Childhood Liver Cancer

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of childhood liver cancer.

Childhood Liver Cancer

General Information

This cancer treatment information summary provides an overview of the prognosis, diagnosis, classification, and treatment of childhood liver cancer.

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation therapists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.¹ At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Liver cancer, a rare malignancy in children and adolescents, is divided into 2 major histologic subgroups: hepatoblastoma and hepatocellular carcinoma. The age of onset of liver cancer in children is related to the histology of the tumor. Hepatoblastomas usually occur before 3 years of age, and about 90% of malignant liver tumors in children younger than 4 years are hepatoblastomas.² The incidence of hepatoblastoma in the United States appears to have doubled in the last 25 years, whereas the incidence of hepatocellular carcinoma in the United States varies little with age between 0 and 19 years and has not changed appreciably over time.^2,3 The cause for the increase is not known, but the increasing survival following very low birthweight premature births, which are known to be associated with hepatoblastoma, may contribute.⁴ In Japan, the risk of hepatoblastoma in children who weighed less than 1000 g at birth is 15 times the risk in normal birthweight children.⁵ In several Asian countries, the incidence of hepatocellular carcinoma in children is more than 10 times that in North America. The high incidence appears to be related to the high incidence of perinatally acquired hepatitis B.The overall survival rate for children with hepatoblastoma is 70% ^6,7,8 but is only 25% for those with hepatocellular carcinoma.^2,9,10,

Cure of hepatoblastoma or hepatocellular carcinoma requires complete, gross tumor resection. If a hepatoblastoma is completely removed, the majority of patients survive, but less than one third of patients have lesions amenable to complete resection at diagnosis. It is thus critically important that a child with probable hepatoblastoma be evaluated by a pediatric surgeon experienced in the resection of hepatoblastoma in children. Chemotherapy can often decrease the size and extent of hepatoblastoma, allowing complete resection.^{6,7,8,11,12,13} Orthotopic liver transplantation provides an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy;^12,13,14 however, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome. Additional courses of chemotherapy, usually consisting of the standard drugs used to treat this cancer, are administered to all patients after surgery that results in positive margins.^6,7,15, Hepatoblastoma is most often unifocal, while hepatocellular carcinoma is often extensively invasive or multicentric. Therefore, resection is possible more often in hepatoblastoma than hepatocellular carcinoma, in which less than 30% are resectable.^16,

Most patients with either hepatoblastoma or hepatocellular carcinoma have a serum tumor marker, alpha-fetoprotein, that parallels disease activity. Lack of a significant decrease of alpha-fetoprotein levels with treatment may predict a poor response to therapy.¹⁷ Absence of elevated alpha-fetoprotein may be a poor prognostic sign in hepatoblastoma; it is associated with the small-cell (anaplastic) histologic variant, which responds very poorly to chemotherapy. Beta-human chorionic gonadotropin (β-hCG) levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity.^18,19,

Hepatoblastoma is part of the constellation of findings associated with the Beckwith-Wiedemann syndrome or its variant, isolated hemihypertrophy.^20,21 Other somatic overgrowth syndromes, such as Simpson-Golabi-Behmel syndrome, may also be associated.²² About 2% of children with hepatoblastoma have hemihypertrophy.²³ Less than 1% of children with hemihypertrophy are at increased risk for developing hepatoblastoma within the first several years of life.²¹ Children with hemihypertrophy are also at increased risk of developing Wilms' tumor or adrenal carcinoma in the early years of life. All children with Beckwith-Wiedemann syndrome or isolated hemihypertrophy should be screened regularly by ultrasound to detect abdominal malignancies at an early stage. Loss of the allele of maternal origin at the 11p15.5 familial Beckwith-Wiedemann syndrome locus occurs in many hepatoblastomas. Thus, the genetic abnormality that results in Beckwith-Wiedemann may be directly involved in the pathogenesis of some cases of hepatoblastoma, and imprinting may play a role.^24,25 There is a clear association between hepatoblastoma and familial adenomatous polyposis (FAP); children in families that carry the FAP gene are at an increased risk for hepatoblastoma, though it occurs in less than 1% of FAP family members.^26,27,28 The predisposition to hepatoblastoma may be limited to a specific subset of FAP mutations.²⁹ It has been recommended that all children with hepatoblastoma be examined for congenital hypertrophy of the retinal pigment epithelium, a marker of FAP mutation carriers in some polyposis families.²⁸ In the absence of FAP germline mutations, childhood hepatoblastomas do not have mutations in the FAP gene; however, they frequently have mutations in the β-catenin gene, the function of which is closely related to FAP.³⁰

Hepatocellular carcinoma is associated with hepatitis B and hepatitis C infection,^31,32, especially in children with perinatally acquired hepatitis B virus. Therefore, widespread hepatitis B immunization may decrease the incidence of hepatocellular carcinoma.³³ Compared with adults, the incubation period from hepatitis virus infection to the genesis of hepatocellular carcinoma is extremely short in a small subset of children with perinatally acquired virus. Mutations in the met/hepatocyte growth factor receptor gene occur in childhood hepatocellular carcinoma, and this could be the mechanism that results in a shortened incubation period.³⁴ Several specific types of nonviral liver injury and cirrhosis in children are associated with hepatocellular carcinoma, including: tyrosinemia, biliary cirrhosis, and alpha-1-antitrypsin deficiency.

¹ Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.

² Darbari A, Sabin KM, Shapiro CN, et al.: Epidemiology of primary hepatic malignancies in U.S. children. Hepatology 38 (3): 560-6, 2003.

³ Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed April 19, 2007.

⁴ Ikeda H, Hachitanda Y, Tanimura M, et al.: Development of unfavorable hepatoblastoma in children of very low birth weight: results of a surgical and pathologic review. Cancer 82 (9): 1789-96, 1998.

⁵ Tanimura M, Matsui I, Abe J, et al.: Increased risk of hepatoblastoma among immature children with a lower birth weight. Cancer Res 58 (14): 3032-5, 1998.

⁶ 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.

⁷ 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.

⁸ 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.

⁹ 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.

¹⁰ Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002.

¹¹ 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.

¹² Czauderna P, Otte JB, Aronson DC, et al.: Guidelines for surgical treatment of hepatoblastoma in the modern era--recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL). Eur J Cancer 41 (7): 1031-6, 2005.

¹³ Tiao GM, Bobey N, Allen S, et al.: The current management of hepatoblastoma: a combination of chemotherapy, conventional resection, and liver transplantation. J Pediatr 146 (2): 204-11, 2005.

¹⁴ Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004.

¹⁵ Schnater JM, Aronson DC, Plaschkes J, et al.: Surgical view of the treatment of patients with hepatoblastoma: results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer 94 (4): 1111-20, 2002.

¹⁶ Exelby PR, Filler RM, Grosfeld JL: Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey--1974. J Pediatr Surg 10 (3): 329-37, 1975.

¹⁷ Van Tornout JM, Buckley JD, Quinn JJ, et al.: Timing and magnitude of decline in alpha-fetoprotein levels in treated children with unresectable or metastatic hepatoblastoma are predictors of outcome: a report from the Children's Cancer Group. J Clin Oncol 15 (3): 1190-7, 1997.

¹⁸ Schneider DT, Calaminus G, Göbel U: Diagnostic value of alpha 1-fetoprotein and beta-human chorionic gonadotropin in infancy and childhood. Pediatr Hematol Oncol 18 (1): 11-26, 2001 Jan-Feb.

¹⁹ Nakagawara A, Ikeda K, Tsuneyoshi M, et al.: Hepatoblastoma producing both alpha-fetoprotein and human chorionic gonadotropin. Clinicopathologic analysis of four cases and a review of the literature. Cancer 56 (7): 1636-42, 1985.

²⁰ Sotelo-Avila C, Gonzalez-Crussi F, Fowler JW: Complete and incomplete forms of Beckwith-Wiedemann syndrome: their oncogenic potential. J Pediatr 96 (1): 47-50, 1980.

²¹ Hoyme HE, Seaver LH, Jones KL, et al.: Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet 79 (4): 274-8, 1998.

²² Buonuomo PS, Ruggiero A, Vasta I, et al.: Second case of hepatoblastoma in a young patient with Simpson-Golabi-Behmel syndrome. Pediatr Hematol Oncol 22 (7): 623-8, 2005 Oct-Nov.

²³ Fraumeni JF Jr, Miller RW, Hill JA: Primary carcinoma of the liver in childhood: an epidemiologic study. J Natl Cancer Inst 40 (5): 1087-99, 1968.

²⁴ Albrecht S, von Schweinitz D, Waha A, et al.: Loss of maternal alleles on chromosome arm 11p in hepatoblastoma. Cancer Res 54 (19): 5041-4, 1994.

²⁵ Mannens M, Hoovers JM, Redeker E, et al.: Parental imprinting of human chromosome region 11p15.3-pter involved in the Beckwith-Wiedemann syndrome and various human neoplasia. Eur J Hum Genet 2 (1): 3-23, 1994.

²⁶ Iwama T, Mishima Y: Mortality in young first-degree relatives of patients with familial adenomatous polyposis. Cancer 73 (8): 2065-8, 1994.

²⁷ Li FP, Thurber WA, Seddon J, et al.: Hepatoblastoma in families with polyposis coli. JAMA 257 (18): 2475-7, 1987.

²⁸ Garber JE, Li FP, Kingston JE, et al.: Hepatoblastoma and familial adenomatous polyposis. J Natl Cancer Inst 80 (20): 1626-8, 1988.

²⁹ Hirschman BA, Pollock BH, Tomlinson GE: The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. J Pediatr 147 (2): 263-6, 2005.

³⁰ Koch A, Denkhaus D, Albrecht S, et al.: Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res 59 (2): 269-73, 1999.

³¹ Ni YH, Chang MH, Hsu HY, et al.: Hepatocellular carcinoma in childhood. Clinical manifestations and prognosis. Cancer 68 (8): 1737-41, 1991.

³² Tsukuma H, Hiyama T, Tanaka S, et al.: Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 328 (25): 1797-801, 1993.

³³ Chang MH, Chen CJ, Lai MS, et al.: Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 336 (26): 1855-9, 1997.

³⁴ Park WS, Dong SM, Kim SY, et al.: Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res 59 (2): 307-10, 1999.

Cellular Classification

The cells of the adult-type hepatocellular carcinoma are epithelial compared with a less differentiated embryonal appearance of hepatoblastoma. Hepatocellular carcinoma also differs from hepatoblastoma in that it often arises in a previously abnormal, cirrhotic liver. Both histologic types more commonly arise in the right lobe of the liver. The hepatocellular nature of the tumor cells may be demonstrated by the finding of alpha-fetoprotein (AFP) or alpha-1-antitrypsin.

Patients with pure fetal histology tumors may not need chemotherapy after complete resection of a stage I tumor.^{1 2,3} For example, in a study of patients with hepatoblastoma and fetal histology tumors, there was a 100% survival rate for patients who received 4 doses of single-agent doxorubicin.⁴ Analysis of patients with resectable hepatoblastoma has suggested that those patients with pure fetal histology tumors have a better prognosis than those having an admixture of more primitive and rapidly dividing embryonal components or other undifferentiated tissues.

In addition, a distinctive histologic variant of hepatocellular carcinoma, termed fibrolamellar carcinoma, has been described in the livers of older children and young adults. Fibrolamellar carcinoma is not associated with cirrhosis and has been associated with an improved prognosis.^5,6,7 The improved outcome may be related to a higher proportion of tumors being less invasive and more resectable, as the outcome in recent prospective studies, when compared stage for stage, is not different from other hepatocellular carcinomas.^8,9,

¹ Ishak KG, Glunz PR: Hepatoblastoma and hepatocarcinoma in infancy and childhood. Report of 47 cases. Cancer 20 (3): 396-422, 1967.

² Weinberg AG, Finegold MJ: Primary hepatic tumors of childhood. Hum Pathol 14 (6): 512-37, 1983.

³ Haas JE, Muczynski KA, Krailo M, et al.: Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer 64 (5): 1082-95, 1989.

⁴ 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.

⁵ Lack EE, Neave C, Vawter GF: Hepatocellular carcinoma. Review of 32 cases in childhood and adolescence. Cancer 52 (8): 1510-5, 1983.

⁶ Craig JR, Peters RL, Edmondson HA, et al.: Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer 46 (2): 372-9, 1980.

⁷ Farhi DC, Shikes RH, Murari PJ, et al.: Hepatocellular carcinoma in young people. Cancer 52 (8): 1516-25, 1983.

⁸ Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002.

⁹ Katzenstein HM, Krailo MD, Malogolowkin MH, et al.: Fibrolamellar hepatocellular carcinoma in children and adolescents. Cancer 97 (8): 2006-12, 2003.

Stage Information

Postsurgical staging

A staging system based on postsurgical extent of tumor and surgical resectability has been used in the United States to group children with liver cancer. This staging system is used to determine treatment.^1,2,3,4 Children diagnosed with stage I and stage II hepatoblastoma have a cure rate of greater than 90% compared with 60% for stage III and approximately 20% for stage IV. In children diagnosed with hepatocellular carcinoma, those with stage I have a good outcome.⁴ Stage II is too rarely seen to predict outcome, and stages III and IV are usually fatal.^5,6,7,

Stage I

• No metastases, tumor completely resected.

Stage II

• No metastases, tumor grossly resected with microscopic residual disease (i.e., positive margins); or tumor rupture, or tumor spill at the time of surgery.

Stage III

• No distant metastases, tumor unresectable or resected with gross residual tumor, or positive lymph nodes.

Stage IV

• Distant metastases regardless of the extent of liver involvement.

Presurgical anatomic staging using imaging techniques

The pretreatment extent of disease (PRETEXT) staging system for hepatoblastoma categorizes the primary tumor based on extent of liver involvement at diagnosis. The staging system was devised for use in an international hepatoblastoma treatment program in which only children with PRETEXT stage 1 hepatoblastoma undergo initial resection of tumor. All others are treated with chemotherapy prior to attempted resection of the primary tumor. The liver tumors are staged by interpretation of computerized tomography or ultrasound with or without additional imaging by magnetic resonance . The presence or absence of metastases is noted in addition to the PRETEXT stage, but does not alter the PRETEXT stage. The imaged liver is divided into 4 quadrants and involvement of each quadrant with tumor is determined. Stage increases and prognosis decreases as the number of quadrants radiologically involved with tumor increases from 1 to 4. Experienced radiologist review is important because it may be difficult to discriminate between real invasion beyond the anatomic border of a given sector and displacement of the anatomic border.^8,9,10 The 5-year overall survival in this international study, in which the study protocol called for treatment of children with preoperative doxorubicin and cisplatin chemotherapy, was 100%, 91%, 68%, and 57% for PRETEXT stages 1 to 4, respectively, including patients with metastasis.^11,12, The PRETEXT staging system has a moderate degree of interobserver variability, and the preoperative PRETEXT stage agrees with postoperative pathologic findings only 51% of the time, with overstaging in 37% of patients and understaging in 12% of patients.^10,

PRETEXT stage 1

• Tumor involves only 1 quadrant; 3 adjoining liver quadrants are free of tumor.

PRETEXT stage 2

• Tumor involves 2 adjoining quadrants; 2 adjoining quadrants are free of tumor.

PRETEXT stage 3

• Tumor involves 3 adjoining quadrants or 2 nonadjoining quadrants; 1 quadrant or 2 nonadjoining quadrants are free of tumor.

PRETEXT stage 4

• Tumor involves all 4 quadrants; there is no quadrant free of tumor.

¹ 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.

² 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.

³ 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.

⁴ Douglass E, Ortega J, Feusner J, et al.: Hepatocellular carcinoma (HCA) in children and adolescents: results from the Pediatric Intergroup Hepatoma Study (CCG 8881/POG 8945). [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-1439, 420, 1994.

⁵ Giacomantonio M, Ein SH, Mancer K, et al.: Thirty years of experience with pediatric primary malignant liver tumors. J Pediatr Surg 19 (5): 523-6, 1984.

⁶ 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.

⁷ Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002.

⁸ Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004.

⁹ Perilongo G, Shafford E, Maibach R, et al.: Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2. Eur J Cancer 40 (3): 411-21, 2004.

¹⁰ Aronson DC, Schnater JM, Staalman CR, et al.: Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol 23 (6): 1245-52, 2005.

¹¹ 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.

¹² Brown J, Perilongo G, Shafford E, et al.: Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer 36 (11): 1418-25, 2000.

Treatment Option Overview

Many of the improvements in survival in childhood cancer have been made using new therapies that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of 2 treatment arms or by evaluating a single new treatment, comparing the results with those previously obtained with standard therapy.

Because of the relative rarity of cancer in children, all children with liver cancer should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is required to determine and implement optimum treatment. Involvement of surgeons with experience in pediatric liver resection is critical, as operative and perioperative mortality may be as high as 5%.^1,

Historically, resection of the primary tumor has been required to cure malignant liver tumors in children.^2,3 Preoperative chemotherapy can convert a nonresectable tumor to a resectable one. Chemotherapy in some cases is able to eradicate pulmonary metastases completely and eliminate multinodular tumor foci in the liver. Chemotherapy has been much more successful in the treatment of hepatoblastoma than in hepatocellular carcinoma.^3,4,5,6,7,8 In recent years, virtually all children with hepatoblastoma have been treated with chemotherapy, and in some centers, even children with resectable hepatoblastoma are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection.^1,9 In an international study, preresection treatment with doxorubicin and cisplatin was given to all children with PRETEXT stage 2, 3, or 4 hepatoblastoma with or without metastases and was well tolerated. PRETEXT stage 1 hepatoblastoma was resected and then treated with the same chemotherapy. Following chemotherapy, and excluding those who received liver transplant (<5% of patients), complete resection was obtained in 87% of children. This strategy resulted in an overall survival of 75% at 5 years after diagnosis for all children entered on the study.⁹ In contrast, the current American Intergroup protocol for treatment of children with hepatoblastoma encourages resection at the time of diagnosis for all tumors amenable to resection without undue risk. The protocol does not treat children with stage I tumors of purely fetal histology with preoperative or postoperative chemotherapy unless they develop progressive disease.¹⁰ Further study will be needed to determine whether presurgical chemotherapy is preferable to resection followed by chemotherapy for children with PRETEXT stage 2, 3, and 4 hepatoblastoma.

Surgical resection of distant disease has also contributed to the cure of children with hepatoblastoma. Resection of pulmonary metastases is recommended when the number of metastases is limited ¹¹ and is often performed at the same time as resection of the primary tumor. When possible, resection of areas of locally invasive disease, such as in the diaphragm, and of isolated brain metastasis is recommended.^12,

Radiation therapy, even in combination with chemotherapy, has not cured children with nonresectable tumors. There may be a role for radiation therapy in the management of incompletely resected hepatoblastoma,^5,13 though a study of 154 patients with hepatoblastoma did not confirm this finding.¹ Eleven patients had tumor found at the surgical margins following hepatic resection and only 2 patients died, neither of whom had a local recurrence. None of the 11 patients underwent a second resection and only one patient received radiation therapy postoperatively. All of the patients were treated with 4 courses of cisplatin and doxorubicin prior to surgery and received 2 courses of postoperative chemotherapy. This study shows that second resection of positive margins and/or radiation therapy may not be necessary in patients with incompletely resected hepatoblastoma whose residual tumor is microscopic.

Liver transplantation has recently been associated with significant success in the treatment of children with unresectable hepatic tumors. A review of the world experience has documented a posttransplant survival rate of 82% for children with hepatoblastomas.¹⁴ Intravenous invasion, positive lymph nodes, and contiguous spread did not have a significant adverse effect on outcome. For children with hepatocellular carcinoma the overall 5-year disease-free survival rate was approximately 60%.¹⁵ In hepatocellular carcinoma, vascular invasion, distant metastases, lymph node involvement, tumor size, and male gender were significant risk factors for recurrence. Pretransplant intra-arterial therapy was very effective in patients with hepatoblastoma but less efficacious in children with hepatocellular carcinoma. Because of the poor prognosis in patients with hepatocellular carcinoma, liver transplant should be considered for disorders such as tyrosinemia and familial intrahepatic cholestasis early in the course, prior to the development of liver failure and malignancy. The fibrolamellar variant of hepatocellular carcinoma may have a better outcome with liver transplant than other hepatocellular carcinomas.^16,

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

¹ Schnater JM, Aronson DC, Plaschkes J, et al.: Surgical view of the treatment of patients with hepatoblastoma: results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer 94 (4): 1111-20, 2002.

² Tomlinson GE, Finegold MJ: Tumors of the Liver. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 4th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins, 2002, pp 847-64.

³ 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.

⁴ 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.

⁵ 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.

⁶ 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.

⁷ Douglass E, Ortega J, Feusner J, et al.: Hepatocellular carcinoma (HCA) in children and adolescents: results from the Pediatric Intergroup Hepatoma Study (CCG 8881/POG 8945). [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-1439, 420, 1994.

⁸ Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002.

⁹ 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.

¹⁰ Katzenstein HM, Children's Oncology Group: Phase III Randomized Study of Postoperative Cisplatin, Vincristine, and Fluorouracil in Children With Hepatoblastoma, COG-P9645, Clinical trial, Closed.

¹¹ Feusner JH, Krailo MD, Haas JE, et al.: Treatment of pulmonary metastases of initial stage I hepatoblastoma in childhood. Report from the Childrens Cancer Group. Cancer 71 (3): 859-64, 1993.

¹² Robertson PL, Muraszko KM, Axtell RA: Hepatoblastoma metastatic to brain: prolonged survival after multiple surgical resections of a solitary brain lesion. J Pediatr Hematol Oncol 19 (2): 168-71, 1997 Mar-Apr.

¹³ 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.

¹⁴ Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004.

¹⁵ Reyes JD, Carr B, Dvorchik I, et al.: Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence. J Pediatr 136 (6): 795-804, 2000.

¹⁶ 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.

Stage I and II Childhood Liver Cancer

Postsurgically staged, stage I and II and presurgically staged, PRETEXT stage 1, 2, and 3 hepatoblastoma

Combination chemotherapy has been demonstrated to have significant benefit in children with hepatoblastoma. Cisplatin-based chemotherapy has resulted in a survival rate of greater than 90% for children with stage I and stage II disease.^1,2,3 Comparable results were obtained in an international study in which children were treated with doxorubicin/cisplatin chemotherapy prior to attempted resection of the liver tumor. In this study, 88% of the children in whom complete resection was achieved following the well-tolerated chemotherapy survived and were event-free 5 years after diagnosis.⁴ In comparison, a survey of children with liver tumors who were treated prior to the consistent use of combination chemotherapy found that 45 of 78 (57%) patients with hepatoblastoma who had complete excision of the tumor survived.⁵ A randomized clinical trial demonstrated comparable efficacy with cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma. Although outcome was nominally higher for children receiving cisplatin/doxorubicin, this difference was not statistically significant, and the combination of cisplatin/vincristine/flourouracil was significantly less toxic than the doses of cisplatin/doxorubicin to which it was compared.^6,

Treatment options

Complete surgical excision followed by 4 courses of combination chemotherapy with cisplatin, vincristine, and fluorouracil or comparable combination chemotherapy.² Completely excised tumor of purely fetal histology may be treated with doxorubicin alone ⁶ or carefully followed without further therapy.^2,

An alternative strategy for PRETEXT stage 2 and 3 hepatoblastoma is initial chemotherapy with 4 to 6 courses of single agent cisplatin ³ or combination doxorubicin/cisplatin chemotherapy followed by attempted resection.⁴ PRETEXT stage 1 tumors may be resected prior to treatment with postresection chemotherapy.^4,

Stage I and II hepatocellular carcinoma

Treatment options

In a randomized trial, 7 of 8 patients with stage I hepatocellular carcinoma survived disease free after adjuvant cisplatin-based chemotherapy.⁷ In a survey of childhood liver tumors treated prior to the consistent use of chemotherapy only 12 of 33 patients with hepatocellular carcinoma who had complete excision of the tumor survived.⁵ It is probable that adjuvant chemotherapy does benefit children with completely resected hepatocellular carcinoma. Treatment with cisplatin and doxorubicin may be recommended as adjuvant therapy since these are active agents in the treatment of hepatocellular carcinoma.⁸ Studies in adults in China suggest that hepatic arterial chemoembolization before surgery may improve the outcome of subsequent hepatectomy.⁹ (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)

¹ 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.

² 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.

³ Perilongo G, Shafford E, Maibach R, et al.: Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2. Eur J Cancer 40 (3): 411-21, 2004.

⁴ 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.

⁵ Exelby PR, Filler RM, Grosfeld JL: Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey--1974. J Pediatr Surg 10 (3): 329-37, 1975.

⁶ 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.

⁷ 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.

⁸ Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002.

⁹ Zhang Z, Liu Q, He J, et al.: The effect of preoperative transcatheter hepatic arterial chemoembolization on disease-free survival after hepatectomy for hepatocellular carcinoma. Cancer 89 (12): 2606-12, 2000.

Stage III Childhood Liver Cancer

Postsurgically staged, stage III and presurgically staged, PRETEXT stage 4 hepatoblastoma

Standard treatment options

In approximately 75% of children and adolescents with initially unresectable hepatoblastoma, tumors can be rendered resectable with cisplatin-based preoperative chemotherapy, and 60% to 65% will survive disease free. A randomized clinical trial demonstrated comparable efficacy with cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma. Although outcome was nominally higher for children receiving cisplatin/doxorubicin, this difference was not statistically significant, and the combination of cisplatin/vincristine/flourouracil was significantly less toxic than the doses of cisplatin/doxorubicin used.¹ However, another chemotherapy regimen including doxorubicin/cisplatin at different doses and schedules demonstrated comparable results with less toxicity.² A combination of ifosfamide, cisplatin, and doxorubicin has also been successfully used in the treatment of advanced-stage disease.³ Patients whose tumors remain unresectable should be considered for liver transplantation.^{2,4,5,6,7,8,9,10,11,12} Alternative approaches such as radiation therapy,^13,14 chemoembolization,^15,16 and direct hepatic infusion of chemotherapeutic agents ¹⁶ may also be utilized.

Stage III 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 23 of 25 patients with stage III disease.⁸ No particular treatment for unresectable hepatocellular carcinoma has proved especially effective in the pediatric age group. A prospective study of 41 patients who were to receive preoperative cisplatin/doxorubicin chemotherapy resulted in some degree of decrease in tumor size with a decrease in alphafetoprotein in about 50% of patients. The responders had a superior tumor resectability and survival, though the overall survival was 28% and only those undergoing complete resection survived.¹⁷ Several therapeutic options have produced successful outcomes with hepatocellular carcinoma, including cryosurgery, intratumoral injection of alcohol, hepatic arterial chemoembolization,^16,18 radiotherapeutic approaches, and liver transplantation.^5,6,7 (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)

¹ 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.

² 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.

³ 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.

⁴ Koneru B, Flye MW, Busuttil RW, et al.: Liver transplantation for hepatoblastoma. The American experience. Ann Surg 213 (2): 118-21, 1991.

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

⁶ 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.

⁷ Reyes JD, Carr B, Dvorchik I, et al.: Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence. J Pediatr 136 (6): 795-804, 2000.

⁸ 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.

⁹ Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004.

¹⁰ Molmenti EP, Wilkinson K, Molmenti H, et al.: Treatment of unresectable hepatoblastoma with liver transplantation in the pediatric population. Am J Transplant 2 (6): 535-8, 2002.

¹¹ Czauderna P, Otte JB, Aronson DC, et al.: Guidelines for surgical treatment of hepatoblastoma in the modern era--recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL). Eur J Cancer 41 (7): 1031-6, 2005.

¹² Tiao GM, Bobey N, Allen S, et al.: The current management of hepatoblastoma: a combination of chemotherapy, conventional resection, and liver transplantation. J Pediatr 146 (2): 204-11, 2005.

¹³ 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.

¹⁴ 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.

¹⁵ Xianliang H, Jianhong L, Xuewu J, et al.: Cure of hepatoblastoma with transcatheter arterial chemoembolization. J Pediatr Hematol Oncol 26 (1): 60-3, 2004.

¹⁶ 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.

¹⁷ Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002.

¹⁸ Zhang Z, Liu Q, He J, et al.: The effect of preoperative transcatheter hepatic arterial chemoembolization on disease-free survival after hepatectomy for hepatocellular carcinoma. Cancer 89 (12): 2606-12, 2000.

Stage IV Childhood Liver Cancer

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.^1,2,3,4 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.^1,2,3,4,5 For patients with PRETEXT stage 4 disease with or without pulmonary metastases who respond to chemotherapy and achieve complete remission of extrahepatic disease, liver transplantation can produce disease-free survival in a high percentage of patients.⁶ If possible, stage IV patients with resected primary tumor should have any remaining pulmonary metastases surgically removed. A randomized clinical trial compared cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma. Although outcome was nominally higher for children receiving cisplatin/doxorubicin, this difference was not statistically significant, and the combination of cisplatin/vincristine/flourouracil was less toxic than the regimen of cisplatin/doxorubicin to which it was compared.³ A combination of ifosfamide, cisplatin, and doxorubicin has also been successfully used in the treatment of advanced-stage disease.⁷ Patients whose tumors remain unresectable should be considered for alternative chemotherapy, such as irinotecan,^8,9 high-dose cisplatin with etoposide, radiation therapy,^2,10 or direct hepatic infusion of chemotherapeutic agents.^11,12 If metastatic disease is controlled, orthotopic liver transplantation ^4,6,13,14,15 has been successful.

Standard treatment options

The standard regimen is 4 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 phase II clinical trials of chemotherapy.

Stage IV hepatocellular carcinoma

In 2 prospective trials, cisplatin plus either vincristine/fluorouracil or continuous infusion doxorubicin was ineffective in adequately treating 25 patients with metastatic hepatocellular carcinoma.^16,17 No particular treatment for unresectable hepatocellular carcinoma has proved 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.)

¹ 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.

² 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.

³ 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.

⁴ 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.

⁵ 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.

⁶ Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004.

⁷ 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.

⁸ Katzenstein HM, Rigsby C, Shaw PH, et al.: Novel therapeutic approaches in the treatment of children with hepatoblastoma. J Pediatr Hematol Oncol 24 (9): 751-5, 2002.

⁹ Palmer RD, Williams DM: Dramatic response of multiply relapsed hepatoblastoma to irinotecan (CPT-11). Med Pediatr Oncol 41 (1): 78-80, 2003.

¹⁰ 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.

¹¹ 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.

¹² 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.

¹³ Koneru B, Flye MW, Busuttil RW, et al.: Liver transplantation for hepatoblastoma. The American experience. Ann Surg 213 (2): 118-21, 1991.

¹⁴ Bilik R, Superina R: Transplantation for unresectable liver tumors in children. Transplant Proc 29 (7): 2834-5, 1997.

¹⁵ 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.

¹⁶ 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.

¹⁷ Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002.

Recurrent Childhood Liver Cancer

Recurrent hepatoblastoma

The prognosis for a patient with recurrent or progressive hepatoblastoma depends on many factors, including the site of recurrence, prior treatment, and individual patient considerations. For example, in patients with stage I hepatoblastoma at initial diagnosis, aggressive surgical treatment of isolated pulmonary metastases that develop in the course of the disease may make extended disease-free survival possible.¹ If possible, isolated metastases should be resected completely in patients whose primary tumor is controlled.² Phase I and phase II clinical trials may be appropriate and should be considered.

Recurrent hepatocellular carcinoma

The prognosis for a patient with recurrent or progressive hepatocellular carcinoma is poor.³ Phase I and phase II clinical trials may be appropriate and should be considered. (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)

¹ Feusner JH, Krailo MD, Haas JE, et al.: Treatment of pulmonary metastases of initial stage I hepatoblastoma in childhood. Report from the Childrens Cancer Group. Cancer 71 (3): 859-64, 1993.

² Robertson PL, Muraszko KM, Axtell RA: Hepatoblastoma metastatic to brain: prolonged survival after multiple surgical resections of a solitary brain lesion. J Pediatr Hematol Oncol 19 (2): 168-71, 1997 Mar-Apr.

³ 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.

Changes to This Summary (10/20/2006)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Stage Information

Added text about the relationship of the PRETEXT staging system and postoperative pathological findings (cited Aronson et al. as reference 10).

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