Hepatoblastoma

As pediatric cancer treatment technology continues to progress, so does the increasing pool of pediatric cancer survivors. In the past, survival studies were based on the fifth year following the diagnosis. Currently, follow-up care is imperative beyond the first 5 years. Although cure is achieved for many children, late effects from treatment occur in many survivors. As this population continues to increase, so does the need for health care providers to monitor and treat these individuals. Pediatric cancer survivors require specific screening to determine the late effects of treatment. Many treatment consequences can be alleviated through proper assessment and treatment.

The progressive development of effective treatments for pediatric cancer has created an epidemic of survival.' Cancer incidence in children age 15 and younger is increasing by 1 % per year, and the cure rate is increasing by 1.4% per year.' Some long-term treatment effects appear shortly after treatment, but other effects may not become apparent until the child matures. Long-term survivors are monitored for both medical and psychologic consequences of cancer treatment.' Often, it is the subtle combination of aging and certain therapies that leads to late-onset dysfunction," or a health or lifestyle change may aggravate a subclinical dysfunction.

Incidence

Cancer is the second leading cause of mortality in American children ages I to 14.5 Cancers occurring before age 20 are typically nonepithelial in origin, such as leukemias, tumors of the brain and nervous system, and lymphomas.6 Leukemia is the most common pediatric cancer; acute lymphoblastic leukemia accounts for 80% of pediatric leukemias. The brain and central nervous system (CNS) are the second most common cancer sites and account for 17.7% of pediatric cancer cases.' The majority of pediatric brain tumors are astrocytomas. Hodgkin's disease accounts for 5.1% of all pediatric cancer cases and non-Hodgkin's lymphoma, including Burkitt's lymphoma, accounts for 5.3% of all pediatric cancer cases.' Soft tissue sarcomas may be seen in children; they develop from mesenchymal tissues, other than bone and cartilage, and originate from muscle, fat, blood vessels, fibrous tissue, or supporting tissue. The most prevalent type of soft tissue sarcoma is rhabdomyosarcoma; rhabdomyosarcoma accounts for 50.9% of soft tissue sarcoma (see Table 1).'

Age, sex, and race are factors in the development of pediatric cancer. Children age 5 and younger are often affected by acute lymphocytic leukemia, neuroblastoma, Wilms' tumor, retinoblastoma, and hepatoblastoma. The incidence of osteosarcoma, Ewing's tumor, Hodgkin's disease, and other lymphomas gradually increases with age.' A predominance of pediatric thyroid cancer occurs in girls and a predominance of Burkitt's lymphoma occurs in boys. Ewing's sarcoma and testicular cancer occur predominantly in Caucasians.7

N Pediatric Survival Rates

The survival rate for acute lymphoblastic leukemia is 73%. Survival rates above 90% have been reported for Hodgkin's disease, retinoblastoma, and germ cell tumors.'

Pediatric cancer survivors are at risk for chronic medical and psychologic problems resulting from the malignancy and its treatment.9 Contributing factors to the development of late-effect abnormalities include the cancer type and treatment, the age at treatment, and therapy duration. The incidence of late-effect abnormalities increases in patients who receive aggressive treatment, patients who are young, and patients who receive therapy for a long time period.

Pediatric cancer survivors must be monitored closely to detect the treatment's potential adverse effects."' If precautionary steps are not taken to protect the patient from undue harm during treatment, more late effects will occur. The possibility of experiencing no late effects from cancer treatment is nearly impossible, but the possibility of experiencing slight late effects is good if a thorough assessment and competent care are provided.

0 Cognitive and Neurologic Effects

Survivors who receive treatment to the CNS are at substantial risk for developing adverse neurologic sequelae (see Table 2). Cranial radiation causes structural changes in the brain, such as the loss of white matter and atrophy. Brain tumor and acute lymphocytic leukemia survivors often experience learning difficulties following treatment with cranial radiation and intrathecal methotrexate. Young children are at the greatest risk for developing severe cognitive disabilities."

Cognitive impairment is assumed to be the result of vascular and biochemical abnormalities resulting from radiotherapy and chemotherapy, but other causative factors may exist, such as social factors.8

Age at treatment is a predictive factor of defects. Declines in IQ are greater in young children who have received CNS radiation.12 Declines are frequently not evident until 3 or more years following the diagnosis, and the impairments are usually centralized among visual motor integration, problem solving, and general memory functions. Evidence also supports that girls are at greater risk than boys for a decline in IQ following cranial radiation at a young age because girls experience rapid brain growth and development during early childhood. As a result of these findings, current treatment does not incorporate cranial irradiation for children younger than age 2. Rather, intrathecal chemotherapy for prophylaxis of the CNS is used in leukemia patients.4

Learning problems may occur in survivors who have had tumors removed or who have received chemotherapy targeting cerebral regions that control vision or hearing. These children experience difficulties in concentrating and understanding simple instructions! Asa result, reading and math performance are often two grade levels below expectation.

Growth Effects

Impaired linear growth and short adult stature are well-known complications of pediatric cancer (see Table 3)13 Growth arrest may be the result of tumor location, surgery, spinal radiation, malnutrition, corticosteroids, or radiation damage to the hypothalamic-pituitary axis." Abnormal growth occurs most frequently in survivors treated with high-dose craniospinal irradiation to the pituitary gland for brain tumors or acute lymphoblastic leukemia. Growth may also be affected by nutritional inadequacies during chemotherapy.' Severe growth failure has been observed more frequently in girls than boys. Short stature may be permanent or even progressive. Damage may occur by a deficiency in growth hormone from damage to the hypothalamic-pituitary axis or by direct damage to the epiphyseal growth plate.

Radiation damage to the hypothalamic-pituitary axis may result in a growth hormone deficiency and, ultimately, linear growth. Height may be affected by radiation to the spine, abdomen, and extremities. Radiation can damage growing bones and lead to slowing or arrest of physeal growth." Spinal deformities, such as scoliosis and kyphosis, can develop from asymmetric exposure to radiation therapy." In these cases, survivors develop unequal proportions of fat and muscle on the irradiated side of the body. Maintaining a normal weight helps lessen this condition.

Growth monitoring is an important component of prepubertal patient follow-up. Recombinant human growth hormone institution can be considered prior to growth cessation." From age 3 to puberty, most children grow a minimum of 5 cm per year. A patient in this age-group who grows less or whose serial heights on growth charts begin to fall into lower percentiles maybe experiencing growth failure." Growth hormone deficiency can be treated successfully, allowing most survivors to reach satisfactory adult heights.

When short stature occurs as a result of cranial irradiation, early puberty often develops. In these cases, suppressing puberty onset while instituting growth hormone therapy may result in a satisfactory adult height."

Functional and cosmetic abnormalities involving the teeth are common in pediatric cancer survivors. Radiation alters the character of saliva and renders the teeth more sensitive to injury and caries." Xerostomia, or dry mouth, is a common complaint; it is caused by medications, radiation to the head and neck, and dehydration. Lack of saliva predisposes the mouth to oral infection and increases the risk of caries, affecting the integrity of the mandible. 16

0 Auditory Effects

Tinnitus and hearing loss, reversible and irreversible, are associated with acute intoxication and long-term administration of several drugs, such as aminoglycosides and antineoplastics (see Table 4). 16 Although the damage mechanism is unclear, biochemical and consequent electrophysiologic changes may occur in the inner ear and eighth cranial nerve impulse transmission. Cisplatin contributes to hearing loss by damaging the outer hair cells of the cochlea. Chronic radiation otitis is the most common otic late effect of radiation."

0 Thyroid Effects

Thyroid dysfunction, specifically hypothyroidism, is a common sequela of CNS radiation for primary brain tumors (see Table 5).23 The dysfunction is caused by direct damage to the hypothalamic-pituitary axis. Hypothyroidism is also common following neck radiation. Most children develop hypothyroidism during the first 2 years following treatment, but new cases can occur up to 6 years following treatment."

Cardiovascular Effects

Potential cardiovascular effects of pediatric cancers are provided in Table 5. The anthracyclines (doxorubicin and daunorubicin) and high-dose cyclophosphamide can cause acute and late-occurring cardiac dysfunction.? The effects of these drugs are cumulative and result directly from the death of myocytes. By the age of 6 months, humans have developed a lifetime supply of myocytes, so further heart growth is the result of hypertrophy of these existing cells. With chemotherapeutic damage to the myocytes, hypertrophy of other myocytes must occur to develop or maintain normal adult cardiac output.14 Cardiac failure can result when the remaining hypertrophied myocytes are unable to adequately compensate. The left ventricle is the most common area of cardiac dysfunction in survivors who received anthracyclines. A decreasing fractional shortening or ejection fraction, in addition to increased afterload and decreased wall thickness, are the hallmarks of anthracycline toxicity.4 In some patients, cardiac function is normal until the body is stressed by events such as pregnancy or weight lifting.

In addition to chemotherapy, radiation can cause cardiac late effects. The heart is commonly in the radiation field when the mediastinum and lungs are treated. Fibrosis is the most common radiation late effect. Coronary artery disease, left ventricular dysfunction, pericarditis, and thickened or leaking valves are some of the effects in survivors who have received heart area radiation.4 Chronic cardiotoxicity commonly appears as cardiomyopathy, pericarditis, or both.

Diagnosis of cardiac effects requires a high level of suspicion in patients treated with anthracyclines or radiation. The majority of patients are asymptomatic. When symptomatic, patients often present with symptoms of heart failure as late as 6 to 10 years following drug exposure.'

0 Pulmonary Effects

Pneumonitis and pulmonary fibrosis with loss of lung volume, diffusing capacity of carbon monoxide, and lung compliance are common cancer therapy sequelae (see Table 5). Bleomycin is the most common drug implicated in pulmonary dysfunction; it causes damage from free radicals and lipid peroxidation.' Cyclophosphamide is not typically associated with pulmonary toxicities, but long-term pulmonic effects can occur when it is used in high doses. The endothelial cell damage and fibrosis that occur as a result of radiation may also cause pulmonary late effects. In addition to direct damage, radiation may lead to hypoplasia of the chest.4 The degree of deformity and dysfunction is related to the patient's age at treatment time and the total radiation dose. Radiated tissue does not grow to its full potential; thus, radiated areas in the chest can result in decreased intrathoracic diameter and diminished lung volume.

0 Gastrointestinal and Hepatic Effects

Fibrosis and enteritis are the most common gastrointestinal abnormalities in long-term survivors who received abdominal radiation (see Table 6). These conditions are often associated with obstruction, ulcers, and malabsorption syndromes.

Although many of the chemotherapeutic drugs used in children are metabolized by, and toxic to, the liver, most effects are reversible and resolve after therapy.' Long-term, lowdose chemotherapy carries a greater risk of liver damage than a high-dose intermittent schedule." Some of the damage may be subclinical and may not become problematic unless the child suffers an additional insult to the liver. Hepatitis is one of the most lethal late effect gastrointestinal toxicities.4

0 Renal and Urologic Effects

Potential renal and urologic effects of pediatric cancer are provided in Table 7. Nephrotoxicity is a common and potentially severe adverse effect of chemotherapy. Many chemotherapeutic drugs can induce renal failure or specific tubular or glomerular lesions. 11 Cisplatin can cause glomerular and tubular damage. Ifosfamide can cause renal Fanconi's syndrome, leading to electrolyte imbalances. The effects of these drugs may be potentiated by aminoglycosides, vancomycin, or amphotericin-B." Unfortunately, these drugs are often used concurrently during treatment because of infection caused by immunosuppression.

Other renal late effects occur because genitourinary tract areas are often included in the radiation field. Radiation to the kidney may cause chronic nephritis. Wilms' tumor treatment almost always involves removal of the affected kidney. While normal lifelong renal function may be maintained with one kidney, frequent tests and protection of the kidney must occur.

The most common urologic complication occurring as a result of chemotherapy is hemorrhagic cystitis." The most common etiologic drug is cyclophosphamide, but it may also occur with ifosfamide. Radiation to the bladder can cause hematuria and chronic cystitis. These effects may be aggravated by dactinomycin, the anthracyclines, or cyclophosphamide.11

Gonadal Effects

Gonotoxic effects of cancer treatment vary depending on the drug used and the patient's sex (see Table 8).17 Age at treatment influences toxicity; younger children are less affected. For both sexes, precocious puberty may result from premature activation of the hypothalamic-pituitary-gonadal axis, and delayed puberty may result from decreased gonadotropin levels. In children who receive high-dose cranial irradiation at a young age, precocious puberty can occur. Damage to gonadal tissue can also occur as a result of receiving high-dose cranial irradiation at a young age. Survivors may require lifelong sex hormone replacement therapy.'

Both germ cell depletion and abnormalities of gonadal endocrine function have been observed in male survivors. Particularly, antineoplastic therapy affects the germinal epithelium, whereas radiotherapy can damage the Leydig's cells in addition to the germinal epithelium, and thus sexual function." Damage to the germinal epithelium of the testes results in raised follicle-stimulating hormone levels, oligospermia, and azoospermia. Leydig's cell damage results in lowered testosterone levels, raised leutinizing hormone levels, and poorly developed secondary sex characteristics. Reduced sperm production, testicular tubular damage, small testes, and gynecomastia have been seen in survivors. Prepubertal boys treated for leukemia, Wilms' tumor, and Hodgkin's disease have been sterile or exhibited elevated gonadotropins and low testosterone levels from direct or scatter testicular radiation." This population is also at increased risk for delayed sexual maturation. Following puberty, alkylating drugs, such as cyclophosphamide, can cause damage to the germinal epithelium of the testes, resulting in a reduced sperm count.

Female gonadal dysfunction usually causes a delayed onset of menarche and anovulatory cycles. Women and girls may experience ovarian failure, primary amenorrhea, or absent secondary sex characteristics, which result from the direct effect on the hypothalamic-pituitary-gonadal axis or ovaries. Prepubertal girls are less likely to experience gonadal injury following therapy with cytotoxic drugs.' Postpubertally, an increase in age correlates with an increase in ovarian sensitivity to chemotherapy damage. The alkylating drugs are particularly damaging to the ovaries. Although immediate ovarian failure may not occur following chemotherapy or radiation, early menopause may result.

Effects on Survivor Fertility and Offspring

Survivor fertility remains uncertain. As more children reach childbearing age, more information regarding fertility will become available.8 Various studies have reported that the risk of infertility in women is age-related, with younger patients more likely to regain fertility than older patients." Male fertility is more sensitive to the effects of chemotherapy and radiation but also exhibits a greater ability to recover.4 Although higher doses of testes radiation may result in permanent azoospermia, research has demonstrated the recovery of fertility within months to years following treatment. Infertile men usually retain sexual function, whereas infertile women experience premature menopause and sexual dysfunction.

The age at which toxic gonadal therapy is received can help predict the effect on female fertility. Prepubertal girls are more resistant to the effects of these therapies, and the sensitivity increases as the postpuberty age increases.'

Survivors who maintain fertility and have no genetic abnormalities related to their disease can have a normal pregnancy and healthy offspring.'A paucity of evidence suggests that children born to survivors are at greater risk of congenital malformation when compared with the rest of the population." However, research indicates that women who receive abdominal irradiation and are fertile have an increased risk of miscarriage and low-birthweight babies. These risks are most likely due to the survivor's decreased uterine vascularity or fibrosis of the uterus or pelvic muscles from radiation treatment.

Another concern involves the genetic implications of cancer treatment on offspring. Studies have shown that offspring may inherit genes that led to cancer in the parent, or they may acquire new germ line mutations that were induced in the parent by therapeutic agents."2 Germ cell mutagenesis occurs when permanent damage occurs to the germ cells, the sperm, and the eggs and is passed to offspring. 17 Direct application of radiation to the pelvic area and the administration of alkylators are extremely mutagenic. Studies have shown an increase in transmission of genetic cancer among offspring of genetic cancer survivors.' However, 5% to 10% of cancers are clearly hereditary: An inherited faulty gene predisposes the person to a high risk of certain cancers.6 See Table 9 for other gonadal effects.

0 Second Malignancies

Second malignant neoplasms are possible long-term effects of pediatric cancer treatment (see Table 10).20 Individuals with a history of pediatric cancer have 10 to 20 times the lifetime risk of a second malignancy. An estimated 3% to 12% of children treated for cancer will develop a new cancer within 20 years after the first diagnosis.' Most second cancers develop in radiation-exposed tissues. Generally, the oncogenic effect of radiation is directly proportional to the dose delivered. For a small percentage of patients, however, the risk for a second malignancy may be due to chance or a malignancy predisposition. Influencing factors for acquiring a secondary malignancy include the original diagnosis, specific therapy, patient age, and genetic factors.

Retinoblastoma is an uncommon childhood tumor, but it is the most common initial neoplasm preceding a second tumor." Survivors of Hodgkin's disease and acute lymphoblastic leukemia are high-risk candidates for second malignancies. For acute lymphoblastic leukemia, radiation to the cranium in children younger than age 6 and treatment with a particular schedule of etoposide appear to confer the greatest risk.10 Research indicates that doxorubicin increases the risk of second malignancies when used with radiation.

The most common second malignancies include leukemia and solid tumors." Radiation-induced leukemia has a latent period of approximately 7 years, whereas secondary solid tumors have a latent period of 10 to 15 years.21 Hodgkin's disease is a common second malignancy, and breast and skin cancers are common following radiation therapy.

Psychosocial Effects

Survivors of pediatric cancer have an increased risk of maladjustment (see Table 11). For the child with cancer, the family is usually the principal source of support, although it may also be a source of anxiety.22 Family functioning prior to the cancer diagnosis and the child's and family's response to the disease influence the survivor's relationship with his or her family.

One of the major challenges for the survivor lies in the transition from adolescence to adulthood. During the disease and treatment, the survivor experienced heightened levels of cohesion with the family, high levels of parental control, and prolonged family dependence. The family relationship may serve as a resource in assisting the survivor's adjustment or may act as a restraint. The relationship must be assessed for severe dependence or independence.

Decision making regarding risk taking may be difficult for cancer-surviving adolescents. Abstract reasoning is often affected by the disease or treatment. The adverse consequences of engaging in unhealthy habits are magnified for long-term survivors.9 For example, tobacco use can have dramatic effects on survivors who received lung radiation therapy.

Subsequent studies of cancer survivors have supported the presence of persistent post-traumatic stress symptoms.23 Risks include intensive treatment regimens, more life-threatening conditions, more sequelae, anxious personality, and female sex. The majority of survivors experience a mild level of post-traumatic stress symptoms, which can be advantageous. Vigilant attention to the body's health and follow-up of problems may have a survival function, given this population's increased risk for long-term complications.230

ACKNOWLEDGMENT

The author gratefully acknowledges the assistance of Linda Sarna, RN, DNSc, FAAN, AOCN, and Nancy Jo Bush, RN, MA, MN, AOCN, in reviewing this article.

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Jennifer Dawn Ward, RNA PNP, MSN, PHN

ABOUT THE AUTHOR

Jennifer Dawn Ward, RN,C, PNP, MSN, PHN, is a pediatric hematology/oncology nurse, City of Hope Medical Center, Duarte, Calif.

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