC cells makes it less sensitive to the usual chemotherapy strategy. Second, unlike other cancers, in which recurrence occurs primarily because of metastasis, there are two different mechanisms of recurrence in HCC. Apart from metastatic recurrence, there is a high risk of de novo carcinogenesis in patients with underlying cirrhosis or hepatitis viral infection. Most of the postresection recurrences occur in the liver remnant, making it impossible to differentiate the origin of recurrence clinically. As the molecular mechanisms of early carcinogenesis and cancer metastasis are different, it is difficult to find an agent that can inhibit both intrahepatic metastasis and de novo carcinogenesis. My previous study has suggested that early recurrence within 1 year after resection is likely to be related to intrahepatic metastasis, whereas late recurrence is likely to be derived from de novo carcinogenesis. In any trial on adjuvant therapy to reduce recurrence after resection of HCC, it is important to consider whether the agent aims to reduce metastatic recurrence or de novo recurrence in the trial design. In the August issue of HEPATOLOGY, Yoshida et al. reported a phase II/III randomized, placebo-controlled trial using yet another approach to inhibit recurrence after resection of HCC. In the trial, 548 patients were randomized to receive 90 mg/day of vitamin K2, 45 mg/day of vitamin K2, or placebo. The trial showed no difference in disease-free survival in the placebo group, compared with the combined treatment group, Abbreviations: HCC, hepatocellular carcinoma; IFN, interferon. Address reprint requests to: Ronnie T.P. Poon, M.B. B.S., M.S., PH.D., F.H. K.A.M.(SURG), F.C.S.H. K. , F.R. C.S. (EDIN), F.A. C.S. , Department of Surgery, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong. E-mail: poontp@hkucc.hku. hk; Fax: 852-28175475. CopyrightVC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.24569 Potential conflict of interest: Nothing to report.