- Email: [email protected]
Liver Transplantation for Cholangiocarcinoma Beyond a Clinical Trial
304
Letters
We used the bootstrap validation algorithm given by Harrell and colleagues,2 using their proposed 200 iterations. As stated in the Methods section, consistency of bootstrap results and potential overfitting were address by the algorithm. We sought to achieve a model with lower dimensionality. We did this by not adding variables to the model if the new variable did not increase the c-statistic by at least 0.01. Dr Fabri suggests using the split-sample, or holdout method, as a final verification. Taking a random sample, as Dr Fabri suggests, has been refuted and referenced in Methods section. To prevent overfitting, a minimum sample size of 10 per variable in the model should be used.3-5 If we had used 10% of the patients, as Dr Fabri suggests, the number of nonsurvivors would have been 18 patients, so overfitting would have occurred when we applied our 9-variable model. We appreciate the opportunity to respond to Dr Fabri’s comments. REFERENCES 1. Box GP, Draper NR. Empirical Model-Building and Response Surfaces. New York: John Wiley & Sons; 1987:424. 2. Harrell FE, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 1996;15:361e387. 3. Draper NR, Smith H. Applied Regression Analysis. Third Edition. New York: John Wiley & Sons; 1998. 4. Ryan T. Modern Regression Methods. New York: John Wiley & Sons; 1997. 5. Good PI, Hardin JW. Common Errors in Statistics (and How to Avoid Them). New York: John Wiley & Sons; 2006.
Disclosure Information: Nothing to disclose.
Liver Transplantation for Cholangiocarcinoma Beyond a Clinical Trial Tetsuji Fujita, Tokyo, Japan
MD
In a comprehensive review of intrahepatic cholangiocarcinoma (ICC),1 Dr Dodson and coauthors suggested that orthotopic liver transplantation is generally contraindicated for ICC, because 5-year survival rates after transplant are usually less than 30%dworse than those of other diseases for which liver transplantation can be considered as a treatment. As briefly mentioned in this review, a Canadian study reported a 3-year survival rate of 30% after
J Am Coll Surg
transplant for patients with early-stage cholangiocarcinoma incidentally found in the explanted liver,2 and in another study based on the Cincinnati Transplant Tumor Registry that enrolled a total of 207 patients, a 5-year survival estimate after transplant for cholangiocarcinoma was 23%, with an operative mortality rate of 10%.3 Consequently, Dodson and coauthors1 argued that liver transplantation should be considered only in the setting of a protocol. These suggestions seem to be reasonable, because 5-year survival rates after liver transplantation for cirrhotic patients with hepatocellular carcinoma usually exceed 60%.4 These findings will not justify the use of a deceased-donor organ for treatment of cholangiocarcinoma unless comparable outcomes are achieved after transplant, because of a shortage of donor organs. It should be noted that the Canadian study included only 10 patients, and in that study, the American Joint Committee on Cancer (AJCC) 5th edition of TNM staging manual was used for tumor staging, without sufficient lymph node assessment,2 posing the possibility of mistaking advanced-stage for early-stage cholangiocarcinoma. In predicting the survival of patients with hilar cholangiocarcinoma, the 5th edition has been shown to be less effective than the 6th edition, and the 6th edition is likely less predictive than the current 7th edition.5 Also regarding the Cincinnati study, the median follow-up period was short (23 months), and larger tumor size and multifocal disease were not associated with tumor recurrence, probably because of insufficient data collection.3 More recent reports from a single center revealed improved survival rates after transplantation for patients with hilar cholangiocarcinoma or ICC, ranging from a 3-year survival rate of 52%,6 to a 4-year survival rate of 61%,7 approaching the threshold of a survival rate that would justify liver transplantation for cholangiocarcinoma, although with high operative mortality rates (14% to 20%). In a recent pooled analysis of 359 patients with cholangiocarcinoma who underwent liver transplantation between 1987 and 2008 in the United States, an overall 5-year probability of survival was 51.4%, with an improvement in survival each year, reaching a survival rate of 58.75% for those undergoing transplantation after 2000.8 In another registry-based study that examined outcomes in 280 patients receiving transplants for otherwise unresectable hilar cholangiocarcinoma or ICC between 1987 and 2005, the overall survival rate was 38%. In subset analysis, patients who received a transplant for known cholangiocarcinoma experienced an improved 5-year survival rate of 68%; those with incidental cholangiocarcinoma found in the examined liver experienced a poor 5-year survival rate of only 20%.9 These findings indicate the importance of accurate tumor staging and neoadjuvant therapy.
Vol. 218, No. 2, February 2014
The success of liver transplantation for cholangiocarcinoma appears to be dependent on selection of patients who have locally advanced tumor without lymph node and intrahepatic metastases, the effectiveness of neoadjuvant chemoradiation, and the use of highly skilled surgical techniques. Under such conditions, a 65% rate of diseasefree 5-year survival rate was achieved in 287 patients with hilar cholangiocarcinoma.10 In current United Network for Organ Sharing (UNOS) policy, the patient with hilar cholangiocarcinoma of 3 cm diameter or less without intra- and extrahepatic metastases is a candidate for liver transplantation if the tumor is responsive to neoadjuvant chemoradiation and a staging laparotomy proves no lymph node metastasis before transplantation.11 The UNOS does not provide treatment guidelines for ICC. An ICC arising from the liver and extending to the hepatic hilum is regarded as a perihilar cholangiocarcinoma. In the 7th edition of the AJCC manual, ICC, perihilar cholangiocarcinoma, and distal bile duct cancer are separately staged. In a comparative analysis of radical resection and liver transplantation for ICC and hilar cholangiocarcinoma by Dr Hong and colleagues,12 ICC and transplantation were independently associated with better survival. They proposed expansion of the tumor size criteria to 8 cm for ICC and 3.5 cm for hilar cholangiocarcinoma in patients with demonstrated good response to neoadjuvant therapy. Currently, more than 6,000 liver transplantations are performed each year in the United States, while about 1% of transplantations are for patients with cholangiocarcinoma. The critical question to be solved is how much priority patients with cholangiocarcinoma should receive in the liver transplant list in comparison to those with other indications. Meanwhile, in specialized centers, liver transplantation preceded by neoadjuvant therapy would be considered as a treatment option for patients with an otherwise unresectable, nonmetastatic cholangiocarcinoma, even beyond the scope of a clinical trial. REFERENCES 1. Dodson RM, Weiss MJ, Cosgrove D, et al. Intrahepatic cholangiocarcinoma: management options and emerging therapies. J Am Coll Surg 2013;217:736e750. 2. Ghali P, Marotta PJ, Yoshida EM, et al. Liver transplantation for incidental cholangiocarcinoma: analysis of the Canadian experience. Liver Transplant 2005;11:1412e1416. 3. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 2000; 69:1633e1637. 4. Taefi A, Abrishami A, Nasseri-Moghaddam S, et al. Surgical resection versus liver transplant for patients with hepatocellular carcinoma. Cochrane Database Syst Rev 2013;6:CD006935. 5. Fujita T. Better staging for tailored treatment of perihilar cholangiocarcinoma. Transl Gastrointest Cancer 2013. http://dx. doi.org/10.3978/j.issn.2224-4778.2013.03.12.
Letters
305
6. Panjala C, Nguyen JH, Al-Hajjaj AN, et al. Impact of neoadjuvant chemoradiation on the tumor burden before liver transplantation for unresectable cholangiocarcinoma. Liver Transpl 2012;18:594e601. 7. Duignan S, Maguire D, Chamarajanagar S, et al. Neoadjuvant chemoradiotherapy followed by liver transplantation for unresectable cholangiocarcinoma: a single-centre national experience. HPB 2013 April 18. [Epub ahead of print]. 8. Salgia RJ, Singal AG, Fu S, et al. Improved post-transplant survival in the United States for patients with cholangiocarcinoma after 2000. Dig Dis Sci 2013 March 16. [Epub ahead of print]. 9. Becker NS, Rodriguez JA, Barshes NR, et al. Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg 2008;12:117e122. 10. Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology 2012;143:88e98. 11. United Network for Organ Sharing Organ Distribution. Organ distribution: allocation of livers. Available at: http://optn. transplant.hrsa.gov/PoliciesandBylaws2/policies/pdfs/policy_8. pdf. Accessed November 11, 2013. 12. Hong JC, Jones CM, Duffy JP, et al. Comparative analysis of resection and liver transplantation for Intrahepatic and hilar cholangiocarcinoma A 24-year experience in a single center. Arch Surg 2011;146:683e689.
Disclosure Information: Nothing to disclose.
Reply Kevin C Soares, MD, Timothy M Pawlik, MD, MPH, PhD, FACS Baltimore, MD We would like to thank Dr Tetsuji Fujita for his interest in this article and his letter. He addresses an important component of cholangiocarcinoma (CC) therapy; the role of orthotopic liver transplantation (OLT). In our review, we focused exclusively on intrahepatic cholangiocarcinoma (ICC) and noted that most reports of OLT for ICC demonstrate 5-year survival rates of approximately 30% or less,1-3 but Dr Fujita’s letter highlights the important role of transplantation for hilar cholangiocarcinoma.4,5 Specifically, Dr Fujita notes that the 4-year survival of patients treated with neoadjuvant therapy and transplantation can approach 60% to 65%.6 The benefit of OLT for hilar cholangiocarcinoma appears to be particularly pronounced for those patients with primary sclerosing cholangitis.7,8 As such, we completely agree with Dr Fujita that transplantation has a defined role in treating some subtypes of cholangiocarcinoma. Although the role of transplantation for hilar cholangiocarcinoma has been established by the pioneering work
Letters
We used the bootstrap validation algorithm given by Harrell and colleagues,2 using their proposed 200 iterations. As stated in the Methods section, consistency of bootstrap results and potential overfitting were address by the algorithm. We sought to achieve a model with lower dimensionality. We did this by not adding variables to the model if the new variable did not increase the c-statistic by at least 0.01. Dr Fabri suggests using the split-sample, or holdout method, as a final verification. Taking a random sample, as Dr Fabri suggests, has been refuted and referenced in Methods section. To prevent overfitting, a minimum sample size of 10 per variable in the model should be used.3-5 If we had used 10% of the patients, as Dr Fabri suggests, the number of nonsurvivors would have been 18 patients, so overfitting would have occurred when we applied our 9-variable model. We appreciate the opportunity to respond to Dr Fabri’s comments. REFERENCES 1. Box GP, Draper NR. Empirical Model-Building and Response Surfaces. New York: John Wiley & Sons; 1987:424. 2. Harrell FE, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 1996;15:361e387. 3. Draper NR, Smith H. Applied Regression Analysis. Third Edition. New York: John Wiley & Sons; 1998. 4. Ryan T. Modern Regression Methods. New York: John Wiley & Sons; 1997. 5. Good PI, Hardin JW. Common Errors in Statistics (and How to Avoid Them). New York: John Wiley & Sons; 2006.
Disclosure Information: Nothing to disclose.
Liver Transplantation for Cholangiocarcinoma Beyond a Clinical Trial Tetsuji Fujita, Tokyo, Japan
MD
In a comprehensive review of intrahepatic cholangiocarcinoma (ICC),1 Dr Dodson and coauthors suggested that orthotopic liver transplantation is generally contraindicated for ICC, because 5-year survival rates after transplant are usually less than 30%dworse than those of other diseases for which liver transplantation can be considered as a treatment. As briefly mentioned in this review, a Canadian study reported a 3-year survival rate of 30% after
J Am Coll Surg
transplant for patients with early-stage cholangiocarcinoma incidentally found in the explanted liver,2 and in another study based on the Cincinnati Transplant Tumor Registry that enrolled a total of 207 patients, a 5-year survival estimate after transplant for cholangiocarcinoma was 23%, with an operative mortality rate of 10%.3 Consequently, Dodson and coauthors1 argued that liver transplantation should be considered only in the setting of a protocol. These suggestions seem to be reasonable, because 5-year survival rates after liver transplantation for cirrhotic patients with hepatocellular carcinoma usually exceed 60%.4 These findings will not justify the use of a deceased-donor organ for treatment of cholangiocarcinoma unless comparable outcomes are achieved after transplant, because of a shortage of donor organs. It should be noted that the Canadian study included only 10 patients, and in that study, the American Joint Committee on Cancer (AJCC) 5th edition of TNM staging manual was used for tumor staging, without sufficient lymph node assessment,2 posing the possibility of mistaking advanced-stage for early-stage cholangiocarcinoma. In predicting the survival of patients with hilar cholangiocarcinoma, the 5th edition has been shown to be less effective than the 6th edition, and the 6th edition is likely less predictive than the current 7th edition.5 Also regarding the Cincinnati study, the median follow-up period was short (23 months), and larger tumor size and multifocal disease were not associated with tumor recurrence, probably because of insufficient data collection.3 More recent reports from a single center revealed improved survival rates after transplantation for patients with hilar cholangiocarcinoma or ICC, ranging from a 3-year survival rate of 52%,6 to a 4-year survival rate of 61%,7 approaching the threshold of a survival rate that would justify liver transplantation for cholangiocarcinoma, although with high operative mortality rates (14% to 20%). In a recent pooled analysis of 359 patients with cholangiocarcinoma who underwent liver transplantation between 1987 and 2008 in the United States, an overall 5-year probability of survival was 51.4%, with an improvement in survival each year, reaching a survival rate of 58.75% for those undergoing transplantation after 2000.8 In another registry-based study that examined outcomes in 280 patients receiving transplants for otherwise unresectable hilar cholangiocarcinoma or ICC between 1987 and 2005, the overall survival rate was 38%. In subset analysis, patients who received a transplant for known cholangiocarcinoma experienced an improved 5-year survival rate of 68%; those with incidental cholangiocarcinoma found in the examined liver experienced a poor 5-year survival rate of only 20%.9 These findings indicate the importance of accurate tumor staging and neoadjuvant therapy.
Vol. 218, No. 2, February 2014
The success of liver transplantation for cholangiocarcinoma appears to be dependent on selection of patients who have locally advanced tumor without lymph node and intrahepatic metastases, the effectiveness of neoadjuvant chemoradiation, and the use of highly skilled surgical techniques. Under such conditions, a 65% rate of diseasefree 5-year survival rate was achieved in 287 patients with hilar cholangiocarcinoma.10 In current United Network for Organ Sharing (UNOS) policy, the patient with hilar cholangiocarcinoma of 3 cm diameter or less without intra- and extrahepatic metastases is a candidate for liver transplantation if the tumor is responsive to neoadjuvant chemoradiation and a staging laparotomy proves no lymph node metastasis before transplantation.11 The UNOS does not provide treatment guidelines for ICC. An ICC arising from the liver and extending to the hepatic hilum is regarded as a perihilar cholangiocarcinoma. In the 7th edition of the AJCC manual, ICC, perihilar cholangiocarcinoma, and distal bile duct cancer are separately staged. In a comparative analysis of radical resection and liver transplantation for ICC and hilar cholangiocarcinoma by Dr Hong and colleagues,12 ICC and transplantation were independently associated with better survival. They proposed expansion of the tumor size criteria to 8 cm for ICC and 3.5 cm for hilar cholangiocarcinoma in patients with demonstrated good response to neoadjuvant therapy. Currently, more than 6,000 liver transplantations are performed each year in the United States, while about 1% of transplantations are for patients with cholangiocarcinoma. The critical question to be solved is how much priority patients with cholangiocarcinoma should receive in the liver transplant list in comparison to those with other indications. Meanwhile, in specialized centers, liver transplantation preceded by neoadjuvant therapy would be considered as a treatment option for patients with an otherwise unresectable, nonmetastatic cholangiocarcinoma, even beyond the scope of a clinical trial. REFERENCES 1. Dodson RM, Weiss MJ, Cosgrove D, et al. Intrahepatic cholangiocarcinoma: management options and emerging therapies. J Am Coll Surg 2013;217:736e750. 2. Ghali P, Marotta PJ, Yoshida EM, et al. Liver transplantation for incidental cholangiocarcinoma: analysis of the Canadian experience. Liver Transplant 2005;11:1412e1416. 3. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 2000; 69:1633e1637. 4. Taefi A, Abrishami A, Nasseri-Moghaddam S, et al. Surgical resection versus liver transplant for patients with hepatocellular carcinoma. Cochrane Database Syst Rev 2013;6:CD006935. 5. Fujita T. Better staging for tailored treatment of perihilar cholangiocarcinoma. Transl Gastrointest Cancer 2013. http://dx. doi.org/10.3978/j.issn.2224-4778.2013.03.12.
Letters
305
6. Panjala C, Nguyen JH, Al-Hajjaj AN, et al. Impact of neoadjuvant chemoradiation on the tumor burden before liver transplantation for unresectable cholangiocarcinoma. Liver Transpl 2012;18:594e601. 7. Duignan S, Maguire D, Chamarajanagar S, et al. Neoadjuvant chemoradiotherapy followed by liver transplantation for unresectable cholangiocarcinoma: a single-centre national experience. HPB 2013 April 18. [Epub ahead of print]. 8. Salgia RJ, Singal AG, Fu S, et al. Improved post-transplant survival in the United States for patients with cholangiocarcinoma after 2000. Dig Dis Sci 2013 March 16. [Epub ahead of print]. 9. Becker NS, Rodriguez JA, Barshes NR, et al. Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg 2008;12:117e122. 10. Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology 2012;143:88e98. 11. United Network for Organ Sharing Organ Distribution. Organ distribution: allocation of livers. Available at: http://optn. transplant.hrsa.gov/PoliciesandBylaws2/policies/pdfs/policy_8. pdf. Accessed November 11, 2013. 12. Hong JC, Jones CM, Duffy JP, et al. Comparative analysis of resection and liver transplantation for Intrahepatic and hilar cholangiocarcinoma A 24-year experience in a single center. Arch Surg 2011;146:683e689.
Disclosure Information: Nothing to disclose.
Reply Kevin C Soares, MD, Timothy M Pawlik, MD, MPH, PhD, FACS Baltimore, MD We would like to thank Dr Tetsuji Fujita for his interest in this article and his letter. He addresses an important component of cholangiocarcinoma (CC) therapy; the role of orthotopic liver transplantation (OLT). In our review, we focused exclusively on intrahepatic cholangiocarcinoma (ICC) and noted that most reports of OLT for ICC demonstrate 5-year survival rates of approximately 30% or less,1-3 but Dr Fujita’s letter highlights the important role of transplantation for hilar cholangiocarcinoma.4,5 Specifically, Dr Fujita notes that the 4-year survival of patients treated with neoadjuvant therapy and transplantation can approach 60% to 65%.6 The benefit of OLT for hilar cholangiocarcinoma appears to be particularly pronounced for those patients with primary sclerosing cholangitis.7,8 As such, we completely agree with Dr Fujita that transplantation has a defined role in treating some subtypes of cholangiocarcinoma. Although the role of transplantation for hilar cholangiocarcinoma has been established by the pioneering work