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

• 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

• 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 epithelial-
type 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.

• 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:

• 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.
 o 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
o The half-life of AFP is 4-9 days, and levels usually fall to within reference
range within 4-6 weeks following resection.
o Other causes of elevated AFP levels include viral hepatitis, cirrhosis,
inflammatory bowel disease, and yolk sac tumors.
o 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.
o Rarely, a hepatoblastoma can recur as a non–AFP-secreting tumor with
metastases, even if the initial tumor was AFP secreting.
o 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.
o 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
o Laboratory- and age-specific AFP values should be used.
o 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

• 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.
 • 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:

• Epithelial type
o Fetal pattern
o Embryonal and fetal pattern
o Macrotrabecular pattern
o Small cell undifferentiated pattern
• Mixed epithelial and mesenchymal type
o With teratoid features
o 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-to-
cytoplasmic (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
o The tumor is completely resectable via wedge resection or lobectomy.
o The tumor has PFH results.
o 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.

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
Drug
Carboplatin (Paraplatin)
Similar to cisplatin,
produces DNA cross-links
that are predominantly
interstrand. Effect is cell
cycle nonspecific
Cisplatin (Platinol)
Binds and cross-links DNA
strands, disrupting cell
function. Usually combined
with etoposide or
doxorubicin.
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).
cross-linking DNA strands.
Dose (Pediatric) Interaction Contraindications
2
500 mg/m /d IV for 2 Nephrotoxicity increases with Documented
d; may use Calvert aminoglycosides and other hypersensitivity;
formula to calculate nephrotoxic drugs; reacts with contraindicated in
dose: Total dose (mg) aluminum, thus, must not significant renal
= target AUC X come into contact with compromise; must
(GFR + 25) aluminum evaluate risks
Requires versus benefits of
prehydration and use in setting of
should be bone marrow
administered with depression,
0.45% NaCl, hearing
potassium chloride, impairment, renal
and mannitol function
impairment, and
infection
20-40 mg/m2/d IV for Increased risk of ototoxicity Documented
5d when administered with hypersensitivity;
Alternative: 90-100 aminoglycosides; increased contraindicated in
mg/m2 IV as single risk of uric acid nephropathy significant renal
dose when administered with compromise; must
Requires probenecid or sulfinpyrazone evaluate risks
prehydration and versus benefits in
should be patients with
administered with hearing
0.45% NaCl, impairment
potassium chloride,
and mannitol
1000-2000 mg/m2/d Allopurinol may increase risk of Documented
IV for 2 d bleeding or infection and enhance hypersensitivity;
Marrow ablation: 60 myelosuppressive effects; may hematuria
potentiate doxorubicin-induced
mg/kg (ideal body
cardiotoxicity; may reduce
weight) digoxin serum levels and
Requires hydration antimicrobial effects of
before and during quinolones
infusion 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.
 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 Dose (Pediatric) Interaction Contraindications

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.
30-75 mg/m2/d IV as May decrease phenytoin
single dose, slow push or and digoxin plasma levels;
continuous infusion phenobarbital may decrease
Alternative: 20 mg/m2/d plasma levels of
IV qd for 4 d doxorubicin; cyclosporine
For very small infants may induce coma or
and children, consider seizures; mercaptopurine
dosing based on weight increases toxicity of
in kg rather than BSA doxorubicin;
cyclophosphamide
increases cardiac toxicity
of doxorubicin
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 Dose (Pediatric) Interaction Contraindications

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.
75-150 mg/m2/d IV for May prolong effects of
3-5 d warfarin and increase
For very small infants clearance of
and children, consider methotrexate;
dosing based on weight cyclosporine and
in kg rather than BSA etoposide have additive
effects in cytotoxicity of
tumor cells
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 Dose (Pediatric) Interaction

5-Fluorouracil (Adrucil)
Prodrug that inhibits
thymidine synthesis and is
incorporated into RNA and
DNA.
Specific to the S phase of
the cell cycle.
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
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 Dose (Pediatric) Interaction Contraindications
Vincristine 1-2 mg/m2 IV push; not to Increased neurotoxicity when Documented
(Oncovin, Vincasar PFS) exceed 2 mg/dose combined with radiotherapy; hypersensitivity;
Binds tubulin, leading to its For very small infants and increased myelosuppression neuromuscular
depolymerization, which children, consider dosing when administered with disease; intrathecal
results in mitotic inhibition based on weight in kg doxorubicin; interacts with administration
and metaphase arrest. Specific rather than BSA probenecid and universally causes
to S and M phases of the cell sulfinpyrazone death
cycle. Used in combination
with doxorubicin and CPM.

Colony-stimulating factors
These agents promote growth and differentiation of myeloid progenitor cells. They may
improve survival and function of granulocytes.

Drug Dose (Pediatric) Interaction Contraindications

5-10 mcg/kg/d SC for 10-14 None reported Sensitivity to yeast- or
Filgrastim (Neupogen) d; initiate 24-26 h after last E coli– derived
dose of chemotherapy; proteins
continue until ANC recovers
G-CSF Used to combat
to >1500-5000/mL
neutropenia, particularly in
Under certain circumstances,
patients receiving
with proper precautions, can
myelosuppressive therapy.
be administered as slow IV
Produced recombinantly in
infusion but dose must be
Escherichia coli for clinical
higher (10 mcg/kg) and
use.
adverse reactions have been
reported
Follow-up

Further Inpatient Care

• 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 follow-
up 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

• 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
 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.

Inpatient & Outpatient Medications

• 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.

Transfer

• 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.
Deterrence/Prevention

• 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

• 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.

Patient Education

• 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
 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 cancer-
preventive lifestyle is encouraged and includes avoiding passive or primary
tobacco exposure, wearing sunscreen, healthy eating habits, maintaining a healthy
weight, and an exercise regimen.