General Information
Cellular Classification
Stage Information

Postsurgical staging         Stage I         Stage II         Stage III         Stage IV Presurgical anatomic staging 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 (10/06/2007)
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General Information

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

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

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

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

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

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]
   
   

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Stage Information

Postsurgical staging

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

• No metastases, tumor completely resected.

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

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

• Distant metastases regardless of the extent of liver involvement.

The pretreatment extent of disease (PRETEXT) staging system for hepatoblastoma categorizes the primary tumor based on extent of liver involvement at diagnosis. The staging system was devised for use in an international hepatoblastoma treatment program in which only children with PRETEXT stage 1 hepatoblastoma undergo initial resection of tumor. All others are treated with chemotherapy prior to attempted resection of the primary tumor. The liver tumors are staged by interpretation of computerized tomography or ultrasound with or without additional imaging by magnetic resonance . The presence or absence of metastases is noted in addition to the PRETEXT stage, but does not alter the PRETEXT stage. The imaged liver is divided into 4 quadrants and involvement of each quadrant with tumor is determined. Stage increases and prognosis decreases as the number of quadrants radiologically involved with tumor increases from 1 to 4. Experienced radiologist review is important because it may be difficult to discriminate between real invasion beyond the anatomic border of a given sector and displacement of the anatomic border.[8-11] The 5-year overall survival in this international study, in which the study protocol called for treatment of children with preoperative doxorubicin and cisplatin chemotherapy, was 100%, 91%, 68%, and 57% for PRETEXT stages 1 to 4, respectively, including patients with metastasis.[12,13] The PRETEXT staging system has a moderate degree of interobserver variability, and the preoperative PRETEXT stage agrees with postoperative pathologic findings only 51% of the time, with overstaging in 37% of patients and understaging in 12% of patients.[10]

• Tumor involves only one quadrant; three adjoining liver quadrants are free of tumor.

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

• Tumor involves three adjoining quadrants or two nonadjoining quadrants; one quadrant or two nonadjoining quadrants are free of tumor.

• 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. Giacomantonio M, Ein SH, Mancer K, et al.: Thirty years of experience with pediatric primary malignant liver tumors. J Pediatr Surg 19 (5): 523-6, 1984.  [PUBMED Abstract]
   
   
6. Katzenstein HM, Krailo MD, Malogolowkin MH, et al.: Hepatocellular carcinoma in children and adolescents: results from the Pediatric Oncology Group and the Children's Cancer Group intergroup study. J Clin Oncol 20 (12): 2789-97, 2002.  [PUBMED Abstract]
   
   
7. Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002.  [PUBMED Abstract]
   
   
8. Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004.  [PUBMED Abstract]
   
   
9. Perilongo G, Shafford E, Maibach R, et al.: Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2. Eur J Cancer 40 (3): 411-21, 2004.  [PUBMED Abstract]
   
   
10. Aronson DC, Schnater JM, Staalman CR, et al.: Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol 23 (6): 1245-52, 2005.  [PUBMED Abstract]
    
    
11. Roebuck DJ, Olsen Ø, Pariente D: Radiological staging in children with hepatoblastoma. Pediatr Radiol 36 (3): 176-82, 2006.  [PUBMED Abstract]
    
    
12. 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]
    
    
13. 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]
    
    

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Treatment Option Overview

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

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

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

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

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

Liver transplantation has recently been associated with significant success in the treatment of children with unresectable hepatic tumors. A review of the world experience has documented a posttransplant survival rate of 82% for children with hepatoblastomas.[14] Intravenous invasion, positive lymph nodes, and contiguous spread did not have a significant adverse effect on outcome. 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.[15] In a separate single-institution study for children with hepatocellular carcinoma, the overall 5-year disease-free survival rate was approximately 60%.[16] In hepatocellular carcinoma, vascular invasion, distant metastases, lymph node involvement, tumor size, and male gender were significant risk factors for recurrence. Pretransplant intra-arterial therapy was very effective in patients with hepatoblastoma but less efficacious in children with hepatocellular carcinoma. Because of the poor prognosis in patients with hepatocellular carcinoma, liver transplant should be considered for disorders such as tyrosinemia and familial intrahepatic cholestasis early in the course, prior to the development of liver failure and malignancy. The fibrolamellar variant of hepatocellular carcinoma may have a better outcome with liver transplant than other hepatocellular carcinomas.[17]

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

References

1. Schnater JM, Aronson DC, Plaschkes J, et al.: Surgical view of the treatment of patients with hepatoblastoma: results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer 94 (4): 1111-20, 2002.  [PUBMED Abstract]
   
   
2. Tomlinson GE, Finegold MJ: Tumors of the Liver. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 4th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins, 2002, pp 847-64. 
   
   
3. Katzenstein HM, Krailo MD, Malogolowkin MH, et al.: Hepatocellular carcinoma in children and adolescents: results from the Pediatric Oncology Group and the Children's Cancer Group intergroup study. J Clin Oncol 20 (12): 2789-97, 2002.  [PUBMED Abstract]
   
   
4. Ortega JA, Krailo MD, Haas JE, et al.: Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (12): 2167-76, 1991.  [PUBMED Abstract]
   
   
5. Douglass EC, Reynolds M, Finegold M, et al.: Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol 11 (1): 96-9, 1993.  [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. Douglass E, Ortega J, Feusner J, et al.: Hepatocellular carcinoma (HCA) in children and adolescents: results from the Pediatric Intergroup Hepatoma Study (CCG 8881/POG 8945). [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-1439, 420, 1994. 
   
   
8. Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002.  [PUBMED Abstract]
   
   
9. Pritchard J, Brown J, Shafford E, et al.: Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach--results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 18 (22): 3819-28, 2000.  [PUBMED Abstract]
   
   
10. Katzenstein HM, Children's Oncology Group: Phase III Randomized Study of Postoperative Cisplatin, Vincristine, and Fluorouracil in Children With Hepatoblastoma, COG-P9645, Clinical trial, Completed.  [PDQ Clinical Trial]
    
    
11. Feusner JH, Krailo MD, Haas JE, et al.: Treatment of pulmonary metastases of initial stage I hepatoblastoma in childhood. Report from the Childrens Cancer Group. Cancer 71 (3): 859-64, 1993.  [PUBMED Abstract]
    
    
12. Robertson PL, Muraszko KM, Axtell RA: Hepatoblastoma metastatic to brain: prolonged survival after multiple surgical resections of a solitary brain lesion. J Pediatr Hematol Oncol 19 (2): 168-71, 1997 Mar-Apr.  [PUBMED Abstract]
    
    
13. Habrand JL, Nehme D, Kalifa C, et al.: Is there a place for radiation therapy in the management of hepatoblastomas and hepatocellular carcinomas in children? Int J Radiat Oncol Biol Phys 23 (3): 525-31, 1992.  [PUBMED Abstract]
    
    
14. Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004.  [PUBMED Abstract]
    
    
15. 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]
    
    
16. 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]
    
    
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]
    
    

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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 an international study in which children were treated with doxorubicin/cisplatin chemotherapy prior to attempted resection of the liver tumor. In this study, 88% of the children in whom complete resection was achieved following the well-tolerated chemotherapy survived and were event-free 5 years after diagnosis.[4] In comparison, a survey of children with liver tumors who were treated prior to the consistent use of combination chemotherapy found that 45 of 78 (57%) patients with hepatoblastoma who had complete excision of the tumor survived.[5] A randomized clinical trial demonstrated comparable efficacy with cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma. Although outcome was nominally higher for children receiving cisplatin/doxorubicin, this difference was not statistically significant, and the combination of cisplatin/vincristine/flourouracil was significantly less toxic than the doses of cisplatin/doxorubicin to which it was compared.[6] Replacement of some cisplatin by carboplatin in the cisplatin/vincristine/doxorubicin regimen was associated with a decrease in event-free survival. [7]

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]

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 for more information.)

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. 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. 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]
    
    

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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]

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. 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. 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]
    
    

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Stage IV Childhood Liver Cancer

Stage IV hepatoblastoma

The outcome for hepatoblastoma that is metastatic at diagnosis is not good, but cure is possible in 25% to 30% of patients.[1-4] 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.

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.

• 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.

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 for more information.)

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. 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. 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]
    
    

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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.

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

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent 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. 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]
   
   

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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.

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Changes to This Summary (10/06/2007)

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.

Minor editorial changes made to this summary.

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More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine

  Information about complementary and alternative forms of treatment for patients with cancer.

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).

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