Central Nervous System
        Neurocognitive
        Psychosocial
Special Senses
        Hearing
        Optic and Orbital
Digestive System
        Dental
        Hepatic
        Digestive Tract
Immune System
        Spleen
Circulatory System
        Cardiovascular
Respiratory System
        Pulmonary
Urinary System
        Renal
Endocrine System
        Thyroid Gland
Neuroendocrine System
Musculoskeletal System
        Bone and Body Composition
        Obesity
Reproductive System
        Gonadal Function
        Reproduction

Central Nervous System

Neurocognitive

Neurocognitive late effects most commonly follow treatment of malignancies that require central nervous system (CNS)-directed therapies, such as cranial radiation or intraventricular/intrathecal (IT) chemotherapy; thus, children with CNS tumors, head and neck sarcomas, and acute lymphoblastic leukemia (ALL) are most commonly affected. Deficits occur in a variety of areas that include the following:[1-6]

• General intelligence.
• Age-appropriate developmental progress.
• Academic achievement (especially in reading, language, and mathematics).
• Visual and perceptual motor skills.
• Nonverbal and verbal memory.
• Receptive and expressive language and attention.

For both CNS tumors and ALL, younger age at time of treatment is associated with an increased neurocognitive deficit.[7-11]

Some studies of children treated with cranial or craniospinal radiation therapy for CNS tumors demonstrated a significant adverse neurocognitive effect of therapy.[4] Other studies using lower doses and more targeted volumes, however, have demonstrated improved results.[12-14] One study supports the hypothesis that medulloblastoma patients demonstrate a decline in intelligence quotient (IQ) values because of an inability to acquire new skills and information at a rate comparable to their healthy same-age peers, not because of a loss of previously acquired information and skills.[15] In a Danish study of 133 children treated for brain tumors, younger age at diagnosis, tumor site in the cerebral hemisphere, hydrocephalus treatment with shunt, and radiation therapy were predictors of lower cognitive functions.[16] Another study evaluated quantitative tissue volumes from magnetic resonance imaging scans, correlating these results with neurocognitive assessments for 40 long-term survivors of pediatric brain tumors treated with radiation therapy with or without chemotherapy 2.6 to 15.3 years earlier (median, 5.7 years) at an age of 1.7 to 14.8 years (median, 6.5 years). Analyses revealed significant impairments in patients’ neurocognitive test performance on all measures. After statistically controlling for age at time of radiation therapy and time from radiation therapy, significant associations were found between normal-appearing white matter volumes and both attentional abilities and IQ, and between attentional abilities and IQ. These associations were also correlated with deficiencies in academic skills such as reading, spelling, and math.[17]

For ALL, studies again show significant neurocognitive impairment [18,19] when cranial radiation is combined with intrathecal chemotherapy. Reduction in the cranial radiation dose may result in less neurocognitive impairment.[11,20-23]

The effects of radiation on the brain are difficult to define, especially when cranial radiation is a part of multimodality therapy that may also include surgery, systemic chemotherapy, or intrathecal chemotherapy. Moreover, tumor-related deficits because of direct invasion of the brain, seizures, and hydrocephalus must be recognized. Studies on CNS prophylaxis for ALL comparing craniospinal radiation therapy with cranial radiation therapy combined with IT methotrexate showed that children who were younger than 5 years at time of treatment and had received radiation therapy and intrathecal chemotherapy had lower IQ scores than those who received craniospinal radiation therapy alone.[24] Similarly, another study found a significant IQ deficit in children treated with 24 Gy of cranial radiation combined with IT methotrexate, as compared with childhood cancer survivors who received no CNS-directed therapy, with the effect greatest among those younger than 5 years.[18] A similar effect on cognition with the addition of intrathecal methotrexate has been found in children treated for medulloblastoma.[25]

Systemic methotrexate in high doses and combined with radiation therapy can lead to a well-described leukoencephalopathy, in which severe neurocognitive deficits are obvious.[2,26,27] Because of its penetrance into the CNS, systemic methotrexate has been used in a variety of low-dose and high-dose regimens for leukemia CNS prophylaxis. The deleterious effects of systemic methotrexate, especially at doses above 1 g/m² may be no different or worse than those of 18 Gy of cranial radiation therapy.[28,29] At lower methotrexate doses, there does not appear to be a consistent pattern of neurocognitive deficits.[30] One long-term study of infants who received high-dose systemic methotrexate combined with intrathecal cytarabine and methotrexate for CNS leukemia prophylaxis and who were tested 3 to 9 years posttreatment showed that cognitive function was in the average range.[31]

Chemotherapy alone for ALL may result in cognitive dysfunction. One study examined 48 children treated for leukemia without cranial radiation therapy and found impairment in tasks of higher-order cognitive functioning and learning disabilities in the area of mathematics.[28] Another study showed that children, particularly females, treated with systemic and IT methotrexate for CNS leukemia prophylaxis showed impairment of verbal memory and coding.[22] One other study reported mild visual and verbal short-term memory deficits in leukemia survivors treated with IT chemotherapy.[32] Another study examined 20 patients treated for leukemia without cranial radiation therapy and found no significant neurocognitive deficits, even when patients were exposed to either IT or high-dose intravenous (IV) methotrexate.[21] More recently, the substitution of dexamethasone for prednisone in the treatment of ALL has been implicated in increasing cognitive dysfunction.[23,31] Treatment intensity and duration can also adversely affect cognitive performance, because of absences from school and interruption of studies.[33]

Many childhood cancer survivors have adverse quality of life or other adverse psychologic outcomes. Incorporation of psychological screening into clinical visits for childhood cancer survivors may be valuable; however, limiting such evaluations to those returning to long-term follow-up clinics may result in a biased subsample of those with more difficulties, and precise prevalence rates may be difficult to establish. A review of behavioral, emotional, and social adjustment among survivors of childhood brain tumors illustrates this point, in whom rates of psychological maladjustment range from 25% to 93%.[35]

Studies in the early 1990s described childhood cancer survivors as generally well adjusted, though a subset had psychological difficulties that resulted in functional impairment.[36-38] Further in-depth analyses have led to the description of posttraumatic stress disorder (PTSD) in some childhood cancer survivors and their mothers. The core features of PTSD include the following:[39]

• Experiencing an event perceived as life threatening, with an accompanying reaction of intense fear, horror, or helplessness.
• Persistent re-experiencing of the event.
• Avoiding things, events, or people surrounding the event or decreased responsiveness to same.
• Experiencing persistent symptoms of increased sleep disturbance, irritability, hypervigilance, and difficulty concentrating.

Because avoidance of places and persons associated with the cancer is part of PTSD, the syndrome may interfere with obtaining appropriate health care. Those with PTSD perceived greater current threats to their lives or the lives of their children. Other risk factors include poor family functioning, decreased social support, and noncancer stressors.[40-45] One study of 78 young adult survivors of childhood cancer found 20.5% met the criteria for PTSD. In contrast, only 4.5% of younger children met the criteria for the syndrome.[40] In several studies performed by the same group of investigators, 9% to 10% of parents of childhood cancer survivors met the criteria for PTSD.[44,46] For more information about PTSD in cancer patients, please see the PDQ summary on Post-traumatic Stress Disorder.

In a study of 101 adult cancer survivors of childhood cancer, psychologic screening was performed during a routine annual evaluation at the survivorship clinic at the Dana Farber Cancer Institute. On the Symptom Checklist 90 Revised, 32 subjects had a positive screen (indicating psychological distress), and 14 subjects reported at least one suicidal symptom. Risk factors for psychological distress included subjects’ dissatisfaction with physical appearance, poor physical health, and treatment with cranial radiation. In this study, the instrument was shown to be feasible in the setting of a clinic visit because the psychological screening was completed in less than 30 minutes. In addition, completion of the instrument itself did not appear to result in distress on the part on the survivors in 80% of cases.[47] For more information about psychological distress and cancer patients, please see the PDQ summary on Normal Adjustment and the Adjustment Disorders.

Hearing loss is a common late effect of survivors of CNS cancers and cancers of the head and neck who received high doses of radiation therapy and platinum chemotherapy. Hearing loss in the speech range (0.5 kHz to 3 kHz), which may compromise language reception and expression, is reported with cumulative doses of cisplatin greater than 360 mg/m², and 25% prevalence of hearing loss is reported with doses greater than 720 mg/m². Fifty percent of children treated with cisplatin doses greater than 450 mg/m² have sensorineural hearing loss (SNHL) in the high frequencies (6 kHz to 8 kHz). Younger age at time of administration increases risk.[48-52] Carboplatin may be less ototoxic, but further follow-up of patients treated with high cumulative doses is necessary before a clear dose-threshold can be established.[48] A German study of children treated for neuroblastoma demonstrated the influence of both cisplatin and carboplatin on hearing. For cisplatin, there was 12% hearing impairment at doses of 1 mg/m² to 200 mg/m², 13% at doses of 201 mg/m² to 400 mg/m², 26% at doses of 401 mg/m² to 600 mg/m², and 22% at 601 mg/m² to 800 mg/m². There was an additional effect of carboplatin when given in high-dose therapy with autologous stem cell infusion, in which 40% of patients developed hearing loss following a dose of 1,500 mg/m².[53] Radiation therapy can result in cochlear damage, with SNHL occurring in about 25% of patients treated with doses approaching 60 Gy, but SNHL is less frequent with lower doses of radiation therapy if cisplatin is not included in the chemotherapy regimen. Data suggest that cochlear doses of 30 Gy to 50 Gy can cause intermediate-frequency SNHL, and that cerebrospinal fluid (CSF) shunting procedures increase the risk.[51,54-56] Cisplatin, at doses as low as 270 mg/m², can result in hearing loss when combined with cranial radiation therapy doses of 40 Gy to 50 Gy.[51,52] The sequence of chemoradiotherapy appears to influence risk. Risk and severity of ototoxicity are greater when cisplatin is administered after cranial radiation.[49]

Orbital complications are common following radiation therapy for childhood head and neck sarcomas, CNS tumors, and retinoblastoma and as part of total-body irradiation (TBI).

For survivors of retinoblastoma, a small orbital volume may result from either enucleation or radiation therapy. Age younger than 1 year may increase risk, but this is not consistent across studies.[57,58] Better management of prosthetic implants and newer methods of delivering radiation therapy are likely to reduce risk.[57,59] Newer strategies for treatment of retinoblastoma use chemotherapy to reduce tumor size, combined with local ophthalmic therapies that include thermotherapy, cryotherapy, and plaque radiation. Such an approach may be associated with local complications that can affect vision. Because these therapies are relatively recent, further follow-up is required to determine long-term effects. Treatment for tumors located near the macula and fovea increase risk of complications leading to visual loss.[59-64]

Survivors of orbital rhabdomyosarcoma are at risk of dry eye, cataract, orbital hypoplasia, ptosis, retinopathy, keratoconjunctivitis, optic neuropathy, lid epithelioma, and impairment of vision following radiation therapy doses of 30 Gy to 65 Gy. The higher dose ranges (>50 Gy) are associated with lid epitheliomas, keratoconjunctivitis, lacrimal duct atrophy, and severe dry eye. Retinitis and optic neuropathy may also result from doses of 50 Gy to 65 Gy and even at lower total doses if the individual fraction size is greater than 2 Gy.[65] Cataracts are reported following lower doses of 10 Gy to 18 Gy.[51,56,66-69]

Patients treated with TBI are also at increased risk of cataracts. Risk ranges from approximately 10% to 60% at 10 years posttreatment, depending on the total dose and fractionation, with a shorter latency period and more severe cataracts noted after single fraction and higher dose or dose-rate TBI. Corticosteroids and graft-versus-host-disease (GVHD) may further increase risk. Young children may actually be at a lower risk than adolescents and adults.[70-75]

Both chemotherapy and radiation therapy can cause multiple cosmetic and functional abnormalities of dentition, most predominantly in children treated before age 3 years who have not yet developed deciduous dentition. However, even older prepubertal children are at risk. Developing teeth are irradiated in the course of treating head and neck sarcomas, Hodgkin lymphoma, neuroblastoma, CNS leukemia, nasopharyngeal cancer, and as a component of TBI. Doses of 20 Gy to 40 Gy can cause root shortening or abnormal curvature, dwarfism, and hypocalcification.[76] More than 85% of survivors of head and neck rhabdomyosarcoma who receive radiation doses greater than 40 Gy may have significant dental abnormalities, including mandibular or maxillary hypoplasia, increased caries, hypodontia, microdontia, root stunting, and xerostomia.[56,67] Chemotherapy for the treatment of leukemia can cause shortening and thinning of the premolar roots as well as enamel abnormalities.[77-79] TBI can cause short, V-shaped roots, microdontia, enamel hypoplasia, and premature apical closure.[80,81] Children who undergo bone marrow transplantation with TBI for neuroblastoma are at substantial risk for a spectrum of abnormalities, and require close surveillance and appropriate interventions.[82]

Salivary gland irradiation incidental to treatment of head and neck malignancies or Hodgkin lymphoma causes a qualitative and quantitative change in salivary flow, which can be reversible after doses of less than 40 Gy but may be irreversible after higher doses, depending on whether sensitizing chemotherapy is also administered.[83,84] Dental caries are the most problematic consequence. The use of topical fluoride can dramatically reduce the frequency of caries, and saliva substitutes and sialagogues can ameliorate sequelae such as xerostomia.[83-85]

It has been reported that the incidence of dental visits for childhood cancer survivors falls below the American Dental Association's recommendation that all adults visit the dentist annually.[86] These findings give health care providers further impetus to encourage routine dental and dental hygiene evaluations for survivors of childhood treatment. For more information about oral complications and cancer patients, please see the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation.

Most chemotherapy agents employed in childhood cancer therapy can have acute hepatotoxic effects. In the modern era, long-term hepatic effects following chemotherapy alone are uncommon. Attention to baseline hepatic function and monitoring during therapy can prevent significant acute effects that may result in chronic hepatic dysfunction.[87] Veno-occlusive disease, which most commonly occurs in the setting of radiation therapy and chemotherapy administered for marrow transplantation, is the most critical hepatic toxicity and occurs acutely. This is characterized by occlusion and obliteration of the central veins of the hepatic lobules, with retrograde congestion and secondary necrosis of hepatocytes. Although there may be a dose effect of radiation therapy, this complication is also reported following conditioning regimens with cyclophosphamide and busulfan alone. Pre-existing hepatic disease, including infection, and GVHD may increase the risk. Long-term complications of veno-occlusive disease depend on severity but can include hepatic insufficiency or failure and portal hypertension.[88-90]

Cumulative dose, volume of liver irradiated, and additional treatment with chemotherapy are important risk factors for hepatic fibrosis. Radiation hepatopathy can occur with doses of 30 Gy to 40 Gy to the entire liver, but significantly higher doses to focal volumes can be given with few clinical complications.[91] Lower doses can be associated with hepatopathy if the child is also receiving sensitizing chemotherapy. This is evident in a series of children treated for Wilms tumor, neuroblastoma, or hepatoma with radiation therapy to the liver and chemotherapy. Fractionated doses of 12 Gy to 25 Gy caused abnormal results in liver function tests and radionuclide scans in 50% of patients; 25 Gy to 35 Gy caused abnormalities in 63% of patients, and greater than 35 Gy was toxic in 86% of patients.[92] In the National Wilms Tumor Study (NWTS), 16 of 303 patients (5.3%) had liver toxicity. The doses of radiation to portions of the liver ranged from less than 15 Gy to greater than 30 Gy, with right flank or whole abdominal radiation increasing risk significantly more than isolated left flank radiation. All the patients received chemotherapy, including vincristine and dactinomycin, and some received doxorubicin.[93]

Patients who received blood transfusions before 1992 are at increased risk of developing hepatitis C infection. Those infected may then progress to chronic active hepatitis and cirrhosis, and have an increased risk of developing hepatocellular carcinoma. The incidence risks range widely from 6% to 49% across studies, but may likely be in the 20% to 25% range overall.[94-101] Therefore, all children who received blood transfusions before 1992 should be screened for hepatitis C virus. Those found to be positive should be referred to gastroenterologists for consideration of therapy in ongoing studies.

New data suggest an association between thioguanine exposure and hepatotoxicity. In a phase III trial (CCG-1952) for ALL, 1,011 patients were randomized to treatment with thioguanine compared with mercaptopurine. There were 200 reports of hepatic veno-occlusive disease, but no fatalities were directly attributed to the syndrome. An additional 32 patients did not have full clinical features of veno-occlusive disease, but did have episodes of thrombocytopenia out of proportion to neutropenia and were felt to have a subclinical form of veno-occlusive disease. An additional 51 patients have developed persistent splenomegaly identified during the end of maintenance or during the first year off therapy, and 25% have documented portal hypertension. Similar results were reported by the United Kingdom Children’s Cooperative Group for their ALL study employing the use of thioguanine.[102]

Late radiation injury to the digestive tract is attributable to vascular injury. Necrosis, ulceration, stenosis or perforation can occur and are characterized by malabsorption, pain, and recurrent episodes of bowel obstruction, as well as perforation and infection.[103,104] In general, fractionated doses of 20 Gy to 30 Gy can be delivered to the small bowel without significant long-term morbidity. Doses greater than 40 Gy are required to cause bowel obstruction or chronic enterocolitis.[105] Sensitizing chemotherapeutic agents such as dactinomycin or anthracyclines can increase this risk.

In a report of 42 survivors of Wilms tumor treated from 1968 to 1994 with megavoltage radiation therapy, dactinomycin and vincristine, with or without doxorubicin, the actuarial incidence of bowel obstruction at 5, 10, and 15 years was 9.5 ± 4.5%, 13.0 ± 5.6%, and 17.0 ± 6.5%, respectively. Of 23 patients, five irradiated within 10 days of surgery and 1 of 19 irradiated after 10 days developed bowel obstruction.[106] In a report from the Intergroup Rhabdomyosarcoma Study Committee, extended follow-up of 86 children and adolescents who were treated for paratesticular rhabdomyosarcoma on the Intergroup Rhabdomyosarcoma Studies I and II (IRS I-II) revealed that four patients who had abdominal radiation therapy had chronic diarrhea.[107]

Splenectomy increases risk of life-threatening invasive bacterial infection.[108] It is no longer standard practice to perform a staging laparotomy for pediatric Hodgkin lymphoma. Therefore, the previously described long-term complications, related to both surgery and altered immune function, should no longer be an issue for most survivors of childhood cancer.[109,110] Children may be rendered asplenic by radiation therapy to the spleen in doses greater than 30 Gy, however, given as involved-field irradiation or as part of nodal irradiation.[111,112] Low-dose involved-field radiation (21 Gy) combined with multiagent chemotherapy does not appear to adversely affect splenic function.[112]

For patients with surgical or functional asplenia, prophylactic antibiotics (generally penicillin) are recommended as daily lifelong treatment. No randomized studies that address the benefit of antibiotics have been conducted in a pediatric oncology population; thus, these recommendations are based on any pediatric population with asplenia.[113-116] As a result, some patients, over time, discontinue use of antibiotics. In these cases, antibiotics—generally penicillin—should be taken at the first onset of febrile illness if the patient is not on daily prophylaxis. Medical care should be sought promptly for fevers higher than 38.5°C. Patients should receive antibiotic prophylaxis for dental work and should be immunized against meningococcus, hemophilus influenzae type B, and Streptococcus pneumoniae.[108]

Childhood cancer survivors exposed to anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone) or thoracic radiation therapy are at risk for long-term cardiac toxicity. The risks to the heart are related to cumulative anthracycline dose, method of administration, amount of radiation delivered to different depths of the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, latency period, and gender.

The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. The pathogenesis of injury differs, however, with radiation primarily affecting the fine vasculature of the heart and anthracyclines directly damaging myocytes.[117] Late effects of radiation to the heart include:[118-120]

• Delayed pericarditis.
• Pancarditis, which includes pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
• Myopathy.
• Coronary artery disease (CAD).
• Functional valve injury.
• Conduction defects.

With current techniques and reduced doses of radiation therapy, however, these effects are unlikely following treatment for childhood cancer. In a study of 635 patients treated for childhood Hodgkin lymphoma, the actuarial risk of pericarditis requiring pericardiectomy was 4% at 17 years posttreatment (occurring only in children treated with higher radiation doses). Only 12 patients died of cardiac disease, including seven deaths from acute myocardial infarction; however, these deaths occurred only in children treated with 42 Gy to 45 Gy. In an analysis of 48 patients treated for Hodgkin lymphoma from 1970 to 1991 with mediastinal therapy (median dose 40 Gy), 43% had unsuspected valvular abnormalities, 75% had a conduction abnormality or arrythmia, and 30% had reduced VO₂ during exercise tests. These abnormalities were noted at a mean of 15.5 years posttherapy suggesting that survivors of Hodgkin lymphoma treated with these doses of mediastinal radiation therapy require long-term cardiology follow-up.[121] Among children treated with 15 Gy to 26 Gy, none developed radiation-associated cardiac problems.[122] It seems safe to conclude that cardiac radiation using sophisticated treatment planning and careful blocking to doses 25 Gy or less is generally safe, and 40 Gy may be administered to small cardiac regions. The risk of delayed CAD after lower radiation doses, however, requires additional study of patients followed for longer periods of time to definitively ascertain lifetime risk. Nontherapeutic risk factors for CAD—such as family history, obesity, hypertension, smoking, diabetes, and hypercholesterolemia—are likely to impact the frequency of disease.[119]

Increased risk of doxorubicin-related cardiomyopathy is associated with female sex, cumulative doses greater than 200 mg/m² to 300 mg/m², younger age at time of exposure, and increased time from exposure.[123-137] Route of administration of doxorubicin may influence risk of cardiomyopathy. One study looked at the effect of continuous (48-hour) versus bolus (1-hour) infusions of doxorubicin in 121 children who received a cumulative dose of 360 mg/m² for treatment of ALL and found no difference in the degree or spectrum of cardiotoxicity in the two groups. Because the follow-up time in this study was relatively short, it is not yet clear whether the frequency of progressive cardiomyopathy will differ between the two groups over time.[130] Another study compared cardiac dysfunction in 113 children who received doxorubicin either by single-dose infusion or by a consecutive divided daily-dose schedule. The divided-dose patients received one-third of the total cycle dose over 20 minutes for 3 consecutive days. Patients treated according to a single-dose schedule received the cycle dose as a 20-minute infusion. There was no significant difference in the incidence of cardiac dysfunction between the divided-dose and single-dose infusion groups.[123] Earlier studies in adults have shown decreased cardiotoxicity with prolonged infusion; thus, further evaluation of this question is warranted.[138-141]

Prevention or amelioration of anthracycline-induced cardiomyopathy is clearly important because the continued use of anthracyclines is required in cancer therapy. Dexrazoxane (DZR) is a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent. Evidence supports its capacity to mitigate cardiac toxicity in patients treated with anthracyclines.[121,142-145] Studies suggest that dexrazoxane is safe and it does not interfere with chemotherapeutic efficacy. There is a single-study experience suggesting that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity; however, at this time, this should not preclude treatment with dexrazoxane.[146,147]

In two closed Pediatric Oncology Group therapeutic phase III studies for Hodgkin lymphoma,[