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Hepatectomy versus radiofrequency ablation for early hepatocellular carcinoma: Reply

2009; Elsevier BV; Volume: 50; Issue: 5 Linguagem: Inglês

10.1016/j.jhep.2009.02.004

1600-0641

Kiyoshi Hasegawa, Masatoshi Makuuchi, Masatoshi Kudo, Masatoshi Okazaki,

Endoplasmic Reticulum Stress and Disease

We thank Dr. Fujita for his comments on our paper [[1]Hasegawa K. Makuuchi M. Takayama T. Kokudo N. Arii S. Okazaki M. et al.for the Liver Cancer Study Group of JapanSurgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey.J Hepatol. 2008; 49: 589-594Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar] describing a retrospective comparison of the clinical effects between surgical resection and percutaneous ablation, including radiofrequency ablation (RFA), for hepatocellular carcinoma (HCC). Four major points were raised in his letter.First, Dr. Fujita mentions the problem of the short follow-up period. We agree that this is one of the limitations of our study, as discussed in the paper [[1]Hasegawa K. Makuuchi M. Takayama T. Kokudo N. Arii S. Okazaki M. et al.for the Liver Cancer Study Group of JapanSurgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey.J Hepatol. 2008; 49: 589-594Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar]. We think that the main reason for the short follow-up period is the long time needed to collect, collate, and analyze the clinical data obtained from a Japanese nationwide survey, because of the large volume of the data. On the other hand, the drop-out rate would have little influence on the follow-up period, because the drop-out rates in the three groups were similar and not significant. We have no information on the reasons for the dropouts.Second, Dr. Fujita proposed the use of the step-wise multiple logistic regression analysis, instead of a Cox’s proportional hazard model. According to the statistician in our group (Yutaka Matsuyama), a Cox’s proportional hazard model is more appropriate to analyze such time-to-event data as those presented in our study. Dr. Fujita has also indicated that the recurrence rate after RFA was too high as compared to the “the local recurrence rates” reported previously. However, we determined the “overall recurrence rates” (and not the “local recurrence rates”) [[1]Hasegawa K. Makuuchi M. Takayama T. Kokudo N. Arii S. Okazaki M. et al.for the Liver Cancer Study Group of JapanSurgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey.J Hepatol. 2008; 49: 589-594Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar], which mainly represent the frequencies of intrahepatic metastasis and second primary carcinogenesis. Extrahepatic recurrence is also included in the overall recurrence rate, although it was noted in a small proportion of the patients. Thus, the overall recurrence rate of 55.4% at 2 years after RFA would be rather compatible with the previously reported rates, that is, the 2-year cumulative recurrence rate of 43.4% [[2]Tateishi R. Shiina S. Teratani T. Obi S. Sato S. Koike Y. et al.Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases.Cancer. 2005; 103: 1201-1209Crossref PubMed Scopus (691) Google Scholar] and the 2-year cumulative event-free survival rate of 37.4% [[3]Choi D. Lim H.K. Rhim H. Kim Y.S. Lee W.J. Paik S.W. et al.Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment: long-term results and prognostic factors in a large single-institution series.Eur Radiol. 2007; 17: 684-692Crossref PubMed Scopus (264) Google Scholar], which suggest that the 2-year overall recurrence rate was about 62.6%.Third, Dr. Fujita raised a question on the definition of local and distant recurrence, and about the effects of surgery on local recurrence. However, we cannot answer this question, because we do not have any data to determine the local recurrence rate. It is impossible to discuss the type of recurrence after surgery and RFA using the data available to us from this study.Dr. Fujita expressed his personal opinion following his third question. He said, “Therefore, incidence of appearance of new lesions in cirrhotic liver appears not to be an adequate measure to evaluate the efficacy of each therapeutic modality for HCC”. We agree that the overall survival is the true endpoint to evaluate the effects of a treatment modality for a malignant disease, as has been advocated [[4]Llovet J.M. Di Bisceglie A.M. Bruix J. Kramer B.S. Lencioni R. Zhu A.X. et al.Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma.J Natl Cancer Inst. 2008; 100: 698-711Crossref PubMed Scopus (1421) Google Scholar]; however, in HCC, the recurrence rate, which may include “incidence of appearance of new lesions”, should also be evaluated, because the overall survival can be easily affected by second or subsequent treatments for recurrence.Dr. Fujita also states, “it appears that RFA has become an equally effective alternative to surgical resection for early HCC”. But, what is his opinion based on? We beg to disagree with this statement, because it is not based on any concrete data. At least our data [[1]Hasegawa K. Makuuchi M. Takayama T. Kokudo N. Arii S. Okazaki M. et al.for the Liver Cancer Study Group of JapanSurgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey.J Hepatol. 2008; 49: 589-594Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar] do not lend support to the notion of equality in clinical effects between surgery and RFA.Finally, Dr. Fujita has proposed that we conduct a subgroup analysis according to the size and number of tumors. We agree with him, because a subgroup analysis would theoretically be useful in a large volume study like ours. However, we abandoned this idea, because the critical limitation of the short follow-up period in our study can still not be overcome. We shall consider a subgroup analysis in a future study, using the latest data being collected now. We thank Dr. Fujita for his comments on our paper [[1]Hasegawa K. Makuuchi M. Takayama T. Kokudo N. Arii S. Okazaki M. et al.for the Liver Cancer Study Group of JapanSurgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey.J Hepatol. 2008; 49: 589-594Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar] describing a retrospective comparison of the clinical effects between surgical resection and percutaneous ablation, including radiofrequency ablation (RFA), for hepatocellular carcinoma (HCC). Four major points were raised in his letter. First, Dr. Fujita mentions the problem of the short follow-up period. We agree that this is one of the limitations of our study, as discussed in the paper [[1]Hasegawa K. Makuuchi M. Takayama T. Kokudo N. Arii S. Okazaki M. et al.for the Liver Cancer Study Group of JapanSurgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey.J Hepatol. 2008; 49: 589-594Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar]. We think that the main reason for the short follow-up period is the long time needed to collect, collate, and analyze the clinical data obtained from a Japanese nationwide survey, because of the large volume of the data. On the other hand, the drop-out rate would have little influence on the follow-up period, because the drop-out rates in the three groups were similar and not significant. We have no information on the reasons for the dropouts. Second, Dr. Fujita proposed the use of the step-wise multiple logistic regression analysis, instead of a Cox’s proportional hazard model. According to the statistician in our group (Yutaka Matsuyama), a Cox’s proportional hazard model is more appropriate to analyze such time-to-event data as those presented in our study. Dr. Fujita has also indicated that the recurrence rate after RFA was too high as compared to the “the local recurrence rates” reported previously. However, we determined the “overall recurrence rates” (and not the “local recurrence rates”) [[1]Hasegawa K. Makuuchi M. Takayama T. Kokudo N. Arii S. Okazaki M. et al.for the Liver Cancer Study Group of JapanSurgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey.J Hepatol. 2008; 49: 589-594Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar], which mainly represent the frequencies of intrahepatic metastasis and second primary carcinogenesis. Extrahepatic recurrence is also included in the overall recurrence rate, although it was noted in a small proportion of the patients. Thus, the overall recurrence rate of 55.4% at 2 years after RFA would be rather compatible with the previously reported rates, that is, the 2-year cumulative recurrence rate of 43.4% [[2]Tateishi R. Shiina S. Teratani T. Obi S. Sato S. Koike Y. et al.Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases.Cancer. 2005; 103: 1201-1209Crossref PubMed Scopus (691) Google Scholar] and the 2-year cumulative event-free survival rate of 37.4% [[3]Choi D. Lim H.K. Rhim H. Kim Y.S. Lee W.J. Paik S.W. et al.Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment: long-term results and prognostic factors in a large single-institution series.Eur Radiol. 2007; 17: 684-692Crossref PubMed Scopus (264) Google Scholar], which suggest that the 2-year overall recurrence rate was about 62.6%. Third, Dr. Fujita raised a question on the definition of local and distant recurrence, and about the effects of surgery on local recurrence. However, we cannot answer this question, because we do not have any data to determine the local recurrence rate. It is impossible to discuss the type of recurrence after surgery and RFA using the data available to us from this study. Dr. Fujita expressed his personal opinion following his third question. He said, “Therefore, incidence of appearance of new lesions in cirrhotic liver appears not to be an adequate measure to evaluate the efficacy of each therapeutic modality for HCC”. We agree that the overall survival is the true endpoint to evaluate the effects of a treatment modality for a malignant disease, as has been advocated [[4]Llovet J.M. Di Bisceglie A.M. Bruix J. Kramer B.S. Lencioni R. Zhu A.X. et al.Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma.J Natl Cancer Inst. 2008; 100: 698-711Crossref PubMed Scopus (1421) Google Scholar]; however, in HCC, the recurrence rate, which may include “incidence of appearance of new lesions”, should also be evaluated, because the overall survival can be easily affected by second or subsequent treatments for recurrence. Dr. Fujita also states, “it appears that RFA has become an equally effective alternative to surgical resection for early HCC”. But, what is his opinion based on? We beg to disagree with this statement, because it is not based on any concrete data. At least our data [[1]Hasegawa K. Makuuchi M. Takayama T. Kokudo N. Arii S. Okazaki M. et al.for the Liver Cancer Study Group of JapanSurgical resection vs. percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japanese nationwide survey.J Hepatol. 2008; 49: 589-594Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar] do not lend support to the notion of equality in clinical effects between surgery and RFA. Finally, Dr. Fujita has proposed that we conduct a subgroup analysis according to the size and number of tumors. We agree with him, because a subgroup analysis would theoretically be useful in a large volume study like ours. However, we abandoned this idea, because the critical limitation of the short follow-up period in our study can still not be overcome. We shall consider a subgroup analysis in a future study, using the latest data being collected now.