Current Clinical Trials

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] Other data have confirmed the high incidence of hepatoblastoma in very low birth weight premature infants.[6] 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, which potentially can be prevented by vaccination.[7] The overall survival rate for children with hepatoblastoma is 70% [8-10] but is only 25% for those with hepatocellular carcinoma.[2,11,12]

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.[8-10,13-15] Orthotopic liver transplantation provides an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy;[14-17] 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.[8,9,18] 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.[19] Orthotopic liver transplantation has also been successful in selected children with hepatocellular carcinoma.[17]

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.[20] 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.[21,22]

Hepatoblastoma is part of the constellation of findings associated with the Beckwith-Wiedemann syndrome or its variant, isolated hemihypertrophy.[23,24] Other somatic overgrowth syndromes, such as Simpson-Golabi-Behmel syndrome, may also be associated.[25] About 2% of children with hepatoblastoma have hemihypertrophy.[26] Less than 1% of children with hemihypertrophy are at increased risk for developing hepatoblastoma within the first several years of life.[24] 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.[27,28] 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.[29-31] The predisposition to hepatoblastoma may be limited to a specific subset of FAP mutations.[32] 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.[31] 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.[33]

Hepatocellular carcinoma is associated with hepatitis B and hepatitis C infection,[34,35] especially in children with perinatally acquired hepatitis B virus. Therefore, widespread hepatitis B immunization may decrease the incidence of hepatocellular carcinoma.[36] 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.[37] 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. Hepatocellular carcinoma in very young children may also arise in children with mutations in the bile salt export pump ABCB11, which causes progressive familial hepatic cholestasis.[38]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood liver cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

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.  [PUBMED Abstract]
   
   
2. Darbari A, Sabin KM, Shapiro CN, et al.: Epidemiology of primary hepatic malignancies in U.S. children. Hepatology 38 (3): 560-6, 2003.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
6. McLaughlin CC, Baptiste MS, Schymura MJ, et al.: Maternal and infant birth characteristics and hepatoblastoma. Am J Epidemiol 163 (9): 818-28, 2006.  [PUBMED Abstract]
   
   
7. Chang MH, Chen TH, Hsu HM, et al.: Prevention of hepatocellular carcinoma by universal vaccination against hepatitis B virus: the effect and problems. Clin Cancer Res 11 (21): 7953-7, 2005.  [PUBMED Abstract]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. 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]
    
    
14. 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.  [PUBMED Abstract]
    
    
15. 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.  [PUBMED Abstract]
    
    
16. 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.  [PUBMED Abstract]
    
    
17. Austin MT, Leys CM, Feurer ID, et al.: Liver transplantation for childhood hepatic malignancy: a review of the United Network for Organ Sharing (UNOS) database. J Pediatr Surg 41 (1): 182-6, 2006.  [PUBMED Abstract]
    
    
18. 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.  [PUBMED Abstract]
    
    
19. 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.  [PUBMED Abstract]
    
    
20. 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.  [PUBMED Abstract]
    
    
21. 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.  [PUBMED Abstract]
    
    
22. 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.  [PUBMED Abstract]
    
    
23. 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.  [PUBMED Abstract]
    
    
24. 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.  [PUBMED Abstract]
    
    
25. 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.  [PUBMED Abstract]
    
    
26. 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.  [PUBMED Abstract]
    
    
27. 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.  [PUBMED Abstract]
    
    
28. 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.  [PUBMED Abstract]
    
    
29. Iwama T, Mishima Y: Mortality in young first-degree relatives of patients with familial adenomatous polyposis. Cancer 73 (8): 2065-8, 1994.  [PUBMED Abstract]
    
    
30. Li FP, Thurber WA, Seddon J, et al.: Hepatoblastoma in families with polyposis coli. JAMA 257 (18): 2475-7, 1987.  [PUBMED Abstract]
    
    
31. Garber JE, Li FP, Kingston JE, et al.: Hepatoblastoma and familial adenomatous polyposis. J Natl Cancer Inst 80 (20): 1626-8, 1988.  [PUBMED Abstract]
    
    
32. 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.  [PUBMED Abstract]
    
    
33. 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.  [PUBMED Abstract]
    
    
34. Ni YH, Chang MH, Hsu HY, et al.: Hepatocellular carcinoma in childhood. Clinical manifestations and prognosis. Cancer 68 (8): 1737-41, 1991.  [PUBMED Abstract]
    
    
35. 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.  [PUBMED Abstract]
    
    
36. 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.  [PUBMED Abstract]
    
    
37. 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.  [PUBMED Abstract]
    
    
38. Knisely AS, Strautnieks SS, Meier Y, et al.: Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 44 (2): 478-86, 2006.  [PUBMED Abstract]
    
    

Back to Top

Next Section >