World J Surg (2015) 39:469–470 DOI 10.1007/s00268-014-2915-2
INVITED COMMENTARY
Is It a Time to Modify the BCLC Guidelines in Terms of the Role of Surgery? Norihiro Kokudo
Published online: 19 December 2014 Ó Socie´te´ Internationale de Chirurgie 2014
Dr. Liu and coworkers in Taichung [1] have posed an important question regarding the surgical indications for hepatocellular carcinoma (HCC) in patients with gastroesophageal varices, which is a contraindication for surgery in the BCLC/EASL/AASLD guidelines. Since their original publication in 1999 [2], these guidelines have been repeatedly reported in prestigious journals [3], and the total number of citations for these publications has already exceeded 10,000. According to the guidelines, patients with portal hypertension (PH), defined by the presence of esophagogastric varices, splenomegaly, a platelet count of less than 100,000, or an elevated hepatic venous pressure gradient (HVPG), are clearly not candidates for liver resection. However, this recommendation was based solely on a small retrospective cohort study conducted in Spain with only 77 resected patients and published in 1999 [4]. The targeted long-term outcome for BCLC-A patients was set at a 5-year overall survival (OS) rate of between 50 and 70 %, and the outcome of patients with PH did not exceed 50 % in that particular study. During the past decade, there have been several reports from both Eastern and Western countries [5–8], including one from our center [9], showing an acceptable outcome within the targeted OS range for patients with PH. However, the above-mentioned guidelines have not yet been modified. The present report provides additional evidence from the Taiwanese population showing the role of liver resection in this setting. Dr. Liu and coworkers have shown that, with
N. Kokudo (&) Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan e-mail: [email protected]
appropriate prophylactic endoscopic treatment for gastroesophageal varices, the short-term and long-term outcomes for HCC patients with PH were comparable to those for patients without PH. Of note, there were no postoperative variceal bleeding events, even among patients with risky varices (F3 and/or positive RC sign), and the 5-year OS of 66.2 % for this subgroup of patients was exactly within the target range proposed by the BCLC guidelines. These results were in accordance with those reported from a Japanese study [9]. What was not consistent was that there was no significant difference in either the OS or the disease-free survival rates between patients with and those without PH in the present study. This may be explained by the small patient number in the PH group and, most importantly, by the extremely careful patient selection that was undertaken. Although no significant differences in tumor factors were observed, in the real world, an unmeasurable difference in tumor factors might exist, including the location of the tumors, the proximity to major vessels, or the tumor morphology. An extremely careful patient selection in PH patients with Child-Pugh B liver function might have canceled the significant difference in patient outcome. According to Ishizawa, the difference in long-term outcome between a PH and a non-PH group was more significant among patients with good liver function, i.e., Child-Pugh A. This tendency should be tested in the present patient cohort. We have to admit that the possible biases mentioned above are the typical limitations of a nonrandomized cohort study, and randomized controlled trials in this setting are not feasible and may not be ethically accepted. However, before considering a modification of the BCLC guidelines, we should not forget that ICG tests, instead of HVPG measurements, are routinely done for surgical candidates in East Asia, including Taiwan and
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Japan. The reason why the presence or absence of PH was included in the BCLC guidelines is that the Child-Pugh classification, which is the gold standard for estimating hepatic functional reserve, is too inaccurate to estimate the operative risk because most surgical candidates are classified as Child-Pugh A, the most favorable subgroup. A simple modification of the BCLC guidelines consisting of the removal of PH as a criterion may be misleading and risky. Another important issue is the short-term outcome. Although most of the postoperative morbidity was not severe (grade I) in the present study, the incidence of ascites and the use of diuretics were more common in the PH group. This risk should not be underestimated, since refractory ascites after liver resection may lead to fatal sequelae. As was pointed out by Ishizawa [10], postoperative management for patients with PH should be meticulous and should be done only in specialized high volume centers. Based on the present data, together with that from previous reports, it may be safe to recommend a modest modification of the BCLC/EASL/AASLD guidelines, in which liver resection is contraindicated for HCC patients with PH. We wish to propose that liver resection could be an acceptable option for small HCCs with PH provided that the ICG test results are normal or only slightly impaired and that risky esophagogastric varices are controlled in experienced tertiary centers.
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World J Surg (2015) 39:469–470
References 1. Liu HT, Cheng SB, Wu CC, Yeh HZ, Chang CS, Wang J (2014) Impact of severe oesophagogastric varices on liver resection for hepatocellular carcinoma in cirrhotic patients. World J Surg. doi:10.1007/s00268-014-2811-9 2. Llovet JM, Bru C, Broux J (1999) Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19:329–338 3. Forner A, Llovet JM, Bruix J (2009) Hepatocellular carcinoma. Lancet 379:1245–1255 4. Llovet JM, Fuster J, Bruix J (1999) Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 30:1434–1440 5. Capussotti L, Ferrero A, Vigano L et al (2006) Portal hypertension: contraindication to liver surgery? World J Surg 30:992–999 6. Kawano Y, Sasaki A, Kai S et al (2008) Short- and long-term outcomes after hepatic resection for hepatocellular carcinoma with concomitant esophageal varices in patients with cirrhosis. Ann Surg Oncol 15:1670–1676 7. Cucchetti A, Ercolani G, Vivarelli M et al (2009) Is portal hypertension a contraindication to hepatic resection? Ann Surg 250:922–928 8. Santambrogio R, Kluger MD, Costa M et al (2013) Hepatic resection for hepatocellular carcinoma in patients with ChildPugh’s A cirrhosis: is clinical evidence of portal hypertension a contraindication? HPB (Oxford) 15:78–84 9. Ishizawa T, Hasegawa K, Aoki T et al (2008) Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 134:1908–1916 10. Ishizawa T, Hasegawa K, Kokudo N et al (2009) Risk factors and management of ascites after liver resection to treat hepatocellular carcinoma. Arch Surg 144:46–51
INVITED COMMENTARY
Is It a Time to Modify the BCLC Guidelines in Terms of the Role of Surgery? Norihiro Kokudo
Published online: 19 December 2014 Ó Socie´te´ Internationale de Chirurgie 2014
Dr. Liu and coworkers in Taichung [1] have posed an important question regarding the surgical indications for hepatocellular carcinoma (HCC) in patients with gastroesophageal varices, which is a contraindication for surgery in the BCLC/EASL/AASLD guidelines. Since their original publication in 1999 [2], these guidelines have been repeatedly reported in prestigious journals [3], and the total number of citations for these publications has already exceeded 10,000. According to the guidelines, patients with portal hypertension (PH), defined by the presence of esophagogastric varices, splenomegaly, a platelet count of less than 100,000, or an elevated hepatic venous pressure gradient (HVPG), are clearly not candidates for liver resection. However, this recommendation was based solely on a small retrospective cohort study conducted in Spain with only 77 resected patients and published in 1999 [4]. The targeted long-term outcome for BCLC-A patients was set at a 5-year overall survival (OS) rate of between 50 and 70 %, and the outcome of patients with PH did not exceed 50 % in that particular study. During the past decade, there have been several reports from both Eastern and Western countries [5–8], including one from our center [9], showing an acceptable outcome within the targeted OS range for patients with PH. However, the above-mentioned guidelines have not yet been modified. The present report provides additional evidence from the Taiwanese population showing the role of liver resection in this setting. Dr. Liu and coworkers have shown that, with
N. Kokudo (&) Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan e-mail: [email protected]
appropriate prophylactic endoscopic treatment for gastroesophageal varices, the short-term and long-term outcomes for HCC patients with PH were comparable to those for patients without PH. Of note, there were no postoperative variceal bleeding events, even among patients with risky varices (F3 and/or positive RC sign), and the 5-year OS of 66.2 % for this subgroup of patients was exactly within the target range proposed by the BCLC guidelines. These results were in accordance with those reported from a Japanese study [9]. What was not consistent was that there was no significant difference in either the OS or the disease-free survival rates between patients with and those without PH in the present study. This may be explained by the small patient number in the PH group and, most importantly, by the extremely careful patient selection that was undertaken. Although no significant differences in tumor factors were observed, in the real world, an unmeasurable difference in tumor factors might exist, including the location of the tumors, the proximity to major vessels, or the tumor morphology. An extremely careful patient selection in PH patients with Child-Pugh B liver function might have canceled the significant difference in patient outcome. According to Ishizawa, the difference in long-term outcome between a PH and a non-PH group was more significant among patients with good liver function, i.e., Child-Pugh A. This tendency should be tested in the present patient cohort. We have to admit that the possible biases mentioned above are the typical limitations of a nonrandomized cohort study, and randomized controlled trials in this setting are not feasible and may not be ethically accepted. However, before considering a modification of the BCLC guidelines, we should not forget that ICG tests, instead of HVPG measurements, are routinely done for surgical candidates in East Asia, including Taiwan and
123
470
Japan. The reason why the presence or absence of PH was included in the BCLC guidelines is that the Child-Pugh classification, which is the gold standard for estimating hepatic functional reserve, is too inaccurate to estimate the operative risk because most surgical candidates are classified as Child-Pugh A, the most favorable subgroup. A simple modification of the BCLC guidelines consisting of the removal of PH as a criterion may be misleading and risky. Another important issue is the short-term outcome. Although most of the postoperative morbidity was not severe (grade I) in the present study, the incidence of ascites and the use of diuretics were more common in the PH group. This risk should not be underestimated, since refractory ascites after liver resection may lead to fatal sequelae. As was pointed out by Ishizawa [10], postoperative management for patients with PH should be meticulous and should be done only in specialized high volume centers. Based on the present data, together with that from previous reports, it may be safe to recommend a modest modification of the BCLC/EASL/AASLD guidelines, in which liver resection is contraindicated for HCC patients with PH. We wish to propose that liver resection could be an acceptable option for small HCCs with PH provided that the ICG test results are normal or only slightly impaired and that risky esophagogastric varices are controlled in experienced tertiary centers.
123
World J Surg (2015) 39:469–470
References 1. Liu HT, Cheng SB, Wu CC, Yeh HZ, Chang CS, Wang J (2014) Impact of severe oesophagogastric varices on liver resection for hepatocellular carcinoma in cirrhotic patients. World J Surg. doi:10.1007/s00268-014-2811-9 2. Llovet JM, Bru C, Broux J (1999) Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19:329–338 3. Forner A, Llovet JM, Bruix J (2009) Hepatocellular carcinoma. Lancet 379:1245–1255 4. Llovet JM, Fuster J, Bruix J (1999) Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 30:1434–1440 5. Capussotti L, Ferrero A, Vigano L et al (2006) Portal hypertension: contraindication to liver surgery? World J Surg 30:992–999 6. Kawano Y, Sasaki A, Kai S et al (2008) Short- and long-term outcomes after hepatic resection for hepatocellular carcinoma with concomitant esophageal varices in patients with cirrhosis. Ann Surg Oncol 15:1670–1676 7. Cucchetti A, Ercolani G, Vivarelli M et al (2009) Is portal hypertension a contraindication to hepatic resection? Ann Surg 250:922–928 8. Santambrogio R, Kluger MD, Costa M et al (2013) Hepatic resection for hepatocellular carcinoma in patients with ChildPugh’s A cirrhosis: is clinical evidence of portal hypertension a contraindication? HPB (Oxford) 15:78–84 9. Ishizawa T, Hasegawa K, Aoki T et al (2008) Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 134:1908–1916 10. Ishizawa T, Hasegawa K, Kokudo N et al (2009) Risk factors and management of ascites after liver resection to treat hepatocellular carcinoma. Arch Surg 144:46–51
