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Is liver transplantation justified for the treatment of HCC in child's a patients? not always
EDITORIAL
Is Liver Transplantation Justified for the Treatment of HCC in Child’s A Patients? Not Always. Carlos O. Esquivel
L
iver transplantation is indicated in a selective group of patients with hepatocellular carcinoma (HCC), particularly in patients with cirrhosis and HCC confined to the liver, but not amenable for resection.1 Reasons for considering patients with HCC not suitable for resection are the presence of liver impairment (Child’s B or C), bilobar involvement by a large tumor, or multiple neoplastic lesions.2 Extensive resections in patients with compromised liver function usually result in significant postoperative morbidity and mortality. As reported in the literature, the outcomes of liver transplantation are better than those of resection for the treatment of HCC, particularly in Child’s B or C patients. 3Moreover, the prognosis after liver transplantation is excellent if the HCC is small (⬍5 cm in diameter), no more than three tumors (less than three each) and no gross vascular invasion.1 More recent studies have shown that these criteria, commonly referred to as the Milan criteria, are rather conservative because patients with multiple small tumors with no vascular invasion fare just as well as patients who meet the Milan criteria.4 There is also evidence that patients with solitary large tumors may also fare very well as long as gross vascular invasion is not present.5 In patients with cirrhosis with normal synthetic function (Child’s A), the decision for recommending liver transplantation over resection becomes a bit more problematic. First, in the past the shortage of cadaveric organs resulted in a mortality rate of up to 25% among patients on the waiting list.6 However, with the implementation of the Model for End-Stage Liver Disease (MELD)-based allocation system, the death rate on the waiting list appeared to be decreasing. Nevertheless, to perform liver transplantation for small HCC in patients with normal synthetic hepatic function still may not be an optimal use of organs, a precious commodity. Second, a premature liver transplant will expose patients to the side effects of immunosuppressive drugs earlier than necessary. Furthermore, the possibility exists that the immunosuppressive regimens used in transplantation predispose to earlier recurrence and metastatic spread of previously undetected, microscopic foci of HCC after liver transplantation for HCC.7 On the other hand, not all cases of Child’s A with HCC are suitable candidates for resection. Several fac-
tors should be taken into consideration in selecting the proper candidates for resection. A significant problem in this particular patient population is the lack of an effective test to predict liver function (liver reserve) after resection. Tests such as indocyanine, caffeine, or galactose clearance or the measurement of hepatic lidocaine metabolism (MEGX) have not been particularly helpful. In Child’s A patients, the location and the size of the HCC as well as the number of the neoplastic lesions appear to be the best outcome predictors after hepatic resection.8 The presence of gross or microscopic vascular invasion, positive resection margins, and nodal involvement also are important prognostic factors.8 For example, a Child’s A patient with a 3- to 5-cm peripheral HCC may be treated safely with a segmental or subsegmental resection. In contrast, the same size tumor in a central location (for example, segment IV) may not suitable for resection. Such a location will require an extensive resection that likely could result in postoperative liver failure, even if the liver function falls into the Child’s A category. Clearly, not all Child’s A patients with HCC should be treated the same. The treatment must be tailored taking into consideration the size of the tumor, number of lesions, location, invasion of vascular structures, and the need for an extensive resection. In addition, the presence of major portal hypertension, even in a Child’s A patient, increases the morbidity and mortality after resection, particularly if the serum bilirubin is elevated.9 Finally, hepatic resection should not be considered the end point in the treatment of HCC in Child’s A patients. Although resection may be successful, patients are left with a carcinogenic environment. Patients with chronic hepatitis B or chronic hepatitis C have an From the Division of Transplantation, Stanford University, Palo Alto, CA. Address reprint requests to Carlos O. Esquivel, MD, PhD, The Arnold and Barbara Silverman Professor of Pediatric Transplantation, 750 Welch Rd, Suite 319, Palo Alto, CA 94304-1510. Telephone: 650-498-5689; FAX: 650-498-5690; E-mail: [email protected]. Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0905-0012$30.00/0 doi:10.1053/jlts.2003.50112
Liver Transplantation, Vol 9, No 5 (May), 2003: pp 521-522
521
522
Carlos O. Esquivel
annual risk of HCC ranging from 1% to 4%. Therefore, resection should be considered a bridge to transplantation should the patient develop the onset of new neoplastic lesions or progressive liver failure later in their clinical course. We have been satisfied in following our resection patients with determinations of alfa-fetoprotein levels every 3 months and biphasic computer tomography scans of the liver every 6 months. Some of our patients have been free of malignancy for several years after resection. It has been argued that a liver transplant may be more difficult in patients who have undergone previous liver resections; however, this argument is not strong enough to recommend liver transplantation for HCC in Child’s A patients. It is unknown whether resection should be considered as the first approach in the treatment of small HCC over chemoembolization, alcohol injection, or radiofrequency ablation in those patients who may have marginal liver function and will likely need liver transplantation in the near future. This should be the subject of future clinical studies.
References 1. Mazzafero V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small
2.
3.
4.
5.
6.
7.
8.
9.
hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-699. Esquivel CO, Keeffe EB, Garcia G, Imperial JC, Millan MT, Monge H, et al. Resection versus transplantation for hepatocellular carcinoma. J Gastroenterol Hepatol 1999;14:S37-S41. Ohnishi K, Tanabe Y, Ryu M, Isono K, Yamamoto Y, Usui S, et al. Prognosis of hepatocellular carcinoma smaller than 5 cm in relation to treatment: Study of 100 patients. Hepatology 1987;7: 1285-1290. Iwatsuki S, Dvorchik I, Marsh JW, Madariaga JR, Carr B, Fung JJ, Starzl TE. Liver transplantation for hepatocellular carcinoma: A proposal of a prognostic scoring system. J Am Coll Surg 2000; 191:389-394. Yao FY, Ferrell L, Bass NM, Bacchetti P, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: Comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl. 2002;8:765774. Merion RM, Wolfe RA, Dykstra DM, Leichtman AB, Gillespie B, Held PJ. Longitudinal assessment of mortality risk among candidates for liver transplantation. Liver Transpl 2003;9:22-30. Vivarelli M, Bellusci R, Cucchetti A, Cavrini G, De Ruvo N, Aden AA, et al. Low recurrence rate of hepatocellular carcinoma after liver transplantation: Better patient selection or lower immunosuppression? Transplantation 2002;74:1746-1751. Yamanaka N, Okamoto E, Toyosaka A, Mitunobu M, Fujihara S, Kato T, et al. Prognostic factors after hepatectomy for hepatocellular carcinomas. A univariate and multivariate analysis. Cancer 1990;65:1104-1110. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: Resection versus transplantation. Hepatology 1999;30:1434-1440.
Is Liver Transplantation Justified for the Treatment of HCC in Child’s A Patients? Not Always. Carlos O. Esquivel
L
iver transplantation is indicated in a selective group of patients with hepatocellular carcinoma (HCC), particularly in patients with cirrhosis and HCC confined to the liver, but not amenable for resection.1 Reasons for considering patients with HCC not suitable for resection are the presence of liver impairment (Child’s B or C), bilobar involvement by a large tumor, or multiple neoplastic lesions.2 Extensive resections in patients with compromised liver function usually result in significant postoperative morbidity and mortality. As reported in the literature, the outcomes of liver transplantation are better than those of resection for the treatment of HCC, particularly in Child’s B or C patients. 3Moreover, the prognosis after liver transplantation is excellent if the HCC is small (⬍5 cm in diameter), no more than three tumors (less than three each) and no gross vascular invasion.1 More recent studies have shown that these criteria, commonly referred to as the Milan criteria, are rather conservative because patients with multiple small tumors with no vascular invasion fare just as well as patients who meet the Milan criteria.4 There is also evidence that patients with solitary large tumors may also fare very well as long as gross vascular invasion is not present.5 In patients with cirrhosis with normal synthetic function (Child’s A), the decision for recommending liver transplantation over resection becomes a bit more problematic. First, in the past the shortage of cadaveric organs resulted in a mortality rate of up to 25% among patients on the waiting list.6 However, with the implementation of the Model for End-Stage Liver Disease (MELD)-based allocation system, the death rate on the waiting list appeared to be decreasing. Nevertheless, to perform liver transplantation for small HCC in patients with normal synthetic hepatic function still may not be an optimal use of organs, a precious commodity. Second, a premature liver transplant will expose patients to the side effects of immunosuppressive drugs earlier than necessary. Furthermore, the possibility exists that the immunosuppressive regimens used in transplantation predispose to earlier recurrence and metastatic spread of previously undetected, microscopic foci of HCC after liver transplantation for HCC.7 On the other hand, not all cases of Child’s A with HCC are suitable candidates for resection. Several fac-
tors should be taken into consideration in selecting the proper candidates for resection. A significant problem in this particular patient population is the lack of an effective test to predict liver function (liver reserve) after resection. Tests such as indocyanine, caffeine, or galactose clearance or the measurement of hepatic lidocaine metabolism (MEGX) have not been particularly helpful. In Child’s A patients, the location and the size of the HCC as well as the number of the neoplastic lesions appear to be the best outcome predictors after hepatic resection.8 The presence of gross or microscopic vascular invasion, positive resection margins, and nodal involvement also are important prognostic factors.8 For example, a Child’s A patient with a 3- to 5-cm peripheral HCC may be treated safely with a segmental or subsegmental resection. In contrast, the same size tumor in a central location (for example, segment IV) may not suitable for resection. Such a location will require an extensive resection that likely could result in postoperative liver failure, even if the liver function falls into the Child’s A category. Clearly, not all Child’s A patients with HCC should be treated the same. The treatment must be tailored taking into consideration the size of the tumor, number of lesions, location, invasion of vascular structures, and the need for an extensive resection. In addition, the presence of major portal hypertension, even in a Child’s A patient, increases the morbidity and mortality after resection, particularly if the serum bilirubin is elevated.9 Finally, hepatic resection should not be considered the end point in the treatment of HCC in Child’s A patients. Although resection may be successful, patients are left with a carcinogenic environment. Patients with chronic hepatitis B or chronic hepatitis C have an From the Division of Transplantation, Stanford University, Palo Alto, CA. Address reprint requests to Carlos O. Esquivel, MD, PhD, The Arnold and Barbara Silverman Professor of Pediatric Transplantation, 750 Welch Rd, Suite 319, Palo Alto, CA 94304-1510. Telephone: 650-498-5689; FAX: 650-498-5690; E-mail: [email protected]. Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0905-0012$30.00/0 doi:10.1053/jlts.2003.50112
Liver Transplantation, Vol 9, No 5 (May), 2003: pp 521-522
521
522
Carlos O. Esquivel
annual risk of HCC ranging from 1% to 4%. Therefore, resection should be considered a bridge to transplantation should the patient develop the onset of new neoplastic lesions or progressive liver failure later in their clinical course. We have been satisfied in following our resection patients with determinations of alfa-fetoprotein levels every 3 months and biphasic computer tomography scans of the liver every 6 months. Some of our patients have been free of malignancy for several years after resection. It has been argued that a liver transplant may be more difficult in patients who have undergone previous liver resections; however, this argument is not strong enough to recommend liver transplantation for HCC in Child’s A patients. It is unknown whether resection should be considered as the first approach in the treatment of small HCC over chemoembolization, alcohol injection, or radiofrequency ablation in those patients who may have marginal liver function and will likely need liver transplantation in the near future. This should be the subject of future clinical studies.
References 1. Mazzafero V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small
2.
3.
4.
5.
6.
7.
8.
9.
hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-699. Esquivel CO, Keeffe EB, Garcia G, Imperial JC, Millan MT, Monge H, et al. Resection versus transplantation for hepatocellular carcinoma. J Gastroenterol Hepatol 1999;14:S37-S41. Ohnishi K, Tanabe Y, Ryu M, Isono K, Yamamoto Y, Usui S, et al. Prognosis of hepatocellular carcinoma smaller than 5 cm in relation to treatment: Study of 100 patients. Hepatology 1987;7: 1285-1290. Iwatsuki S, Dvorchik I, Marsh JW, Madariaga JR, Carr B, Fung JJ, Starzl TE. Liver transplantation for hepatocellular carcinoma: A proposal of a prognostic scoring system. J Am Coll Surg 2000; 191:389-394. Yao FY, Ferrell L, Bass NM, Bacchetti P, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: Comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl. 2002;8:765774. Merion RM, Wolfe RA, Dykstra DM, Leichtman AB, Gillespie B, Held PJ. Longitudinal assessment of mortality risk among candidates for liver transplantation. Liver Transpl 2003;9:22-30. Vivarelli M, Bellusci R, Cucchetti A, Cavrini G, De Ruvo N, Aden AA, et al. Low recurrence rate of hepatocellular carcinoma after liver transplantation: Better patient selection or lower immunosuppression? Transplantation 2002;74:1746-1751. Yamanaka N, Okamoto E, Toyosaka A, Mitunobu M, Fujihara S, Kato T, et al. Prognostic factors after hepatectomy for hepatocellular carcinomas. A univariate and multivariate analysis. Cancer 1990;65:1104-1110. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: Resection versus transplantation. Hepatology 1999;30:1434-1440.