Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the late effects of treatment for childhood cancers and is organized by organ system. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

• Risk factors.
• Late effects by body system.
• Second malignant neoplasms.
• Monitoring for late effects.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

General Information

During the past 3 decades, multimodality therapy for childhood cancer has resulted in markedly improved survival. For the period from 1985 to 1997, the 5-year survival rate for childhood cancer reported by the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program is 75%. [1] The therapy responsible for this survival can also produce adverse long-term health-related outcomes that manifest months to years after completion of cancer treatment, and are commonly referred to as late effects. It has been clearly demonstrated that long-term survivors of childhood cancer carry a high burden of morbidity with one-third of the survivors reporting severe or life threatening complications 30 years after diagnosis of their primary cancer. [2] Long-term survivors of childhood cancer are at an 8.4-fold increased risk of premature death when compared with an age-matched and gender-matched general population, with increases in cause-specific mortality seen for deaths due to second cancers, and cardiac and pulmonary causes. [3] Late effects include organ dysfunction, second malignant neoplasms, and adverse psychosocial sequelae. Unfortunately, the majority of childhood cancer survivors do not receive recommended risk-based care. The Childhood Cancer Survivor Study reported that 88.8% of survivors were receiving some form of medical care, but only 31.5% reported care that focused on their prior cancer (survivor-focused care) and 17.8% reported survivor-focused care that included advice about risk reduction and discussion or ordering of screening tests. [4]

Risk factors for late effects include:
• Tumor-related factors
  • Direct tissue effects.
  • Tumor-induced organ dysfunction.
  • Mechanical effects.


• Treatment-related factors
  • Radiation therapy: Total dose and fraction size, organ or tissue volume, and machine energy are the most critical factors.
  • Chemotherapy: Agent type, single and cumulative dose and schedule may modify risk.
  • Surgery: Technique and site are relevant.


• Host-related factors
  • Developmental status.
  • Genetic predisposition.
  • Inherent tissue sensitivities and capacity for normal tissue repair.
  • Function of organs not affected by radiation therapy or chemotherapy.
  • Premorbid state.

Several comprehensive reviews and books that address late effects of childhood cancer and its therapy have been published. [5] [6] [7] [8] [9] [10] [11] [12] An example of specific recommendations for surveillance based on therapeutic exposure can be found in the Children's Oncology Group long-term follow-up guidelines.[Survivorship Guidelines]

Table 1. Common Agents Associated With Therapy Late Effects

Information concerning late effects is summarized in tables throughout the summary. Tables in the Common Late Effects of Childhood Cancer by Body System section of the summary have been modified from another review, with author permission. [8]

References:

1. Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed April 19, 2007.
2. Oeffinger KC, Mertens AC, Sklar CA, et al.: Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 355 (15): 1572-82, 2006.
3. Mertens AC, Liu Q, Neglia JP, et al.: Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 100 (19): 1368-79, 2008.
4. Nathan PC, Greenberg ML, Ness KK, et al.: Medical care in long-term survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 26 (27): 4401-9, 2008.
5. Oeffinger KC, Hudson MM: Long-term complications following childhood and adolescent cancer: foundations for providing risk-based health care for survivors. CA Cancer J Clin 54 (4): 208-36, 2004 Jul-Aug.
6. Meister LA, Meadows AT: Late effects of childhood cancer therapy. Curr Probl Pediatr 23 (3): 102-31, 1993.
7. Schwartz CL: Long-term survivors of childhood cancer: the late effects of therapy. Oncologist 4 (1): 45-54, 1999.
8. Schwartz C L, Hobbie WL, Constine LS, et al., eds.: Survivors of Childhood Cancer: Assessment and Management. St. Louis, Mo: Mosby, 1994.
9. Constine LS: Late effects of cancer treatment. In: Halperin EC, Constine LS, Tarbell NJ, et al.: Pediatric Radiation Oncology. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 1999, pp 457-537.
10. Green DM, D'Angio GJ, eds.: Late Effects of Treatment for Childhood Cancer. New York, NY: Wiley-Liss, Inc., 1992.
11. Friedman DL, Meadows AT: Late effects of childhood cancer therapy. Pediatr Clin North Am 49 (5): 1083-106, x, 2002.
12. Smith M, Hare ML: An overview of progress in childhood cancer survival. J Pediatr Oncol Nurs 21 (3): 160-4, 2004 May-Jun.

Common Late Effects of Childhood Cancer by Body System

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] [2] [3] [4] [5] [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] [8] [9] [10] [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] [13] [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 children with ALL, studies again show significant neurocognitive impairment [18] [19] when cranial radiation is combined with IT chemotherapy. Reduction in the cranial radiation dose may result in less neurocognitive impairment. [11] [20] [21] [22] [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 IT chemotherapy. Moreover, tumor-related deficits because of direct invasion of the brain, seizures, and hydrocephalus must be recognized. [24] 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. [25] 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 IT methotrexate has been found in children treated for medulloblastoma. [26]

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] [27] [28] 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. [29] [30] At lower methotrexate doses, there does not appear to be a consistent pattern of neurocognitive deficits. [31] 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. [32]

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. [29] 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. [33] 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] In general, patients who receive IT chemotherapy without cranial radiation as CNS therapy appear to have a low incidence of neurocognitive sequelae, and the deficits that develop represent relatively modest declines in a limited number of domains of neuropsychological functioning. [34] [35] [36] This modest decline is especially seen in young children and girls. [37] Controversy exists about whether patients who receive dexamethasone are at higher risk for neurocognitive disturbances, [38] although long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment did not demonstrate any meaningful differences in cognitive functioning based on corticosteroid randomization. [39] Treatment intensity and duration can also adversely affect cognitive performance, because of absences from school and interruption of studies. [40]

Cognitive and academic consequences of stem cell transplantation in children has also been evaluated. In a report from the St. Jude Children’s Research Hospital in which 268 patients were treated with stem cell transplant, minimal risk of late cognitive and academic sequelae was seen. Subgroups of patients were at relatively higher risk, including those undergoing unrelated donor transplantation, receiving total-body irradiation, and those with graft-versus-host disease. However, these differences were small relative to differences in premorbid functioning, particularly those associated with socioeconomic status. [41]

Table 2. CNS Late Effects^a

Psychosocial

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%. [43]

Studies in the early 1990s described childhood cancer survivors as generally well adjusted, though a subset had psychological difficulties that resulted in functional impairment. [44] [45] [46] 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: [47]

• 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. [48] [49] [50] [51] [52] [53] 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. [48] In several studies performed by the same group of investigators, 9% to 10% of parents of childhood cancer survivors met the criteria for PTSD. [52] [54] 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. [55] For more information about psychological distress and cancer patients, please see the PDQ summary on Normal Adjustment and Distress.

Special Senses

Hearing

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. [56] [57] [58] [59] [60] 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. [56] 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. [61] 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. [59] [62] [63] [64] [65] 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. [59] [60] The sequence of chemoradiotherapy appears to influence risk. Risk and severity of ototoxicity are greater when cisplatin is administered after cranial radiation. [57]

Table 3. Ear Late Effects^a

Optic and orbital

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. [66] [67] Better management of prosthetic implants and newer methods of delivering radiation therapy are likely to reduce risk. [66] [68] 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. [68] [69] [70] [71] [72] [73]

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. [74] Cataracts are reported following lower doses of 10 Gy to 18 Gy. [59] [64] [75] [76] [77] [78]

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. [79] [80] [81] [82] [83] [84]

Table 4. Eye Late Effects^a

Digestive System

Dental

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. [85] 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. [64] [76] Chemotherapy for the treatment of leukemia can cause shortening and thinning of the premolar roots as well as enamel abnormalities. [86] [87] [88] TBI can cause short, V-shaped roots, microdontia, enamel hypoplasia, and premature apical closure. [89] [90] 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. [91]

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. [92] [93] 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. [92] [93] [94]

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. [95] 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.

Table 5. Dental Late Effects^a

Hepatic

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. [96] 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. [97] [98] [99]

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. [100] 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. [101] 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. [102]

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. [103] [104] [105] [106] [107] [108] [109] [110] 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. [111]

Table 6. Hepatic Late Effects^a

Digestive tract

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. [112] [113] 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. [114] 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 one of 19 irradiated after 10 days developed bowel obstruction. [115] 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 revealed that four patients who had abdominal radiation therapy had chronic diarrhea. [116]

Table 7. Gastrointestinal (GI) Late Effects^a

Immune System

Spleen

Splenectomy increases risk of life-threatening invasive bacterial infection. [117] 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. [118] [119] 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. [120] [121] Low-dose involved-field radiation (21 Gy) combined with multiagent chemotherapy does not appear to adversely affect splenic function. [121]

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. [122] [123] [124] [125] 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. [117]

Table 8. Spleen Late Effects^a

Circulatory System

Cardiovascular

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. [126] Late effects of radiation to the heart include: [127] [128] [129]

• 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. [130] Among children treated with 15 Gy to 26 Gy, none developed radiation-associated cardiac problems. [131] 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. [128] [132]

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. [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] 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. [140] 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. [133] Earlier studies in adults have shown decreased cardiotoxicity with prolonged infusion; thus, further evaluation of this question is warranted. [148] [149] [150] [151]

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. [130] [152] [153] [154] [155] 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. [156] [157]

In two closed Pediatric Oncology Group therapeutic phase III studies for Hodgkin lymphoma, [158] [159] myocardial toxicity is being measured clinically and sequentially over time by echocardiography and electrocardiography, as well as by the determination of levels of cardiac troponin T (cTnT), a protein that is elevated after myocardial damage. [154] [160] [161] [162] [163] [164]

The angiotensin-converting enzyme inhibitor enalapril has been used in the attempt to ameliorate doxorubicin-induced left ventricular (LV) dysfunction. Although a transient improvement in LV function and structure was noted in 18 children, LV wall thinning continued to deteriorate; thus the intervention with enalapril was not considered successful. [153] For this reason, studies to date in anthracycline-treated cancer survivors have not demonstrated a benefit of enalapril in preventing progressive cardiac toxicity. [152] [153]

Rhythm disturbances are also reported after doxorubicin exposure. One study looked at electrocardiograms (ECGs) in 52 long-term survivors of childhood cancer who had been treated with anthracyclines. Prolongation of corrected QT interval (QTc) of more than 0.43 was noted in 6 of 22 patients who had received cumulative anthracycline doses greater than 300 mg/m², as compared with 0 of 15 patients who had received lower anthracycline doses. Thoracic radiation therapy increased the risk in both groups, though the higher anthracycline dose group still demonstrated a higher frequency of prolongation of QTc. Exercise further prolonged the QTc in 6 of 10 patients evaluated. [165]

Although much of the data on doxorubicin and radiation-associated cardiac dysfunction are from survivors of Hodgkin lymphoma and ALL, survivors of other childhood cancers are also at risk. Children who receive spinal radiation for treatment of CNS tumors have been demonstrated to show low maximal cardiac index on exercise testing and pathologic Q-waves in inferior leads on ECG testing, and higher posterior-wall stress. [166] A study of self-reported late effects among 1,607 survivors of childhood brain tumors in the Childhood Cancer Survivor Study (CCSS) revealed that cardiovascular conditions were reported in 18% of patients. Compared with siblings, risk was elevated for stroke, blood clots, and angina-like symptoms. [167] A follow-up study of Wilms tumor survivors reported a cumulative risk of congestive heart failure of 4.4% at 20 years posttreatment for those who received doxorubicin as part of their initial therapy and 17.4% at 20 years posttreatment when doxorubicin was received as part of therapy for relapsed disease. Risk factors for congestive heart failure in this cohort included female gender, lung irradiation with doses greater than 20 Gy, left-sided abdominal irradiation, and doxorubicin dose greater than 300 mg/m². [135] Children who require hematopoietic stem cell transplantation (HSCT) are at especially high risk of cardiac toxicity. They may have received anthracyclines or radiation therapy with the heart in the field as part of their initial cancer therapy, and they are subsequently exposed to conditioning regimens that may include high-dose cyclophosphamide and TBI. [168] [169] [170] [171] [172]

A number of studies have examined cardiac function after radiation therapy and anthracycline exposure using cardiopulmonary exercise stress tests and have found abnormalities in exercise endurance, cardiac output, aerobic capacity, echocardiography during exercise testing, and ectopic rhythms. [165] [171] [172] [173] [174] [175] [176] Specific abnormalities of cardiac function may progress over time after therapy, as suggested by a report targeting parameters of LV contractility. [177] It remains unclear whether these abnormalities will have clinical impact. Asymptomatic cardiotoxicity can be demonstrated in patients who have normal clinical assessments, and abnormalities can be linked to lower self-reported health and New York Heart Association cardiac function scores. [178] Clearly, additional studies with long-term follow-up will be necessary to determine optimal screening modalities and frequencies.

More time is needed before the effects of reduction in the dose of anthracyclines, thoracic radiation therapy, or other protective measures (i.e., dexrazoxane) are known.

Table 9. Cardiac Late Effects^a

Respiratory System

Pulmonary

Pulmonary fibrotic disease is seen as a late complication of radiation therapy. In the modern management of pediatric malignancies, radiation therapy is often given in combination with chemotherapy. Many chemotherapeutic agents induce lung damage on their own or potentiate the damaging effects of radiation to the lung. Thus, the potential for acute or chronic pulmonary sequelae must be considered in the context of the specific chemotherapeutic agents and the radiation dose administered, as well as the volume of lung irradiated and the fractional radiation therapy doses. Acute pneumonitis manifested by fever, congestion, cough, and dyspnea can follow radiation therapy alone at doses greater than 40 Gy to focal lung volumes, or after lower doses when combined with dactinomycin or anthracyclines. Fatal pneumonitis is possible after radiation therapy alone at doses to the whole lung greater than 20 Gy, but is possible after lower doses when combined with chemotherapy. Infection, GVHD in the setting of BMT, and pre-existing pulmonary compromise (e.g., asthma) all may influence this risk. Changes in lung function have been reported in children treated with whole-lung radiation therapy for metastatic Wilms tumor. A dose of 12 Gy to 14 Gy reduced total lung capacity and vital capacity to about 70% of predicted values, and even lower if the patient had undergone thoracotomy. Fractionation of dose decreases this risk. [179] [180] Administration of bleomycin alone can produce pulmonary toxicity and, when combined with radiation therapy, can heighten radiation reactions. Chemotherapeutic agents such as doxorubicin, dactinomycin, and busulfan are radiomimetic agents and can reactivate latent radiation damage. [179] [180] [181]

The development of bleomycin-associated pulmonary fibrosis with permanent restrictive disease is dose dependent, usually occurring at doses greater than 200 U/m² to 400 U/m², higher than those used in pediatric malignancies. [181] [182] [183] One study evaluated lung function in 20 pediatric Hodgkin lymphoma patients treated with MOPP (mechlorethamine [HN 2], vincristine [Oncovin], prednisone, and procarbazine)/ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) and 15 Gy to 25 Gy mantle radiation and found 55% to have abnormal diffusing capacity. [184] Another study evaluated serial pulmonary function in children treated with COP (cyclophosphamide, vincristine, and prednisone)/ABVD and mantle radiation therapy and found 65% to 73% to have only mildly decreased or normal diffusing capacity. [185] One other study reviewed pulmonary toxicity in survivors of childhood ALL, Hodgkin lymphoma, and non-Hodgkin lymphoma (NHL) and found some abnormalities as measured by pulmonary function testing. [186] [187] Clinical symptoms were uncommon and generally did not correlate with pulmonary function test results in these studies.

Patients who are treated with HSCT are at increased risk of pulmonary toxicity, related to pre-existing pulmonary dysfunction (e.g., asthma, pretransplant therapy), the preparative regimen that may include cyclophosphamide, busulfan, carmustine, TBI, and the presence of GVHD. [188] [189] [190] [191] [192] [193] [194] Although most survivors of transplant are not clinically compromised, restrictive lung disease may occur. Obstructive disease is less common, as is late onset pulmonary syndrome, which includes the spectrum of restrictive and obstructive disease. Bronchiolitis obliterans with or without organizing pneumonia, diffuse alveolar damage, and interstitial pneumonia may occur as a component of this syndrome, generally between 6 and 12 months posttransplant. Cough, dyspnea, or wheezing may occur with either normal chest x-ray or diffuse/patchy infiltrates; however, most patients are symptom free. [192] [193]

The true prevalence or incidence of pulmonary dysfunction in childhood cancer survivors is not clear. For children treated with HSCT, there is significant clinical disease. No large cohort studies have been performed with clinical evaluations coupled with functional and quality-of-life assessments. An analysis of self-reported pulmonary complications of 12,390 survivors of common childhood malignancies has been reported by the CCSS. This cohort includes children treated with both conventional and myeloablative therapies. Compared with siblings, survivors had an increased relative risk (RR) of lung fibrosis, recurrent pneumonia, chronic cough, pleurisy, use of supplemental oxygen therapy, abnormal chest wall, exercise-induced shortness of breath and bronchitis, with RRs ranging from 1.2 to 13.0 (highest for lung fibrosis and lowest for bronchitis). The 25-year cumulative incidence of lung fibrosis was 5% for those who received chest radiation therapy and less than 1% for those who received pulmonary toxic chemotherapy. For more subjective complaints, the 25-year cumulative incidences were higher, as follows: chronic cough, 15% for combined chest radiation therapy and pulmonary toxic chemotherapy, 12% chest radiation therapy alone, 6% pulmonary toxic chemotherapy alone; exercise-induced shortness of breath, 20% chest radiation therapy and pulmonary toxic chemotherapy, 15% chest radiation therapy alone, 6% pulmonary toxic chemotherapy alone. Treatment-related risk factors included chest radiation for lung fibrosis, supplemental oxygen therapy, recurrent pneumonia, exercise-induced shortness of breath, and chronic cough. Cyclophosphamide increased risk for exercise-induced shortness of breath, supplemental oxygen therapy, chronic cough, bronchitis, and recurrent pneumonia. Bleomycin increased risk for supplemental oxygen therapy, bronchitis, and chronic cough. Busulfan increased risk of chronic cough and pleurisy. Doxorubicin was associated with an increased risk of emphysema, supplemental oxygen therapy, chronic cough, and shortness of breath. Nitrosoureas were associated with an increased risk of supplemental oxygen therapy. Three survivors had undergone a lung transplant, and another three survivors developed adenocarcinoma of the lung as a second malignancy. Risk continues to increase with time since diagnosis. [195] With changes in the doses of radiation therapy employed since the late 1980s, the incidence of these abnormalities is likely to decrease.

Table 10. Pulmonary Late Effects^a

Urinary System

Renal

Cisplatin at doses greater than 200 mg/m² can result in glomerular or tubular injury and renal insufficiency. Other nephrotoxic agents such as aminoglycosides, amphotericin, and ifosfamide may further increase risk. Effects can be seen acutely and may progress after completion of therapy. [58] [196] [197] [198] Studies in the early 1990s have shown that carboplatin has less acute nephrotoxicity than cisplatin. [199] [200] [201] Only a few small studies examining children treated with carboplatin, however, have evaluated short-term and long-term nephrotoxicity, finding nothing significant to date. [202] [203] As with ototoxicity, however, additional follow-up in larger numbers of survivors treated with carboplatin must be evaluated before potential renal toxicity can be better defined.

Ifosfamide can also cause glomerular and tubular toxicity, with renal tubular acidosis, and Fanconi syndrome. Doses greater than 60 g/m² to 100 g/m², age younger than 5 years at time of treatment, and combination with cisplatin and carboplatin increase risk. Abnormalities in glomerular filtration are less common, and when found are usually not clinically significant. More common are abnormalities with proximal tubular function greater than distal tubular function, though the prevalence of these findings is uncertain and further study of larger cohorts with longer follow-up is required. [204] [205] [206] [207] [208]

Radiation nephropathy is dose-related. Doses greater than 25 Gy to both kidneys can cause renal failure at delayed intervals of more than 6 months. [209] [210] The effect of radiation therapy on the kidney has best been examined in survivors of pediatric Wilms tumor, where unilateral nephrectomy is also common. Unilateral irradiation to doses of 14 Gy to 20 Gy may reduce the ability of the contralateral (untreated) kidney to undergo compensatory hypertrophy. [211] One study examined the spectrum of renal failure in 55 patients among the 5,823 patients treated for Wilms tumor. The incidence of renal failure at 16 years postdiagnosis was 0.6% for patients with unilateral disease and 13% for patients with bilateral disease. The most common etiologies of renal failure were bilateral nephrectomy for persistent or recurrent tumor, progressive tumor in the remaining kidney without nephrectomy, Denys-Drash syndrome (DDS), and radiation nephritis. [212] Long-term renal function was subsequently evaluated in 81 children with synchronous bilateral Wilms tumor who received treatment. With a median follow-up of 27 months, 28 patients had elevated blood urea nitrogen (BUN) and/or serum creatinine levels. Of those, 18 had moderate renal insufficiency and ten had marked renal insufficiency. There was no dose response to chemotherapy, and tumor recurrence requiring additional surgery increased the risk of renal dysfunction. Those with less than one kidney remaining had more marked dysfunction. [213] In another study from the National Wilms Tumor Group of children treated from 1969 to 1995, 58 of 5,976 developed renal failure with a median follow-up of 11 years. Patients with bilateral disease and unilateral disease had a 20-year renal failure incidence of 5.5% and 1.0%, respectively. Treatment for Wilms tumor without flank or abdominal radiation therapy was not associated with significant nephrotoxicity in a study of 40 Wilms tumor survivors treated in England. [214] Patients with predisposition syndromes such as DDS, WAGR (Wilms tumor, Aniridia, Genitourinary abnormalities, Mental retardation) syndrome, or male genitourinary anomalies had much higher incidence of renal failure at 20 years; 62.4%, 38.3% and 10.9%, respectively. Presence of intralobar nephrogenic rests in the unilateral disease group without a defined syndrome resulted in an elevated cumulative risk of renal failure at 20 years of 3.3%, compared with 0.7% without this pathologic finding. [215]

In the setting of HSCT, fewer than 15% of children will develop chronic renal insufficiency or hypertension; the risk is related to the nephrotoxic agents used and the TBI-fractionation scheme and interfraction interval. [192]

Table 11. Kidney and Bladder Late Effects^a

Endocrine System

Thyroid gland

Thyroid dysfunction, manifested by primary hypothyroidism, hyperthyroidism, goiter, or nodules, is a common delayed effect of radiation therapy fields that include the thyroid gland incidental to treating Hodgkin lymphoma, brain tumors, head and neck sarcomas, and ALL. Of children treated with radiation therapy, most develop hypothyroidism within the first 2 to 5 years posttreatment, but new cases can occur later. Reports of thyroid dysfunction differ depending on the dose of radiation, the length of follow-up, and the biochemical criteria utilized to make the diagnosis. [216] The most frequently reported abnormalities include elevated thyroid-stimulating hormone (TSH), depressed thyroxine (T₄), or both. [217] [218] [219] [220] Compensated hypothyroidism includes an elevated TSH with a normal T₄ and is asymptomatic. The natural history is unclear, but most endocrinologists support treatment. Uncompensated hypothyroidism includes both an elevated TSH and a depressed T₄. Thyroid hormone replacement is beneficial for correction of the metabolic abnormality, and has positive implications for cardiac, gastrointestinal, and neurocognitive function.

The incidence of hypothyroidism should decrease with lower cumulative doses of radiation therapy employed in newer protocols. In a study of 1,677 children and adults with Hodgkin’s lymphoma who were treated with radiation therapy between 1961 and 1989, the actuarial risk at 26 years posttreatment for overt or subclinical hypothyroidism was 47%, with a peak incidence at 2 to 3 years posttreatment. [221] In a study of Hodgkin lymphoma patients treated between 1962 and 1979, hypothyroidism occurred in four of 24 patients who received mantle doses less than 26 Gy but in 74 of 95 patients who received greater than 26 Gy. The peak incidence occurred at 3 to 5 years posttreatment, with a median of 4.6 years. [222] A cohort of childhood Hodgkin lymphoma survivors treated between 1970 and 1986 were evaluated for thyroid disease by use of a self-report questionnaire in the CCSS. Among 1,791 survivors, 34% reported that they had been diagnosed with at least one thyroid abnormality. For hypothyroidism, there was a clear dose response, with a 20-year risk of 20% for those who received less than 35 Gy, 30% for those who received 35 Gy to 44.9 Gy, and 50% for those who received greater than 45 Gy to the thyroid gland. The RR for hypothyroidism was 17.1; for hyperthyroidism 8.0; and for thyroid nodules, 27.0. Elapsed time since diagnosis was a risk factor for both hypothyroidism and hyperthyroidism, where the risk increased in the first 3 to 5 years after diagnosis. For nodules, the risk increased beginning at 10 years after diagnosis. Females were at increased risk for hypothyroidism and thyroid nodules. [223] (See Second Malignant Neoplasms section of this summary for information about secondary thyroid cancers.) Survivors of pediatric HSCT are at increased risk of thyroid dysfunction, with the risk being much lower (15%–16%) after fractionated TBI, as opposed to single-dose TBI (46%–48%). Non-TBI-containing regimens historically were not associated with an increased risk. However, in a report from the Fred Hutchinson Cancer Research Center, the increased risk of thyroid dysfunction was not different between children receiving a TBI or a busulfan-based regimen (p = .48). [224] Other high-dose therapies have not been studied. While mildly elevated TSH is common, it is usually accompanied by normal thyroxine concentration. [225] [226]

Table 12. Thyroid Late Effects^a

Neuroendocrine System

Other endocrine abnormalities can occur after cranial irradiation, including growth hormone (GH) deficiency, delayed or precocious puberty, and hypopituitarism. Hypothalamic dysfunction is most common, though pituitary insufficiency may occur. [167] [217] [227] [228] [229] [230]

The potential for neuroendocrine damage is likely to decrease because of the use of more focused radiation therapy and a decrease in dose for some conditions such as medulloblastoma. Approximately 60% to 80% of irradiated pediatric brain tumor patients who have received doses greater than 30 Gy will have impaired serum GH response to provocative stimulation, usually within 5 years of treatment. The dose-response relationship has a threshold of 18 Gy to 20 Gy; the higher the radiation dose, the earlier the GH deficiency will occur after treatment. A study of conformal radiation therapy in children with CNS tumors indicates that GH insufficiency can usually be demonstrated within 12 months of radiation therapy, depending on hypothalamic dose-volume effects. [231] Children treated with CNS irradiation for leukemia are also at increased risk of GH deficiency. One study evaluated 127 patients with ALL treated with 24 Gy, 18 Gy, or no cranial irradiation. The change in height, compared with population norms expressed as the standard deviation score (SDS), was significant for all three groups with a dose-response of -0.49 ± 0.14 for the no radiation therapy group, -0.65 ± 0.15 for the 18 Gy radiation therapy group, and -1.38 ± 0.16 for the 24 Gy group. [232] Another study found similar results in 118 ALL survivors treated with 24 Gy cranial irradiation, in which 74% had SDS score of -1 or greater and the remainder -2 or greater. [233]

Children who receive HSCT with TBI have a significant risk of GH deficiency. Risk is increased with single-dose as opposed to fractionated radiation, pretransplant cranial irradiation, female gender, and posttreatment complications such as GVHD. [234] [235] [236] [237] Regimens containing busulfan and cyclophosphamide also increase risk. [237] Hyperfractionation of the TBI dose markedly reduces risk, without pretransplant cranial radiation. [238] In a review of late effects after HSCT, one group discussed this risk at length. The mean loss of height is estimated to be approximately 1 height-SDS (6 cm) compared with the mean height at time of SCT and mean genetic height. [239] In a report from the European Group for Blood and Marrow Transplantation, among 181 patients with aplastic anemia, leukemias, and lymphomas who underwent HSCT before puberty, an overall decrease in final height-SDS value was found compared with height at transplant and genetic height. The type of transplantation, GVHD, GH, or steroid treatment did not influence final height. TBI (single dose radiation therapy more than fractionated dose radiation therapy), male gender, and young age at transplant, were found to be major factors for long-term height loss. Most patients (140 of 181) reached adult height within the normal range of the general population. [240]

GH deficiency should be treated with replacement therapy. Some controversy surrounds this, with a concern over increased risk of recurrence and second malignancies. Most studies, however, are limited by selection bias and small sample size. One study evaluated 361 GH-treated cancer survivors enrolled in the CCSS and compared risk of recurrence, risk of secondary neoplasm, and risk of death among survivors who did and did not receive treatment with GH. The RR of disease recurrence was 0.83 (95% confidence interval [CI], 0.37–1.86) for GH-treated survivors. GH-treated subjects were diagnosed with 15 second malignant neoplasms, all solid tumors, for an overall RR of 3.21 (95% CI, 1.88–5.46), mainly because of a small excess number of second neoplasms observed in survivors of acute leukemia. However, a review of existing data suggests that treatment with GH is not associated with an increased risk of CNS tumor progression or recurrence, or new or recurrent leukemia. [241] In general, the data addressing second malignancies should be interpreted with caution given the small number of events. [242] [243]

Pubertal growth can be adversely affected by cranial radiation. Doses greater than 50 Gy may result in gonadotrophin deficiency, while doses in the range of 18 Gy to 47 Gy can result in precocious puberty. Precocious puberty has been reported in some children receiving cranial irradiation, mostly in girls who receive doses greater than 24 Gy cranial radiation. Earlier puberty and earlier peak height velocity, however, are seen in girls treated with 18 Gy cranial radiation. [244] [245] Another study showed that the age of pubertal onset is positively correlated with age at the time of cranial irradiation. The impact of early puberty in a child with radiation-associated GH deficiency is significant, and timing of GH is especially important for GH-deficient females also at risk of precocious puberty. [246] With higher doses of cranial irradiation (>35 Gy), deficiencies in the gonadotropins can be seen, with a cumulative incidence of 10% to 20% at 5 to 10 years posttreatment. [247] One other study documented non-GH abnormalities in 20 children treated with irradiation for brain tumors not involving the hypothalamic-pituitary (H-P) region, including low free T₄ levels because of hypothalamic or pituitary injury and low luteinizing hormone (LH) and estradiol with oligomenorrhea. [227] Adrenocorticotropin deficiencies and hyperprolactinemia are relatively rare in children because these conditions develop only with doses greater than 50 Gy. [227] [248]

Table 13. Neuroendocrine Late Effects^a

Musculoskeletal System

Bone and body composition

Chondroblasts and chondrocytes are affected by radiation therapy in growing children, which can result in soft tissue hypoplasia and diminution of bone growth. These effects are associated with the total and fractional radiation dose, and the inclusion of the epiphyses in the radiation field. [249] [250] [251] Craniospinal radiation results in both abnormal GH secretion and effects on the vertebral bodies. [252]

Osteonecrosis has been reported in survivors of ALL who were treated by conventional therapy or by HSCT, with corticosteroids representing a significant risk factor. [253] [254] [255] [256] [257] [258] In trials of the former Children's Cancer Group (CCG) for ALL, the incidence of osteonecrosis has decreased, with fewer continuous days of corticosteroids during delayed intensification. However, it continues to be a problem. In the closed CCG 1961 protocol, among 2,077 accrued patients, unifocal osteonecrosis was seen in 19 patients, and multifocal disease in 74. [259] In a report from the CCSS, the cumulative incidence of osteonecrosis was 0.43% and a rate ratio of 6.2 compared with siblings, adjusted for age and gender. Forty-four percent developed osteonecrosis in a previous radiation field, and the RR was greatest among survivors of SCT for ALL, acute myelogenous leukemia and chronic myelogenous leukemia (26.9, 66.6, and 93.1, respectively). Nontransplantation patients with ALL and bone sarcoma were also at increased risk for osteonecrosis. Older age at diagnosis, shorter elapsed time, older treatment era, exposure to dexamethasone (± prednisone), and gonadal and nongonadal radiation, were independently associated with osteonecrosis. [260]

Bone mineral density in childhood cancer survivors may be reduced, especially in children treated for ALL, in whom it has been best studied. An increased incidence of fractures and osteonecrosis also occurs in these patients. Risk factors include increased age at time of exposure, estrogen deficiency, female gender, corticosteroid use and type, GH deficiency, and cranial radiation. Prevalence, chronicity, and severity are not consistent across studies; therefore, the risk remains poorly defined. [261] [262] [263] [264] [265] [266] [267] [268] [269] Decreased bone mineral density has also been reported in patients treated for bone and soft tissue sarcomas, [270] [271] [272] Wilms tumor, [273] and CNS tumors. [274] For survivors of HSCT, again there is a lack of consensus regarding the risk and incidence of decreased bone mineral density posttransplant. [275] [276] [277] [278] [279] Further research into the type and frequency of screening, the population at highest risk, and interventions are clearly indicated, especially for survivors of ALL, lymphomas, brain tumors, and sarcomas. Bisphosphonates, calcium supplements, and hormone replacement therapy are potential interventions that are being used in the general population at risk for decreased bone mineral density. [280] [281]

Obesity

Abnormal body composition is also reported in excess in survivors of pediatric ALL. One study evaluated obesity in 1,764 ALL survivors followed in the CCSS, and compared them with a cohort of 2,565 siblings. The odds ratio for being obese was 2.6 for female survivors and 1.9 for male survivors who received doses of radiation greater than 20 Gy. The highest risk was for females treated at age 4 years and younger with cranial radiation doses of greater than 20 Gy. Risk of obesity was not increased among ALL survivors treated with chemotherapy alone or with doses of cranial radiation of 10 Gy to 19 Gy. [282] Similar findings were reported in an updated report from the CCSS. [283] Genetic predisposition may be an important factor in risk for obesity in these ALL survivors. The CCSS has found higher BMI to be associated with a polymorphism in the leptin receptor gene. [284] Similar findings were reported by one group in which BMI Z-score, skinfold thickness, percent fat by dual energy x-ray absorptiometry (DEXA), and ratio of central to peripheral fat, were higher in girls treated for ALL compared with siblings or patients treated for other malignancies. [285] Another study found increased obesity in survivors of childhood ALL, with risk increased in younger children, those who were thinner at time of diagnosis, and those with premature adiposity rebound. [286] [287] A study from Denmark reports reduced lean body mass among survivors of childhood NHL and Hodgkin lymphoma. [288] Children treated for brain tumors are at risk for development of obesity because of hypothalamic dysfunction resulting from the tumor, surgery, or irradiation. [289]

A number of endocrinologic and metabolic findings, including increased BMI, can be summarized as the metabolic syndrome. This includes insulin resistance, hyperglycemia, hyperinsulinemia, hypertension, hyperlipidemia, and obesity. It is, at least in part, because of disturbances of the H-P axis, but more research is required to better understand all of the presentations of the syndrome, its incidence, and its prevalence in survivors of childhood cancer. [290] [291] [292]

Table 14. Musculoskeletal Late Effects^a

Reproductive System

Gonadal function

Alkylating agents are the chemotherapeutic agents most responsible for gonadal toxicity.

Male Gonadal Function

Spermatogenesis is highly sensitive to cyclophosphamide, with a dose-effect exhibited that is exacerbated by coadministration of other alkylating agents, such as procarbazine. [293] [294] [295] [296] [297] [298] [299] This is illustrated by a study in which long-term gonadal toxicity was compared among survivors of Hodgkin lymphoma and NHL. Both groups had received comparable median cumulative doses of cyclophosphamide, but only the patients with Hodgkin lymphoma received procarbazine. The incidence of gonadal toxicity was more than three times higher in the men in the Hodgkin lymphoma group. The only men in the NHL group who had elevation of FSH had received higher doses of cyclophosphamide than the mean. [300] With the common use of multiagent therapy that includes cyclophosphamide, sarcoma patients are also at increased risk of infertility, again with a dose-response effect. [116] [301] [302] While boys who are younger at the time of treatment experience less of an effect on germinal epithelium, prepubertal boys are not spared because there is less reserve of stem spermatogonia with higher proliferative potential. [294] Reduction of alkylating agent therapy in multiagent protocols has resulted in reduction in the risk for male infertility. [296] [297] [298] [303] [304] Review of the available studies has led to the consensus that males who receive less than 4 gram/m² of cyclophosphamide without any other alkylating agents and without either testicular or cranial radiation are likely to retain their fertility. Doses greater than 9 gram/m² are unlikely to result in any conservation of fertility.

Ifosfamide has been used as part of multimodality therapy for a variety of childhood cancers, often in combination with cyclophosphamide and/or abdominopelvic radiation therapy. Little is known about its long-term gonadal toxicity. A study was performed to evaluate fertility in 96 male patients treated with ifosfamide and no other alkylating agents for osteosarcoma. Eleven patients were prepubertal and 85 were postpubertal at the time of chemotherapy. Of the 96 patients, 26 underwent sperm analysis, and 20 showed oligospermia or azoospermia. Patients who received high-dose ifosfamide showed a higher incidence of azoospermia. Six patients were normospermic and had received either no ifosfamide or lower doses of ifosfamide. Eight patients fathered a total of 12 children. [305]

The degree and permanency of radiation therapy-induced damage to the male reproductive system are dose, field and schedule, and age dependent. The germinal epithelium is damaged by much lower doses (<1 Gy) of radiation therapy than are Leydig cells (20 Gy–30 Gy). [306] Although temporary oligospermia can occur after these very low radiation doses, permanent azoospermia results from higher doses of greater than 3 Gy to 4 Gy. The potential for a return of spermatogenesis in the intermediate dose range of 1 Gy to 3 Gy is variable. [307] [308] One study evaluated the effect of 12 Gy radiation to the abdomen on testicular function of long-term ALL survivors and found 55% to have evidence of germ cell dysfunction. [309] Scatter from abdominal radiation with doses greater than 20 Gy for Hodgkin disease can cause transient elevation in FSH and oligospermia but not with lower doses. [310]

Table 15. Male Gonadal Late Effects^a

Female Gonadal Function

Unlike the situation in males, hormonal function and potential for fertility are synchronous in females. Prepubertal females possess their lifetime supply of oocytes, with no new oogonia formed after birth. Risks of menstrual irregularity, ovarian failure, and infertility increase with age at treatment. [296] [306] [311] [312] [313] [314] Therefore, amenorrhea and premature ovarian failure occur more commonly in adult women treated with cyclophosphamide and other alkylating agents than in adolescents. Prepubertal females tolerate cumulative doses as high as 25 gram/m². [312] [315] Two large studies of survivors treated through the 1980s, however, have shown elevated RRs for infertility and early menopause in female survivors of childhood cancer. [316] [317] A study of 2,498 survivors and 3,509 siblings treated between 1945 and 1975, found a 7% fertility deficit among female survivors as compared with their siblings. Forty-two percent of those with alkylating agent exposure and abdominal radiation experienced menopause by age 31 years. [316] Another study of 719 survivors treated between 1964 and 1988 found a 15.5% failure to conceive. [317] Mechlorethamine and procarbazine together are perhaps the most damaging of the agents. Substitution of cyclophosphamide for mechlorethamine appears to have significantly reduced the risk of ovarian dysfunction, which is then further lessened by reduction in total dose of both agents. [318] More time is needed before the effect on premature menopause can be evaluated.

As with males, the effects of ifosfamide on reproductive function are only beginning to be evaluated. An Italian study compared the residual ovarian function and the fertility of two groups of female patients treated at different times at one institution by neoadjuvant chemotherapy for osteosarcoma. From 1997 to 2000, one group of 31 females received chemotherapy that included high-dose ifosfamide, high-dose methotrexate, doxorubicin, and cisplatin. In this group of patients, an oral contraceptive (OC) was given in an attempt to prevent postchemotherapy ovarian failure. Another group of 90 patients was treated between 1974 and 1995 with the same drugs without OC or other treatment to protect ovarian function. Early chemotherapy-induced menopause occurred in 3 of 19 postpubertal patients who received the OC and in 3 of 71 postpubertal patients in the control group. [319]

The ovary is sensitive to the effects of ionizing radiation. Adverse ovarian effects vary depending on factors such as dose, schedule, and age. The younger the child, the larger the oocyte pool, and the later the menopause. [306] While radiation doses greater than 8 Gy are associated with ovarian ablation, lower doses may not cause infertility. [307] [308] Younger girls are more resistant than adolescents. Whole abdomen doses of 20 Gy to 30 Gy are associated with primary or premature secondary ovarian failure. [316] [320] Abdominal radiation therapy at similar doses can lead to reduced uterine volume and decreased elasticity, increasing risk of spontaneous miscarriage, premature birth, and intrauterine growth retardation. [321]

Table 16. Female Gonadal Late Effects^a

Reproduction

With more childhood cancer survivors retaining their fertility, pregnancy outcome data are now available. In a study of 4,029 pregnancies among 1,915 women followed in the CCSS, there were 63% live births, 1% stillbirths, 15% miscarriages, 17% abortions, and 3% unknown or in gestation. Risk of miscarriage was 3.6-fold higher in women treated with craniospinal radiation and 1.7-fold higher in those treated with pelvic radiation. Chemotherapy exposure alone did not increase risk of miscarriage. Compared with siblings, survivors were less likely to have live births, more likely to have medical abortions, and more likely to have low-birth-weight babies. [322] In the same cohort, another study evaluated pregnancy outcomes of partners of male survivors. Among 4,106 sexually active males, 1,227 reported they sired 2,323 pregnancies, which resulted in 69% live births, 13% miscarriages, 13% abortions, and 5% unknown or in gestation at the time of analysis. Compared with partners of male siblings, there was decreased risk of live births (RR = 0.77), but no significant differences of pregnancy outcome by treatment. [323] In the NWTS, records were obtained for 427 pregnancies of more than 20-weeks duration. In this group, there were 409 single and 12 twin live births. Early or threatened labor, malposition of the fetus, lower birth weight (<2,500 g), and premature delivery (<36 weeks) were more frequent among women who had received flank radiation, in a dose-dependent manner. Congenital anomalies in the offspring were also more common in this group. [324] Results from a Denmark study confirm the association of uterine radiation with spontaneous but not other types of abortion. Thirty-four thousand pregnancies were evaluated in a population of 1,688 female survivors of childhood cancer in the Danish Cancer Registry. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in the population were identified. No significant differences were seen between survivors and comparison women in the proportions of livebirths, stillbirths, or all types of abortions combined. Survivors with a history of neuroendocrine or abdominal radiation therapy had an increased risk of spontaneous abortion. Thus the pregnancy outcomes of survivors were similar to those of comparison women with the exception of spontaneous abortion. [325]

Preservation of fertility and successful pregnancies may occur after HSCT, though the conditioning regimens that include TBI, cyclophosphamide, and busulfan are highly gonadal-toxic. In a group of 21 females who had received a BMT in the prepubertal years, 12 (57%) were found to have ovarian failure when examined between ages 11 and 21 years, and the association with busulfan was significant. [326] One study evaluated pregnancy outcomes in a group of females treated with BMT. Among 708 women who were postpubertal at the time of transplant, 116 regained normal ovarian function and 32 became pregnant. Among 82 women who were prepubertal at the time of transplant, 23 had normal ovarian function and nine became pregnant. Of the 72 pregnancies in these 41 women, 16 occurred in those treated with TBI and 50% resulted in early termination. Among the 56 pregnancies in women treated with cyclophosphamide without either TBI or busulfan, 21% resulted in early termination. There were no pregnancies among the 73 women treated with busulfan and cyclophosphamide, and only one retained ovarian function. [327]

Progress in reproductive endocrinology has resulted in the availability of several options for preserving or permitting fertility in patients about to receive potentially toxic chemotherapy or radiation therapy. [306] [311] For males, cryopreservation of spermatozoa before treatment is an effective method to circumvent the sterilizing effect of therapy. Although pretreatment semen quality in patients with cancer has been shown to be less than that noted in healthy donors, the percentage decline in semen quality and the effect of cryodamage to spermatozoa from patients with cancer is similar to that of normal donors. [328] [329] [330] [331] For those unable to bank sperm, newer technologies such as testis sperm extraction may be an option, as demonstrated for male survivors of germ cell tumors who had postchemotherapy nonobstructive azoospermia. [332] Further micromanipulative technologic advances such as intracytoplasmic sperm injection and similar techniques may be able to render sperm extracted surgically, or even poor-quality cryopreserved spermatozoa from cancer patients, capable of successful fertilization. [332] [333] In prepubertal and postpubertal females, cryopreservation of ovarian cortical tissue or enzymatically extracted follicles and the in vitro maturation of prenatal follicles are of potential clinical use. To date, most of this technology has been performed in laboratory animals. [334] [335] [336] Another option available to the postpubertal female is the stimulation of ovaries with exogenous gonadotropins and retrieval of mature oocytes for cryopreservation. However, only a few oocytes can be harvested after stimulation of the ovaries. [335] In vitro fertilization and subsequent embryo cryopreservation have also been successful. These options may not be readily available to the pediatric and adolescent patient, and the necessary delay in cancer therapy for ovarian stimulation or in vitro fertilization cycles renders these interventions often impractical. [336] Furthermore, all these approaches harbor the risk that malignant cells will be present in the specimen and reintroduced in the patient at a later date. Those with hematologic or gonadal tumors would be at greatest risk for this eventuality. [335] [336]

For childhood cancer survivors who have offspring, there is concern about congenital anomalies, genetic disease, or risk of cancer in the offspring. In the report from the National Wilms Tumor Group, congenital anomalies were marginally increased in offspring of females who had received flank radiation therapy. [324] In a report of 2,198 offspring of adult survivors treated for childhood cancer between 1945 and 1975 compared with 4,544 offspring of sibling controls, there were no differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations. There was similarly no effect of type of childhood cancer treatment on the occurrence of genetic disease in the offspring. A population-based study of 2,630 live-born offspring of childhood cancer survivors versus 5,504 live-born offspring of the survivors' siblings found no differences in proportion of abnormal karyotypes or incidence of Down syndrome or Turner syndrome between survivor and sibling offspring. [337] Survivors treated with abdominal radiation therapy and/or alkylating agents did not have an increased risk of offspring with genetic disease, compared with survivors not exposed to these agents. [338] Similar results were reported in a single-institution study of 247 offspring of 148 cancer survivors. [339]

With increased use of assisted fertility techniques in survivors of childhood cancer, the risk of congenital anomalies will need to be followed closely in light of reports of increased anomalies in offspring born by in vitro fertilization or intracytoplasmic sperm injection. [340] [341] [342] [343] [344]

In a study of 5,847 offspring of survivors of childhood cancers treated in five Scandinavian countries, in the absence of a hereditary cancer syndrome (such as hereditary retinoblastoma), there was no increased risk of cancer. [345] Preliminary data from the CCSS indicate that risk for cancer in offspring was not significantly elevated (standardized incidence ratio [SIR] = 1.67; 95% CI, 0.80–3.50), but this was based on a small number of offspring (n = 11). Among survivors who themselves had second or subsequent malignant neoplasms (SMNs), however, the risk of cancer in offspring was significantly elevated (SIR = 15.08; 95% CI, 5.29–43.02 and much higher than for offspring of CCSS non-SMN cases (SIR = 1.0; 95% CI, 0.38–2.67) (P <.001). [346] Further follow-up of offspring is required to see if patterns of cancer in offspring change over time. For more information about sexuality and reproductive issues and cancer patients, please see the PDQ Sexuality and Reproductive Issues summary.

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Second Malignant Neoplasms

Several large studies have examined the incidence and spectrum of second malignant neoplasms (SMNs) in childhood cancer survivors, in whom the cumulative risk at 20 years posttreatment varies from 3% to 10% and is three to 20 times greater than that expected in the general population. The magnitude of risk and the type of second cancers substantially differ according to the primary malignancy; the type, dose, and combinations of therapy received; and the presence of genetic predispositions. [1] A number of treatment-related risk factors have been identified. Notably, radiation therapy is associated with the development of solid tumors as well as leukemia. This risk appears to be highest when exposure occurs at a young age, and increases with total dose of radiation and time interval following irradiation for solid tumors. [1] [2] [3] Alkylating agents, platinums, and topoisomerase II inhibitors are associated with the development of leukemia. [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Epipodophyllotoxins are known to increase the risk for secondary leukemia, and anthracyclines may also increase this risk after treatment for solid tumors. [14] The more commonly reported second cancers in childhood cancer survivors are breast, thyroid and bone cancers, and therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML). T-MDS/AML has been associated with specific chemotherapeutic agents, such as alkylating agents and topoisomerase II inhibitors. [3] [6] A dose-dependent relationship is noted with alkylating agents, which typically cause t-MDS/AML after latencies of 5 to 10 years. Cytogenetic abnormalities in the alkylating agent-associated t-MDS/AML characteristically involve chromosomes 5 or 7. T-MDS/AML associated with exposure to topoisomerase II inhibitors classically has a shorter latency, no preceding dysplastic phase, and cytogenetic abnormalities involving chromosome 11q23. While the risk of solid tumors continues to climb with increasing follow-up, the risk for t-MDS/AML plateaus after 5 to 10 years. [14]

In an analysis of SMN in the Childhood Cancer Survival Study (CCSS), which excluded patients with retinoblastoma, the standardized incidence ratio (SIR) was 6.4, with a 20-year incidence of 3.2% and an absolute excess risk of 1.88 malignancies per 1,000 years of patient follow-up. Risk of SMN was elevated for all primary childhood cancer diagnoses, with the lowest SIR reported for non-Hodgkin lymphoma (3.2) and the highest for Hodgkin lymphoma (9.7). Risk was elevated for secondary leukemia, lymphoma, central nervous system tumors, soft tissue and bone sarcomas, melanoma, and breast and thyroid cancer, with the lowest SIR reported for lymphoma (1.5) and the higher SIRs reported for breast cancer (16.2) and bone sarcoma (19.1). In multivariate analyses adjusted for radiation exposures, SMNs were independently associated with female sex, younger age at diagnosis of childhood cancer, childhood cancer diagnosis of Hodgkin lymphoma, or soft tissue sarcoma and exposure to alkylating agents. [2] The CCSS has also reported an association between gene polymorphisms in glutathione-S-transferase M1 (GSTM1), glutathione-S-transferase T1 (GSTT1), and XRCC1, and susceptibility to radiation therapy-related SMNs in childhood Hodgkin lymphoma survivors. [15] The risk of leukemia appears to plateau at 10 to 15 years posttherapy, while the risk of second solid malignancies rises with ongoing follow-up, with a lifetime risk still unknown. [2] [3] [12] The complexity of risk factors associated with secondary malignancies is illustrated by a recent report on secondary sarcomas in childhood cancer survivors, in whom risk was increased by radiation therapy, higher doses of anthracyclines or alkylating agents, a history of other secondary neoplasms, and a primary diagnosis of sarcoma. [16]

Several studies have examined the risk of SMNs in survivors of Hodgkin lymphoma, in whom the incidence of secondary breast and thyroid cancer is particularly high. [17] Survivors of Hodgkin lymphoma are also at increased risk of second leukemia, sarcoma, melanoma, and lung, thyroid, and gastrointestinal cancer. Female patients treated with mantle radiation for Hodgkin lymphoma before age 30 years are at a significantly higher risk of developing radiation-related breast cancer, in comparison with those treated in their adult years. Female survivors of Hodgkin lymphoma may also be an increased risk for non-breast secondary malignancies. [1] [18] Although these data suggest an increased risk in female survivors, even after accounting for breast cancer, other studies exist that do not demonstrate this association. This variation in data illustrates the complexities of analysis that relate to population selection and differences in therapy administered. While the gender effect is not consistent among studies, diagnosis at younger age and therapy for relapsed disease are uniformly associated with increased risk. [2] [3] [4] [5] [8] [9] [12] [19] [20] [21] [22]

Several studies have reported an association between the treatment of neuroblastoma and the development of SMNs. Survivors of neuroblastoma treated with alkylating agents, topoisomerase II inhibitors, (131)I-metaiodobenzylguanidine [(131)I-MIBG], platinums, and/or radiation have an increased risk of developing secondary leukemias, bone marrow disorders (e.g., myelodysplastic syndrome), as well as some solid tumors (e.g., breast cancer and thyroid cancer). [2] [23] [24] [25] [26] [27] Patients who undergo bone marrow transplantation have a risk of developing SMNs, especially solid tumors. This increased risk has been observed even 20 years posttransplant. [28]

Until more is learned about the pathophysiology of SMNs and the interindividual variation in susceptibility, targeted preventive strategies are limited. For the future, children who received radiation or chemotherapeutic agents with known carcinogenic effects should be so informed and should be seen regularly by a health care provider who is familiar with their treatment and risks and who can evaluate early signs and symptoms appropriately.

Genetic Predisposition to Cancer

Patients may be at risk of SMNs by virtue of a cancer predisposition syndrome, which also placed them at risk for their primary cancer. This limited population should be targeted for education, counseling, and extraordinary surveillance because of their genetic predisposition to cancer. [29] This includes children with the genetic form of retinoblastoma. In these individuals, the SMN risk approaches 50% at 50 years from treatment if they received external-beam radiation therapy, and 25% at 50 years from treatment without previous radiation therapy treatment. [30] [31] Data from the Netherlands demonstrate the spectrum of second malignancies that can occur in this setting, notably epithelial cancers (lung, bladder, and breast) in addition to the known occurrence of sarcomas. In this report, the cumulative incidence of any second malignancy 40 years after treatment for retinoblastoma approached 30%. [32] Neurofibromatosis also increases the risk of additional neoplasms, some not associated with therapy. [33] [34] Breast cancer at an early age, sarcoma, and other cancers can be expected in children with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome. [35] [36] Since hepatoblastoma and fibromas have been associated with familial polyposis coli, children with those tumors should be examined for the polyposis gene (APC) and screened for colon cancer, as appropriate. [37] [38]

Full understanding of the pathogenesis of SMNs requires further study of the additive risks or protective effects in treated patients conferred by environmental exposures, dietary influences, and viral exposures. Genetic studies, including the investigation of polymorphisms in genes encoding for xenobiotic metabolizing and DNA-repair enzymes, may provide valuable information on genotype-environment interactions and interindividual susceptibility. Children’s Oncology Group studies of Hodgkin disease are addressing such issues. [39]

References:

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2. Neglia JP, Friedman DL, Yasui Y, et al.: Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst 93 (8): 618-29, 2001.
3. Bhatia S, Robison LL, Oberlin O, et al.: Breast cancer and other second neoplasms after childhood Hodgkin's disease. N Engl J Med 334 (12): 745-51, 1996.
4. Mauch PM, Kalish LA, Marcus KC, et al.: Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin's disease: long-term analysis of risk factors and outcome. Blood 87 (9): 3625-32, 1996.
5. Metayer C, Lynch CF, Clarke EA, et al.: Second cancers among long-term survivors of Hodgkin's disease diagnosed in childhood and adolescence. J Clin Oncol 18 (12): 2435-43, 2000.
6. Breslow NE, Takashima JR, Whitton JA, et al.: Second malignant neoplasms following treatment for Wilm's tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 13 (8): 1851-9, 1995.
7. Paulussen M, Ahrens S, Lehnert M, et al.: Second malignancies after Ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study. Ann Oncol 12 (11): 1619-30, 2001.
8. Sankila R, Garwicz S, Olsen JH, et al.: Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: a population-based cohort study in the five Nordic countries. Association of the Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and Oncology. J Clin Oncol 14 (5): 1442-6, 1996.
9. Swerdlow AJ, Barber JA, Hudson GV, et al.: Risk of second malignancy after Hodgkin's disease in a collaborative British cohort: the relation to age at treatment. J Clin Oncol 18 (3): 498-509, 2000.
10. Smith MA, Rubinstein L, Anderson JR, et al.: Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17 (2): 569-77, 1999.
11. Inskip PD: Thyroid cancer after radiotherapy for childhood cancer. Med Pediatr Oncol 36 (5): 568-73, 2001.
12. Wolden SL, Lamborn KR, Cleary SF, et al.: Second cancers following pediatric Hodgkin's disease. J Clin Oncol 16 (2): 536-44, 1998.
13. Travis LB, Holowaty EJ, Bergfeldt K, et al.: Risk of leukemia after platinum-based chemotherapy for ovarian cancer. N Engl J Med 340 (5): 351-7, 1999.
14. Le Deley MC, Leblanc T, Shamsaldin A, et al.: Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Société Française d'Oncologie Pédiatrique. J Clin Oncol 21 (6): 1074-81, 2003.
15. Mertens AC, Mitby PA, Radloff G, et al.: XRCC1 and glutathione-S-transferase gene polymorphisms and susceptibility to radiotherapy-related malignancies in survivors of Hodgkin disease. Cancer 101 (6): 1463-72, 2004.
16. Henderson TO, Whitton J, Stovall M, et al.: Secondary sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 99 (4): 300-8, 2007.
17. Sigurdson AJ, Ronckers CM, Mertens AC, et al.: Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study. Lancet 365 (9476): 2014-23, 2005 Jun 11-17.
18. Constine LS, Tarbell N, Hudson MM, et al.: Subsequent malignancies in children treated for Hodgkin's disease: associations with gender and radiation dose. Int J Radiat Oncol Biol Phys 72 (1): 24-33, 2008.
19. Green DM, Hyland A, Barcos MP, et al.: Second malignant neoplasms after treatment for Hodgkin's disease in childhood or adolescence. J Clin Oncol 18 (7): 1492-9, 2000.
20. Bhatia S, Ramsay NK, Steinbuch M, et al.: Malignant neoplasms following bone marrow transplantation. Blood 87 (9): 3633-9, 1996.
21. van Leeuwen FE, Klokman WJ, Veer MB, et al.: Long-term risk of second malignancy in survivors of Hodgkin's disease treated during adolescence or young adulthood. J Clin Oncol 18 (3): 487-97, 2000.
22. Acharya S, Sarafoglou K, LaQuaglia M, et al.: Thyroid neoplasms after therapeutic radiation for malignancies during childhood or adolescence. Cancer 97 (10): 2397-403, 2003.
23. Garaventa A, Gambini C, Villavecchia G, et al.: Second malignancies in children with neuroblastoma after combined treatment with 131I-metaiodobenzylguanidine. Cancer 97 (5): 1332-8, 2003.
24. Kushner BH, Cheung NK, Kramer K, et al.: Neuroblastoma and treatment-related myelodysplasia/leukemia: the Memorial Sloan-Kettering experience and a literature review. J Clin Oncol 16 (12): 3880-9, 1998.
25. Kushner BH, Kramer K, LaQuaglia MP, et al.: Reduction from seven to five cycles of intensive induction chemotherapy in children with high-risk neuroblastoma. J Clin Oncol 22 (24): 4888-92, 2004.
26. Rubino C, Adjadj E, Guérin S, et al.: Long-term risk of second malignant neoplasms after neuroblastoma in childhood: role of treatment. Int J Cancer 107 (5): 791-6, 2003.
27. Weiss B, Vora A, Huberty J, et al.: Secondary myelodysplastic syndrome and leukemia following 131I-metaiodobenzylguanidine therapy for relapsed neuroblastoma. J Pediatr Hematol Oncol 25 (7): 543-7, 2003.
28. Baker KS, DeFor TE, Burns LJ, et al.: New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol 21 (7): 1352-8, 2003.
29. Friedman DL, Meadows AT: Pediatric tumors. In: Neugut AI, Meadows AT, Robinson E, eds.: Multiple Primary Cancers. Philadelphia, Pa.: Lippincott Williams & Wilkins, 1999, pp 235-56.
30. Wong FL, Boice JD Jr, Abramson DH, et al.: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 278 (15): 1262-7, 1997.
31. Kleinerman RA, Tucker MA, Tarone RE, et al.: Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol 23 (10): 2272-9, 2005.
32. Marees T, Moll AC, Imhof SM, et al.: Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up. J Natl Cancer Inst 100 (24): 1771-9, 2008.
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Screening

Since second cancers remain a significant threat to the health of childhood cancer survivors, vigilant screening is important for those at risk. Risk for therapy-related myelodysplasia and acute myeloid leukemia usually manifests within 10 years following exposure. Most other second cancers are associated with radiation exposure. Screening recommendations include careful annual physical examination of the skin and soft tissues in the radiation field with radiographic or other cancer screening evaluations as indicated. Since outcome after breast cancer is closely linked to stage at diagnosis, close surveillance resulting in early diagnosis should confer survival advantage. [1] Mammography, the most widely accepted screening tool for breast cancer in the general population, may not be the ideal screening tool in isolation for radiation-related breast cancers occurring in relatively young women with dense breasts, hence the recommendations by the American Cancer Society to use adjunct screening with magnetic resonance imaging (MRI). [2] Thus, specialized considerations for females who received radiation with potential impact to the breast (i.e., radiation doses of 20 Gy or higher to the mantle, mediastinal, whole lung, and axillary fields) include monthly breast self-examination beginning at puberty, annual clinical breast examinations beginning at puberty until age 25 years, and then a clinical breast examination every 6 months, with annual mammograms and MRIs beginning 8 years after radiation, or at age 25 years (whichever occurs later). [3]

References:

1. Diller L, Medeiros Nancarrow C, Shaffer K, et al.: Breast cancer screening in women previously treated for Hodgkin's disease: a prospective cohort study. J Clin Oncol 20 (8): 2085-91, 2002.
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3. Bhatia S, Constine LS: Late morbidity after successful treatment of children with cancer. Cancer J 15 (3): 174-80, 2009 May-Jun.

Mortality

Two studies of very large cohorts of survivors have reported more premature mortality compared with the general population. The most common causes of death were relapse of the primary cancer, second malignancy, and cardiac toxicity. [1] [2] Despite high premature morbidity rates, overall mortality has decreased over time. This reduction is related to a decrease in deaths from the primary cancer without an associated increase in mortality from second cancers or treatment-related toxicities. The former reflects improvements in therapeutic efficacy, and the latter reflects changes in therapy made subsequent to studying the causes of late effects. The expectation that mortality rates in survivors will continue to exceed those in the general population is based on the long-term sequelae that are likely to increase with attained age. If patients treated on therapeutic protocols are followed for long periods into adulthood, it will be possible to evaluate the excess lifetime mortality in relation to specific therapeutic interventions.

References:

1. Mertens AC, Yasui Y, Neglia JP, et al.: Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 19 (13): 3163-72, 2001.
2. Möller TR, Garwicz S, Barlow L, et al.: Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: a population-based study in the Nordic countries. J Clin Oncol 19 (13): 3173-81, 2001.

Monitoring for Late Effects

The need for long-term follow-up for childhood cancer survivors is supported by the American Society of Pediatric Hematology/Oncology, the International Society of Pediatric Oncology, and the American Academy of Pediatrics. Survivors should seek care from professionals with expertise in the recognition and management of late effects. [1] [2] [3] [4] [5] Comprehensive monitoring guidelines for late effects have been developed within the Children’s Oncology Group. [6]

As the number of survivors of childhood cancer is expected to increase, there is some urgency in determining where long-term follow-up should take place. [7] It will be difficult for the usual pediatric oncology clinical services to accommodate the demands of the ever-enlarging population of survivors. Transition of care from the pediatric to the adult health care setting is necessary for most childhood cancer survivors. The most important requirement in providing transition services is the coordination between primary and subspecialty, pediatric, and adult health care providers as well as between the family, healthcare, educational, vocational, and social service systems. [3] [8] [9]

Health-promoting behaviors should be stressed for survivors of childhood cancer, and targeted educational efforts are worthwhile. [10] Smoking, excess alcohol use, and illicit drug use increase risk of organ toxicity and, potentially, second malignant neoplasms. The impact of health behaviors on adverse health-related outcomes has not been well studied in childhood cancer survivors.

Part of long-term follow-up should also be focused on appropriate screening for educational and vocational services. A report from the Childhood Cancer Survivor Study demonstrated that childhood cancer survivors are more likely to require special education services (23%) than their siblings (8%), with survivors of central nervous system (CNS) tumors, leukemia, and Hodgkin disease at greatest risk. Similarly, survivors of CNS tumors, leukemia, neuroblastoma, and non-Hodgkin lymphoma were less likely than their siblings to complete high school or college. [11] Among adult survivors, 5.2% had never been employed, compared with 1.4% of the siblings (overall risk [OR] = 3.36). Risk was elevated for all childhood cancer diagnoses except Wilms tumor. In survivors of CNS tumors, in whom the risk was highest for unemployment, the OR was 9.10, (95% confidence interval [CI], 6.32–13.11). Compared with survivors of non-CNS tumors who received no or low doses (<30 Gy) of cranial radiation, the risk of never having been employed was 5.4 times greater among survivors of CNS tumors who had been treated with greater than 30 Gy of cranial radiation therapy (95% CI, 4.18–6.97). The risk was similarly increased for those who were treated with greater than 30 Gy of cranial radiation therapy for non-CNS tumors (OR = 4.70; 95% CI, 3.11–6.94), and to a lesser extent for survivors of CNS tumors who received less than 30 Gy of cranial radiation therapy (OR = 2.14; 95% CI, 1.36–3.24). [12]

Lack of health insurance remains a significant issue for survivors of childhood cancer because of health issues, unemployment, and other societal issues. Such issues may negatively affect health-related outcomes because appropriate screening for long-term morbidity cannot be appropriately performed. [13] [14] [15] [16] [17]

References:

1. Arceci RJ, Reaman GH, Cohen AR, et al.: Position statement for the need to define pediatric hematology/oncology programs: a model of subspecialty care for chronic childhood diseases. Health Care Policy and Public Issues Committee of the American Society of Pediatric Hematology/Oncology. J Pediatr Hematol Oncol 20 (2): 98-103, 1998 Mar-Apr.
2. Masera G, Chesler MA, Jankovic M, et al.: SIOP Working Committee on psychosocial issues in pediatric oncology: guidelines for communication of the diagnosis. Med Pediatr Oncol 28 (5): 382-5, 1997.
3. Harvey J, Hobbie WL, Shaw S, et al.: Providing quality care in childhood cancer survivorship: learning from the past, looking to the future. J Pediatr Oncol Nurs 16 (3): 117-25, 1999.
4. Meadows AT, Varricchio C, Crosson K, et al.: Research issues in cancer survivorship: report of a workshop sponsored by the Office of Cancer Survivorship, National Cancer Institute. Cancer Epidemiol Biomarkers Prev 7 (12): 1145-51, 1998.
5. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.
6. Children's Oncology Group.: Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. Version 1.2, March 2004. Available online. Last accessed April 19, 2007.
7. Goldsby RE, Ablin AR: Surviving childhood cancer; now what? Controversies regarding long-term follow-up. Pediatr Blood Cancer 43 (3): 211-4, 2004.
8. Hobbie WL, Hollen PJ: Pediatric nurse practitioners specializing with survivors of childhood cancer. J Pediatr Health Care 7 (1): 24-30, 1993 Jan-Feb.
9. Blum RW: Transition to adult health care: setting the stage. J Adolesc Health 17 (1): 3-5, 1995.
10. Hudson MM, Tyc VL, Jayawardene DA, et al.: Feasibility of implementing health promotion interventions to improve health-related quality of life. Int J Cancer Suppl 12: 138-42, 1999.
11. Mitby PA, Robison LL, Whitton JA, et al.: Utilization of special education services and educational attainment among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 97 (4): 1115-26, 2003.
12. Pang JW, Friedman DL, Whitton JA, et al.: Employment status of adult survivors of pediatric cancers: a report from the Childhood Cancer Survivor Study (CCSS). [Abstract] 7th International Conference on Long-term Complications of Treatment of Children and Adolescents for Cancer, June 28-29, 2002, Niagara-on-the-Lake, Canada A-8, 19-20, 2002.
13. Leung W, Hudson MM, Strickland DK, et al.: Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 18 (18): 3273-9, 2000.
14. Hays DM: Adult survivors of childhood cancer. Employment and insurance issues in different age groups. Cancer 71 (10 Suppl): 3306-9, 1993.
15. Monaco GP, Fiduccia D, Smith G: Legal and societal issues facing survivors of childhood cancer. Pediatr Clin North Am 44 (4): 1043-58, 1997.
16. Richardson RC, Nelson MB, Meeske K: Young adult survivors of childhood cancer: attending to emerging medical and psychosocial needs. J Pediatr Oncol Nurs 16 (3): 136-44, 1999.
17. Vann JC, Biddle AK, Daeschner CW, et al.: Health insurance access to young adult survivors of childhood cancer in North Carolina. Med Pediatr Oncol 25 (5): 389-95, 1995.

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Changes to This Summary (11/05/2009)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Common Late Effects of Childhood Cancer by Body System

Added text to state that patients who have received IT chemotherapy without cranial radiation as CNS therapy appear to have a low incidence of neurocognitive sequelae (cited Jansen et al., Espy et al., Copeland et al., von der Weid et al., Waber et al., and Kadan-Lottick et al., as references 34, 35, 36, 37, 38, and 39, respectively).

Added Armenian et al. as reference 132.

Added Mattano et al. as reference 259.

Added Kaste et al. as reference 272.

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