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Transarterial Chemoembolization Before Liver Transplantation in 60 Patients With Hepatocellular Carcinoma
Transarterial Chemoembolization Before Liver Transplantation in 60 Patients With Hepatocellular Carcinoma G. Otto, M. Heise, C. Moench, S. Herber, F. Bittinger, M. Schuchmann, M. Hoppe-Lotichius, and M. Pitton ABSTRACT Tumor recurrence is a major problem after orthotopic liver transplantation (OLT) in patients with hepatocellular carcinoma (HCC). In 60 patients OLT was performed for HCC after pretreatment by repeated transarterial chemoembolization (TACE). Forty-four recipients exceeded the Milan criteria. Recurrence-free 5-year survival was 65.2% and 5-year freedom from recurrence was 73.2%. During the waiting time, 14 patients experienced minimal change, which did not fulfill the definition of tumor progression according to official oncological criteria. Five-year freedom from recurrence among patients with stable compared with progressive disease was 93.3% versus 28.1%, respectively (P ⫽ .0001). A strict TACE pretreatment protocol may select patients with obviously biologically less aggressive tumors, who are suitable for OLT even if the HCC exceeds the commonly accepted listing criteria.
R
ESULTS AFTER orthotopic liver transplantation (OLT) in patients with hepatocellular carcinoma (HCC) are hampered by tumor recurrence. Selection of patients amenable to this therapeutic approach is crucial for a favorable outcome. OLT is deemed to be indicated if the Milan criteria are fulfilled.1 Among other approaches, transarterial chemoembolization (TACE) is widely used to bridge the waiting time.2– 4 We recently reported 50 patients with repeatedly performed TACE; herein we selected patients suitable for OLT even if the tumor exceeded the Milan criteria.5
PATIENTS AND METHODS Between January 1998 and January 2006, 113 patients without a contraindication for OLT were included in a TACE protocol. The 36 who responded to TACE according to the RECIST criteria6 were thereafter listed for transplantation, in contrast to 24 patients who met the Milan criteria and were immediately listed. Eleven patients died while on waiting list; 4 developed extrahepatic disease; and 11 patients were still on the waiting list (January 2006). OLT was performed in 60 patients with HCC after TACE pretreatment. In 16, the Milan criteria were fulfilled, whereas 44 exceeded the Mc. Before transplantation, TACE was performed every 6 weeks using mitomycin and lipiodol until transplantation. Increase in size or additional nodules during the waiting time was considered as “progress during waiting time” if confirmed by two independent observers, even if the RECIST definition was not fulfilled. Every © 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 39, 537–539 (2007)
3 months extrahepatic tumor growth was excluded by thoracic and abdominal computed tomography. TOR inhibitors were not used. Table 1 summarizes the patients characteristics. All data were prospectively collected in our transplant database. Details of the TACE approach and of the tumor assessment have been described elsewhere.5
RESULTS
Patients within the Milan criteria received a media of four (range, 2 to 10), and patients beyond these criteria five (range, 2 to 14) cycles of TACE. After a median follow-up of 802 days, the recurrence-free 5-year survival was 65.2% and 5-year freedom from recurrence was 73.2%. Freedom from recurrence after 5 years for patients within and beyond the Milan criteria was 82.0% and 70.5%, respectively (P ⫽ .4845). During waiting time, 14 patients initially exceeding and 2 patients meeting the Milan criteria had From the Department of Transplantation and Hepatobiliary Surgery (G.O., M.H., C.M., M.H.-L.), the Department of Radiology (S.H., M.P.), the Institute of Pathology (F.B.), and 1st Medical Clinic of the University of Mainz (M.S.), Mainz, Germany. Address reprint requests to Prof Dr Gerd Otto, Department of Transplantation and Hepatobiliopancreatic Surgery, University of Mainz, 55131 Mainz, Germany. E-mail: otto@transplantation. klinik.uni-mainz.de 0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2006.12.007 537
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“progressive disease,” whereas 44 patients remained stable until OLT. The 5-year freedom from recurrence in patients with stable compared with progressive disease was 93.3% versus 28.1%, respectively (P ⫽ .0001). Figure 1 shows survival and recurrence-free survival (Fig 1A), freedom from recurrence according to the Milan criteria (Fig 1B) and freedom from recurrence according to tumor progression during waiting time (Fig 1C). TACE without progress during waiting time and one to three tumor nodules in the specimen were significant predictors of tumor recurrence in the Cox analysis (P ⫽ .001, risk ratio 10.8 and P ⫽ .006, risk ratio 0.165, respectively; Table 2).
DISCUSSION
So far, pretreatment before OLT has usually been performed to bridge the waiting time.2,7 In one study, downstaging was obviousy capable of influencing tumor recurrence.3 The principal difference of our approach compared with former studies was the number of TACE procedures performed before OLT. Whereas in previous studies the number of TACE procedures were one or two,2– 4,7 repeatedly performed TACE according to a strict protocol was performed in our patients. Freedom from recurrence was not influenced by the classification of the patients according to the Milan criteria or by downstaging to a stage meeting them, but rather the stability of the disease during pretreatment by TACE. Tumor recurrence occurred in only 3 of 44 patients with stable disease compared with 8 of 16 patients with tumor progression during the waiting time. It is highly desirable to select patients with HCC suitable for OLT not only to save scarce organs, but also to prevent accelerated tumor growth due to immunosuppression. The prognosis after OLT may be influenced by prognostic markers, such as the loss of heterozygosity,8 DNA ploidy,9 and other metrics.10 The present update corroborates our former statement that also a strictly used pretreatment protocol with TACE may select patients with obviously
Fig 1. Survival, recurrence-free survival (A), freedom from recurrence according to the Milan criteria (B) and freedom from recurrence according to tumor progress during waiting time during TACE pretreatment (C) in 60 patients after liver transplantation for hepatocellular carcinoma.
Table 1. Characteristics of 60 Patients Following TACE Pretreatment Before LT Characteristics
n
Median follow-up (range) Age Male/female Milan criteria fulfilled/exceeded* 1–3 nodules/multiple nodules (initial CT) 1–3 nodules/multiple nodules (specimen) Tumor diameter ⱕ3 cm/⬎3 cm (initial CT) Tumor diameter ⱕ3 cm/⬎3 cm (specimen) T classification: T1/T2/T3 (specimen) G1/G2/G3 Angioinvasion yes/no Child A/B/C Initial disease (HCV/HBV/alcoholic/others)
802 (1–2832) days 60.1 (33.6–70.5) 46–14 16–44 39–21 46–14 32–28 40–20 26/25/9 2/44/14 12/48 39/12/9 17/9/25/9
*Classification according to the maximal number of patients exceeding the Milan criteria either in the CT scan or in the pathomorphologic evaluation.
biologically less aggressive tumors leading to a favorable prognosis even among patients exceeding the commonly accepted listing criteria. These results may have implications for the future treatment of these patients including living donation.
Table 2. Posttransplant Freedom From Recurrence: Multivariate Analysis RR
95% Confidence Interval for RR
Predictor
n
Significance
1, 2, 3 vs multiple nodules (in specimen) Progress
46/14
.006
0.165
0.046–0.597
44/16
.001
10.765
2.741–42.281
TRANSARTERIAL CHEMOEMBOLIZATION
REFERENCES 1. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinoman in patients with cirrhosis. N Engl J Med 334:693, 1996 2. Decaens T, Roudot-Thoraval F, Bresson-Hadni S, et al: Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma. Liver Transpl 11:767, 2005 3. Majno PE, Adam R, Bismuth H, et al: Influence of preoperative transarterial lipiodol chemoembolization of resection and transplantation for hepatocellular carcinoma in patients with cirrhosis. Ann Surg 226:688, 1997 4. Roayaie S, Frischer JS, Emre SH, et al: Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg 235:533, 2002 5. Otto G, Herber S, Heise M, et al: Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma. Liver Transpl 12:1260, 2006
539 6. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guideline to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205, 2000 7. Yao FY, Kinkhabwala M, LaBerge JM, et al: The impact of pre-operative loco-regional therapy on outcome after liver transplantation for hepatocellular carcinoma. Am J Transplant 5:795, 2005 8. Marsh JW, Finkelstein SD, Demetris AJ, et al: Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determing recurrence-free survival. Liver Transpl 9:664, 2003 9. Mise K, Tashiro S, Yogita S, et al: Assessment of the biological malignancy of hepatocellular carcinoma: relationship to clinicopathological factors and prognosis. Clin Cancer Res 4:1475, 1998 10. Fiorentino MF, Altimari A, Ravaioli M, et al: Predictive value of biological markers for hepatocellular carcinoma patients treated with orthotipic liver transplantation. Clin Cancer Res 10: 1789, 2004
R
ESULTS AFTER orthotopic liver transplantation (OLT) in patients with hepatocellular carcinoma (HCC) are hampered by tumor recurrence. Selection of patients amenable to this therapeutic approach is crucial for a favorable outcome. OLT is deemed to be indicated if the Milan criteria are fulfilled.1 Among other approaches, transarterial chemoembolization (TACE) is widely used to bridge the waiting time.2– 4 We recently reported 50 patients with repeatedly performed TACE; herein we selected patients suitable for OLT even if the tumor exceeded the Milan criteria.5
PATIENTS AND METHODS Between January 1998 and January 2006, 113 patients without a contraindication for OLT were included in a TACE protocol. The 36 who responded to TACE according to the RECIST criteria6 were thereafter listed for transplantation, in contrast to 24 patients who met the Milan criteria and were immediately listed. Eleven patients died while on waiting list; 4 developed extrahepatic disease; and 11 patients were still on the waiting list (January 2006). OLT was performed in 60 patients with HCC after TACE pretreatment. In 16, the Milan criteria were fulfilled, whereas 44 exceeded the Mc. Before transplantation, TACE was performed every 6 weeks using mitomycin and lipiodol until transplantation. Increase in size or additional nodules during the waiting time was considered as “progress during waiting time” if confirmed by two independent observers, even if the RECIST definition was not fulfilled. Every © 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 39, 537–539 (2007)
3 months extrahepatic tumor growth was excluded by thoracic and abdominal computed tomography. TOR inhibitors were not used. Table 1 summarizes the patients characteristics. All data were prospectively collected in our transplant database. Details of the TACE approach and of the tumor assessment have been described elsewhere.5
RESULTS
Patients within the Milan criteria received a media of four (range, 2 to 10), and patients beyond these criteria five (range, 2 to 14) cycles of TACE. After a median follow-up of 802 days, the recurrence-free 5-year survival was 65.2% and 5-year freedom from recurrence was 73.2%. Freedom from recurrence after 5 years for patients within and beyond the Milan criteria was 82.0% and 70.5%, respectively (P ⫽ .4845). During waiting time, 14 patients initially exceeding and 2 patients meeting the Milan criteria had From the Department of Transplantation and Hepatobiliary Surgery (G.O., M.H., C.M., M.H.-L.), the Department of Radiology (S.H., M.P.), the Institute of Pathology (F.B.), and 1st Medical Clinic of the University of Mainz (M.S.), Mainz, Germany. Address reprint requests to Prof Dr Gerd Otto, Department of Transplantation and Hepatobiliopancreatic Surgery, University of Mainz, 55131 Mainz, Germany. E-mail: otto@transplantation. klinik.uni-mainz.de 0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2006.12.007 537
538
OTTO, HEISE, MOENCH ET AL
“progressive disease,” whereas 44 patients remained stable until OLT. The 5-year freedom from recurrence in patients with stable compared with progressive disease was 93.3% versus 28.1%, respectively (P ⫽ .0001). Figure 1 shows survival and recurrence-free survival (Fig 1A), freedom from recurrence according to the Milan criteria (Fig 1B) and freedom from recurrence according to tumor progression during waiting time (Fig 1C). TACE without progress during waiting time and one to three tumor nodules in the specimen were significant predictors of tumor recurrence in the Cox analysis (P ⫽ .001, risk ratio 10.8 and P ⫽ .006, risk ratio 0.165, respectively; Table 2).
DISCUSSION
So far, pretreatment before OLT has usually been performed to bridge the waiting time.2,7 In one study, downstaging was obviousy capable of influencing tumor recurrence.3 The principal difference of our approach compared with former studies was the number of TACE procedures performed before OLT. Whereas in previous studies the number of TACE procedures were one or two,2– 4,7 repeatedly performed TACE according to a strict protocol was performed in our patients. Freedom from recurrence was not influenced by the classification of the patients according to the Milan criteria or by downstaging to a stage meeting them, but rather the stability of the disease during pretreatment by TACE. Tumor recurrence occurred in only 3 of 44 patients with stable disease compared with 8 of 16 patients with tumor progression during the waiting time. It is highly desirable to select patients with HCC suitable for OLT not only to save scarce organs, but also to prevent accelerated tumor growth due to immunosuppression. The prognosis after OLT may be influenced by prognostic markers, such as the loss of heterozygosity,8 DNA ploidy,9 and other metrics.10 The present update corroborates our former statement that also a strictly used pretreatment protocol with TACE may select patients with obviously
Fig 1. Survival, recurrence-free survival (A), freedom from recurrence according to the Milan criteria (B) and freedom from recurrence according to tumor progress during waiting time during TACE pretreatment (C) in 60 patients after liver transplantation for hepatocellular carcinoma.
Table 1. Characteristics of 60 Patients Following TACE Pretreatment Before LT Characteristics
n
Median follow-up (range) Age Male/female Milan criteria fulfilled/exceeded* 1–3 nodules/multiple nodules (initial CT) 1–3 nodules/multiple nodules (specimen) Tumor diameter ⱕ3 cm/⬎3 cm (initial CT) Tumor diameter ⱕ3 cm/⬎3 cm (specimen) T classification: T1/T2/T3 (specimen) G1/G2/G3 Angioinvasion yes/no Child A/B/C Initial disease (HCV/HBV/alcoholic/others)
802 (1–2832) days 60.1 (33.6–70.5) 46–14 16–44 39–21 46–14 32–28 40–20 26/25/9 2/44/14 12/48 39/12/9 17/9/25/9
*Classification according to the maximal number of patients exceeding the Milan criteria either in the CT scan or in the pathomorphologic evaluation.
biologically less aggressive tumors leading to a favorable prognosis even among patients exceeding the commonly accepted listing criteria. These results may have implications for the future treatment of these patients including living donation.
Table 2. Posttransplant Freedom From Recurrence: Multivariate Analysis RR
95% Confidence Interval for RR
Predictor
n
Significance
1, 2, 3 vs multiple nodules (in specimen) Progress
46/14
.006
0.165
0.046–0.597
44/16
.001
10.765
2.741–42.281
TRANSARTERIAL CHEMOEMBOLIZATION
REFERENCES 1. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinoman in patients with cirrhosis. N Engl J Med 334:693, 1996 2. Decaens T, Roudot-Thoraval F, Bresson-Hadni S, et al: Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma. Liver Transpl 11:767, 2005 3. Majno PE, Adam R, Bismuth H, et al: Influence of preoperative transarterial lipiodol chemoembolization of resection and transplantation for hepatocellular carcinoma in patients with cirrhosis. Ann Surg 226:688, 1997 4. Roayaie S, Frischer JS, Emre SH, et al: Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg 235:533, 2002 5. Otto G, Herber S, Heise M, et al: Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma. Liver Transpl 12:1260, 2006
539 6. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guideline to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205, 2000 7. Yao FY, Kinkhabwala M, LaBerge JM, et al: The impact of pre-operative loco-regional therapy on outcome after liver transplantation for hepatocellular carcinoma. Am J Transplant 5:795, 2005 8. Marsh JW, Finkelstein SD, Demetris AJ, et al: Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determing recurrence-free survival. Liver Transpl 9:664, 2003 9. Mise K, Tashiro S, Yogita S, et al: Assessment of the biological malignancy of hepatocellular carcinoma: relationship to clinicopathological factors and prognosis. Clin Cancer Res 4:1475, 1998 10. Fiorentino MF, Altimari A, Ravaioli M, et al: Predictive value of biological markers for hepatocellular carcinoma patients treated with orthotipic liver transplantation. Clin Cancer Res 10: 1789, 2004