Pediatric Hepatocellular Carcinoma Medication
- Author: Paulette Mehta, MD, MPH; Chief Editor: Max J Coppes, MD, PhD, MBA more...
Unfortunately, complete surgical resection of hepatocellular carcinoma (HCC) is possible in fewer than 30% of children at diagnosis. Hepatocellular carcinoma is only partially chemosensitive; thus, chemotherapy and radiation have limited efficacy as adjuvant or neoadjuvant therapy, although one or both are often used to temporarily control disease. In patients who are chemosensitive, chemotherapy may allow a meaningful reduction in tumor size before surgical control, in some cases rendering unresectable tumors resectable. Several combination chemotherapy regimens have been used.
One widely used regimen in children is doxorubicin and cisplatin (PLADO). Resectability rate and, hence, survival rate is higher among children who respond to neoadjuvant chemotherapy compared with children who do not.
Alternative regimens include the following:
Ifosfamide, carboplatin, and etoposide (ICE)
5-Fluorouracil in combination with vincristine, Adriamycin, and cyclophosphamide 
Gemcitabine and carboplatin (recently gained acceptance as potentially active against hepatocellular carcinoma)
Recent trials in adults have demonstrated the efficacy of tyrosine kinase inhibitors like sorafenib in patient with locally advanced hepatocellular carcinoma. The efficacy and safety of these therapeutic measures in children remains to be determined.[4, 5]
Chemoembolization into isolated branches of the hepatic artery may benefit patients with nonmetastatic but unresectable or recurrent tumor. This is the more commonly used approach in adults, in whom systemic chemotherapy has had essentially no impact on disease-free survival.
Because the liver plays a key role in chemically inactivating many chemotherapeutic agents, the child with an underlying liver disease or extensive hepatic involvement with hepatocellular carcinoma warrants careful observation. Numerous reports associate hepatic coma with chemotherapy initiation.
Chemotherapy is used for tumor size reduction to allow for subsequent resection, in the setting of positive resection margins after surgery, and as palliation in the setting of advanced regional or metastatic disease.
When given postoperatively, chemotherapy is usually initiated approximately 4 weeks after surgery to allow liver regeneration. A minimum of 2 weeks should pass after surgery before administration of cytotoxic agents.
These drugs have achieved partial response rates in patients. Although suggested doses are supplied, these doses widely vary among protocols, and the information cannot be used to design patient treatment plans.
An anthracycline antibiotic derived from Streptomyces peucetius susp caesius. Doxorubicin is a DNA-intercalating agent that interferes with DNA and RNA synthesis.
A planar, inorganic compound that interacts with DNA. The mechanism of action is to cause intrastrand crosslinks that interfere with replication.
Prodrug inhibits thymidine synthesis and is incorporated into RNA and DNA. Specific to the S phase of the cell cycle.
Antineoplastic induced vomiting is stimulated through the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center (VC) in the brain. Increased activity of central neurotransmitters, dopamine in CTZ, or acetylcholine in VC appears to be a major mediator for inducing vomiting. Following administration of antineoplastic agents, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With serotonin release and subsequent binding to 5-HT3–receptors, vagal neurons are stimulated and transmit signals to the VC, resulting in nausea and vomiting.
Antineoplastic agents may cause nausea and vomiting so intolerable that patients may refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents before and following cancer treatment is often essential to ensure administration of the entire chemotherapy regimen.
The 5-HT antagonists are highly effective at controlling cisplatin-induced nausea.
Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin).
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. 2002 Jun 15. 20(12):2798-804. [Medline].
Chou R, Cuevas C, Fu R, Devine B, Wasson N, Ginsburg A, et al. Imaging Techniques for the Diagnosis of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. Ann Intern Med. 2015 May 19. 162 (10):697-711. [Medline].
Evans AE, Land VJ, Newton WA, Randolph JG, Sather HN, Tefft M. Combination chemotherapy (vincristine, adriamycin, cyclophosphamide, and 5-fluorouracil) in the treatment of children with malignant hepatoma. Cancer. 1982 Sep 1. 50(5):821-6. [Medline].
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24. 359(4):378-90. [Medline].
Schmid I, Häberle B, Albert MH, Corbacioglu S, Fröhlich B, Graf N, et al. Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma. Pediatr Blood Cancer. 2012 Apr. 58(4):539-44. [Medline].
Zhang XF, Liu XM, Wei T, Liu C, Li MX, Long ZD, et al. Clinical characteristics and outcome of hepatocellular carcinoma in children and adolescents. Pediatr Surg Int. 2013 Aug. 29(8):763-70. [Medline].
Romano F, Stroppa P, Bravi M, et al. Favorable outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma. Pediatr Transplant. 2011 Sep. 15(6):573-9. [Medline].
Koniaris LG, Levi DM, Pedroso FE, et al. Is surgical resection superior to transplantation in the treatment of hepatocellular carcinoma?. Ann Surg. 2011 Sep. 254(3):527-38. [Medline].
Alagille D, Odievre M. Liver and Biliary Tract Disease in Children. New York, NY: John Wiley & Sons; 1979. 331.
Berman MM, Libbey NP, Foster JH. Hepatocellular carcinoma. Polygonal cell type with fibrous stroma--an atypical variant with a favorable prognosis. Cancer. 1980 Sep 15. 46(6):1448-55. [Medline].
Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005 Nov. 42(5):1208-36. [Medline].
Chlebowski RT, Tong M, Weissman J, et al. Hepatocellular carcinoma. Diagnostic and prognostic features in North American patients. Cancer. 1984 Jun 15. 53(12):2701-6. [Medline].
Evans AE, Land VJ, Newton WA, et al. Combination chemotherapy (vincristine, adriamycin, cyclophosphamide, and 5-fluorouracil) in the treatment of children with malignant hepatoma. Cancer. 1982 Sep 1. 50(5):821-6. [Medline].
Farmer DG, Rosove MH, Shaked A, Busuttil RW. Current treatment modalities for hepatocellular carcinoma. Ann Intern Med. 1994. 219:236-47. [Medline].
Giacomantonio M, Ein SH, Mancer K, Stephens CA. Thirty years of experience with pediatric primary malignant liver tumors. J Pediatr Surg. 1984 Oct. 19(5):523-6. [Medline].
Greensberg M, Filler RM. Hepatic tumors. Pizzo PA, Poplack DG, eds. Principles and Practices of Pediatric Oncology. Philadelphia, PA: JB Lippincott Co; 1993.
Jeffers LJ, Dubow RA, Zieve L, et al. Hepatic encephalopathy and orotic aciduria associated with hepatocellular carcinoma in a noncirrhotic liver. Hepatology. 1988 Jan-Feb. 8(1):78-81. [Medline].
Kew MC, Fisher JW. Serum erythropoietin concentrations in patients with hepatocellular carcinoma. Cancer. 1986 Dec 1. 58(11):2485-8. [Medline].
Levy LJ, Swinburne LM, Boulton RP, Losowsky MS. Primary hepatocellular carcinoma presenting as fulminant hepatic failure in a young woman. Postgrad Med J. 1986 Dec. 62(734):1135-7. [Medline].
Mitchell RB, Wagner JE, Karp JE, et al. Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases. Am J Med. 1988 Nov. 85(5):662-7. [Medline].
Morita K, Okabe I, Uchino J, et al. The proposed Japanese TNM classification of primary liver carcinoma in infants and children. Jpn J Clin Oncol. 1983 Jun. 13(2):361-9. [Medline].
Noda T, Sasaki Y, Yamada T, et al. Adult capillary hemangioma of the liver: report of a case. Surg Today. 2005. 35(9):796-9. [Medline].
Paradinas FJ, Melia WM, Wilkinson ML, et al. High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma. Br Med J (Clin Res Ed). 1982 Sep 25. 285(6345):840-2. [Medline].
Ringe B, Wittekind C, Bechstein WO, et al. The role of liver transplantation in hepatobiliary malignancy. A retrospective analysis of 95 patients with particular regard to tumor stage and recurrence. Ann Surg. 1989 Jan. 209(1):88-98. [Medline].
Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet. 1999 Apr 10. 353(9160):1253-7. [Medline].
Vaillo A, Rodriguez-Recio FJ, Gutierrez-Martin A, et al. Fine needle aspiration cytology of clear cell carcinoma of the gallbladder with hepatic infiltration: a case report. Acta Cytol. 2004 Jul-Aug. 48(4):560-4. [Medline].
Winter SS, Rose E, Katz R. Hyperammonemia after chemotherapy in an adolescent with hepatocellular carcinoma. J Pediatr Gastroenterol Nutr. 1997 Nov. 25(5):537-40. [Medline].
Young JL Jr, Miller RW. Incidence of malignant tumors in U. S. children. J Pediatr. 1975 Feb. 86(2):254-8. [Medline].