Reply to: ““Wait and see” policy for early hepatocellular carcinoma”
Authors: Yutaka Midorikawa, Tadatoshi Takayama
Journal: Journal of Hepatology (2013)

“Wait and see” policy for early hepatocellular carcinomaJournal of HepatologyVol. 59Issue 3PreviewWe would like to comment on the recent article by Midorikawa and colleagues [1] about the management of early hepatocellular carcinoma (HCC). The authors suggest a “wait and see” policy when these lesions are recognized in a cirrhotic liver since the difference between the benefit of resection and observation was negligible in this subgroup of patients. In the authors’ opinion, only overt HCC should be promptly treated whereas early HCC lesions should not be submitted to any form of therapy (including liver resection and percutaneous ablation) because of the treatment-related risks of liver function damage and severe complications. Full-Text PDF Open AccessMarginal survival benefit in the treatment of early hepatocellular carcinomaJournal of HepatologyVol. 58Issue 2PreviewEarly treatment has been recommended for hepatocellular carcinoma (HCC) due to its high cure rate. However, the reported survival benefits of treating early HCC may be affected by lead time. Full-Text PDF Is early hepatocellular carcinoma (HCC) really a life-threatening disease?We would like to thank Dr. Francica for his interest in our recently published article on the marginal survival benefit of surgery for early HCC [[1]Midorikawa Y. Takayama T. Shimada K. Nakayama H. Higaki T. Moriguchi M. et al.Marginal survival benefit in the treatment of early hepatocellular carcinoma.J Hepatol. 2013; 58: 306-311Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. Although our data did not refer to the treatment for early HCC by radiofrequency ablation (RFA), we had expected their proposal that early HCC patients are good candidates for RFA because of its low complication rate and high curability. Yet, we believe that their point of view is absolutely not objective owing to the reasons described below.First, the cirrhotic liver harboring early HCC is in quite a highly carcinogenic state, and despite complete removal of early HCCs, most of the patients have second primary HCCs, which really need to be cured, as shown in Fig. 3B of our article [[1]Midorikawa Y. Takayama T. Shimada K. Nakayama H. Higaki T. Moriguchi M. et al.Marginal survival benefit in the treatment of early hepatocellular carcinoma.J Hepatol. 2013; 58: 306-311Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. In addition to the long lead-time required for early HCC to become overt HCC, it is not too late if early HCCs are resected or ablated by RFA at the stage of ‘real’ HCC. Thus, early HCC is not a target lesion for treatment, but a signaling lesion for a second primary HCC.Next, it cannot be determined whether early HCC (small hypovascular tumors) treated by RFA are actually HCC or not because needle biopsy is not usually performed in patients who receive RFA, as reported by Livraghi et al. [[2]Livraghi T. Lazzaroni S. Meloni F. Solbiati L. Risk of tumour seeding after percutaneous radiofrequency ablation for hepatocellular carcinoma.Br J Surg. 2005; 92: 856-858Crossref PubMed Scopus (152) Google Scholar], in their study, needle biopsy was performed only in 18.3% of patients. This fact suggests that good outcomes by RFA might be overestimated because of treatment for precursor lesions of HCC. Actually, an apparently low neoplastic-seeding rate by RFA in high-volume centers as described above can be achieved by avoiding needle biopsy. We therefore do not assume that good outcomes of RFA necessarily lead to lower morbidity.Finally, whether RFA for small HCCs is as effective as liver resection also remains controversial because of the small numbers of patients enrolled in randomized controlled trials. One randomized controlled trial performed by Feng et al. [[3]Feng K. Yan J. Li X. Xia F. Ma K. Wang S. et al.A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma.J Hepatol. 2012; 57: 794-802Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar] suggested that the outcomes of liver resection and RFA are not significantly different in patients with small HCCs. However, their study group comprised only 168 patients. They concluded that the result of percutaneous RFA depended on tumor location, and recommended open or laparoscopic ‘surgery’. It is therefore difficult to standardize the use of RFA for the treatment of early HCC. In addition, a Markov model analysis performed by Cho et al. [[4]Cho Y.K. Kim J.K. Kim W.T. Chung J.W. Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma: a Markov model analysis.Hepatology. 2010; 51: 1284-1290Crossref PubMed Scopus (180) Google Scholar] revealed that overall survival after RFA was identical to that after liver resection, provided that RFA was followed by liver resection in patients with initial local failure. On the other hand, another randomized controlled trial in larger numbers of patients reported that liver resection was significantly more advantageous [[5]Huang J. Yan L. Cheng Z. Wu H. Du L. Wang J. et al.A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria.Ann Surg. 2010; 252: 903-912Crossref PubMed Scopus (585) Google Scholar]. Thus, it cannot be simply concluded that liver resection and RFA are of similar effectiveness for the treatment of small HCC. To answer the question whether liver resection is superior to RFA or not, a nationwide randomized controlled trial involving 600 patients is now ongoing in Japan [[6]Hasegawa K. Kokudo N. Shiina S. Tateishi R. Makuuchi M. Surgery versus radiofrequency ablation for small hepatocellular carcinoma: start of a randomized controlled trial (SURF trial).Hepatol Res. 2010; 40: 851-852Crossref PubMed Scopus (27) Google Scholar].We should estimate treatment outcomes for early HCC from the stand point of biological characteristics, which differ from those of other types of cancers, including prostate cancer. Our experience with patients with treated and untreated early HCC suggests that early HCC pathologically definable as cancer might clinically be a precancerous lesion. Therefore, the good outcomes obtained by RFA for small HCCs that may include early HCC are likely to be overestimated by lead-time bias.Taken together, we advocate that early HCC is not a life-threatening disease and, therefore, both liver resection and RFA are unnecessary treatments for early HCC that cannot be justified, regardless of minimal invasiveness or lower morbidity.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Is early hepatocellular carcinoma (HCC) really a life-threatening disease? We would like to thank Dr. Francica for his interest in our recently published article on the marginal survival benefit of surgery for early HCC [[1]Midorikawa Y. Takayama T. Shimada K. Nakayama H. Higaki T. Moriguchi M. et al.Marginal survival benefit in the treatment of early hepatocellular carcinoma.J Hepatol. 2013; 58: 306-311Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. Although our data did not refer to the treatment for early HCC by radiofrequency ablation (RFA), we had expected their proposal that early HCC patients are good candidates for RFA because of its low complication rate and high curability. Yet, we believe that their point of view is absolutely not objective owing to the reasons described below. First, the cirrhotic liver harboring early HCC is in quite a highly carcinogenic state, and despite complete removal of early HCCs, most of the patients have second primary HCCs, which really need to be cured, as shown in Fig. 3B of our article [[1]Midorikawa Y. Takayama T. Shimada K. Nakayama H. Higaki T. Moriguchi M. et al.Marginal survival benefit in the treatment of early hepatocellular carcinoma.J Hepatol. 2013; 58: 306-311Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. In addition to the long lead-time required for early HCC to become overt HCC, it is not too late if early HCCs are resected or ablated by RFA at the stage of ‘real’ HCC. Thus, early HCC is not a target lesion for treatment, but a signaling lesion for a second primary HCC. Next, it cannot be determined whether early HCC (small hypovascular tumors) treated by RFA are actually HCC or not because needle biopsy is not usually performed in patients who receive RFA, as reported by Livraghi et al. [[2]Livraghi T. Lazzaroni S. Meloni F. Solbiati L. Risk of tumour seeding after percutaneous radiofrequency ablation for hepatocellular carcinoma.Br J Surg. 2005; 92: 856-858Crossref PubMed Scopus (152) Google Scholar], in their study, needle biopsy was performed only in 18.3% of patients. This fact suggests that good outcomes by RFA might be overestimated because of treatment for precursor lesions of HCC. Actually, an apparently low neoplastic-seeding rate by RFA in high-volume centers as described above can be achieved by avoiding needle biopsy. We therefore do not assume that good outcomes of RFA necessarily lead to lower morbidity. Finally, whether RFA for small HCCs is as effective as liver resection also remains controversial because of the small numbers of patients enrolled in randomized controlled trials. One randomized controlled trial performed by Feng et al. [[3]Feng K. Yan J. Li X. Xia F. Ma K. Wang S. et al.A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma.J Hepatol. 2012; 57: 794-802Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar] suggested that the outcomes of liver resection and RFA are not significantly different in patients with small HCCs. However, their study group comprised only 168 patients. They concluded that the result of percutaneous RFA depended on tumor location, and recommended open or laparoscopic ‘surgery’. It is therefore difficult to standardize the use of RFA for the treatment of early HCC. In addition, a Markov model analysis performed by Cho et al. [[4]Cho Y.K. Kim J.K. Kim W.T. Chung J.W. Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma: a Markov model analysis.Hepatology. 2010; 51: 1284-1290Crossref PubMed Scopus (180) Google Scholar] revealed that overall survival after RFA was identical to that after liver resection, provided that RFA was followed by liver resection in patients with initial local failure. On the other hand, another randomized controlled trial in larger numbers of patients reported that liver resection was significantly more advantageous [[5]Huang J. Yan L. Cheng Z. Wu H. Du L. Wang J. et al.A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria.Ann Surg. 2010; 252: 903-912Crossref PubMed Scopus (585) Google Scholar]. Thus, it cannot be simply concluded that liver resection and RFA are of similar effectiveness for the treatment of small HCC. To answer the question whether liver resection is superior to RFA or not, a nationwide randomized controlled trial involving 600 patients is now ongoing in Japan [[6]Hasegawa K. Kokudo N. Shiina S. Tateishi R. Makuuchi M. Surgery versus radiofrequency ablation for small hepatocellular carcinoma: start of a randomized controlled trial (SURF trial).Hepatol Res. 2010; 40: 851-852Crossref PubMed Scopus (27) Google Scholar]. We should estimate treatment outcomes for early HCC from the stand point of biological characteristics, which differ from those of other types of cancers, including prostate cancer. Our experience with patients with treated and untreated early HCC suggests that early HCC pathologically definable as cancer might clinically be a precancerous lesion. Therefore, the good outcomes obtained by RFA for small HCCs that may include early HCC are likely to be overestimated by lead-time bias. Taken together, we advocate that early HCC is not a life-threatening disease and, therefore, both liver resection and RFA are unnecessary treatments for early HCC that cannot be justified, regardless of minimal invasiveness or lower morbidity. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.