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Childhood Liver Cancer Treatment (PDQ®)     
Last Modified: 12/08/2008
Health Professional Version
Table of Contents

Purpose of This PDQ Summary
General Information
Hepatoblastoma and Hepatocellular Carcinoma
        Epidemiology
        Syndromes, genetics and other risk factors
        Undifferentiated Embryonal Sarcoma of the Liver
Cellular Classification
Hepatoblastoma and Hepatocellular Carcinoma
Undifferentiated Embryonal Sarcoma of the Liver
Stage Information
Postsurgical Staging for Childhood Liver Cancer
        Stage I
        Stage II
        Stage III
        Stage IV
Presurgical Anatomic Staging for Hepatoblastoma and Hepatocellular Carcinoma Using Imaging Techniques
        PRETEXT stage 1
        PRETEXT stage 2
        PRETEXT stage 3
        PRETEXT stage 4
Treatment Option Overview
Stage I and II Childhood Liver Cancer
Postsurgically staged, stage I and II and presurgically staged, PRETEXT stage 1, 2, and 3 hepatoblastoma
        Treatment options
Stage I and II hepatocellular carcinoma
        Treatment options
Current Clinical Trials
Stage III Childhood Liver Cancer
Postsurgically staged, stage III and presurgically staged, PRETEXT stage 4 hepatoblastoma
        Standard treatment options
Stage III hepatocellular carcinoma
Current Clinical Trials
Stage IV Childhood Liver Cancer
Stage IV hepatoblastoma
        Standard treatment options
Stage IV hepatocellular carcinoma
Current Clinical Trials
Recurrent Childhood Liver Cancer
Recurrent hepatoblastoma
Recurrent hepatocellular carcinoma
Current Clinical Trials
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Changes to This Summary (12/08/2008)
More Information

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood liver cancer. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board 1.

Information about the following is included in this summary:

  • Cellular classification.
  • Stage information.
  • Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system 2 in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version 3, which is written in less-technical language, and in Spanish 4.

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.

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 5 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 6.

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 7 for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Hepatoblastoma and Hepatocellular Carcinoma

Epidemiology

Liver cancer is a rare malignancy in children and adolescents and is divided into two major histologic subgroups: hepatoblastoma and hepatocellular carcinoma. The incidence of hepatic tumors in children 14 years and younger is 2.4 per 100,000, of which 2 per 100,000 have hepatoblastoma. The incidence of hepatocellular carcinoma is negligible in children aged younger than 14 years.[SEER Cancer Statistics Review 8] The age of onset of liver cancer in children is related to tumor histology. Hepatoblastomas usually occur before the age of 3 years, and approximately 90% of malignant liver tumors in children aged 4 years and younger 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 has minimal variance between the ages of 0 and 19 years and has not changed appreciably over time.[2,3] The cause for the increase in incidence of hepatoblastoma is unknown, but the increasing survival of very low birthweight premature infants, which is known to be associated with hepatoblastoma, may contribute.[4] In Japan, the risk of hepatoblastoma in children who weighed less than 1,000 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 and administration of hepatitis B immune globulin to the newborn.[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]

Prognosis and tumor markers

Cure of hepatoblastoma or hepatocellular carcinoma requires 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. Thus, it is 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.[8-10,13,14] Orthotopic liver transplantation provides an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy;[14-16] however, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome. This is probably because additional courses of chemotherapy generally are administered after resection to all patients except those with stage I and pure fetal histology, whether the resection occurs before or after chemotherapy.[8,9,17] 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. Orthotopic liver transplantation has also been successful in selected children with hepatocellular carcinoma.[16]

A biopsy of the tumor is always indicated to secure the diagnosis of a liver tumor except in infants with hepatic hemangiomas or hemangioendotheliomas, in whom the imaging may be diagnostic. Ninety percent of patients with hepatoblastoma and two-thirds of patients with hepatocellular carcinoma have a serum tumor marker, alpha-fetoprotein (AFP), that parallels disease activity, however, elevation of alpha-fetoprotein is not diagnostic of hepatic malignancy.[18] Lack of a significant decrease of AFP levels with treatment may predict a poor response to therapy.[19] Absence of elevated AFP may be a poor prognostic sign in hepatoblastoma.[20-22] Beta-human chorionic gonadotropin (Beta-hCG) levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity.[23,24]

Syndromes, genetics and other risk factors

The incidence of hepatoblastoma is increased 1,000 to 10,000-fold in infants and children with Beckwith-Wiedemann syndrome (BWS).[25,26] Hepatoblastoma is also increased in hemihypertophy,[27] an overgrowth syndrome caused by the same epigenetic changes in chromosome 11p15.5 that cause many cases of BWS, but in a genetically mosaic fashion.[26,28] BWS can be caused by either genetic mutations and be familial, or much more commonly by epigenetic changes and be sporadic. Either mechanism can be associated with an increased incidence of embryonal tumors including Wilms tumor and hepatoblastoma.[26] The gene dosage and ensuing increase in expression of insulin-like growth factor 2 (IGF-2) has been implicated in the macrosomia and embryonal tumors in BWS and hemihypertrophy.[26,29] Changes in the IGF-2 locus also occur in the embryonal tumors associated with BWS when they arise in children who do not have BWS.[30,31] All children with BWS or isolated hemihypertrophy should be screened regularly by ultrasound to detect abdominal malignancies at an early stage. Screening using AFP levels has helped in the early detection of hepatoblastoma in children with BWS or hemihypertrophy.[32] Other somatic overgrowth syndromes, such as Simpson-Golabi-Behmel syndrome, may also be associated with hepatoblastoma.[33]

There is a clear association between hepatoblastoma and familial adenomatous polyposis (FAP); children in families that carry the FAP gene are at an 800-fold increased risk for hepatoblastoma, though it occurs in less than 1% of FAP family members.[34-36] The predisposition to hepatoblastoma may be limited to a specific subset of FAP mutations.[37] 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 70% of polyposis families.[35] In the absence of FAP germline mutations, childhood hepatoblastomas do not have mutations in the FAP gene; however, they frequently have mutations in the beta-catenin gene, the function of which is closely related to FAP.[38]

Hepatocellular carcinoma is associated with hepatitis B and hepatitis C infection,[39,40] especially in children with perinatally acquired hepatitis B virus. Widespread hepatitis B immunization has decreased the incidence of hepatocellular carcinoma in Asia.[7] 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.[41] Several specific types of nonviral liver injury and cirrhosis are associated with hepatocellular carcinoma in children including tyrosinemia and biliary cirrhosis. Hepatocellular carcinoma may also arise in very young children with mutations in the bile salt export pump ABCB11, which causes progressive familial hepatic cholestasis.[42]

Undifferentiated Embryonal Sarcoma of the Liver

Undifferentated embryonal sarcoma of the liver (UESL) is the third most common liver malignancy in children and adolescents, comprising 9% to 13 % of liver tumors. It presents as an abdominal mass, often with pain or malaise, usually between the ages of 5 and 10 years. It may be solid or cystic on imaging, frequently with central necrosis. Distinctive features are characteristic intracellular hyaline globules and marked anaplasia on a mesenchymal background.[43]

It is important to make the diagnostic distinction between UESL and biliary tract rhabdomyosarcoma (BTR) as they share some common clinical and pathologic features but treatment differs between the two. Clinically, UESL tends to occur in older children (median age 10.5 years for UESL vs. mean age 3.4 years for BTR), often arises in the right lobe of the liver (vs. hilum for BTR), and does not often present with biliary obstruction (vs. jaundice as a common presenting symptom in BTR). Surgery alone may achieve local control for UESL while surgery and radiotherapy are required for BTR. Chemotherapy regimens used to treat UESL differ from those used to treat BTR.[44] Refer to the PDQ summary on PDQ Childhood Rhabdomyosarcoma 9 for more information.)

It has been suggested that some UESLs arise from mesenchymal hamartomas of the liver (MHL), which are large benign multicystic masses that present in the first two years of life.[44] Strong clinical and histological evidence suggest that UESL can arise within a preexisting MHL. Many MHLs have a characteristic translocation with a breakpoint at 19q13.4 and several UESLs have the same translocation.[45,46]

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. 10 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. 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]

  16. 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]

  17. 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]

  18. Boman F, Bossard C, Fabre M, et al.: Mesenchymal hamartomas of the liver may be associated with increased serum alpha foetoprotein concentrations and mimic hepatoblastomas. Eur J Pediatr Surg 14 (1): 63-6, 2004.  [PUBMED Abstract]

  19. 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]

  20. 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.  [PUBMED Abstract]

  21. 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.  [PUBMED Abstract]

  22. D'Antiga L, Vallortigara F, Cillo U, et al.: Features predicting unresectability in hepatoblastoma. Cancer 110 (5): 1050-8, 2007.  [PUBMED Abstract]

  23. 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]

  24. 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]

  25. DeBaun MR, Tucker MA: Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr 132 (3 Pt 1): 398-400, 1998.  [PUBMED Abstract]

  26. Weksberg R, Shuman C, Smith AC: Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet 137C (1): 12-23, 2005.  [PUBMED Abstract]

  27. 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]

  28. Sparago A, Russo S, Cerrato F, et al.: Mechanisms causing imprinting defects in familial Beckwith-Wiedemann syndrome with Wilms' tumour. Hum Mol Genet 16 (3): 254-64, 2007.  [PUBMED Abstract]

  29. Algar EM, St Heaps L, Darmanian A, et al.: Paternally inherited submicroscopic duplication at 11p15.5 implicates insulin-like growth factor II in overgrowth and Wilms' tumorigenesis. Cancer Res 67 (5): 2360-5, 2007.  [PUBMED Abstract]

  30. Steenman M, Westerveld A, Mannens M: Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways. Genes Chromosomes Cancer 28 (1): 1-13, 2000.  [PUBMED Abstract]

  31. Albrecht S, Hartmann W, Houshdaran F, et al.: Allelic loss but absence of mutations in the polyspecific transporter gene BWR1A on 11p15.5 in hepatoblastoma. Int J Cancer 111 (4): 627-32, 2004.  [PUBMED Abstract]

  32. Clericuzio CL, Chen E, McNeil DE, et al.: Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr 143 (2): 270-2, 2003.  [PUBMED Abstract]

  33. 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]

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

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

  36. Giardiello FM, Petersen GM, Brensinger JD, et al.: Hepatoblastoma and APC gene mutation in familial adenomatous polyposis. Gut 39 (96): 867-9, 1996.  [PUBMED Abstract]

  37. 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]

  38. 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]

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

  40. 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]

  41. 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]

  42. 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]

  43. Stocker JT: Hepatic tumors in children. Clin Liver Dis 5 (1): 259-81, viii-ix, 2001.  [PUBMED Abstract]

  44. Nicol K, Savell V, Moore J, et al.: Distinguishing undifferentiated embryonal sarcoma of the liver from biliary tract rhabdomyosarcoma: a Children's Oncology Group study. Pediatr Dev Pathol 10 (2): 89-97, 2007 Mar-Apr.  [PUBMED Abstract]

  45. Stringer MD, Alizai NK: Mesenchymal hamartoma of the liver: a systematic review. J Pediatr Surg 40 (11): 1681-90, 2005.  [PUBMED Abstract]

  46. O'Sullivan MJ, Swanson PE, Knoll J, et al.: Undifferentiated embryonal sarcoma with unusual features arising within mesenchymal hamartoma of the liver: report of a case and review of the literature. Pediatr Dev Pathol 4 (5): 482-9, 2001 Sep-Oct.  [PUBMED Abstract]

Cellular Classification



Hepatoblastoma and Hepatocellular Carcinoma

The cells of the adult-type hepatocellular carcinoma are epithelial while hepatoblastoma has a less differentiated embryonal appearance. 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.

Analysis of patients with initially resected hepatoblastoma tumors (prior to receiving chemotherapy) 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 a study of patients with hepatoblastoma and pure fetal histology tumors, there was a 100% survival rate for patients who received four doses of single-agent doxorubicin.[1] This suggested that patients with pure fetal histology tumors might not need chemotherapy after complete resection of a stage I tumor.[2,3] In the Children's Oncology Group study P9645 11, patients with stage I pure fetal histology hepatoblastoma with two or fewer mitoses per 10 high power fields were not treated with chemotherapy. Completely resected tumors of pure fetal histology must have a careful and thorough histologic examination, because small foci of undifferentiated small cell histology indicates a need for aggressive chemotherapy.[4]

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

Undifferentiated Embryonal Sarcoma of the Liver

Undifferentiated embryonal sarcoma of the liver is a distinct clinical and pathologic entity and accounts for 2% to 15% of pediatric hepatic malignancies.[10]

References

  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.  [PUBMED Abstract]

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

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

  4. Haas JE, Feusner JH, Finegold MJ: Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Cancer 92 (12): 3130-4, 2001.  [PUBMED Abstract]

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

  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.  [PUBMED Abstract]

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

  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.  [PUBMED Abstract]

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

  10. Nicol K, Savell V, Moore J, et al.: Distinguishing undifferentiated embryonal sarcoma of the liver from biliary tract rhabdomyosarcoma: a Children's Oncology Group study. Pediatr Dev Pathol 10 (2): 89-97, 2007 Mar-Apr.  [PUBMED Abstract]

Stage Information

There are two standard surgical staging systems for pediatric liver tumors. The Children's Oncology Group (COG) uses a postsurgical-based staging system, while the International Childhood Liver Tumour Strategy Group (SIOPEL) uses a presurgical-based staging system. Both systems are used in the United States.

Postsurgical Staging for Childhood Liver Cancer

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.[1-3] 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]

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 for Hepatoblastoma and Hepatocellular Carcinoma 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.[7,8] 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] 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.[8] The 5-year OS in the first 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. Patients with lung metastasis had a 25% OS.[10,11] The 5-year OS for PRETEXT staged hepatocellular carcinoma was stages 1 to 2: 44%; stage 3: 22%; and stage 4: 8%.[6] The second international study compared 3-year OS among hepatoblastoma patients by PRETEXT stage absent of extrahepatic disease (PRETEXT stages 1– 4: 100%, 95%, 84% and 61%, respectively) and also prospectively analyzed patients by presence of intraabdominal extrahepatic disease without distant metastasis (58%) and distant metastases (44%).[12] Patients who underwent orthotopic liver transplant are included in all the international study results.[13] The COG plans to prospectively stage hepatoblastoma patients using the PRETEXT system in order to compare COG study results to the international studies.

PRETEXT stage 1
  • Tumor involves only one quadrant; three adjoining liver quadrants are free of tumor.
PRETEXT stage 2
  • Tumor involves two adjoining quadrants; two adjoining quadrants are free of tumor.
PRETEXT stage 3
  • Tumor involves three adjoining quadrants or two nonadjoining quadrants; one quadrant or two nonadjoining quadrants are free of tumor.
PRETEXT stage 4
  • Tumor involves all four quadrants; there is no quadrant free of tumor.

References

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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. 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]

  6. 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]

  7. 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.  [PUBMED Abstract]

  8. 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.  [PUBMED Abstract]

  9. Roebuck DJ, Olsen Ø, Pariente D: Radiological staging in children with hepatoblastoma. Pediatr Radiol 36 (3): 176-82, 2006.  [PUBMED Abstract]

  10. 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]

  11. 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]

  12. 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.  [PUBMED Abstract]

  13. 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]

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 two 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.[1]

Historically, resection of the primary tumor has been required to cure malignant liver tumors in children.[2-6] Since these tumors occur infrequently, surgeons with experience in pediatric liver resection and transplantation should be involved early in the decision making process concerning the timing and extent of resection. Initial resection versus delayed resection will depend upon the size of the tumor, multifocality, and vascular involvement. While vascular involvement was initially thought to be a contraindication to resection experienced liver surgeons are able to perform aggressive approaches avoiding transplantation.[7,8] In a group of adult patients that were initially thought to be nonresectable, 85% of the patients were resected using an aggressive approach to the tumor with a mortality of 6%.[8] The resection margins were clear in over 90% of the patients. Accomplishing a complete resection is imperative since rescue transplant of incompletely resected patients has an inferior outcome compared to patients who are transplanted as the primary surgical therapy.[9]

In pediatric liver tumors there remain two standard surgical approaches: an attempt at initial surgical resection or a biopsy followed by chemotherapy, or a delayed attempt at surgical resection. If tumor can be completely excised by an experienced surgical team, less postoperative chemotherapy may be needed. If preoperative chemotherapy is to be administered it is very important to consult frequently with the surgical team concerning timing of resection as prolonged chemotherapy can lead to unnecessary delays and in rare cases even tumor progression. In COG trials, it is currently recommended that surgery be performed initially if a complete resection can be accomplished. In Europe, using the PRETEXT system, only patients with PRETEXT stage 1 receive resection surgery.

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.[5,6,10-14] 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.[13-15] 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 in the study.[13] Identical overall results were seen in a followup international study.[14] In contrast, an 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 (COG-P9645 11) did not treat children with stage I tumors of purely fetal histology with preoperative or postoperative chemotherapy unless they developed progressive disease. 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 [16,17] 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.[18] Tumor rupture at presentation resulting in major hemorrhage which can be controlled by transcatheter arterial embolization or partial resection to stabilize the patient, does not preclude a favorable outcome when followed by chemotherapy and definitive surgery.[19]

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,[11,20] though a study of 154 patients with hepatoblastoma did not confirm this finding.[15] 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.[9] Intravenous invasion, positive lymph nodes, and contiguous spread did not have a significant adverse effect on outcome. The United Network for Organ Sharing (UNOS) Standard Transplant and Research Files registry reported all children less than 18 years of age listed for a liver transplant in the United States from October, 1987 through July, 2004. Of these children, 135 had hepatoblastoma and 41 had hepatocellular carcinoma and both groups received liver transplant with 5-year survival rates of 69% and 63%, respectively. The 10-year survival rates were similar to the 5-year rates.[21] In a separate three-institution study for children with hepatocellular carcinoma, the overall 5-year disease-free survival rate was approximately 60%.[22] 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.

References

  1. 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]

  2. Andres AM, Hernandez F, Lopez-Santamaría M, et al.: Surgery of liver tumors in children in the last 15 years. Eur J Pediatr Surg 17 (6): 387-92, 2007.  [PUBMED Abstract]

  3. 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]

  4. 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]

  5. 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]

  6. 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]

  7. D'Antiga L, Vallortigara F, Cillo U, et al.: Features predicting unresectability in hepatoblastoma. Cancer 110 (5): 1050-8, 2007.  [PUBMED Abstract]

  8. Hemming AW, Reed AI, Fujita S, et al.: Role for extending hepatic resection using an aggressive approach to liver surgery. J Am Coll Surg 206 (5): 870-5; discussion 875-8, 2008.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  10. 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]

  11. 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]

  12. 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]

  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. 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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  16. 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.  [PUBMED Abstract]

  17. 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]

  18. 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.  [PUBMED Abstract]

  19. Madanur MA, Battula N, Davenport M, et al.: Staged resection for a ruptured hepatoblastoma: a 6-year follow-up. Pediatr Surg Int 23 (6): 609-11, 2007.  [PUBMED Abstract]

  20. 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]

  21. 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]

  22. 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.  [PUBMED Abstract]

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.[1-3]Comparable results were obtained in aninternational 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] Replacement of some cisplatin by carboplatin in the cisplatin/vincristine/doxorubicinregimen was associated with a decrease in event-free survival.[7]

Treatment options

An alternative strategy for PRETEXT stage 2 and 3 hepatoblastoma is initial chemotherapy with four to six 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, seven of eight patients with stage I hepatocellular carcinoma survived disease free after adjuvant cisplatin-based chemotherapy.[8] 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.[9] Studies in adults in China suggest that hepatic arterial chemoembolization before surgery may improve the outcome of subsequent hepatectomy.[10] (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment 12 for more information.)

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I and II childhood liver cancer 13. 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 14.

References

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  7. Malogolowkin MH, Katzenstein H, Krailo MD, et al.: Intensified platinum therapy is an ineffective strategy for improving outcome in pediatric patients with advanced hepatoblastoma. J Clin Oncol 24 (18): 2879-84, 2006.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  9. 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]

  10. 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.  [PUBMED Abstract]

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.[2,4-13] Alternative approaches such as radiation therapy,[14,15] chemoembolization,[16,17] and direct hepatic infusion of chemotherapeutic agents [17] may also be utilized.Replacement of some cisplatin by carboplatin in the cisplatin/vincristine/doxorubicin regimen was associated with a decrease in event-free survival.[18]

Stage III hepatocellular carcinoma Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III childhood liver cancer 15. 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 14.

References

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

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

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

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  13. 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]

  14. 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]

  15. 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]

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

  17. 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]

  18. Malogolowkin MH, Katzenstein H, Krailo MD, et al.: Intensified platinum therapy is an ineffective strategy for improving outcome in pediatric patients with advanced hepatoblastoma. J Clin Oncol 24 (18): 2879-84, 2006.  [PUBMED Abstract]

Stage IV Childhood Liver Cancer



Stage IV hepatoblastoma

The outcome for hepatoblastoma that is metastaticat 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] 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] Replacement of some cisplatin by carboplatin in the cisplatin/vincristine/doxorubicin regimen was associated with a decrease in event-free survival.[7] A combination of ifosfamide, cisplatin, and doxorubicin has also been successfully used in the treatment of advanced-stage disease.[8] Patients whose tumors remain unresectable should be considered for alternative chemotherapy, such as irinotecan,[9,10] high-dose cisplatin with etoposide, radiation therapy,[2,11] or direct hepatic infusion of chemotherapeutic agents.[12,13]If metastatic disease is controlled, orthotopic liver transplantation [4,6,14-17] has been successful.

Standard treatment options

The standard regimen is four courses of cisplatin/vincristine/fluorouracil [3] or doxorubicin/cisplatin combination chemotherapy followed by attempted complete tumor resection. If the tumor is completely removed, two postoperative courses of the same chemotherapy should be given. If the tumor is not resectable after four 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 two prospective trials, cisplatin plus either vincristine/fluorouracil or continuous infusion doxorubicin was ineffective in adequately treating 25 patients with metastatic hepatocellular carcinoma.[18,19] 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 12 for more information.)

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV childhood liver cancer 16. 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 14.

References

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  7. Malogolowkin MH, Katzenstein H, Krailo MD, et al.: Intensified platinum therapy is an ineffective strategy for improving outcome in pediatric patients with advanced hepatoblastoma. J Clin Oncol 24 (18): 2879-84, 2006.  [PUBMED Abstract]

  8. 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]

  9. 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.  [PUBMED Abstract]

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

  11. 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]

  12. 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]

  13. 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]

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

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

  16. 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]

  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. 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]

  19. 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]

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 12 for more information.)

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent childhood liver cancer 17. 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 14.

References

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.

Chat online

The NCI's LiveHelp® 18 online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.

Write to us

For more information from the NCI, please write to this address:

NCI Public Inquiries Office
Suite 3036A
6116 Executive Boulevard, MSC8322
Bethesda, MD 20892-8322

Search the NCI Web site

The NCI Web site 19 provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use our “Best Bets” search box in the upper right hand corner of each Web page. The results that are most closely related to your search term will be listed as Best Bets at the top of the list of search results.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator 20. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237), TTY at 1-800-332-8615.

Changes to This Summary (12/08/2008)

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.

This summary was extensively revised.

More Information

About PDQ

Additional PDQ Summaries

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).


Table of Links

1http://www.cancer.gov/cancerinfo/pdq/pediatric-treatment-board
2http://www.cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment/HealthPr
ofessional
3http://www.cancer.gov/cancertopics/pdq/treatment/childliver/Patient
4http://www.cancer.gov/espanol/pdq/tratamiento/higadoinfantil/HealthProfessional
5http://cancer.gov/cancerinfo/pdq/supportivecare
6http://cancer.gov/clinicaltrials
7http://www.cancer.gov/cancertopics/pdq/treatment/lateeffects/HealthProfessional
8http://seer.cancer.gov/csr/1975_2005
9http://www.cancer.gov/cancertopics/pdq/treatment/childrhabdomyosarcoma/HealthPr
ofessional
10http://seer.cancer.gov/publications/childhood
11http://www.cancer.gov/search/viewclinicaltrials.aspx?version= heal
thprofessional &cdrid=67200
12http://www.cancer.gov/cancertopics/pdq/treatment/adult-primary-liver/HealthProf
essional
13http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=43642&tt=1&a
mp;format=2&cn=1
14http://www.cancer.gov/clinicaltrials
15http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=43717&tt=1&a
mp;format=2&cn=1
16http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=43718&tt=1&a
mp;format=2&cn=1
17http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=43719&tt=1&a
mp;format=2&cn=1
18https://cissecure.nci.nih.gov/livehelp/welcome.asp
19http://cancer.gov
20https://cissecure.nci.nih.gov/ncipubs
21http://cancer.gov/cancerinfo/pdq/cancerdatabase
22http://cancer.gov/cancerinfo/pdq/adulttreatment
23http://cancer.gov/cancerinfo/pdq/pediatrictreatment
24http://cancer.gov/cancerinfo/pdq/screening
25http://cancer.gov/cancerinfo/pdq/prevention
26http://cancer.gov/cancerinfo/pdq/genetics
27http://cancer.gov/cancerinfo/pdq/cam