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Stage IV Childhood Liver Cancer
Stage IV hepatoblastoma
Stage IV hepatocellular carcinoma

Stage IV hepatoblastoma

The outcome for hepatoblastoma that is metastatic at diagnosis is not good, but cure is possible in 25% to 30% of patients.[1-4] In a study employing a well-tolerated regimen of doxorubicin/cisplatin chemotherapy, over 50% of patients with metastases at presentation survived 5 years from diagnosis. Half of these survivors developed progressive disease that was successfully treated with surgery and other interventions.[1-5] If possible, stage IV patients with resected primary tumor should have any remaining pulmonary metastases surgically removed. A randomized clinical trial has demonstrated equal efficacy with cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma; the combination of cisplatin/vincristine/fluorouracil, however, resulted in considerably less toxicity.[3] A combination of ifosfamide, cisplatin, and doxorubicin has also been successfully used in the treatment of advanced-stage disease.[6] Patients whose tumors remain unresectable should be considered for alternative chemotherapy, such as high-dose cisplatin with etoposide,[7] radiation therapy,[2,8] direct hepatic infusion of chemotherapeutic agents,[9,10] or, if metastatic disease is controlled, orthotopic liver transplantation.[4,11-13]

Standard treatment options
Four courses of cisplatin/vincristine/fluorouracil [3] or doxorubicin/cisplatin combination chemotherapy followed by attempted complete tumor resection. If the tumor is completely removed, 2 postoperative courses of the same chemotherapy should be given. If the tumor is not resectable after 4 courses of chemotherapy, alternative therapies should be considered.

Alternative therapies
Chemotherapy with high-dose cisplatin/etoposide or continuous infusion of doxorubicin.

Radiation therapy followed by re-exploration if metastatic disease is controlled.

Chemoembolization by hepatic arterial infusion.

Orthotopic liver transplantation if metastatic disease is controlled.

Phase I or II clinical trials of chemotherapy.

Stage IV hepatocellular carcinoma
In a randomized trial, cisplatin plus either vincristine/fluorouracil or doxorubicin given by continuous infusion was ineffective in adequately treating unresectable hepatocellular carcinoma. Therapy failed in 13 of 13 patients with stage IV disease.[14] No particular treatment for unresectable hepatocellular carcinoma has proved especially effective in the pediatric age group. Occasional patients may benefit from treatment with cisplatin/doxorubicin therapy, especially if localized hepatic tumor shrinks adequately to allow resection of disease. (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)


Ortega JA, Krailo MD, Haas JE, et al.: Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (12): 2167-76, 1991. [PUBMED Abstract]

Douglass EC, Reynolds M, Finegold M, et al.: Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol 11 (1): 96-9, 1993. [PUBMED Abstract]

Ortega JA, Douglass EC, Feusner JH, et al.: Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol 18 (14): 2665-75, 2000.  [PUBMED Abstract]

Perilongo G, Brown J, Shafford E, et al.: Hepatoblastoma presenting with lung metastases: treatment results of the first cooperative, prospective study of the International Society of Paediatric Oncology on childhood liver tumors. Cancer 89 (8): 1845-53, 2000. [PUBMED Abstract]

Pritchard J, Brown J, Shafford E, et al.: Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach--results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 18 (22): 3819-28, 2000.  [PUBMED Abstract]

von Schweinitz D, Hecker H, Harms D, et al.: Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma--a report from the German Cooperative Pediatric Liver Tumor Study HB-89. J Pediatr Surg 30 (6): 845-52, 1995.  [PUBMED Abstract]

Douglass EC, Pediatric Oncology Group: Phase II Study of CBDCA and CBDCA/5-FU/VCR in Pediatric Patients with Unresectable or Metastatic (Stage III/IV) Hepatoblastoma, with CDDP/VP-16 for Those Who Remain Unresectable Following Initial Chemotherapy (Summary Last Modified 09/93), POG-9345, Clinical trial, Closed. [PDQ Clinical Trial]

Habrand JL, Nehme D, Kalifa C, et al.: Is there a place for radiation therapy in the management of hepatoblastomas and hepatocellular carcinomas in children? Int J Radiat Oncol Biol Phys 23 (3): 525-31, 1992.  [PUBMED Abstract]

Sue K, Ikeda K, Nakagawara A, et al.: Intrahepatic arterial injections of cisplatin-phosphatidylcholine-Lipiodol suspension in two unresectable hepatoblastoma cases. Med Pediatr Oncol 17 (6): 496-500, 1989.  [PUBMED Abstract]

Malogolowkin MH, Stanley P, Steele DA, et al.: Feasibility and toxicity of chemoembolization for children with liver tumors. J Clin Oncol 18 (6): 1279-84, 2000.  [PUBMED Abstract]

Koneru B, Flye MW, Busuttil RW, et al.: Liver transplantation for hepatoblastoma. The American experience. Ann Surg 213 (2): 118-21, 1991.  [PUBMED Abstract]

Bilik R, Superina R: Transplantation for unresectable liver tumors in children. Transplant Proc 29 (7): 2834-5, 1997.  [PUBMED Abstract]

Laine J, Jalanko H, Saarinen-Pihkala UM, et al.: Successful liver transplantation after induction chemotherapy in children with inoperable, multifocal primary hepatic malignancy. Transplantation 67 (10): 1369-72, 1999. [PUBMED Abstract]

Katzenstein HM, Krailo MD, Malogolowkin MH, et al.: Hepatocellular carcinoma in children and adolescents: results from the Pediatric Oncology Group and the Children's Cancer Group intergroup study. J Clin Oncol 20 (12): 2789-97, 2002. [PUBMED Abstract]

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