Hepatoblastoma

Hepatoblastoma INTRODUCTION Background Hepatoblastoma is the most common liver cancer in children, although it is relatively uncommon compared with other solid tumors in the pediatric age group. During the past several years, pathologic variations of hepatoblastoma have been identified, and techniques for establishing the diagnosis of childhood hepatic tumors have improved. Surgical techniques and adjuvant chemotherapy have markedly improved the prognosis of children with hepatoblastoma. Complete surgical resection of the tumor at diagnosis, followed by adjuvant chemotherapy, is associated with 100% survival rates, but the outlook remains poor in children with residual disease after initial resection, even if they receive aggressive adjuvant therapy. Considerable controversy has surrounded the discrepancy between US and international hepatoblastoma therapeutic protocols; surgery and staging are initially advised in the United States, whereas adjuvant therapy is strongly considered internationally. Significant data now support a role for preoperative neoadjuvant chemotherapy if the tumor is inoperable or if the tumor is unlikely to achieve gross total resection at initial diagnosis. Early involvement of hepatologists and liver transplant teams is recommended if the tumor may not be completely resectable even with preoperative adjuvant chemotherapy. Liver transplantation is playing an increasing role in cases in which the tumor is deemed nonresectable after chemotherapy is administered or in "rescue" transplantation when initial surgery and chemotherapy are not successful. Finally, reports state that aggressive surgical intervention may be warranted for isolated pulmonary metastases. Pathophysiology Hepatoblastomas originate from immature liver precursor cells and present morphologic features that mimic normal liver development. Hepatoblastomas are usually unifocal and affect the right lobe of the liver more often than the left lobe. Microvascular spread can extend beyond the apparently encapsulated tumor. Grossly, the tumor is a tan bulging mass with a pseudocapsule. Cirrhosis is not associated with this tumor. Metastases affect the lungs and the porta hepatis; bone metastases are very rare. CNS involvement has been reported at diagnosis and during relapse. The identification of distinct subtypes and further molecular biological information derived regarding liver ontogenesis and growth regulation of hepatic tumors has recently helped pave the way for a more comprehensive classification system for this disease. Patients with familial adenomatous polyposis (FAP), a syndrome of early-onset colonic polyps and adenocarcinoma, frequently develop hepatoblastomas. Germline mutations in

the APC tumor suppressor gene occur in patients with FAP, and mutations in the APC tumor suppressor gene are frequently detected in the colonic polyps and adenocarcinomas associated with FAP. One study estimated that 1 in 20 hepatoblastomas is probably associated with FAP. Interestingly, APC mutations, although common in patients with hepatoblastoma and FAP, are rare in patients with sporadic hepatoblastomas. Recently, Sanders and Furman reported 2 brothers with hepatoblastoma who had a significant family history of early-onset colon cancer.Testing of the younger brother revealed a deletion in exon 15 of the APC gene consistent with a diagnosis of FAP. Loss of function mutations in APC lead to intracellular accumulation of the protooncogene -catenin, an effector of Wnt signal transduction. -catenin mutations have been shown to be common in sporadic hepatoblastomas, occurring in as many as 67% of patients. Furthermore, a study in a mouse model of hepatoblastomas induced by toxin exposure detected mutations of the -catenin protooncogene in 100% of the tumors analyzed (27 of 27). This finding suggests that alterations in the Wnt signaling pathway likely contribute to the neoplastic process in this particular tumor. Recent studies on other components of the Wnt signaling pathway have also demonstrated a likely role for constitutive activation of this pathway in the etiology of hepatoblastoma.Overexpression of human Dickkopf-1, a known antagonist of the Wnt pathway, has been found in hepatoblastoma. The authors postulate that this may be a direct negative feedback mechanism resulting from increased β-catenin commonly found in this tumor. A mutation in the axin gene, also a known antagonist of β-catenin accumulation, has been found in hepatoblastoma and may contribute to the etiology of the smaller percentage of hepatoblastomas in which β-catenin mutations have not been identified, thus implicating the constitutive activation of the Wnt pathway in a significant fraction of hepatoblastomas. Kuroda et al demonstrated a potential role for transcriptional targeting of tumors with strong β-catenin/T-cell factor activity with oncolytic herpes simplex virus vector. The hedgehog pathway has also been evaluated and has been found to be a potential therapeutic target for hepatoblastomas in which the Hh pathway is overexpressed or reactivated at an inappropriate time. Increasing evidence suggests that hepatoblastoma is derived from a pluripotent stem cell. This further supports the hypothesis that this tumor arises from a developmental error during hepatogenesis and supports the hypothesis that research particularly focused on these developmental processes governing liver maturation and growth may ultimately lead to more effective targeted therapy for this disease.

Clinical Manifestations Hepatoblastoma generally presents as a large, asymptomatic abdominal mass. It arises from the right lobe three times more often than the left and is usually uniformical. As the disease progresses, weight loss, anorexia, vomiting, and abdominal pain may ensue. Metastatic spread of hepatoblastoma most commonly involves regional lymph nodes and the lungs. A valuable serum tumor marker, α-fetoprotein (AFP), is used in the diagnosis and monitoring of hepatic tumors. AFP level is elevated in almost all hepatoblastomas. Bilirubin and liver enzymes are usually normal. Anemia is common, and throbocytosis occurs in about a third of patients. Hepatitis B and C serology should be obtained but are usually negative in hepatoblastoma. Diagnostic imaging should include plain radiographs and ultrasonography of the abdomen to characterize the hepatic mass. Ultrasonography can differentiate malignant hepatic masses from benign vascular lesions. Either CT or MRI is an accurate method of defining the extent of intrahepatic tumor involvement and the potential for surgical resection. Evaluation for metastatic disease should include CT of the chest and bone scan. Clinical History •

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Patients with hepatoblastoma are usually asymptomatic at diagnosis. Disease is advanced at diagnosis in approximately 40% of patients, and 20% have pulmonary metastases. Children with advanced disease may have anorexia. Severe osteopenia is present in most patients and regresses with resection of the tumor. Symptoms associated with osteopenia are rare with the exception of pathologic fracture, which is often incidentally identified on routine imaging studies during evaluation of these children. Rarely, patients in whom the tumor has ruptured present with symptoms consistent with acute abdomen. Occasionally, patients present with severe anemia resulting from tumor rupture and hemorrhage. Family history of early onset intestinal polyps or adenocarcinoma may reveal familial adenomatous polyposis (FAP). A history of hemihypertrophy or BWS should prompt screening using AFP as a marker to detect hepatoblastoma in these patients. For such patients, AFP monitoring should be performed every 3 months until the child is aged at least 4 years. Children who survive hepatoblastoma should be considered for evaluation of FAP, and those patients found to carry an APC mutation need close surveillance because of their increased risk for colonic polyps and frank progression to adenocarcinoma. Diagnosing primary malignant liver tumors before clinical signs and symptoms develop is important. Children with a history of chronic hepatitis B infection who have advanced liver disease should be monitored at least every 6-12 months with serum AFP levels and abdominal ultrasonography. Many children with hepatitis B infection are immunotolerant, do not have significant liver abnormalities, and are not at increased risk for liver cancer. Any child with

documented cirrhosis for any reason should be periodically monitored with serum AFP level and ultrasonography because of their increased risk of developing a hepatic malignancy associated with advanced liver disease. Physical • • •

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Hepatoblastoma is usually diagnosed as an asymptomatic abdominal mass. Approximately 10% of patients have incidental findings of hemihypertrophy. Hepatoblastoma can be associated with isosexual precocity. Penile and testicular enlargement without pubic hair is seen in patients with tumors that secrete the b subunit of human chorionic gonadotropin (b-hCG). Late features of BWS, such as midface hypoplasia and slitlike indentations of the earlobe, may occur, but this is rare. Patients with BWS and those with hemihypertrophy should be monitored with serial abdominal ultrasonography and serum AFP level every 3 months until at least age 4 years; some would argue that these patients should be monitored until age 7 years because of the risk of Wilms tumor as well. Other associated syndromes and malformations include the following: o Talipes equinovarus o Persistent ductus arteriosus o Tetralogy of Fallot o Extrahepatic biliary atresia o Renal anomalies (dysplastic kidney, horseshoe kidney) o Cleft palate o Dysplasia of the earlobes o Goldenhar syndrome o Prader-Willi syndrome o Meckel diverticulum Hepatoblastoma is also seen in association with Simpson-Golabi-Behmel syndrome. Routine screening with AFP level monitoring and abdominal ultrasonography is suggested in these patients, who are also at risk for developing Wilms tumor.

Causes As with other pediatric malignancies, the cause of hepatoblastoma is generally unknown. Cancer has been postulated to arise from unregulated cellular differentiation and proliferation. Similarities between the developing fetal liver and the fetal epithelialtype cells of hepatoblastoma are striking. Developing cells of the early fetal liver and the cells of fetal hepatoblastoma are similar in size and configuration. A developmental disturbance during liver formation in embryogenesis likely results in aberrant proliferation of these undifferentiated cells. Increasing data support a role for aberrant transduction of the Wnt/β-catenin signaling pathway and its molecular targets in hepatoblastoma tumorigenesis. Research in this area

may ultimately contribute not only toward a better understanding of this malignant neoplasm but may also lead to more specific molecular-targeted therapies. • • •

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Hepatoblastoma, like Wilms tumor, is associated with BWS and hemihypertrophy, suggesting gestational oncogenic events. Persons with dysplastic kidney or Meckel diverticulum have a higher incidence of this tumor. Hepatoblastoma has also been reported to be associated with maternal oral contraceptive exposure, fetal alcohol syndrome, and gestational exposure to gonadotropins. Studies performed in Europe suggest an association between LBW, VLBW, and prematurity and hepatoblastoma. The suspected correlation between LBW, prematurity (<1000 g), and hepatoblastoma has now been confirmed in both the United States and Japan.19, 20 Patients with FAP have a significantly increased incidence of hepatoblastoma and should therefore be screened in early childhood with AFP measurements. A child with neurofibromatosis type 1 (NF1) who developed hepatoblastoma was reported.21 Hepatoblastoma has also been reported in association with other cancer predisposition syndromes including FAP, BWS, Li-Fraumeni syndrome, trisomy 18, and glycogen storage disorders. Premature infants, particularly those born with LBW or VLBW, are at significantly increased risk of developing hepatoblastoma. The presence of erythropoietin receptors in hepatoblastomas has been postulated to potentially contribute to this increased incidence because many premature infants with LBW or VLBW receive this medication during their time in neonatal intensive care.

Workup Laboratory Studies Diagnostic evaluation of a child in whom a liver tumor is suggested should include the following: •

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CBC count with differential should be obtained. o Normochromic normocytic anemia is often present. o Thrombocytosis may be present. In a study by Ortega et al, 60% of patients had platelet counts greater than 500 X 109/L, and 12% had platelet counts greater than 1000 X 109/L.17 Liver enzyme levels are moderately elevated in 15-30% of patients. AFP is a major serum protein synthesized by fetal liver cells, yolk sacs, and the GI tract. AFP is found in high concentrations in fetal serum and in children with hepatoblastoma, hepatocellular carcinoma, germ cell tumors, or teratocarcinoma. The tumor's ability to synthesize AFP reflects its fetal origin. Embryonal tumors produce less AFP than fetal tumors.

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Levels of AFP in hepatoblastoma are often as high as 100,000-300,000 mcg/mL. Ortega et al found AFP levels elevated for age in 97% of patients.17 The half-life of AFP is 4-9 days, and levels usually fall to within reference range within 4-6 weeks following resection. Other causes of elevated AFP levels include viral hepatitis, cirrhosis, inflammatory bowel disease, and yolk sac tumors. Although elevated AFP levels are not specific for hepatoblastoma, they provide an excellent marker for response to therapy, disease progression, and detection of recurrent disease. Rarely, a hepatoblastoma can recur as a non–AFP-secreting tumor with metastases, even if the initial tumor was AFP secreting. Interpretation of AFP levels can be difficult because hepatoblastoma tends to occur within the first 2 years of life. Reference range AFP levels are comparatively high at birth and even higher in premature infants, which can complicate interpretation of this value. By age 1 year, adult levels of 3-15 mcg/mL have been reached. Data from the German Cooperative Pediatric Liver Tumor Study showed that both very low (<100 ng/L) and very high (>1,000,000 ng/L) AFP levels are associated with poorer prognosis than intermediate AFP levels.22 Laboratory- and age-specific AFP values should be used. Baseline testing of glomerular filtration rate (GFR) or creatinine clearance should be performed before cisplatin administration; follow-up studies are needed periodically to assess nephrotoxicity.

Imaging Studies •

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Abdominal radiography o Plain abdominal films reveal a right upper quadrant abdominal mass. o Calcification is seen in approximately 6% of hepatic masses and 12% of hemangiomas. Ultrasonography o Abdominal ultrasonography allows assessment of tumor size and anatomy, which helps in surgical planning. o The mass usually appears hyperechoic on abdominal ultrasound images, which is particularly useful in determining vascular involvement (vessels have lower attenuation than surrounding parenchyma). o Baseline echocardiography is needed before anthracycline (doxorubicin) administration; follow-up studies are needed to assess cardiotoxicity. CT scanning o CT scanning of the abdomen using contrast reveals patchy enhancement. o CT scanning reveals involvement of nearby structures. Regional lymph nodes are almost never involved. o CT scanning of the chest is warranted to assess for pulmonary metastases.

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MRI: This is believed to be superior to CT scanning but does not necessarily add to the anatomic detail seen on CT scans. Radionuclide bone scanning: This is recommended to evaluate for bone metastases when a patient is symptomatic. Positron emission tomography (PET) scanning: Studies support a potential role for PET scanning at diagnosis and for follow-up evaluation in hepatoblastoma.

Other Tests •

A baseline audiology evaluation is needed before cisplatin or carboplatin administration; follow-up studies are needed to assess ototoxicity.

Procedures •

Pathologic diagnosis: Before commencing therapy, surgical diagnosis must be made. Surgical resection is the usual manner in which material for pathologic assessment is obtained. Open biopsy is performed when complete surgical resection is not possible. Needle biopsy is not recommended because these lesions usually are highly vascular.

Histologic Findings Standardizing criteria for histologic classification of hepatoblastoma has been suggested because of the significant variation in the current medical literature. Particular attention to the subtypes of this tumor and direct correlation with clinical outcomes is increasingly being incorporated into all major protocols internationally. Six histologic variants of hepatoblastoma have been described, as follows: •

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Epithelial type o

Fetal pattern

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Embryonal and fetal pattern

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Macrotrabecular pattern

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Small cell undifferentiated pattern

Mixed epithelial and mesenchymal type o

With teratoid features

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Without teratoid features

Pure epithelial tumors account for approximately 56% of cases; they contain varying amounts of fetal cells, embryonal cells, or both. Within this group, purely fetal tumors account for 31% of hepatoblastomas; embryonal tumors account for 19% of hepatoblastomas; and macrotrabecular tumors and small cell undifferentiated types each

account for 3% of hepatoblastomas. The remaining 44% of hepatoblastomas are mixed tumors containing primitive mesenchymal tissue and specialized derived components, such as myofibroblastic, chondroid, and osteoid tissues in addition to epithelial elements. Mixed tumors may express teratoid features. Teratoid hepatoblastomas are admixed with various heterologous structures of epithelial or mesenchymal origin. Fetal cells are smaller than normal hepatocytes and have low nuclear-tocytoplasmic (N/C) ratios and infrequent mitoses; cells form slender cords. Embryonal cells have a higher N/C ratio and more mitoses; they resemble early ducts of embryonal liver. Extramedullary hematopoiesis can be associated with mixed tumors. In tumors that have been completely resected, pure fetal histologic (PFH) results (with a 92% rate of disease-free survival) are associated with better prognosis than other histologic types, which have an overall disease-free survival rate of 57%. The absence of mitoses is a good prognostic sign. In advanced disease in which tumors cannot be completely resected, PFH results do not predict a better outcome. Staging Staging of hepatoblastoma is based on degree of surgical resection, histologic evaluation, and presence of metastatic disease. The system cited here is based on the work of von Schweinitz et al. •

Stage I The tumor is completely resectable via wedge resection or lobectomy. The tumor has PFH results. The AFP level is within reference range within 4 weeks of surgery. Stage IIA o The tumor is completely resectable. o The tumor has histologic results other than PFH (UH). Stage IIB o The tumor is completely resectable. o AFP findings are negative at time of diagnosis (ie, no marker to follow). Stage IIC o The tumor is completely resected or rendered completely resectable by initial radiotherapy or chemotherapy or microscopic residual disease is present. o The AFP level is elevated 4 weeks after resection. Stage III (any of the following) o The tumor is initially unresectable but is confined to one lobe of liver. o Gross residual disease is present after surgery. o Tumor ruptures or spills preoperatively or intraoperatively. o Regional lymph nodes are involved. Stage IV: Distant bone or lung metastasis is present. o o o

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European groups have also developed a staging system through SIOPEL-1; the system uses the predictive value of pretreatment extent of disease (PRETEXT) in order to stage

patients and determine which therapy is most appropriate.18 Using this system, physicians are able to refer higher risk patients for evaluation by liver transplant teams earlier with improved outcomes. These groups also advocate for chemotherapy treatment of lung metastases followed by surgical resection, with attempts for negative surgical margins providing optimal outcomes. Which staging regimen is preferred among the Children’s Cancer Group (CCG) staging, Pediatric Oncology Group (POG) staging, and the European group staging is still actively discussed. However, for comparability reasons, following one staging regimen has been suggested, and international collaboration with consistency is ideal for this rare tumor. Treatment In general, the cure of malignant hepatic tumors in children depends on complete resection of the primary tumor. As much as 85% of the liver can be resected, with hepatic regeneration noted within 3-4 months after surgery. Cisplatin in combination with vincristine and 5-fluorouracil or doxorubicin is effective treatment for hepatoblastoma and increase the chances of cure after complete surgical resection. In low-stage tumors, survival rates more than 90% can be achieved with multimodal treatment, including surgery and adjuvant chemotherapy. With tumors unresectable at diagnosis, survival rates approximately 60% can be obtained. Metastatic disease further reduces survival, but complete regression of disease can often be obtained with chemotherapy and surgical resection of the primary tumor and isolated pulmonary metastatic disease resulting in survival rates about 25%. Consultations A multidisciplinary approach in children with malignancy is necessary to ensure that appropriate care is safely administered with minimal toxicity. The team usually consists of specialized pediatric nurses, pediatric surgeons, pharmacologists with expertise in dealing with chemotherapy in children, nutritionists, social workers, child life specialists, and subspecialists in areas such as pediatric gastroenterology, neurology, cardiology, and infectious diseases. Early referral to liver transplant centers is encouraged for nonresectable tumors or those that show chemotherapy resistance. Referral to a radiation oncologist with pediatric experience may also be indicated. Diet Adequate nutrition is necessary for childhood growth and development. Maintaining adequate nutritional status is also important to maximize response to therapy. Many of the treatments may result in compromised nutritional status. Children undergoing radiotherapy or chemotherapy, particularly children younger than 5 years, typically require enteral or parenteral supplementation, often with electrolyte supplementation as well. Occupational therapists and child life specialists may be consulted to help with behavioral issues related to feeding, particularly in infants and toddlers.

Activity Specific postoperative limitations on activity may be necessary, and, occasionally, some activities are limited because of central line placement or severe immunosuppression and myelosuppression associated with therapy; otherwise, no specific limitations are placed on activity. Most children are encouraged to attend daycare or school and participate in normal play essential to childhood development. Contact sports should be avoided during therapy, especially during periods of thrombocytopenia. Medication All chemotherapy orders are written and countersigned by pediatric oncologists. Most children are treated according to clinical protocols used in multiple institutions. For patients with refractory disease, a phase I or II trial is usually considered. Information on clinical trials is usually accessible through the National Cancer Institute (NCI) Web site and linked sites. The resources presented below should serve as guidelines only. Antineoplastic agents have a narrow therapeutic index, and effective doses usually cause significant toxic effects. Any physician or other practitioner caring for children with cancer must be familiar with the indications, appropriate dosages, and toxic effects of the chemotherapy agents prescribed. They must also be familiar with any special considerations regarding age, weight, pharmacokinetic variations (ie, drug absorption, distribution, metabolism, excretion), coexisting medical problems, or possible pharmacokinetic interactions. To minimize risk to the patient, only practitioners familiar with the toxic effects and potential complications should prescribe antineoplastic agents. Full discussion of the agents typically used in treating hepatoblastoma is beyond the scope of this article, but brief summaries of the drugs most commonly used are provided below.

Antineoplastic agents, alkylating agents, metal salts The mechanism of action is similar to that of alkylating agents, namely, binding and cross-linking DNA strands. Drug

Dose (Pediatric)

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Carboplatin (Paraplatin) Similar to cisplatin, produces DNA cross-links that are predominantly interstrand. Effect is cell cycle nonspecific

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500 mg/m /d IV for 2 d; may use Calvert formula to calculate dose: Total dose (mg) = target AUC X (GFR + 25) Requires prehydration and should be administered with 0.45% NaCl, potassium chloride, and mannitol

Nephrotoxicity increases with aminoglycosides and other nephrotoxic drugs; reacts with aluminum, thus, must not come into contact with aluminum

Cisplatin (Platinol) Binds and cross-links DNA strands, disrupting cell function. Usually combined with etoposide or doxorubicin.

20-40 mg/m2/d IV for 5d Alternative: 90-100 mg/m2 IV as single dose Requires prehydration and should be administered with 0.45% NaCl, potassium chloride, and mannitol 1000-2000 mg/m2/d IV for 2 d Marrow ablation: 60 mg/kg (ideal body weight) Requires hydration before and during infusion

Increased risk of ototoxicity when administered with aminoglycosides; increased risk of uric acid nephropathy when administered with probenecid or sulfinpyrazone

Documented hypersensitivity; contraindicated in significant renal compromise; must evaluate risks versus benefits of use in setting of bone marrow depression, hearing impairment, renal function impairment, and infection Documented hypersensitivity; contraindicated in significant renal compromise; must evaluate risks versus benefits in patients with hearing impairment

Cyclophosphamide (Cytoxan, Neosar) After metabolism by hepatic microsomal enzymes, produces active alkylating metabolites that probably damage DNA. Usually administered with doxorubicin and VCR or doxorubicin and cisplatin. Also an immunosuppressant. Administered with mesna to prevent urotoxicity (ie, hemorrhagic cystitis).

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones Chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity; increased risk of cardiomyopathy when administered at higher doses and combined with radiotherapy.

Documented hypersensitivity; hematuria

Antitumor antibiotics, natural products These agents are usually derived from microorganisms and have various antitumor mechanisms. All interfere with the DNA structure or the breakage-resealing process. Drug Doxorubicin (Adriamycin) Causes DNA strand breakage mediated by effects on topoisomerase II. Intercalates into DNA and inhibits DNA polymerase. Usually combined with VCR and CPM or with cisplatin.

Dose (Pediatric) 30-75 mg/m2/d IV as single dose, slow push or continuous infusion Alternative: 20 mg/m2/d IV qd for 4 d For very small infants and children, consider dosing based on weight in kg rather than BSA

Interaction May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels of doxorubicin; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity of doxorubicin; cyclophosphamide increases cardiac toxicity of doxorubicin

Contraindications Documented hypersensitivity; severe heart failure, cardiomyopathy, and impaired cardiac function; preexisting myelosuppression

Topoisomerase II inhibitors, natural products These plant alkaloids inhibit the topoisomerases that interfere with the normal DNA breakage-resealing reaction and cause single-strand breaks in DNA. Drug Etoposide (Toposar, VePesid) Interacts with topoisomerase II and produces single-strand breaks in DNA. Arrests cells in late S phase or G2 phase. Typically combined with ifosfamide, cisplatin, or carboplatin.

Dose (Pediatric) 75-150 mg/m2/d IV for 3-5 d For very small infants and children, consider dosing based on weight in kg rather than BSA

Interaction May prolong effects of warfarin and increase clearance of methotrexate; cyclosporine and etoposide have additive effects in cytotoxicity of tumor cells

Contraindications Documented hypersensitivity; consider using etoposide phosphate (Etopophos) in such patients

Antineoplastic antimetabolites These agents are close structural analogs of vital intermediates in the biosynthetic pathways of nucleic acids and proteins. They either inhibit synthesis of cellular macromolecules and their building blocks or are incorporated into the macromolecules, resulting in a defective product. Drug 5-Fluorouracil (Adrucil) Prodrug that inhibits thymidine synthesis and is incorporated into RNA and DNA. Specific to the S phase of the cell cycle.

Dose (Pediatric) 500 mg/m2 IV push as single dose or qd for 5 d 800-1200 mg/m2 continuous IV infusion over 24-120 h No guidelines available for modifying dose in patients with hepatic or renal dysfunction

Interaction Increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, and thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents; clearance delayed and toxicity increased by thymidine competing for enzyme that catabolizes 5-FU; intracellular activation and incorporation into RNA increased by methotrexate.

Documented hypersensitivity; inherited deficiency of catabolic enzyme dihydropyrimidine dehydrogenase (associated with severe 5-FU toxicity)

Mitotic inhibitors, natural products These plant alkaloids bind to microtubular proteins, inhibiting RNA synthesis by disrupting DNA formation. Drug Vincristine (Oncovin, Vincasar PFS) Binds tubulin, leading to its depolymerization, which results in mitotic inhibition and metaphase arrest. Specific to S and M phases of the cell cycle. Used in combination with doxorubicin and CPM.

Dose (Pediatric) 1-2 mg/m2 IV push; not to exceed 2 mg/dose For very small infants and children, consider dosing based on weight in kg rather than BSA

Interaction Increased neurotoxicity when combined with radiotherapy; increased myelosuppression when administered with doxorubicin; interacts with probenecid and sulfinpyrazone

Contraindications Documented hypersensitivity; neuromuscular disease; intrathecal administration universally causes death

Colony-stimulating factors These agents promote growth and differentiation of myeloid progenitor cells. They may improve survival and function of granulocytes. Drug Filgrastim (Neupogen) G-CSF Used to combat neutropenia, particularly in patients receiving myelosuppressive therapy. Produced recombinantly in Escherichia coli for clinical use.

Dose (Pediatric) 5-10 mcg/kg/d SC for 10-14 d; initiate 24-26 h after last dose of chemotherapy; continue until ANC recovers to >1500-5000/mL Under certain circumstances, with proper precautions, can be administered as slow IV infusion but dose must be higher (10 mcg/kg) and adverse reactions have been reported

Interaction None reported

Contraindications Sensitivity to yeast- or E coli– derived proteins

Follow-up Further Inpatient Care •

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Follow-up care: Children may be admitted to the hospital to expedite the diagnostic workup or when severe signs or symptoms are present. For medically stable patients, the workup can be performed in the outpatient setting. A central line is typically placed when the patient is scheduled for biopsy or resection. Double-lumen central lines are preferred if vessel access is adequate because this allows concurrent administration of multiple parenteral medications. Multidisciplinary evaluation: The child is initially evaluated by a pediatric oncologist and surgeons with expertise in childhood malignancies. Evaluation should be performed at a pediatric cancer center. Once the diagnosis is established and the staging workup is completed, the patient and family are instructed on the diagnosis and therapeutic options. Most children and families are offered participation in cooperative group trials. Once the treatment plan is developed, chemotherapy is most frequently administered in the inpatient setting. However, with improvements in supportive care, some chemotherapy may be administered in the outpatient setting. Following completion of the treatment cycle, patients are discharged home with detailed instructions for home care and outpatient followup visits. Patients who undergo liver transplantation require a multidisciplinary team with experienced hepatologist and liver transplant surgeons as well as the team outlined above.

Further Outpatient Care • • •

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Patients are periodically monitored in the clinic after each course of therapy to assess for complications and response to therapy. Myelosuppression and pancytopenia are common complications, and a CBC count with a platelet count is obtained once or twice weekly. Some drugs, such as cisplatin and carboplatin, affect renal function and require close monitoring of electrolytes and oral or parenteral electrolyte supplementation. Blood product support is provided when the hemoglobin drops below 8 g/dL, symptoms of anemia are present, the platelet count drops below 10,000 X 109/L, or any signs of bleeding are evident. Fever must be treated as a medical emergency during therapy because the risk of a bacterial or fungal infection is high in patients with myelosuppression. Children with central lines are susceptible to bacteremia and life-threatening sepsis. In addition, all children with central lines must receive appropriate antimicrobial prophylaxis against subacute bacterial endocarditis (SBE) for all procedures, including dental procedures. Close contact with the liver transplant team is required for patients who require this treatment. All medical decisions for patients with this complex condition

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should be communicated to all members of the team including oncologists, primary surgeon, hepatologists, and transplant surgeons. Late effects clinics are available at most major oncology centers, and children with hepatoblastoma should be referred to these clinics if they remain disease free for more than 2 years. Even if the risk of recurrence decreases with time, these children are still at risk for late effects, which include secondary cancers (etoposide and anthracycline), cardiotoxicity (anthracycline), renal toxicity (platinum agents), ototoxicity (platinum agents), and potential speech and developmental delays due to therapy administered. Psychosocial team members, child life experts, medical social workers, nutritionists, and all care providers can help families adjust to life after cancer and can also help encourage a cancer preventive lifestyle for these at-risk patients.

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Infection prophylaxis: Chemotherapy agents cause myelosuppression and immunosuppression. Prophylaxis against Pneumocystis jiroveci, which causes Pneumocystis carinii pneumonia, is recommended for all patients. The drug of choice is trimethoprim-sulfamethoxazole (2.5 mg/kg/dose of trimethoprim administered orally twice daily) administered on 3 consecutive days per week. Prophylaxis is initiated before chemotherapy and is continued for at least 3 months after completing therapy. Colony-stimulating factors: Granulocyte colony-stimulating factor (G-CSF) support has become common in pediatric oncology as the intensity of chemotherapy has increased. The doses recommended are 5-10 mcg/kg/d, starting 24-36 hours after the last dose of chemotherapy. G-CSF administration is continued for 10-14 days or until the absolute neutrophil count (ANC) is greater than 2,000-10,000/mcL. Erythropoietin: The use of erythropoietin is discouraged because of reports that hepatoblastoma has receptors for this agent and may therefore be stimulated to grow from exogenous sources.

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With supervision by the oncology team, routine care can be performed by the primary care provider for patient convenience. CBC counts and blood chemistries may be obtained and blood products may be administered by primary care providers. Some patients may even be evaluated and treated for febrile neutropenia by the primary care provider. However, the primary care provider must maintain close contact with the subspecialist physicians and transfer the patient to the pediatric oncology center for any complications that require specialized care.

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The cause of hepatoblastoma is unknown. Because onset of hepatoblastoma is in patients at a young age, investigators have focused on events before conception and during gestation. Factors for which evidence is limited or inconsistent include medications, hormones, birth characteristics, congenital anomalies, previous spontaneous abortion or fetal death, alcohol consumption, tobacco use, and paternal occupational exposures. Children with hemihypertrophy or BWS and children born to individuals affected by familial adenomatous polyposis (FAP) should be screened regularly using blood AFP levels as dictated in current protocols. Children found to harbor a FAP mutation should be monitored periodically for the development of polyps by a gastroenterologist as they reach the teenage years.

Complications •

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At diagnosis: Tumor rupture may occur, resulting in acute abdomen or severe hemorrhage, both of which constitute medical emergencies. Intraoperative and postoperative complications may occur as a result of resection or biopsy procedures. During therapy: Complications can develop with the administration of chemotherapy. Myelosuppression and immunosuppression place the patient at risk for bleeding and infection. After several cycles of therapy, organ toxicity may occur; for example, renal function or hearing may be impaired. Posttransplantation: Complications due to liver transplantation can develop and require close long-term follow-up by the liver transplant team. Long term: Particular attention must be paid to cardiac, renal, and hearing status to assess for the toxic effects of anthracyclines, cisplatin, or carboplatin. Psychosocial effects of frequent painful procedures, hospitalizations, and interference with normal childhood growth and development must be addressed, and children and families must be referred to appropriate specialists when needed. The family's psychosocial needs are affected greatly by having a child with cancer.

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Medications: To ensure compliance and good medical care, patient and family understanding regarding the importance of treatment and the toxic effects of the medications is critical. In addition, patients and their families should learn to recognize and identify signs and symptoms of complications that require urgent medical care. Long-term follow-up surveillance: After completion of therapy, patients in whom treatment was successful require close surveillance for any signs or symptoms of recurrent disease. Follow-up care includes monitoring AFP levels, physical examination, and diagnostic imaging. Because most recurrences occur during the first 2 years following treatment, most protocols recommend close follow-up

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monitoring during this interval. Hepatoblastoma does not usually recur more than 3 years after completion of therapy. Long-term issues: Growth and development and long-term toxic effects on organs are long-term issues. Patients who remain free of recurrent disease for 5 years are considered cured; long-term follow-up monitoring to assess the impact of therapy on growth, development, and organ toxicity is essential. Patients are usually monitored by pediatric oncologists, but some sequelae may require the involvement of other subspecialist health care providers. Other issues: Most centers have late effects clinics, and all children treated for cancer should continue to see their oncology providers regularly to monitor for potential long-term complications of therapy. When appropriate, most centers help transition to an adult provider, with guidelines on what to watch for and which tests should be performed to monitor for potential late effects. A cancerpreventive lifestyle is encouraged and includes avoiding passive or primary tobacco exposure, wearing sunscreen, healthy eating habits, maintaining a healthy weight, and an exercise regimen.