- Email: [email protected]
Can we expand the indications for liver transplantation among hepatocellular carcinoma patients with increased tumor size?
Malignancy indications
Can We Expand the Indications for Liver Transplantation Among Hepatocellular Carcinoma Patients With Increased Tumor Size? J.A. Ferna´ndez, R. Robles, C. Marin, F. Sa´nchez-Bueno, P. Ramirez, J.A. Pons, M.C. Garre, D. Pe´rez, A. Parrilla, J.C. Navalo´n, and P. Parrilla ABSTRACT Introduction: Due to the scarcity of donors and the fact that size is the main prognostic factor, Milan criteria have been used since 1996 to select hepatocellular carcinoma (HCC) patients for liver transplantation. In 2001 UCSF criteria showed that including layer tumors did not reduce the survival results. The objective of this paper was to evaluate whether HCC tumor sizes exceeding the Milan criteria adversely influence survival rates. Patients and methods: Between May 1988 and July 2001, 53 patients were transplanted due to HCC and cirrhosis. The etiology of cirrhosis was HCV in 23 cases and HBV in 6. In 11 cases the HCC were incidental by discovered namely, a mean/ diameter of 1.8 cm (versus 2.6 cm in nonincidental HCC). Sixty-two percent of tumors met the Milan criteria, and 68% the USCF criteria. Results. The actuarial survival was 79% at 1 year and 62% at 5 years. The survival of patients with incidental HCC was 82% at 1 year and 82% at 5 years, which is better than the survival of those with nonincidental HCC (78% at 1 year and 57% at 5 years, P ⬍ .05). According to Milan criteria, the survival patients with early tumors was 82% at 1 year and 68% at 5 years, and for advanced tumors (NS), 75% and 54%, respectively. Comparison of early versus advanced tumors according to UCSF criteria showed survivals of 84% versus 64% at 1 year (P ⬍ .05) and 67% versus 48% at 5 years (P ⬍ .05), respectively. Conclusion. Increasing the HCC size among LT according to the California criteria did not reduce survival rates compared with the Milan criteria.
0041-1345/03/$–see front matter doi:10.1016/s0041-1345(03)00723-1
© 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1818
Transplantation Proceedings, 35, 1818 –1820 (2003)
EXPANDED INDICATIONS
T
1819
HE SELECTION of patients with hepatocellular carcinoma (HCC) and cirrhosis for liver transplantation (LT) is based on prognostic systems using tumor size as the main prognostic factor.1 The milan system limits LT to patients with one lesion ⬍5 cm in diameter or no more than 3 lesions, of which none should exceed 3 cm. The use of this system achieves a survival rate of 70% at 5 years.2 This system may be too restrictive, because we are disregarding a large number of patients who can benefit from LT without treatment. Recently, expanded criteria have been published (UCSF criteria) that limit LT to patients with solitary lesions ⬍6.5 cm in diameter or no more than 3 lesions, the largest ⬍4.5 cm, with a total tumoral diameter ⬍8 cm. This system has been reported to obtain survival rates similar to those achieved with the Milan criteria.3 The goal of this paper was to evaluate whether HCC tumor sizes exceeding the Milan criteria adversely influence LT survival rates.
tumors exceeding the Milan criteria. If we compare tumors meeting and exceeding the UCSF criteria, the survivals were 84% versus 64% at 1 year (P ⬍ .05) and 67% versus 48% at 5 years (P ⬍ .05), respectively. The univariate statistical analysis identified the main prognostic factors as tumor size, Child’s classification, incidental, UCSF criteria, degree of tumor differentiation, and the presence of satellitosis. Whereas in the multivariate analysis, the only prognostic factor was tumor size: ⬍2 cm diameter displayed better survival rates than tumors ⬎2 cm (90% versus 75% at 1 year, NS, and 90% versus 53% at 5 years, P ⬍ .001). In contrast, tumors ⬍5 cm showed no difference in survival rates when compared with tumors of ⬎5 cm (81% versus 73% at 1 year and 67% versus 51% at 5 years). Tumors ⬍6.5 cm showed better survival rates than tumors ⬎6.5 cm (84% versus 70% at 1 year, NS; and 67% versus 20% at 5 years, P ⬍ .001).
PATIENTS AND METHODS
DISCUSSION
Between May 1988 and July 2001, 53 patients underwent LT due to HCC and cirrhosis. There were 44 men and 9 women of a median age of 53 years. The etiology of cirrhosis was HCV in 23 cases, alcohol in 17 cases, HBV in 6 cases, HCV⫹HBV in 2 cases, alcohol⫹HBV in 2 cases, autoimmune cirrhosis in 1 case, primary biliary cirrhosis in 1 case, and hemochromatosis in 1 case. At the time of LT, 53% of the patients were Child’s A, 30% Child’s B, and 17% Child’s C. All patients were transplanted using the piggy-back technique plus a lymphadenectomy of the portal pedicle.
The main factor that limits the use of LT in the management of HCC is the scarcity of donors.1,4 For this reason, we must reserve LT for patients with a good prognosis. The observation that patients with incidental HCC have excellent survival rates5 suggested that the best patients to transplant, in terms of prognosis, would be patients with small HCC. In 1996, Mazzaferro et al2 published excellent results using strict selection criteria based on tumor size (Milan criteria). Although these criteria have been widely accepted and adopted by UNOS, some authors3 argue that the criteria are too restrictive, because of favorable outcomes after LT6,7 among a subset of patients with tumor stages exceeding the Milan criteria (pT2). Using expanded criteria (UCSF criteria) Yao et al,8 and others9 –11 have provided evidence that it is possible to achieve satisfactory patient survival using more liberal criteria T. The use of expanded criteria for LT has several problems: first, we do not know the limit of tumor size for LT. There is no consensus on the largest tumor diameters for solitary or multifocal lesions that will result in acceptably low recurrence rates. Second, the poor results obtained with LT for large tumors may be acceptables from an oncologic point of view. Third, tumor size is not the real prognostic factor.12,13 Other factors are prognostic: DNA heterogenety,14 –16 tumor differentiation degree, and vascular invasion12,17 show a greater impact on prognosis than size. The use of these factors is limited due to the need for a pre-LT biopsy, with its attendant risks (tumoral seeding,18 bleeding, and others). Fourth, because the selection of patients occurs preoperative based on tumor size, there is a dependency on radiologic imaging, which underestimates tumor size in about 27%– 49%2,19 –21 of cases. In our opinion, it is preferable to use a liver in a patient who may ultimately suffer HCC recurrence than to withhold a liver from a patient who ultimately could have been “cured.”22
RESULTS
In 41 cases, HCC was unilobar (77%) and bilobar in 12 cases (33%). There was one nodule in 36 cases (68%), two to three nodules in 11 cases (19%), and more than three nodules in 5 cases. One case was classified as pT0N1M0. Eleven cases (21%) were incidental, with 1.3 (range, 1–3) mean number of nodules and 1.8 cm (range, 0.3– 4.0) mean diameter. In contrast, 42 cases were nonincidental, with a 2.1 (range, 1–5) mean number of nodules and 2.6 cm (range, 0.3– 0.16) mean diameter (P ⬍ .05). Thirty-three cases (62%) met Milan criteria and 36 (68%) the UCSF criteria. The survival rates for the entire group were 79% at 1 year and 62% at 5 years. The survival of patients with incidental HCC was 82% at 1 year and 82% at 5 years, which is better than the survival of patients with nonincidental HC (78% at 1 year and 57% at 5 years, P ⬍ .05). The survival of patients meeting the Milan criteria was 82% at 1 year and 68% at 5 years, and 75% at 1 year and 54% at 5 years (NS) for From the Departments of Surgery (J.A.F., R.R., F.S.B., P.R., J.C.N., P.P.), Biostatistic (D.R.), Digestive Diseases (J.A.P, M.C.G.), and Radiology (A.P.), Liver Transplant Unit, Hospital Universitario Virgen de la Arrixaca. Address reprint requests to J.A. Ferna´ ndez, Servicio de Cirugı´a l, Hospital Virgen de la Arrixaca, El Palmar S/N (Murcia), 30120, Spain. E-mail: [email protected]
1820
REFERENCES 1. Frilling A, Malago M, Broelsch CE: Dig Dis 19:333, 2001 2. Mazzaferro V, Regala E, Doci R, et al: N Engl J Med 334:693, 1996 3. Yao FY, Ferrell L, Bass NM, et al: Hepatology 33:1394, 2001 4. Llovet JM, Bruix J, Gores GJ: Hepatology 31:1019, 2000 5. Iwatsuki S, Gordon RD, Shaw BW Jr, et al: Ann Surg 202:401, 1985 6. Bismuth H, Chiche L, Adam R, et al: Ann Surg 218:145, 1993 7. Figueras J, Jaurrieta E, Valis C, et al: Hepatology 25:1485, 1997 8. United Network for Organ Sharing: Retrieved from URL: http://www.unos.org 9. Marsh JW, Dvorchik L, Iwatsuki S: Transplantation 60S:S139, 2000 10. Tan KC, Rela M, Ryder SD, et al: Br J Surg 82:253, 1995 11. McPeake JR, O’Grady JG, Zaman S, et al: J Hepatol 18:226, 1993
FERNA´ NDEZ, ROBLES, MARI´N ET AL 12. Klintmalm GB: Ann Surg 4:479, 1998 13. Fung J, Marsh W: Liver Transpl 8:775, 2002 14. Kirimlioglu H, Dvorchick I, Ruppert K, et al: Hepatology 34:502, 2001 15. Okada S, Ishii H, Nose H, et al: Cancer 75:444, 1995 16. Iwao Y, Kim Yl, Kaketani K, et al: Hepatogastroenterology 40:491, 1993 17. Jonas S, Bechstein WO, Steinmu ¨ller T, et al: Hepatology 33:1080, 2001 18. Takamori R, Wong LL, Dang C, et al: Liver Transpl 6:67, 2000 19. Michel J, Suc B, Montpeyroux F, et al: J Hepatol 26:1274, 1997 20. Llovet JM, Bruix J, Fuster J, et al: Hepatology 27:1572, 1998 21. Herrero JI, Sangro B, Quiroga J, et al: Liver Transpl 7:631, 2001 22. Yao F: Gastroenterology 122:579, 2002
Can We Expand the Indications for Liver Transplantation Among Hepatocellular Carcinoma Patients With Increased Tumor Size? J.A. Ferna´ndez, R. Robles, C. Marin, F. Sa´nchez-Bueno, P. Ramirez, J.A. Pons, M.C. Garre, D. Pe´rez, A. Parrilla, J.C. Navalo´n, and P. Parrilla ABSTRACT Introduction: Due to the scarcity of donors and the fact that size is the main prognostic factor, Milan criteria have been used since 1996 to select hepatocellular carcinoma (HCC) patients for liver transplantation. In 2001 UCSF criteria showed that including layer tumors did not reduce the survival results. The objective of this paper was to evaluate whether HCC tumor sizes exceeding the Milan criteria adversely influence survival rates. Patients and methods: Between May 1988 and July 2001, 53 patients were transplanted due to HCC and cirrhosis. The etiology of cirrhosis was HCV in 23 cases and HBV in 6. In 11 cases the HCC were incidental by discovered namely, a mean/ diameter of 1.8 cm (versus 2.6 cm in nonincidental HCC). Sixty-two percent of tumors met the Milan criteria, and 68% the USCF criteria. Results. The actuarial survival was 79% at 1 year and 62% at 5 years. The survival of patients with incidental HCC was 82% at 1 year and 82% at 5 years, which is better than the survival of those with nonincidental HCC (78% at 1 year and 57% at 5 years, P ⬍ .05). According to Milan criteria, the survival patients with early tumors was 82% at 1 year and 68% at 5 years, and for advanced tumors (NS), 75% and 54%, respectively. Comparison of early versus advanced tumors according to UCSF criteria showed survivals of 84% versus 64% at 1 year (P ⬍ .05) and 67% versus 48% at 5 years (P ⬍ .05), respectively. Conclusion. Increasing the HCC size among LT according to the California criteria did not reduce survival rates compared with the Milan criteria.
0041-1345/03/$–see front matter doi:10.1016/s0041-1345(03)00723-1
© 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1818
Transplantation Proceedings, 35, 1818 –1820 (2003)
EXPANDED INDICATIONS
T
1819
HE SELECTION of patients with hepatocellular carcinoma (HCC) and cirrhosis for liver transplantation (LT) is based on prognostic systems using tumor size as the main prognostic factor.1 The milan system limits LT to patients with one lesion ⬍5 cm in diameter or no more than 3 lesions, of which none should exceed 3 cm. The use of this system achieves a survival rate of 70% at 5 years.2 This system may be too restrictive, because we are disregarding a large number of patients who can benefit from LT without treatment. Recently, expanded criteria have been published (UCSF criteria) that limit LT to patients with solitary lesions ⬍6.5 cm in diameter or no more than 3 lesions, the largest ⬍4.5 cm, with a total tumoral diameter ⬍8 cm. This system has been reported to obtain survival rates similar to those achieved with the Milan criteria.3 The goal of this paper was to evaluate whether HCC tumor sizes exceeding the Milan criteria adversely influence LT survival rates.
tumors exceeding the Milan criteria. If we compare tumors meeting and exceeding the UCSF criteria, the survivals were 84% versus 64% at 1 year (P ⬍ .05) and 67% versus 48% at 5 years (P ⬍ .05), respectively. The univariate statistical analysis identified the main prognostic factors as tumor size, Child’s classification, incidental, UCSF criteria, degree of tumor differentiation, and the presence of satellitosis. Whereas in the multivariate analysis, the only prognostic factor was tumor size: ⬍2 cm diameter displayed better survival rates than tumors ⬎2 cm (90% versus 75% at 1 year, NS, and 90% versus 53% at 5 years, P ⬍ .001). In contrast, tumors ⬍5 cm showed no difference in survival rates when compared with tumors of ⬎5 cm (81% versus 73% at 1 year and 67% versus 51% at 5 years). Tumors ⬍6.5 cm showed better survival rates than tumors ⬎6.5 cm (84% versus 70% at 1 year, NS; and 67% versus 20% at 5 years, P ⬍ .001).
PATIENTS AND METHODS
DISCUSSION
Between May 1988 and July 2001, 53 patients underwent LT due to HCC and cirrhosis. There were 44 men and 9 women of a median age of 53 years. The etiology of cirrhosis was HCV in 23 cases, alcohol in 17 cases, HBV in 6 cases, HCV⫹HBV in 2 cases, alcohol⫹HBV in 2 cases, autoimmune cirrhosis in 1 case, primary biliary cirrhosis in 1 case, and hemochromatosis in 1 case. At the time of LT, 53% of the patients were Child’s A, 30% Child’s B, and 17% Child’s C. All patients were transplanted using the piggy-back technique plus a lymphadenectomy of the portal pedicle.
The main factor that limits the use of LT in the management of HCC is the scarcity of donors.1,4 For this reason, we must reserve LT for patients with a good prognosis. The observation that patients with incidental HCC have excellent survival rates5 suggested that the best patients to transplant, in terms of prognosis, would be patients with small HCC. In 1996, Mazzaferro et al2 published excellent results using strict selection criteria based on tumor size (Milan criteria). Although these criteria have been widely accepted and adopted by UNOS, some authors3 argue that the criteria are too restrictive, because of favorable outcomes after LT6,7 among a subset of patients with tumor stages exceeding the Milan criteria (pT2). Using expanded criteria (UCSF criteria) Yao et al,8 and others9 –11 have provided evidence that it is possible to achieve satisfactory patient survival using more liberal criteria T. The use of expanded criteria for LT has several problems: first, we do not know the limit of tumor size for LT. There is no consensus on the largest tumor diameters for solitary or multifocal lesions that will result in acceptably low recurrence rates. Second, the poor results obtained with LT for large tumors may be acceptables from an oncologic point of view. Third, tumor size is not the real prognostic factor.12,13 Other factors are prognostic: DNA heterogenety,14 –16 tumor differentiation degree, and vascular invasion12,17 show a greater impact on prognosis than size. The use of these factors is limited due to the need for a pre-LT biopsy, with its attendant risks (tumoral seeding,18 bleeding, and others). Fourth, because the selection of patients occurs preoperative based on tumor size, there is a dependency on radiologic imaging, which underestimates tumor size in about 27%– 49%2,19 –21 of cases. In our opinion, it is preferable to use a liver in a patient who may ultimately suffer HCC recurrence than to withhold a liver from a patient who ultimately could have been “cured.”22
RESULTS
In 41 cases, HCC was unilobar (77%) and bilobar in 12 cases (33%). There was one nodule in 36 cases (68%), two to three nodules in 11 cases (19%), and more than three nodules in 5 cases. One case was classified as pT0N1M0. Eleven cases (21%) were incidental, with 1.3 (range, 1–3) mean number of nodules and 1.8 cm (range, 0.3– 4.0) mean diameter. In contrast, 42 cases were nonincidental, with a 2.1 (range, 1–5) mean number of nodules and 2.6 cm (range, 0.3– 0.16) mean diameter (P ⬍ .05). Thirty-three cases (62%) met Milan criteria and 36 (68%) the UCSF criteria. The survival rates for the entire group were 79% at 1 year and 62% at 5 years. The survival of patients with incidental HCC was 82% at 1 year and 82% at 5 years, which is better than the survival of patients with nonincidental HC (78% at 1 year and 57% at 5 years, P ⬍ .05). The survival of patients meeting the Milan criteria was 82% at 1 year and 68% at 5 years, and 75% at 1 year and 54% at 5 years (NS) for From the Departments of Surgery (J.A.F., R.R., F.S.B., P.R., J.C.N., P.P.), Biostatistic (D.R.), Digestive Diseases (J.A.P, M.C.G.), and Radiology (A.P.), Liver Transplant Unit, Hospital Universitario Virgen de la Arrixaca. Address reprint requests to J.A. Ferna´ ndez, Servicio de Cirugı´a l, Hospital Virgen de la Arrixaca, El Palmar S/N (Murcia), 30120, Spain. E-mail: [email protected]
1820
REFERENCES 1. Frilling A, Malago M, Broelsch CE: Dig Dis 19:333, 2001 2. Mazzaferro V, Regala E, Doci R, et al: N Engl J Med 334:693, 1996 3. Yao FY, Ferrell L, Bass NM, et al: Hepatology 33:1394, 2001 4. Llovet JM, Bruix J, Gores GJ: Hepatology 31:1019, 2000 5. Iwatsuki S, Gordon RD, Shaw BW Jr, et al: Ann Surg 202:401, 1985 6. Bismuth H, Chiche L, Adam R, et al: Ann Surg 218:145, 1993 7. Figueras J, Jaurrieta E, Valis C, et al: Hepatology 25:1485, 1997 8. United Network for Organ Sharing: Retrieved from URL: http://www.unos.org 9. Marsh JW, Dvorchik L, Iwatsuki S: Transplantation 60S:S139, 2000 10. Tan KC, Rela M, Ryder SD, et al: Br J Surg 82:253, 1995 11. McPeake JR, O’Grady JG, Zaman S, et al: J Hepatol 18:226, 1993
FERNA´ NDEZ, ROBLES, MARI´N ET AL 12. Klintmalm GB: Ann Surg 4:479, 1998 13. Fung J, Marsh W: Liver Transpl 8:775, 2002 14. Kirimlioglu H, Dvorchick I, Ruppert K, et al: Hepatology 34:502, 2001 15. Okada S, Ishii H, Nose H, et al: Cancer 75:444, 1995 16. Iwao Y, Kim Yl, Kaketani K, et al: Hepatogastroenterology 40:491, 1993 17. Jonas S, Bechstein WO, Steinmu ¨ller T, et al: Hepatology 33:1080, 2001 18. Takamori R, Wong LL, Dang C, et al: Liver Transpl 6:67, 2000 19. Michel J, Suc B, Montpeyroux F, et al: J Hepatol 26:1274, 1997 20. Llovet JM, Bruix J, Fuster J, et al: Hepatology 27:1572, 1998 21. Herrero JI, Sangro B, Quiroga J, et al: Liver Transpl 7:631, 2001 22. Yao F: Gastroenterology 122:579, 2002