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Primary Care Management of the Childhood Cancer Survivor

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Learning Impairment After Cancer Therapy

For all children, the cancer experience can have significant effects on psychosocial functioning, particularly in the educational arena. Certainly the impact of school absenteeism related to the acute effects of cancer or its treatment cannot be minimized.2 In addition, because brain maturation continues into adulthood, children are at particular risk for learning impairments after central nervous system (CNS) irradiation and neurotoxic chemotherapy.3 Furthermore, depending on the location of

Natural History of Neurocognitive and Neurosensory Impairment

By virtue of their tumor location or need for CNS-directed therapy, certain diagnostic groups, listed in Table II, are especially vulnerable to negative effects on neurocognitive functioning. The extent of neurocognitive dysfunction is often discovered as the child fails to progress normally through developmental milestones. Both longitudinal and cross-sectional studies have demonstrated a progressive decrease in standard IQ scores over approximately 3 to 5 years.4 This decline over time is

Effects of Irradiation

Cranial radiation therapy (CRT) is an important modality for treating malignant brain tumors and leukemia with CNS involvement. Technological advances have allowed improved targeting of the specific tumor site, reducing ionizing radiation to surrounding brain parenchyma. Neurocognitive difficulties secondary to ionizing radiation may include impairments in attention and concentration, short-term memory, visual-spatial relationships, arithmetic, or problem solving.5 Affected children demonstrate

Effects of Chemotherapy

Although many antineoplastic agents cause acute side effects (eg, fatigue, anemia, chronic nausea) that predispose to neuropsychological impairment, these effects are generally self-limited. However, some chemotherapy exposures may result in specific late neurocognitive effects; for example, the use of high-dose intravenous and intrathecal methotrexate to treat childhood acute lymphoblastic leukemia (ALL) has been occasionally associated with white matter changes (leukoencephalopathy) and

Assessment and Intervention

For all children with a history of cancer, the development of a specific school reentry plan is important to reduce psychosocial stress and facilitate an informative dialogue with the child’s teachers and fellow students. In addition, high-risk children should be formally tested for neurocognitive sequelae and vision/hearing deficits. A comprehensive neurocognitive assessment with attention to subtest performance, rather than the full-scale IQ score, is essential for the development of an

Impact of Cancer on Growth and Physical Development

The location and type of a child’s primary tumor can have important effects on future growth and physical development. Therapy directed at the tumor, such as surgery, chemotherapy, or radiation, can have profound consequences on the neuroendocrine system, as well as direct effects on bone growth and development.

Effect of Radiation Exposure

Because of radiation therapy, survivors of brain and facial cancers are at highest risk for injury to the hypothalamic-pituitary axis (HPA) and commonly manifest symptoms of endocrine dysfunction. The likelihood of pituitary hormone deficits is directly correlated with cumulative radiation dose and time elapsed since completion of radiotherapy.9 On the other hand, age at the time of treatment has an inverse relationship with HPA dysfunction.9

The most common endocrinopathy after hypothalamic

Disordered Linear Growth

Multiple factors can cause growth dysfunction and suboptimal height attainment in the childhood cancer survivor, including GHD, hypothyroidism, or early onset of puberty leading to premature closure of growth plates.9 Nonendocrine factors impacting growth include poor nutrition, chronic illness, history of exposure to irradiation, and surgical interventions that injure or ablate growth plates.9 Radiation directed at the spine can impair growth of vertebrae and impact final torso length.

Growth Hormone Deficiency

The likelihood of GHD after CRT is directly correlated with increasing radiation dose and fraction size to the HPA and time elapsed since treatment.9 GHD in the context of chemotherapy alone has also been rarely reported, but no specific chemotherapeutic agents have been identified as causative factors.13 A child with a persistent suboptimal growth rate, failure to demonstrate catch-up growth, or lack of a pubertal growth spurt should be evaluated for possible GHD.

Hypothyroidism

Irradiation of the following areas is commonly associated with increased risk of hypothyroidism: cranium, nasopharynx, oropharynx, cervical spine, neck, and mediastinum. Hypothyroidism after chemotherapy alone is rare.13 Hypothyroidism can be primary (thyroid gland secretory failure), central (resulting from hypothalamic or pituitary injury), or mixed. Central hypothyroidism, resulting in a deficiency of thyroid-releasing hormone or TSH, is occasionally recognized in children exposed to CRT or

Pubertal Disorders

Because there is a dose-dependent relationship between radiation exposure and HPA damage, children who receive >30 to 40 Gy may commonly acquire gonadotropin deficiency, and those with lower exposure may occasionally experience early onset or rapid tempo puberty.14 The pathogenesis of early puberty is thought to result from the loss of cortical inhibition of hypothalamic gonadotropin-releasing hormone secretion.15 Rapid-tempo puberty may occur in children with early or normal onset of puberty

Obesity and Metabolic Syndrome

Overweight and obesity are important health concerns in pediatric cancer survivors because of the increased attendant risk for diabetes and cardiovascular disease in adulthood. Survivors of brain tumors or ALL who have undergone CRT commonly develop obesity. An analysis of ALL survivors from the Childhood Cancer Survivor Study cohort found that the odds of obesity were increased 1.86 times for males and 2.59 times for females exposed to >20 Gy of CRT compared with sibling controls.16 Among

Bone and Dental Health

Osteopenia and osteoporosis have occasionally been described in survivors of childhood cancer.19 Risk factors include hormonal deficiencies (GHD, hypothyroidism, and hypogonadism), specific chemotherapy exposures (methotrexate and steroids), CRT or total body irradiation, poor nutrition (calcium and vitamin D intake), lack of physical activity, and factors related to chronic illness.19 Subclinical bone mineral density deficits in children and adolescents are an active area of investigation.

Male Gonadal Function and Fertility

Normal spermatogenesis and sex hormone production may be disrupted by all therapeutic modalities used in the treatment of various childhood malignancies, including surgery, radiotherapy, and chemotherapy. Because of their faster cell division, germ cells (and their supporting Sertoli cells) are more vulnerable to toxicity from cancer therapy than the testosterone-producing Leydig cells.22 Thus, infertility is more common than androgen insufficiency after treatment for cancer.

Compared with

Specific Organ Toxicity in Pediatric Cancer Survivors

Because contemporary cancer treatment uses risk-based strategies to cure children with the least toxicity, few children exposed to conventional cancer therapy today will suffer from significant organ toxicity during childhood. Nonetheless, some of the more serious organ toxicities related to the contemporary treatment of childhood cancer warrant mention.

Cardiovascular Toxicity

Children exposed to anthracycline agents (eg, doxorubicin, daunorubicin, idarubicin) or thoracic irradiation involving the cardiovascular structures are at increased risk for cardiac-related health problems. Previous studies have reported that specific risk factors related to anthracycline toxicity include higher cumulative dose, female sex, and young age at the time of treatment.25 Late-onset anthracycline toxicity (occurring more than 1 year after therapy) generally manifests as left

Pulmonary Toxicity

Chronic pulmonary toxicity primarily manifests as restrictive lung disease. Treatment risk factors mainly include exposure to bleomycin, the nitrosoureas (eg, lomustine, carmustine), busulfan, or, more frequently, chest or total body irradiation.27 The risk of chronic pulmonary disease appears to be largely dependent on the cumulative exposure to any of these agents. Combined modality therapy with chest irradiation and a pulmonary toxic agent such as bleomycin further increases risk.27

Gastrointestinal Toxicity

Late gastrointestinal (GI) tract toxicity is uncommon but can be serious or even life-threatening when it occurs. Chronic GI effects are rare, seen most often in survivors of abdominal sarcomas treated with radiation.28 Dactinomycin and the anthracyclines have radiomimetic effects that may contribute to late-onset radiation-associated GI complications.28 In addition, abdominal surgery carries a lifetime risk of developing adhesive or obstructive complications, especially in the context of

Liver Toxicity

Chronic hepatic toxicity is rarely reported in childhood cancer survivors treated with contemporary protocols. Not only is the liver generally tolerant of moderate radiation exposure, it also is quite resilient after administration of hepatotoxic chemotherapy agents such as methotrexate, mercaptopurine, and dactinomycin.28 Nevertheless, liver fibrosis, hepatic veno-occlusive disease, and portal hypertension have been described.29 The advent of effective screening methods for hepatitis B and C

Renal Toxicity

Renal toxicity associated with specific cancer treatment modalities is still occasionally observed. Because the kidneys are paired organs, surgical removal or radiation to 1 kidney is generally well tolerated; however, bilateral renal irradiation is associated with the development of tubular damage and subsequent renal dysfunction.30 Chemotherapeutic agents known to cause chronic nephrotoxicity include cisplatin, carboplatin (to a lesser extent), and ifosfamide.31, 32 Methotrexate also can

Discussion

With significant treatment advances has come a growing number of pediatric malignancy survivors, with an estimated 300,000 survivors residing in the United States today.1 To maximize the quality of life of the cancer survivor, the pediatric oncologist has a responsibility to provide a comprehensive treatment summary that will help the survivor and his or her primary physician recognize possible health risks and adverse health effects. Education of community pediatricians and family physicians

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    Supported in part by Cancer Center Support (CORE) grant CA 21765 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC).

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