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Successful Use of Sirolimus in a Patient With Bulky Ovarian Metastasis of Hepatocellular Carcinoma After Liver Transplantation
COMPLICATIONS Malignancy Successful Use of Sirolimus in a Patient With Bulky Ovarian Metastasis of Hepatocellular Carcinoma After Liver Transplantation D.L. Stippel, H.U. Kasper, K. Schleimer, U. Töx, C. Bangard, A.H. Hölscher, and K.T.E. Beckurts ABSTRACT This 44-year-old woman developed multifocal hepatocellular carcinoma (HCC) within hepatitis B–induced liver cirrhosis. At the time of listing for transplantation the HCC had progressed beyond the Milan criteria. Due to her young age, high grade of histological differentiation according to biopsy, and lack of therapeutic alternatives, she was listed for transplantation. She received an organ from the Eurotransplant marginal liver list. Immunosuppression was reduced to tacrolimus monotherapy within 4 months. Five months after transplantation bilateral bulky ovarian metastases were seen on computed tomography (CT) scan. A bilateral salphingo-oophorectomy was performed and immunosuppression switched to sirolimus monotherapy. Fourteen months after this procedure and 19 months after transplantation, the patient is asymptomatic with stable liver function. She is free of recurrence as judged by CT scan, bone scan, and ␣-fetoprotein. In conclusion, radical surgical treatment and immunosuppression using sirolimus may achieve tumor-free survival in selected patients with advanced or recurrent HCC.
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RTHOTOPIC LIVER TRANSPLANTATION (OLTX) for hepatocellular carcinoma (HCC) in cirrhotic livers is commonly restricted to patients with a single tumor ⱕ 5 cm or with up to three nodules ⱕ 3 cm.1 This criterion produces a 5-year survival rate of up to 74%.2 Analysis of large single-center experiences2,3 and data from international registries4 have identified vascular invasion and grade of histological differentiation to be independent prognostic factors for recurrence-free survival after liver transplantation. Recently the immunosuppressive regimen has been evaluated as an additional independent factor. The cumulative dosage of cyclosporine within the first year seems to significantly influence the recurrence-free survival,5 overriding the Milano criteria. Sirolimus in contrast to calcineurin inhibitors has been shown to inhibit growth of human hepatoma cells in vitro.6 It has been used in different clinical settings characterized by posttransplantat neoplastic disease.7 On the other hand, there is a controversy regarding the side effects (wound healing complications, hepatic artery thrombosis) of sirolimus as the primary immunosuppressant after liver transplantation.8,9
CASE REPORT
A 44-year-old woman referred to the interdisciplinary transplant conference in May 2002 suffered from chronic hepatitis B and D with a low replication rate (HBV-DNA ⬍ 2000 copies/mL). A routine ultrasound examination had disclosed a hepatic mass of 8 cm in diameter. The ␣-fetoprotein level was 19,628 kU/L. Liver biopsy confirmed the diagnosis of a well-differentiated hepatocellular carcinoma (G1–2). Computed tomography showed multifocal involvement of the right liver lobe; a 12cm diameter nodule, a second of 5 cm, and further nodules smaller than 2 cm diameter. There was no sign of vascular invasion. The Child classification yielded eight From the Department of Visceral and Vascular Surgery (D.L.S., K.S., A.H.H., K.T.E.B.), Institute of Pathology (H.U.K.), Department of Internal Medicine IV (U.T.), and Institute of Radiology (C.B.), University of Cologne, Köln, Germany. Address reprint requests to Dirk L. Stippel, MD, Department of Visceral and Vascular Surgery, University of Cologne, Joseph Stelzmann Straße 9, 50931 Köln, Germany. E-mail: dirk. [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.03.013
Transplantation Proceedings, 37, 2185–2187 (2005)
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points: Child B. Extrahepatic metastasis was excluded by computed tomography of the abdomen, chest, and brain as well as whole-body bone scan. Prognostic evaluation according to the CLIP classification10 showed three points, which predicted a mean survival of 7 months without transplantation. Considering the dismal prognosis and the young age, the patient was put on the liver transplantation waiting list. Since the average waiting time for an organ was between 12 and 16 months at the time of listing, the patient was also listed on the marginal liver list. Patients on this list are offered livers that were rejected by at least three centers for medical reasons during the regular Eurotransplant organ allocation, shortening the waiting time for the individual patient on this list. Informed consent was obtained for listing on the marginal liver list. During the waiting time transarterial chemoembolization (TACE) was performed three times. After the third TACE the right hepatic artery was occluded. In November 2002, after a waiting time of 5 months, an organ offer from the marginal liver list was accepted. This organ from a 55-year-old male donor was considered marginal due to seven septic episodes in the intensive care unit. At hepatectomy an en bloc resection including part of the right diaphragm was performed. Except for the diaphragm, no sign of extrahepatic spread of the HCC was evident intraoperatively. Histopathological workup of the liver
STIPPEL, KASPER, SCHLEIMER ET AL
specimen revealed a pT4N0(0/6)M0V1G2–3 tumor. The T4 category was due to the invasion of the diaphragm as clinically suspected. The V1 category was secondary to microscopic vascular invasion. The posttransplant course was uneventful. The immunosuppression consisted of lowdose steroids and tacrolimus, aiming at a trough level of 7 to 11 ng/mL. To prevent reinfection with hepatitis B virus, prophylaxis was initiated using anti-HBs antibodies and lamivudine. The ␣-fetoprotein showed a sharp drop to 23 kU/L, which, however, was still elevated (normal range ⬍ 7 kU/L). Ultrasound examinations during follow-up did not indicate a recurrence in the asymptomatic patient. Steroids were discontinued in March 2003. A rise in ␣-fetoprotein up to 58 kU/L was noticed 5 months after transplantation in April 2003. At the same time a positive HBs-antigen and a positive anti-HBe antibody documented a viral escape variant and reinfection with hepatitis B. Computed tomography of the abdomen and chest showed bilateral ovarian masses (Fig 1). The tumor marker CA 12–5 was within normal range. On laparotomy isolated bilateral ovarian masses were found. Subsequently, a bilateral salphingo-oophorectomy was performed. Histopathological examination revealed a 7.5 ⫻ 5 ⫻ 3 cm metastasis in the right ovary and a 11 ⫻ 11 ⫻ 8 cm metastasis in the left ovary. Both were secondary to the hepatocellular carcinoma.
Fig 1. (Left) Computed tomography of pelvis and lower abdomen showing the bilateral ovarian metastasis. (Right) Right and left ovary specimens.
SIROLIMUS AND HEPATOCELLULAR CARCINOMA
After the ovarectomy, immunosuppression was stepwise altered from monotherapy with tacrolimus (trough level 7 to 11 ng/mL), to combined tacrolimus (trough level 4 to 8 ng/mL) and sirolimus (trough level 5 to 10 ng/mL) therapy and finally to sirolimus monotherapy (trough level 5 to 10 ng/mL). Liver function was stable during this switch, which took place over a period of 3 months. Hepatitis B reinfection was treated with lamivudine (100 mg daily). During the 14-month follow-up ␣-fetoprotein was always ⱕ 2 kU/L. The last workup in June 2004, including computed tomography and whole-body scan, failed to reveal any sign of recurrence. The hepatitis B reinfection was successfully treated. The first negative PCR for HBV-DNA was recorded in October 2003. Prophylaxis with lamivudin will be continued for another year. The patient is asymptomatic with a stable normal liver function. DISCUSSION
Commonly recurrence of hepatocellular carcinoma after OLTX occurs within the first year after transplantation. Lung metastasis, bone metastasis, or hepatic sites are the usual locations.3,11,12 Metastasis to the abdomen is seen less often; ovarian metastasis has been described in less than 10 cases.13 The prognosis of patients with recurrent disease after OLTX is limited to months due to the rapid progression of the recurrent cancer under immunosuppression. Experience in treating posttransplant lymphoproliferative disease has established the regimen of surgical resection of bulky tumor and drastic reduction of the immunosuppression.7,14 The therapeutic effect of reduced immunosuppression has not been fully established for other cancer entities. However, the report from the Bologna group suggests a similar relationship for hepatocellular carcinoma and calcineurin inhibitor– based immunosuppression.5 The in vitro effects of sirolimus6 on human hepatoma cell lines and the experimental studies in immunosuppressed mice15 encouraged us to perform a radical resection and switch this patient onto sirolimus monotherapy. In the reported patient this strategy provided a recurrence free survival. In conclusion, a surgical resection of localized recurrence of HCC after OLTX may offer some patients a chance of survival under the condition of tailored immunosuppression, such as sirolimus monotherapy.
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REFERENCES 1. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693, 1996 2. Jonas S, Bechstein WO, Steinmuller T, et al: Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 33:1080, 2001 3. Tamura S, Kato T, Berho M, et al: Impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation. Arch Surg 136:25, 2001 4. Klintmalm GB: Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome. Ann Surg 228:479, 1998 5. Vivarelli M, Bellusci R, Cucchetti A, et al: Low recurrence rate of hepatocellular carcinoma after liver transplantation: better patient selection or lower immunosuppression? Transplantation 74:1746, 2002 6. Schumacher G, Oidtmann M, Rosewicz S, et al: Sirolimus inhibits growth of human hepatoma cells in contrast to tacrolimus which promotes cell growth. Transplant Proc 34:1392, 2002 7. Jimenez-Rivera C, Avitzur Y, Fecteau AH, et al: Sirolimus for pediatric liver transplant recipients with post-transplant lymphoproliferative disease and hepatoblastoma. Pediatr Transplant 8:243, 2004 8. Dunkelberg JC, Trotter JF, Wachs M, et al: Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications. Liver Transpl 9:463, 2003 9. Fung J, Marcos A: Rapamycin: friend, foe, or misunderstood? Liver Transpl 9:469, 2003 10. Investigators C: Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. The Cancer of the Liver Italian Program (CLIP) Investigators. Hepatology 31:840, 2000 11. Michel J, Suc B, Fourtanier G, et al: Recurrence of hepatocellular carcinoma in cirrhotic patients after liver resection or transplantation. Transplant Proc 27:1798, 1995 12. Si MS, Amersi F, Golish SR, et al: Prevalence of metastases in hepatocellular carcinoma: risk factors and impact on survival. Am Surg 69:879, 2003 13. de Groot ME, Dukel L, Chadha-Ajwani S, et al: Massive solitary metastasis of hepatocellular carcinoma in the ovary two years after liver transplantation. Eur J Obstet Gynecol Reprod Biol 90:109, 2000 14. Mazariegos GV: Withdrawal of immunosuppression in liver transplantation: lessons learned from PTLD. Pediatr Transplant 8:210, 2004 15. Koehl GE, Andrassy J, Guba M, et al: Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice. Transplantation 77:1319, 2004
O
RTHOTOPIC LIVER TRANSPLANTATION (OLTX) for hepatocellular carcinoma (HCC) in cirrhotic livers is commonly restricted to patients with a single tumor ⱕ 5 cm or with up to three nodules ⱕ 3 cm.1 This criterion produces a 5-year survival rate of up to 74%.2 Analysis of large single-center experiences2,3 and data from international registries4 have identified vascular invasion and grade of histological differentiation to be independent prognostic factors for recurrence-free survival after liver transplantation. Recently the immunosuppressive regimen has been evaluated as an additional independent factor. The cumulative dosage of cyclosporine within the first year seems to significantly influence the recurrence-free survival,5 overriding the Milano criteria. Sirolimus in contrast to calcineurin inhibitors has been shown to inhibit growth of human hepatoma cells in vitro.6 It has been used in different clinical settings characterized by posttransplantat neoplastic disease.7 On the other hand, there is a controversy regarding the side effects (wound healing complications, hepatic artery thrombosis) of sirolimus as the primary immunosuppressant after liver transplantation.8,9
CASE REPORT
A 44-year-old woman referred to the interdisciplinary transplant conference in May 2002 suffered from chronic hepatitis B and D with a low replication rate (HBV-DNA ⬍ 2000 copies/mL). A routine ultrasound examination had disclosed a hepatic mass of 8 cm in diameter. The ␣-fetoprotein level was 19,628 kU/L. Liver biopsy confirmed the diagnosis of a well-differentiated hepatocellular carcinoma (G1–2). Computed tomography showed multifocal involvement of the right liver lobe; a 12cm diameter nodule, a second of 5 cm, and further nodules smaller than 2 cm diameter. There was no sign of vascular invasion. The Child classification yielded eight From the Department of Visceral and Vascular Surgery (D.L.S., K.S., A.H.H., K.T.E.B.), Institute of Pathology (H.U.K.), Department of Internal Medicine IV (U.T.), and Institute of Radiology (C.B.), University of Cologne, Köln, Germany. Address reprint requests to Dirk L. Stippel, MD, Department of Visceral and Vascular Surgery, University of Cologne, Joseph Stelzmann Straße 9, 50931 Köln, Germany. E-mail: dirk. [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.03.013
Transplantation Proceedings, 37, 2185–2187 (2005)
2185
2186
points: Child B. Extrahepatic metastasis was excluded by computed tomography of the abdomen, chest, and brain as well as whole-body bone scan. Prognostic evaluation according to the CLIP classification10 showed three points, which predicted a mean survival of 7 months without transplantation. Considering the dismal prognosis and the young age, the patient was put on the liver transplantation waiting list. Since the average waiting time for an organ was between 12 and 16 months at the time of listing, the patient was also listed on the marginal liver list. Patients on this list are offered livers that were rejected by at least three centers for medical reasons during the regular Eurotransplant organ allocation, shortening the waiting time for the individual patient on this list. Informed consent was obtained for listing on the marginal liver list. During the waiting time transarterial chemoembolization (TACE) was performed three times. After the third TACE the right hepatic artery was occluded. In November 2002, after a waiting time of 5 months, an organ offer from the marginal liver list was accepted. This organ from a 55-year-old male donor was considered marginal due to seven septic episodes in the intensive care unit. At hepatectomy an en bloc resection including part of the right diaphragm was performed. Except for the diaphragm, no sign of extrahepatic spread of the HCC was evident intraoperatively. Histopathological workup of the liver
STIPPEL, KASPER, SCHLEIMER ET AL
specimen revealed a pT4N0(0/6)M0V1G2–3 tumor. The T4 category was due to the invasion of the diaphragm as clinically suspected. The V1 category was secondary to microscopic vascular invasion. The posttransplant course was uneventful. The immunosuppression consisted of lowdose steroids and tacrolimus, aiming at a trough level of 7 to 11 ng/mL. To prevent reinfection with hepatitis B virus, prophylaxis was initiated using anti-HBs antibodies and lamivudine. The ␣-fetoprotein showed a sharp drop to 23 kU/L, which, however, was still elevated (normal range ⬍ 7 kU/L). Ultrasound examinations during follow-up did not indicate a recurrence in the asymptomatic patient. Steroids were discontinued in March 2003. A rise in ␣-fetoprotein up to 58 kU/L was noticed 5 months after transplantation in April 2003. At the same time a positive HBs-antigen and a positive anti-HBe antibody documented a viral escape variant and reinfection with hepatitis B. Computed tomography of the abdomen and chest showed bilateral ovarian masses (Fig 1). The tumor marker CA 12–5 was within normal range. On laparotomy isolated bilateral ovarian masses were found. Subsequently, a bilateral salphingo-oophorectomy was performed. Histopathological examination revealed a 7.5 ⫻ 5 ⫻ 3 cm metastasis in the right ovary and a 11 ⫻ 11 ⫻ 8 cm metastasis in the left ovary. Both were secondary to the hepatocellular carcinoma.
Fig 1. (Left) Computed tomography of pelvis and lower abdomen showing the bilateral ovarian metastasis. (Right) Right and left ovary specimens.
SIROLIMUS AND HEPATOCELLULAR CARCINOMA
After the ovarectomy, immunosuppression was stepwise altered from monotherapy with tacrolimus (trough level 7 to 11 ng/mL), to combined tacrolimus (trough level 4 to 8 ng/mL) and sirolimus (trough level 5 to 10 ng/mL) therapy and finally to sirolimus monotherapy (trough level 5 to 10 ng/mL). Liver function was stable during this switch, which took place over a period of 3 months. Hepatitis B reinfection was treated with lamivudine (100 mg daily). During the 14-month follow-up ␣-fetoprotein was always ⱕ 2 kU/L. The last workup in June 2004, including computed tomography and whole-body scan, failed to reveal any sign of recurrence. The hepatitis B reinfection was successfully treated. The first negative PCR for HBV-DNA was recorded in October 2003. Prophylaxis with lamivudin will be continued for another year. The patient is asymptomatic with a stable normal liver function. DISCUSSION
Commonly recurrence of hepatocellular carcinoma after OLTX occurs within the first year after transplantation. Lung metastasis, bone metastasis, or hepatic sites are the usual locations.3,11,12 Metastasis to the abdomen is seen less often; ovarian metastasis has been described in less than 10 cases.13 The prognosis of patients with recurrent disease after OLTX is limited to months due to the rapid progression of the recurrent cancer under immunosuppression. Experience in treating posttransplant lymphoproliferative disease has established the regimen of surgical resection of bulky tumor and drastic reduction of the immunosuppression.7,14 The therapeutic effect of reduced immunosuppression has not been fully established for other cancer entities. However, the report from the Bologna group suggests a similar relationship for hepatocellular carcinoma and calcineurin inhibitor– based immunosuppression.5 The in vitro effects of sirolimus6 on human hepatoma cell lines and the experimental studies in immunosuppressed mice15 encouraged us to perform a radical resection and switch this patient onto sirolimus monotherapy. In the reported patient this strategy provided a recurrence free survival. In conclusion, a surgical resection of localized recurrence of HCC after OLTX may offer some patients a chance of survival under the condition of tailored immunosuppression, such as sirolimus monotherapy.
2187
REFERENCES 1. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693, 1996 2. Jonas S, Bechstein WO, Steinmuller T, et al: Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 33:1080, 2001 3. Tamura S, Kato T, Berho M, et al: Impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation. Arch Surg 136:25, 2001 4. Klintmalm GB: Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome. Ann Surg 228:479, 1998 5. Vivarelli M, Bellusci R, Cucchetti A, et al: Low recurrence rate of hepatocellular carcinoma after liver transplantation: better patient selection or lower immunosuppression? Transplantation 74:1746, 2002 6. Schumacher G, Oidtmann M, Rosewicz S, et al: Sirolimus inhibits growth of human hepatoma cells in contrast to tacrolimus which promotes cell growth. Transplant Proc 34:1392, 2002 7. Jimenez-Rivera C, Avitzur Y, Fecteau AH, et al: Sirolimus for pediatric liver transplant recipients with post-transplant lymphoproliferative disease and hepatoblastoma. Pediatr Transplant 8:243, 2004 8. Dunkelberg JC, Trotter JF, Wachs M, et al: Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications. Liver Transpl 9:463, 2003 9. Fung J, Marcos A: Rapamycin: friend, foe, or misunderstood? Liver Transpl 9:469, 2003 10. Investigators C: Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. The Cancer of the Liver Italian Program (CLIP) Investigators. Hepatology 31:840, 2000 11. Michel J, Suc B, Fourtanier G, et al: Recurrence of hepatocellular carcinoma in cirrhotic patients after liver resection or transplantation. Transplant Proc 27:1798, 1995 12. Si MS, Amersi F, Golish SR, et al: Prevalence of metastases in hepatocellular carcinoma: risk factors and impact on survival. Am Surg 69:879, 2003 13. de Groot ME, Dukel L, Chadha-Ajwani S, et al: Massive solitary metastasis of hepatocellular carcinoma in the ovary two years after liver transplantation. Eur J Obstet Gynecol Reprod Biol 90:109, 2000 14. Mazariegos GV: Withdrawal of immunosuppression in liver transplantation: lessons learned from PTLD. Pediatr Transplant 8:210, 2004 15. Koehl GE, Andrassy J, Guba M, et al: Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice. Transplantation 77:1319, 2004