General Information
Common Late Effects of Childhood Cancer by Body System

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

Second Malignant Neoplasms
Mortality
Monitoring for Late Effects
Changes to This Summary (07/22/04)
More Information

General Information

During the past 3 decades, multimodality therapy for childhood cancer has resulted in markedly improved survival. For the period 1985-1997, the 5-year survival rate for childhood cancer reported by the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) 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.” Late effects include organ dysfunction, second malignant neoplasms, and adverse psychosocial sequelae.

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 radiotherapy or chemotherapy
  • Premorbid state

Several comprehensive reviews and books that address late effects of childhood cancer and its therapy have been published.[2-8] This summary will discuss some of these late effects in detail by organ system and will address issues of second malignant neoplasms, mortality, and monitoring.

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 other reviews, with author permission.[5]

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. ¹ Last accessed March 5, 2004. 
   
   
2. Marina N: Long-term survivors of childhood cancer. The medical consequences of cure. Pediatr Clin North Am 44 (4): 1021-42, 1997.  [PUBMED Abstract]
   
   
3. Meister LA, Meadows AT: Late effects of childhood cancer therapy. Curr Probl Pediatr 23 (3): 102-31, 1993.  [PUBMED Abstract]
   
   
4. Schwartz CL: Long-term survivors of childhood cancer: the late effects of therapy. Oncologist 4 (1): 45-54, 1999.  [PUBMED Abstract]
   
   
5. Schwartz C L, Hobbie WL, Constine LS, et al., eds.: Survivors of Childhood Cancer: Assessment and Management. St. Louis, Mo: Mosby, 1994. 
   
   
6. 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. 
   
   
7. Green DM, D'Angio GJ, eds.: Late Effects of Treatment for Childhood Cancer. New York, NY: Wiley-Liss, Inc., 1992. 
   
   
8. Friedman DL, Meadows AT: Late effects of childhood cancer therapy. Pediatr Clin North Am 49 (5): 1083-106, x, 2002.  [PUBMED Abstract]
   
   

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 chemotherapy; thus, children with CNS tumors, head and neck sarcomas, and acute lymphoblastic leukemia (ALL) are most commonly affected. Deficits occur in a variety of areas that include the following:[1-6]

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

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

Some studies of children treated with cranial or craniospinal radiation therapy for CNS tumors demonstrated a significant adverse neurocognitive effect of therapy.[4] Other studies using lower doses and more targeted volumes have demonstrated improved results, however.[12-14] One study supports the hypothesis that medulloblastoma patients demonstrate a decline in intelligence quotient (IQ) values because of an inability to acquire new skills and information at a rate comparable to their healthy same-age peers, not because of a loss of previously acquired information and skills.[15] In a Danish study of 133 children treated for brain tumors, younger age at diagnosis, tumor site in the cerebral hemisphere, hydrocephalus treatment with shunt, and radiation therapy were predictors of lower cognitive functions.[16] Another study evaluated quantitative tissue volumes from magnetic resonance imaging scans, correlating these results with neurocognitive assessments for 40 long-term survivors of pediatric brain tumors treated with radiation therapy (RT) 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 RT and time from RT, significant associations were found between normal-appearing white matter (NAWM) volumes and both attentional abilities and IQ, and between attentional abilities and IQ. These associations were also correlated with deficiencies in academic skills such as reading, spelling, and math.[17]

For ALL, studies again show significant neurocognitive impairment.[18] Even when combined with intrathecal chemotherapy, reduction in the cranial radiation dose has resulted in less neurocognitive impairment.[11,19-22]

The effects of radiation on the brain are difficult to define, especially when cranial radiation is a part of multimodality therapy that may also include surgery, systemic chemotherapy, or intrathecal chemotherapy. Moreover, tumor-related deficits due to direct invasion of the brain, seizures, and hydrocephalus must be recognized. Studies on CNS prophylaxis for ALL comparing craniospinal radiotherapy with cranial radiotherapy combined with intrathecal methotrexate (MTX) showed that children who were younger than 5 years at time of treatment and had received radiotherapy and intrathecal chemotherapy had lower IQ scores than those who received craniospinal radiotherapy alone.[23] Similarly, another study found a significant IQ deficit in children treated with 24 Gy of cranial radiation combined with intrathecal MTX, as compared with childhood cancer survivors who received no CNS-directed therapy, with the effect greatest among those younger than 5 years.[18] A similar effect on cognition with the addition of intrathecal methotrexate has been found in children treated for medulloblastoma.[24]

Systemic MTX in high doses and combined with radiotherapy can lead to a well-described leukoencephalopathy, where severe neurocognitive deficits are obvious.[2,25,26] Due to its penetrance into the CNS, systemic MTX has been used in a variety of low-dose and high-dose regimens for leukemia CNS prophylaxis. The deleterious effects of systemic MTX, especially at doses above 1 g/m² may be no different or worse than those of 18 Gy of cranial radiotherapy.[27,28] At lower MTX doses, there does not appear to be a consistent pattern of neurocognitive deficits.[29] One long-term study of infants who received high-dose systemic MTX combined with intrathecal cytarabine and MTX for CNS leukemia prophylaxis and who were tested 3 to 9 years posttreatment showed that cognitive function was in the average range.[30]

Chemotherapy alone for ALL may result in cognitive dysfunction. One study examined 48 children treated for leukemia without cranial radiotherapy and found impairment in tasks of higher-order cognitive functioning and learning disabilities in the area of mathematics.[27] Another study showed that children, particularly females, treated with systemic and intrathecal MTX for CNS leukemia prophylaxis showed impairment of verbal memory and coding.[21] One other study reported mild visual and verbal short-term memory deficits in leukemia survivors treated with intrathecal chemotherapy.[31] Another study examined 20 patients treated for leukemia without cranial radiotherapy and found no significant neurocognitive deficits, even when patients were exposed to either intrathecal or high-dose intravenous MTX.[20] More recently, the substitution of dexamethasone for prednisone in the treatment of ALL has been implicated in increasing cognitive dysfunction.[22,30] Treatment intensity and duration can also adversely affect cognitive performance, due to absences from school and interruption of studies.[32]

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, where rates of psychological maladjustment range from 25% to 93%.[34]

Studies in the early 1990s described childhood cancer survivors as generally well adjusted, although a subset had psychological difficulties that resulted in functional impairment.[35-37] 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 which include the following:[38]

• 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.[39-44] 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.[39] In several studies performed by the same group of investigators, 9% to 10% of parents of childhood cancer survivors met the criteria for PTSD.[43,45]

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 1 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.[46]

Hearing loss is a common late effect of survivors of CNS cancers and cancers of the head and neck who received high doses of radiotherapy and platinum chemotherapy. Hearing loss in the speech range (0.5 to 3 kHz), which may compromise language reception and expression, is reported with cumulative doses of cisplatin >360mg/m², and 25% prevalence of hearing loss is reported with doses >720 mg/m². Fifty percent of children treated with cisplatin doses >450 mg/m² have sensorineural hearing loss (SNHL) in the high frequencies (6 to 8 kHz). Younger age at time of administration increases risk.[47-51] 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.[47] 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 600mg/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, where 40% of patients developed hearing loss following a dose of 1,500 mg/m².[52] Radiotherapy 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.[50,53-55] Cisplatin, at doses as low as 270 mg/m², can result in hearing loss when combined with cranial radiotherapy doses of 40 Gy to 50 Gy.[50,51] The sequence of chemoradiotherapy appears to influence risk. Risk and severity of ototoxicity are greater when cisplatin is administered after cranial radiation.[48]

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 radiotherapy. Age younger than 1 year may increase risk, but this is not consistent across studies.[56,57] Better management of prosthetic implants and newer methods of delivering radiotherapy are likely to reduce risk.[56,58] 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.[58-63]

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 (RT) 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 >2 Gy.[64] Cataracts are reported following lower doses of 10 Gy to 18 Gy.[50,55,65-68]

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.[69-74]

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’s 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.[75] More than 85% of survivors of head and neck rhabdomyosarcoma who receive radiation doses >40 Gy may have significant dental abnormalities, including mandibular or maxillary hypoplasia, increased caries, hypodontia, microdontia, root stunting, and xerostomia.[55,66] Chemotherapy for the treatment of leukemia can cause shortening and thinning of the premolar roots as well as enamel abnormalities.[76-78] TBI can cause short, V-shaped roots, microdontia, enamel hypoplasia, and premature apical closure.[79,80] 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.[81]

Salivary gland irradiation incidental to treatment of head and neck malignancies or Hodgkin’s lymphoma causes a qualitative and quantitative change in salivary flow, which can be reversible after doses of <40 Gy but may be irreversible after higher doses, depending on whether sensitizing chemotherapy is also administered.[82,83] 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.[82-84]

These findings give further impetus to perform routine dental and dental hygiene evaluations for survivors of childhood treatment.

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.[85] Veno-occlusive disease, which most commonly occurs in the setting of radiotherapy 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 radiotherapy, this complication is also reported following conditioning regimens with cyclophosphamide and busulfan alone. Preexisting 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.[86-88]

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.[89] 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 radiotherapy 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%, and >35 Gy was toxic in 86%.[90] In the National Wilms’ Tumor Study, 16 of 303 patients (5.3%) had liver toxicity. The doses of radiation to portions of the liver ranged from <15 Gy to >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.[91]

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.[92-99] 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 1 phase III trial for acute lymphoblastic leukemia, 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.[100] Similar results were reported by the United Kingdom Children’s Cooperative Group for their ALL study employing the use of thioguanine.[101]

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.[102,103] In general, fractionated doses of 20 Gy to 30 Gy can be delivered to the small bowel without significant long-term morbidity. Doses >40 Gy are required to cause bowel obstruction or chronic enterocolitis.[104] 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 radiotherapy, 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, 5 irradiated within 10 days of surgery and 1 of 19 irradiated after 10 days developed bowel obstruction.[105] In a report from the Intergroup Rhabdomyosarcoma Study Committee, extended follow-up of 86 children and adolescents who were treated for paratesticular rhabdomyosarcoma on the Intergroup Rhabdomyosarcoma Studies I and II (IRS I-II) revealed that 4 patients who had abdominal radiotherapy had chronic diarrhea.[106]

Splenectomy increases risk of life-threatening invasive bacterial infection.[107] It is no longer standard practice to perform a staging laparotomy for pediatric Hodgkin’s 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.[108,109] However, children may be rendered asplenic by radiation therapy to the spleen in doses >30 Gy, given as involved-field irradiation or as part of nodal irradiation.[110,111] Low-dose involved-field radiation (21 Gy) combined with multiagent chemotherapy does not appear to adversely affect splenic function.[111]

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.[112-115] 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 >38.5° C. Patients should receive antibiotic prophylaxis for dental work and should be immunized against meningococcus, hemophilus influenzae B, and Streptococcus pneumoniae.[107]

Childhood cancer survivors exposed to anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone) or thoracic radiotherapy 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 radiotherapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiotherapy 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.[116] Late effects of radiation to the heart include:[117-119]

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

However, with current techniques and reduced doses of radiotherapy, these effects are unlikely following treatment for childhood cancer. In a study of 635 patients treated for childhood Hodgkin’s 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 7 deaths from acute myocardial infarction; however, these deaths only occurred in children treated with 42 Gy to 45 Gy. Among children treated with 15 Gy to 26 Gy, none developed radiation-associated cardiac problems.[120] It seems safe to conclude that cardiac radiation using sophisticated treatment planning and careful blocking to doses ≤25 Gy is generally safe, and 40 Gy may be administered to small cardiac regions. However, the risk of delayed CAD after lower radiation doses 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.[118]

Increased risk of doxorubicin-related cardiomyopathy is associated with female sex, cumulative doses >200 mg/m² to 300mg/m², younger age at time of exposure, and increased time from exposure.[121-134] 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 2 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 2 groups over time.[128] 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.[121] Earlier studies in adults have shown decreased cardiotoxicity with prolonged infusion; thus, further evaluation of this question is warranted.[135-138]

Prevention or amelioration of anthracycline-induced cardiomyopathy is of utmost importance as 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. Dexrazoxane has been shown to prevent cardiac toxicity in adults and children treated with anthracyclines.[139-143]

In 2 closed Pediatric Oncology Group (POG) therapeutic phase III studies for Hodgkin’s lymphoma,[144,145] myocardial toxicity is being measured clinically and sequentially over time by echocardiography and electrocardiography (ECG), as well as by the determination of levels of cardiac troponin T (cTnT), a protein that is elevated after myocardial damage.[139,146-150]

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.[151]

Rhythm disturbances are also reported after doxorubicin exposure. One study looked at ECGs in 52 long-term survivors of childhood cancer who had been treated with anthracyclines. Prolongation of corrected QT interval (QTc) of >0.43 were noted in 6 of 22 patients who had received cumulative anthracycline doses >300 mg/m², as compared with 0 of 15 patients who had received lower anthracycline doses. Thoracic radiotherapy increased the risk in both groups, although 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.[152]

Although much of the data on doxorubicin and radiation-associated cardiac dysfunction are from survivors of Hodgkin’s 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.[153] 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%. Compared with siblings, risk was elevated for stroke, blood clots, and angina-like symptoms.[154] 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 where 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 >20 Gy, left-sided abdominal irradiation, and doxorubicin dose >300 mg/m².[123] Children who require hematopoietic stem cell transplantation (HSCT) are at especially high risk of cardiac toxicity. They may have received anthracyclines or radiotherapy 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.[155-159]

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.[152,158-163] Specific abnormalities of cardiac function may progress over time after therapy, as suggested by a report targeting parameters of LV contractility.[164] However, it remains unclear whether these abnormalities will have clinical impact; additional follow-up of these findings is required.

It is important to note that more time is needed before the effects of reduction in the dose of anthracyclines or thoracic radiotherapy are known.

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 (RT) doses. Acute pneumonitis manifested by fever, congestion, cough, and dyspnea can follow RT alone at doses >40 Gy to focal lung volumes, or after lower doses when combined with dactinomycin or anthracyclines. Fatal pneumonitis is possible after RT alone at doses to the whole lung >20 Gy, but is possible after lower doses when combined with chemotherapy. Infection, graft-versus-host disease (GVHD) in the setting of bone marrow transplantation (BMT), and preexisting pulmonary compromise (e.g., asthma) all may influence this risk. Changes in lung function have been reported in children treated with whole-lung RT 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.[165,166] 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.[165-167]

The development of bleomycin-associated pulmonary fibrosis with permanent restrictive disease is dose dependent, usually occurring at doses >200 U/m² to 400 U/m², higher than those used in pediatric malignancies.[167-169] One study evaluated lung function in 20 pediatric Hodgkin’s lymphoma patients treated with MOPP/AVBD and 15 Gy to 25 Gy mantle radiation and found 55% to have abnormal diffusing capacity.[170] Another study evaluated serial pulmonary function in children treated with COP/ABVD and mantle radiotherapy and found 65% to 73% to have only mildly decreased or normal diffusing capacity.[171] One other study reviewed pulmonary toxicity in survivors of childhood ALL, Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma (NHL) and found some abnormalities as measured by pulmonary function testing.[172,173]  [Note: clinical symptoms were uncommon and generally did not correlate with pulmonary function test results in these studies.]

Patients who are treated with hematopoietic stem cell transplantation (HSCT) are at increased risk of pulmonary toxicity, related to preexisting pulmonary dysfunction (e.g., asthma, pretransplant therapy), the preparative regimen that may include cyclophosphamide, busulfan, carmustine, and TBI, and the presence of GVHD.[174-179] 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 (LOPS), 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.[178,179]

It is not clear what the true prevalence or incidence of pulmonary dysfunction is in childhood cancer survivors. 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 of lung fibrosis, recurrent pneumonia, chronic cough, pleurisy, use of supplemental oxygen therapy, abnormal chest wall, exercise-induced shortness of breath and bronchitis, with relative risks 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 radiotherapy (CRT) and <1% for those who received pulmonary toxic chemotherapy (PTC). For more subjective complaints, the 25-year cumulative incidences were higher, as follows: chronic cough, 15% for combined CRT and PTC, 12% CRT alone, 6% PTC alone; exercise-induced shortness of breath, 20% CRT and PTC, 15% CRT alone, 6% PTC 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. Nitrosureas were associated with an increased risk of supplemental oxygen therapy. Three survivors had undergone a lung transplant, and another 3 survivors developed adenocarcinoma of the lung as a second malignancy. Risk continues to increase with time since diagnosis.[180] With changes in the doses of radiotherapy employed since the late 1980s, the incidence of these abnormalities is likely to decrease.

Cisplatin at doses >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.[49,181-183] Studies in the early 1990s have shown that carboplatin has less acute nephrotoxicity than cisplatin.[184-186] However, only a few small studies examining children treated with carboplatin have evaluated short-term and long-term nephrotoxicity, finding nothing significant to date.[187,188] However, as with ototoxicity, 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’s syndrome. Doses >60 gm/m² to 100 gm/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 > distal tubular function, although the prevalence of these findings is uncertain and further study of larger cohorts with longer follow-up is required.[189-193]

Radiation nephropathy is dose-related. Doses >25 Gy to both kidneys can cause renal failure at delayed intervals of >6 months.[194,195] The effect of radiotherapy 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.[196] 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, and radiation nephritis.[197] 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 and/or serum creatinine levels. Of those, 18 had moderate and 10 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 1 kidney remaining had more marked dysfunction.[198] 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 radiotherapy was not associated with significant nephrotoxicity in a study of 40 Wilms' tumor survivors treated in England.[199] Patients with predisposition syndromes such as Denys-Drash syndrome (DDS), WAGR syndrome (Wilms’ tumor-aniridia-genitourinary-retardation syndrome), or male genitourinary anomalies had much higher incidence of renal failure at 20 years of 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.[200]

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.[178]

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’s 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.[201] For example, criteria for diagnosis of hypothyroidism, the most frequently reported abnormality, include elevated thyroid-stimulating hormone (TSH), depressed thyroxine (T4), or both.[202-205] Compensated hypothyroidism includes an elevated TSH with a normal T4 and is often asymptomatic. The natural history is unclear, but most endocrinologists support treatment, especially in those who are symptomatic. 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 radiotherapy 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 2-3 years posttreatment.[206] In a study of Hodgkin’s lymphoma patients treated between 1962 and 1979, hypothyroidism occurred in 4 of 24 patients who received mantle doses <26 Gy but in 74 of 95 patients who received >26 Gy. The peak incidence occurred at 3 to 5 years posttreatment, with a median of 4.6 years.[207] A cohort of childhood Hodgkin’s 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 1 thyroid abnormality. For hypothyroidism, there was a clear dose response, with a 20-year risk of 20% for those who received <35 Gy, 30% for those who received 35 Gy to 44.9 Gy, and 50% for those who received >45 Gy to the thyroid gland. The relative risk 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.[208] 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 do not appear to increase risk. While mildly elevated TSH is common, it is usually accompanied by normal thyroxine concentration.[209,210]

Other endocrine abnormalities can occur after cranial irradiation, including growth hormone deficiency, delayed or precocious puberty, and hypopituitarism. Hypothalamic dysfunction is most common, although pituitary insufficiency may occur.[154,202,211-214]

The potential for neuroendocrine damage is likely to decrease due to 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 >30 Gy will have impaired serum growth hormone (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 radiotherapy 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.[215] Children treated with CNS irradiation for leukemia are also at increased risk of growth hormone 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 at the standard deviation score (SDS), was significant for all 3 groups with a dose-response of -0.49 ± 0.14 for the no RT group, -0.65 ± 0.15 for the 18 Gy RT group, and 1.38 ± 0.16 for the 24 Gy group.[216] Another study found similar results in 118 ALL survivors treated with 24 Gy cranial irradiation, where 74% had SDS score of ≥-1 and the remainder ≥-2.[217]

Children who receive HSCT with TBI have a significant risk of growth hormone deficiency. Risk is increased with single-dose as opposed to fractionated radiation, pretransplant cranial irradiation, female gender, and posttreatment complications such as GVHD.[218-221] Regimens containing busulfan and cyclophosphamide also increase risk.[221] Hyperfractionation of the TBI dose markedly reduces risk, without pretransplant cranial radiation.[222] In a review of late effects after HSCT, 1 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.[223] 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, growth hormone, or steroid treatment did not influence final height. TBI (single dose radiotherapy more than fractionated dose radiotherapy), male gender, and young age at transplant, were found to be major factors for long-term height loss. Most patients (140/181) reached adult height within the normal range of the general population.[224]

Growth hormone deficiency should be treated with replacement therapy. There has been some controversy surrounding this, with a concern over increased risk of recurrence and second malignancies. However, most studies 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 (SN), and risk of death among survivors who did and did not receive treatment with growth hormone. The relative risk of disease recurrence was 0.83 (95% CI 0.37-1.86) for growth hormone-treated survivors. Growth hormone-treated subjects were diagnosed with 15 second malignant neoplasms, all solid tumors, for an overall relative risk of 3.21 (95% CI 1.88-5.46), mainly due to a small excess number of second neoplasms observed in survivors of acute leukemia. The data surrounding second malignancies need to be interpreted with caution given the small number of events.[225]

Pubertal growth can be adversely affected by cranial radiation. Doses >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 >24 Gy cranial radiation. However, earlier puberty and earlier peak height velocity are seen in girls treated with 18 Gy cranial radiation.[226,227] Another study showed that the age of pubertal onset is positively correlated with the 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.[228] 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.[229] 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 due to hypothalamic or pituitary injury and low luteinizing hormone (LH) and estradiol with oligomenorrhea.[211] Adrenocorticotropin deficiencies and hyperprolactinemia are relatively rare in children because these conditions develop only with doses >50 Gy.[211,230]

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.[231-233] Craniospinal radiation results in both abnormal growth hormone secretion and effects on the vertebral bodies.[234]

Avascular necrosis has been reported in survivors of ALL who were treated by conventional therapy or by hematopoietic stem cell transplantation (HSCT), with corticosteroids representing a significant risk factor.[235-239] In trials of the former Children’s Cancer Group (CCG) for ALL, the incidence of avascular necrosis 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.[240]

Bone mineral density in childhood cancer survivors may be reduced, especially in children treated for ALL, where 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, growth hormone deficiency and cranial radiation. Prevalence, chronicity, and severity are not consistent across studies; therefore, the risk remains poorly defined.[241-249] There are also reports of decreased bone mineral density in patients treated for osteosarcoma,[250,251] Wilms’ tumor,[252] and CNS tumors.[253] For survivors of HSCT, again there is a lack of consensus regarding the risk and incidence of decreased bone mineral density posttransplant.[254-257] 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.[258,259]

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 >20 Gy. The highest risk was for females treated at 4 years of age and younger with cranial radiation doses of >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.[260] Similar findings were reported by 1 group where body mass index 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.[261] 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.[262,263] A report from Denmark reveals that there is reduced lean body mass among survivors of childhood non-Hodgkin’s lymphoma and Hodgkin’s lymphoma.[264] Children treated for brain tumors are at risk for development of obesity due to hypothalamic dysfunction resulting from the tumor, surgery, or irradiation.[265]

A number of endocrinologic and metabolic findings, including increased body mass index, can be summarized as “the metabolic syndrome.” This includes insulin resistance, hyperglycemia, hyperinsulinemia, hypertension, hyperlipidemia, and obesity. It is, at least in part, due to 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.[266,267]

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.[268-274] This is illustrated by a study in which long-term gonadal toxicity was compared among survivors of Hodgkin’s lymphoma and NHL. Both groups had received comparable median cumulative doses of cyclophosphamide, but only the patients with Hodgkin’s lymphoma received procarbazine. The incidence of gonadal toxicity was more than 3 times higher in the men in the Hodgkin’s lymphoma group. The only men in the NHL group who had elevation of follicle-stimulating hormone (FSH) had received higher doses of cyclophosphamide than the mean.[275] 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.[106,276,277] 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.[269] Reduction of alkylating agent therapy in multiagent protocols has resulted in reduction in the risk for male infertility,[271-273,278,279] Review of the available studies has led to the consensus that males who receive <4 g/m² of cyclophosphamide without any other alkylating agents and without either testicular or cranial radiation are likely to retain their fertility. Doses >9 g/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 radiotherapy. 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.[280]

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 (20-30 Gy).[281] Although temporary oligospermia can occur after these very low radiation doses, permanent azoospermia results from higher doses of >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.[282,283] 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.[284] Scatter from abdominal radiation with doses >20 Gy for Hodgkin’s disease can cause transient elevation in FSH and oligospermia, but not with lower doses.[285]

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. Risk of menstrual irregularity, ovarian failure, and infertility increase with age at treatment.[271,281,286-289] 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 g/m².[287,290] However, 2 large studies of survivors treated through the 1980s have shown elevated relative risks for infertility and early menopause in female survivors of childhood cancer.[291,292] 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.[291] Another study of 719 survivors treated between 1964 and 1988 found a 15.5% failure to conceive.[292] 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.[293] 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 2 groups of female patients treated at different times at 1 institution by neoadjuvant chemotherapy for osteosarcoma. From 1997 to 2000, 1 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.[294]

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.[281] While radiation doses >8 Gy are associated with ovarian ablation, lower doses may not cause infertility.[282,283] 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.[291,295] Abdominal radiotherapy at similar doses can lead to reduced uterine volume and decreased elasticity, increasing risk of spontaneous miscarriage, premature birth, and intrauterine growth retardation.[296]

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.[297] 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 (relative risk (RR) 0.77), but no significant differences of pregnancy outcome by treatment.[298] In the National Wilms’ Tumor Study, records were obtained for 427 pregnancies of >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.[299]

Preservation of fertility and successful pregnancies may occur after HSCT, although 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.[300] 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 9 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 1 retained ovarian function.[301]

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.[281,286] 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.[302-305] 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.[306] 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.[306,307] 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.[308-310] 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.[309] 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.[310] 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.[309,310]

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 radiotherapy.[299] 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. Survivors treated with abdominal radiotherapy and/or alkylating agents did not have an increased risk of offspring with genetic disease, compared with survivors not exposed to these agents.[311] Similar results were reported in a single-institution study of 247 offspring of 148 cancer survivors.[312]

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.[313-317]

In a study of 5,847 offspring of survivors of childhood cancers treated in 5 Scandinavian countries, in the absence of a hereditary cancer syndrome (such as hereditary retinoblastoma), there was no increased risk of cancer.[318] 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). However, among survivors who themselves had second or subsequent malignant neoplasms (SMNs), risk of cancer in offspring was significantly elevated, SIR = 15.08; 95% confidence interval (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).[319] Further follow-up of offspring is required to see if patterns of cancer in offspring change over time.

References

1. Duffner PK, Cohen ME: Long-term consequences of CNS treatment for childhood cancer, Part II: Clinical consequences. Pediatr Neurol 7 (4): 237-42, 1991 Jul-Aug.  [PUBMED Abstract]
   
   
2. Duffner PK, Cohen ME: The long-term effects of central nervous system therapy on children with brain tumors. Neurol Clin 9 (2): 479-95, 1991.  [PUBMED Abstract]
   
   
3. Glauser TA, Packer RJ: Cognitive deficits in long-term survivors of childhood brain tumors. Childs Nerv Syst 7 (1): 2-12, 1991.  [PUBMED Abstract]
   
   
4. Packer RJ, Meadows AT, Rorke LB, et al.: Long-term sequelae of cancer treatment on the central nervous system in childhood. Med Pediatr Oncol 15 (5): 241-53, 1987.  [PUBMED Abstract]
   
   
5. Rodgers J, Britton PG, Morris RG, et al.: Memory after treatment for acute lymphoblastic leukaemia. Arch Dis Child 67 (3): 266-8, 1992.  [PUBMED Abstract]
   
   
6. Stehbens JA, Kaleita TA, Noll RB, et al.: CNS prophylaxis of childhood leukemia: what are the long-term neurological, neuropsychological, and behavioral effects? Neuropsychol Rev 2 (2): 147-77, 1991.  [PUBMED Abstract]
   
   
7. Cohen BH, Packer RJ, Siegel KR, et al.: Brain tumors in children under 2 years: treatment, survival and long-term prognosis. Pediatr Neurosurg 19 (4): 171-9, 1993 Jul-Aug.  [PUBMED Abstract]
   
   
8. Mulhern RK, Hancock J, Fairclough D, et al.: Neuropsychological status of children treated for brain tumors: a critical review and integrative analysis. Med Pediatr Oncol 20 (3): 181-91, 1992.  [PUBMED Abstract]
   
   
9. Radcliffe J, Bunin GR, Sutton LN, et al.: Cognitive deficits in long-term survivors of childhood medulloblastoma and other noncortical tumors: age-dependent effects of whole brain radiation. Int J Dev Neurosci 12 (4): 327-34, 1994.  [PUBMED Abstract]
   
   
10. Roman DD, Sperduto PW: Neuropsychological effects of cranial radiation: current knowledge and future directions. Int J Radiat Oncol Biol Phys 31 (4): 983-98, 1995.  [PUBMED Abstract]
    
    
11. Silber JH, Radcliffe J, Peckham V, et al.: Whole-brain irradiation and decline in intelligence: the influence of dose and age on IQ score. J Clin Oncol 10 (9): 1390-6, 1992.  [PUBMED Abstract]
    
    
12. Ris MD, Packer R, Goldwein J, et al.: Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study. J Clin Oncol 19 (15): 3470-6, 2001.  [PUBMED Abstract]
    
    
13. Mulhern RK, Kepner JL, Thomas PR, et al.: Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: a Pediatric Oncology Group study. J Clin Oncol 16 (5): 1723-8, 1998.  [PUBMED Abstract]
    
    
14. Packer RJ, Goldwein J, Nicholson HS, et al.: Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. J Clin Oncol 17 (7): 2127-36, 1999.  [PUBMED Abstract]
    
    
15. Palmer SL, Goloubeva O, Reddick WE, et al.: Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis. J Clin Oncol 19 (8): 2302-8, 2001.  [PUBMED Abstract]
    
    
16. Reimers TS, Ehrenfels S, Mortensen EL, et al.: Cognitive deficits in long-term survivors of childhood brain tumors: Identification of predictive factors. Med Pediatr Oncol 40 (1): 26-34, 2003.  [PUBMED Abstract]
    
    
17. Reddick WE, White HA, Glass JO, et al.: Developmental model relating white matter volume to neurocognitive deficits in pediatric brain tumor survivors. Cancer 97 (10): 2512-9, 2003.  [PUBMED Abstract]
    
    
18. Meadows AT, Gordon J, Massari DJ, et al.: Declines in IQ scores and cognitive dysfunctions in children with acute lymphocytic leukaemia treated with cranial irradiation. Lancet 2 (8254): 1015-8, 1981.  [PUBMED Abstract]
    
    
19. Haupt R, Fears TR, Robison LL, et al.: Educational attainment in long-term survivors of childhood acute lymphoblastic leukemia. JAMA 272 (18): 1427-32, 1994.  [PUBMED Abstract]
    
    
20. Kingma A, Van Dommelen RI, Mooyaart EL, et al.: No major cognitive impairment in young children with acute lymphoblastic leukemia using chemotherapy only: a prospective longitudinal study. J Pediatr Hematol Oncol 24 (2): 106-14, 2002.  [PUBMED Abstract]
    
    
21. Waber DP, Tarbell NJ, Fairclough D, et al.: Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice. J Clin Oncol 13 (10): 2490-6, 1995.  [PUBMED Abstract]
    
    
22. Waber DP, Shapiro BL, Carpentieri SC, et al.: Excellent therapeutic efficacy and minimal late neurotoxicity in children treated with 18 grays of cranial radiation therapy for high-risk acute lymphoblastic leukemia: a 7-year follow-up study of the Dana-Farber Cancer Institute Consortium Protocol 87-01. Cancer 92 (1): 15-22, 2001.  [PUBMED Abstract]
    
    
23. Bleyer WA, Fallavollita J, Robison L, et al.: Influence of age, sex, and concurrent intrathecal methotrexate therapy on intellectual function after cranial irradiation during childhood: a report from the Children's Cancer Study Group. Pediatr Hematol Oncol 7 (4): 329-38, 1990.  [PUBMED Abstract]
    
    
24. Riva D, Giorgi C, Nichelli F, et al.: Intrathecal methotrexate affects cognitive function in children with medulloblastoma. Neurology 59 (1): 48-53, 2002.  [PUBMED Abstract]
    
    
25. Bleyer WA: Neurologic sequelae of methotrexate and ionizing radiation: a new classification. Cancer Treat Rep 65 (Suppl 1): 89-98, 1981.  [PUBMED Abstract]
    
    
26. Cohen ME, Duffner PK: Long-term consequences of CNS treatment for childhood cancer, Part I: Pathologic consequences and potential for oncogenesis. Pediatr Neurol 7 (3): 157-63, 1991 May-Jun.  [PUBMED Abstract]
    
    
27. Brown RT, Madan-Swain A, Pais R, et al.: Chemotherapy for acute lymphocytic leukemia: cognitive and academic sequelae. J Pediatr 121 (6): 885-9, 1992.  [PUBMED Abstract]
    
    
28. Ochs J, Mulhern R, Fairclough D, et al.: Comparison of neuropsychologic functioning and clinical indicators of neurotoxicity in long-term survivors of childhood leukemia given cranial radiation or parenteral methotrexate: a prospective study. J Clin Oncol 9 (1): 145-51, 1991.  [PUBMED Abstract]
    
    
29. Butler RW, Hill JM, Steinherz PG, et al.: Neuropsychologic effects of cranial irradiation, intrathecal methotrexate, and systemic methotrexate in childhood cancer. J Clin Oncol 12 (12): 2621-9, 1994.  [PUBMED Abstract]
    
    
30. Kaleita TA, Reaman GH, MacLean WE, et al.: Neurodevelopmental outcome of infants with acute lymphoblastic leukemia: a Children's Cancer Group report. Cancer 85 (8): 1859-65, 1999.  [PUBMED Abstract]
    
    
31. Hill DE, Ciesielski KT, Sethre-Hofstad L, et al.: Visual and verbal short-term memory deficits in childhood leukemia survivors after intrathecal chemotherapy. J Pediatr Psychol 22 (6): 861-70, 1997.  [PUBMED Abstract]
    
    
32. Williams KS, Ochs J, Williams JM, et al.: Parental report of everyday cognitive abilities among children treated for acute lymphoblastic leukemia. J Pediatr Psychol 16 (1): 13-26, 1991.  [PUBMED Abstract]
    
    
33. Schwartz C L, Hobbie WL, Constine LS, et al., eds.: Survivors of Childhood Cancer: Assessment and Management. St. Louis, Mo: Mosby, 1994. 
    
    
34. Fuemmeler BF, Elkin TD, Mullins LL: Survivors of childhood brain tumors: behavioral, emotional, and social adjustment. Clin Psychol Rev 22 (4): 547-85, 2002.  [PUBMED Abstract]
    
    
35. Gray RE, Doan BD, Shermer P, et al.: Psychologic adaptation of survivors of childhood cancer. Cancer 70 (11): 2713-21, 1992.  [PUBMED Abstract]
    
    
36. Kazak AE: Implications of survival: pediatric oncology patients and their families . In: Bearison DJ, Mulhern RK, eds.: Pediatric Psychooncology: Psychologocial Perspectives on Children with Cancer. New York, NY: Oxford University Press, 1994, pp 171-92. 
    
    
37. Zeltzer LK: Cancer in adolescents and young adults psychosocial aspects. Long-term survivors. Cancer 71 (10 Suppl): 3463-8, 1993.  [PUBMED Abstract]
    
    
38. American Psychiatric Association.: Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. 4th ed. Washington, DC: American Psychiatric Association, 1994. 
    
    
39. Hobbie WL, Stuber M, Meeske K, et al.: Symptoms of posttraumatic stress in young adult survivors of childhood cancer. J Clin Oncol 18 (24): 4060-6, 2000.  [PUBMED Abstract]
    
    
40. Kazak AE, Barakat LP, Meeske K, et al.: Posttraumatic stress, family functioning, and social support in survivors of childhood leukemia and their mothers and fathers. J Consult Clin Psychol 65 (1): 120-9, 1997.  [PUBMED Abstract]
    
    
41. Kazak AE, Simms S, Barakat L, et al.: Surviving cancer competently intervention program (SCCIP): a cognitive-behavioral and family therapy intervention for adolescent survivors of childhood cancer and their families. Fam Process 38 (2): 175-91, 1999 Summer.  [PUBMED Abstract]
    
    
42. Rourke MT, Stuber ML, Hobbie WL, et al.: Posttraumatic stress disorder: understanding the psychosocial impact of surviving childhood cancer into young adulthood. J Pediatr Oncol Nurs 16 (3): 126-35, 1999.  [PUBMED Abstract]
    
    
43. Stuber ML, Kazak AE, Meeske K, et al.: Predictors of posttraumatic stress symptoms in childhood cancer survivors. Pediatrics 100 (6): 958-64, 1997.  [PUBMED Abstract]
    
    
44. Meeske KA, Ruccione K, Globe DR, et al.: Posttraumatic stress, quality of life, and psychological distress in young adult survivors of childhood cancer. Oncol Nurs Forum 28 (3): 481-9, 2001.  [PUBMED Abstract]
    
    
45. Kazak AE, Stuber ML, Barakat LP, et al.: Predicting posttraumatic stress symptoms in mothers and fathers of survivors of childhood cancers. J Am Acad Child Adolesc Psychiatry 37 (8): 823-31, 1998.  [PUBMED Abstract]
    
    
46. Recklitis C, O'Leary T, Diller L: Utility of routine psychological screening in the childhood cancer survivor clinic. J Clin Oncol 21 (5): 787-92, 2003.  [PUBMED Abstract]
    
    
47. Landier W: Hearing loss related to ototoxicity in children with cancer. J Pediatr Oncol Nurs 15 (4): 195-206, 1998.  [PUBMED Abstract]
    
    
48. McHaney VA, Thibadoux G, Hayes FA, et al.: Hearing loss in children receiving cisplatin chemotherapy. J Pediatr 102 (2): 314-7, 1983.  [PUBMED Abstract]
    
    
49. McKeage MJ: Comparative adverse effect profiles of platinum drugs. Drug Saf 13 (4): 228-44, 1995.  [PUBMED Abstract]
    
    
50. Raney RB, Asmar L, Vassilopoulou-Sellin R, et al.: Late complications of therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the head and neck: A descriptive report from the Intergroup Rhabdomyosarcoma Studies (IRS)-II and - III. IRS Group of the Children's Cancer Group and the Pediatric Oncology Group. Med Pediatr Oncol 33 (4): 362-71, 1999.  [PUBMED Abstract]
    
    
51. Schell MJ, McHaney VA, Green AA, et al.: Hearing loss in children and young adults receiving cisplatin with or without prior cranial irradiation. J Clin Oncol 7 (6): 754-60, 1989.  [PUBMED Abstract]
    
    
52. Simon T, Hero B, Dupuis W, et al.: The incidence of hearing impairment after successful treatment of neuroblastoma. Klin Padiatr 214 (4): 149-52, 2002 Jul-Aug.  [PUBMED Abstract]
    
    
53. Huang E, Teh BS, Strother DR, et al.: Intensity-modulated radiation therapy for pediatric medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys 52 (3): 599-605, 2002.  [PUBMED Abstract]
    
    
54. Merchant TE, Gould CJ, Xiong X, et al.: Early neuro-otologic effects of three-dimensional irradiation in children with primary brain tumors. [Abstract] Int J Radiat Oncol Biol Phys 54 (Suppl 2): A-1073, 201, 2002. 
    
    
55. Paulino AC, Simon JH, Zhen W, et al.: Long-term effects in children treated with radiotherapy for head and neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 48 (5): 1489-95, 2000.  [PUBMED Abstract]
    
    
56. Kaste SC, Chen G, Fontanesi J, et al.: Orbital development in long-term survivors of retinoblastoma. J Clin Oncol 15 (3): 1183-9, 1997.  [PUBMED Abstract]
    
    
57. Peylan-Ramu N, Bin-Nun A, Skleir-Levy M, et al.: Orbital growth retardation in retinoblastoma survivors: work in progress. Med Pediatr Oncol 37 (5): 465-70, 2001.  [PUBMED Abstract]
    
    
58. Shields CL, Shields JA: Recent developments in the management of retinoblastoma. J Pediatr Ophthalmol Strabismus 36 (1): 8-18; quiz 35-6, 1999 Jan-Feb.  [PUBMED Abstract]
    
    
59. Shields CL, Shields JA, Cater J, et al.: Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors. Ophthalmology 108 (11): 2116-21, 2001.  [PUBMED Abstract]
    
    
60. Weiss AH, Karr DJ, Kalina RE, et al.: Visual outcomes of macular retinoblastoma after external beam radiation therapy. Ophthalmology 101 (7): 1244-9, 1994.  [PUBMED Abstract]
    
    
61. Buckley EG, Heath H: Visual acuity after successful treatment of large macular retinoblastoma. J Pediatr Ophthalmol Strabismus 29 (2): 103-6, 1992 Mar-Apr.  [PUBMED Abstract]
    
    
62. Fontanesi J, Pratt CB, Kun LE, et al.: Treatment outcome and dose-response relationship in infants younger than 1 year treated for retinoblastoma with primary irradiation. Med Pediatr Oncol 26 (5): 297-304, 1996.  [PUBMED Abstract]
    
    
63. Shields JA, Shields CL: Pediatric ocular and periocular tumors. Pediatr Ann 30 (8): 491-501, 2001.  [PUBMED Abstract]
    
    
64. Kline LB, Kim JY, Ceballos R: Radiation optic neuropathy. Ophthalmology 92 (8): 1118-26, 1985.  [PUBMED Abstract]
    
    
65. Parsons JT, Bova FJ, Mendenhall WM, et al.: Response of the normal eye to high dose radiotherapy. Oncology (Huntingt) 10 (6): 837-47; discussion 847-8, 851-2, 1996.  [PUBMED Abstract]
    
    
66. Paulino AC: Role of radiation therapy in parameningeal rhabdomyosarcoma. Cancer Invest 17 (3): 223-30, 1999.  [PUBMED Abstract]
    
    
67. Oberlin O, Rey A, Anderson J, et al.: Treatment of orbital rhabdomyosarcoma: survival and late effects of treatment--results of an international workshop. J Clin Oncol 19 (1): 197-204, 2001.  [PUBMED Abstract]
    
    
68. Raney RB, Anderson JR, Kollath J, et al.: Late effects of therapy in 94 patients with localized rhabdomyosarcoma of the orbit: Report from the Intergroup Rhabdomyosarcoma Study (IRS)-III, 1984-1991. Med Pediatr Oncol 34 (6): 413-20, 2000.  [PUBMED Abstract]
    
    
69. van Kempen-Harteveld ML, Struikmans H, Kal HB, et al.: Cataract-free interval and severity of cataract after total body irradiation and bone marrow transplantation: influence of treatment parameters. Int J Radiat Oncol Biol Phys 48 (3): 807-15, 2000.  [PUBMED Abstract]
    
    
70. van Kempen-Harteveld ML, Belkacémi Y, Kal HB, et al.: Dose-effect relationship for cataract induction after single-dose total body irradiation and bone marrow transplantation for acute leukemia. Int J Radiat Oncol Biol Phys 52 (5): 1367-74, 2002.  [PUBMED Abstract]
    
    
71. van Kempen-Harteveld ML, Struikmans H, Kal HB, et al.: Cataract after total body irradiation and bone marrow transplantation: degree of visual impairment. Int J Radiat Oncol Biol Phys 52 (5): 1375-80, 2002.  [PUBMED Abstract]
    
    
72. Belkacemi Y, Labopin M, Vernant JP, et al.: Cataracts after total body irradiation and bone marrow transplantation in patients with acute leukemia in complete remission: a study of the European Group for Blood and Marrow Transplantation. Int J Radiat Oncol Biol Phys 41 (3): 659-68, 1998.  [PUBMED Abstract]
    
    
73. Holmström G, Borgström B, Calissendorff B: Cataract in children after bone marrow transplantation: relation to conditioning regimen. Acta Ophthalmol Scand 80 (2): 211-5, 2002.  [PUBMED Abstract]
    
    
74. Zierhut D, Lohr F, Schraube P, et al.: Cataract incidence after total-body irradiation. Int J Radiat Oncol Biol Phys 46 (1): 131-5, 2000.  [PUBMED Abstract]
    
    
75. Maguire A, Craft AW, Evans RG, et al.: The long-term effects of treatment on the dental condition of children surviving malignant disease. Cancer 60 (10): 2570-5, 1987.  [PUBMED Abstract]
    
    
76. Alpaslan G, Alpaslan C, Gögen H, et al.: Disturbances in oral and dental structures in patients with pediatric lymphoma after chemotherapy: a preliminary report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 87 (3): 317-21, 1999.  [PUBMED Abstract]
    
    
77. Kaste SC, Hopkins KP, Jones D, et al.: Dental abnormalities in children treated for acute lymphoblastic leukemia. Leukemia 11 (6): 792-6, 1997.  [PUBMED Abstract]
    
    
78. O'Sullivan EA, Duggal MS, Bailey CC: Changes in the oral health of children during treatment for acute lymphoblastic leukaemia. Int J Paediatr Dent 4 (1): 31-4, 1994.  [PUBMED Abstract]
    
    
79. Dahllöf G, Barr M, Bolme P, et al.: Disturbances in dental development after total body irradiation in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 65 (1): 41-4, 1988.  [PUBMED Abstract]
    
    
80. Duggal MS: Root surface areas in long-term survivors of childhood cancer. Oral Oncol 39 (2): 178-83, 2003.  [PUBMED Abstract]
    
    
81. Hölttä P, Alaluusua S, Saarinen-Pihkala UM, et al.: Long-term adverse effects on dentition in children with poor-risk neuroblastoma treated with high-dose chemotherapy and autologous stem cell transplantation with or without total body irradiation. Bone Marrow Transplant 29 (2): 121-7, 2002.  [PUBMED Abstract]
    
    
82. Makkonen TA, Nordman E: Estimation of long-term salivary gland damage induced by radiotherapy. Acta Oncol 26 (4): 307-12, 1987.  [PUBMED Abstract]
    
    
83. Maxymiw WG, Wood RE: The role of dentistry in head and neck radiation therapy. J Can Dent Assoc 55 (3): 193-8, 1989.  [PUBMED Abstract]
    
    
84. Myers RE, Mitchell DL: Fluoride for the head and neck radiation patient. Mil Med 153 (8): 411-3, 1988.  [PUBMED Abstract]
    
    
85. King PD, Perry MC: Hepatotoxicity of chemotherapy. Oncologist 6 (2): 162-76, 2001.  [PUBMED Abstract]
    
    
86. Bearman SI: The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 85 (11): 3005-20, 1995.  [PUBMED Abstract]
    
    
87. Carreras E, Bertz H, Arcese W, et al.: Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood 92 (10): 3599-604, 1998.  [PUBMED Abstract]
    
    
88. Hasegawa S, Horibe K, Kawabe T, et al.: Veno-occlusive disease of the liver after allogeneic bone marrow transplantation in children with hematologic malignancies: incidence, onset time and risk factors. Bone Marrow Transplant 22 (12): 1191-7, 1998.  [PUBMED Abstract]
    
    
89. Dawson LA, Ten Haken RK, Lawrence TS: Partial irradiation of the liver. Semin Radiat Oncol 11 (3): 240-6, 2001.  [PUBMED Abstract]
    
    
90. Tefft M, Mitus A, Das L, et al.: Irradiation of the liver in children: review of experience in the acute and chronic phases, and in the intact normal and partially resected. Am J Roentgenol Radium Ther Nucl Med 108 (2): 365-85, 1970.  [PUBMED Abstract]
    
    
91. Thomas PR, Tefft M, D'Angio GJ, et al.: Acute toxicities associated with radiation in the second National Wilms' Tumor Study. J Clin Oncol 6 (11): 1694-8, 1988.  [PUBMED Abstract]
    
    
92. Strickland DK, Jenkins JJ, Hudson MM: Hepatitis C infection and hepatocellular carcinoma after treatment of childhood cancer. J Pediatr Hematol Oncol 23 (8): 527-9, 2001.  [PUBMED Abstract]
    
    
93. Matsuzaki A, Ishii E, Nagatoshi Y, et al.: Long-term outcome of treatment with protocols AL841, AL851, and ALHR88 in children with acute lymphoblastic leukemia: results obtained by the Kyushu-Yamaguchi Children's Cancer Study Group. Int J Hematol 73 (3): 369-77, 2001.  [PUBMED Abstract]
    
    
94. Randall RJ: Hepatitis C virus infection and long-term survivors of childhood cancer: issues for the pediatric oncology nurse. J Pediatr Oncol Nurs 18 (1): 4-15, 2001 Jan-Feb.  [PUBMED Abstract]
    
    
95. Leung W, Hudson M, Zhu Y, et al.: Late effects in survivors of infant leukemia. Leukemia 14 (7): 1185-90, 2000.  [PUBMED Abstract]
    
    
96. 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.  [PUBMED Abstract]
    
    
97. Utili R, Zampino R, Bellopede P, et al.: Dual or single hepatitis B and C virus infections in childhood cancer survivors: long-term follow-up and effect of interferon treatment. Blood 94 (12): 4046-52, 1999.  [PUBMED Abstract]
    
    
98. Locasciulli A, Testa M, Pontisso P, et al.: Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 90 (11): 4628-33, 1997.  [PUBMED Abstract]
    
    
99. Aricò M, Maggiore G, Silini E, et al.: Hepatitis C virus infection in children treated for acute lymphoblastic leukemia. Blood 84 (9): 2919-22, 1994.  [PUBMED Abstract]
    
    
100. Stork LC, Children's Cancer Group: Phase III Randomized Study of Oral Mercaptopurine vs Oral Thioguanine and of Intrathecal MTX vs Triple Intrathecal Chemotherapy (Methotrexate, Catarabine, and Hydrocortisone) During Consolidation, Interim Maintenance, and Maintenance for Newly Diagnosed Standard Risk Childhood Acute Lymphoblastic Leukemia (Summary Last Modified 04/2000), CCG-1952, Clinical trial, Closed.  [PDQ Clinical Trial] ²
     
     
101. Vora AJ, Mitchell C, Kinsey S, et al.: Thioguanine-related veno-occlusive disease (VOD) of the liver in children with acute lymphoblastic leukaemia (ALL): report from United Kingdom Medical Research Council (UK MRC) trial ALL97. [Abstract] Blood 100 (11 Pt 1): A-126, 36a, 2002. 
     
     
102. Churnratanakul S, Wirzba B, Lam T, et al.: Radiation and the small intestine. Future perspectives for preventive therapy. Dig Dis 8 (1): 45-60, 1990.  [PUBMED Abstract]
     
     
103. Sher ME, Bauer J: Radiation-induced enteropathy. Am J Gastroenterol 85 (2): 121-8, 1990.  [PUBMED Abstract]
     
     
104. Emami B, Lyman J, Brown A, et al.: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21 (1): 109-22, 1991.  [PUBMED Abstract]
     
     
105. Paulino AC, Wen BC, Brown CK, et al.: Late effects in children treated with radiation therapy for Wilms' tumor. Int J Radiat Oncol Biol Phys 46 (5): 1239-46, 2000.  [PUBMED Abstract]
     
     
106. Heyn R, Raney RB Jr, Hays DM, et al.: Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee. J Clin Oncol 10 (4): 614-23, 1992.  [PUBMED Abstract]
     
     
107. Pickering LK, Peter G, Baker CJ, eds.: 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, Ill: American Academy of Pediatrics, 2000. 
     
     
108. Kaiser CW: Complications from staging laparotomy for Hodgkin disease. J Surg Oncol 16 (4): 319-25, 1981.  [PUBMED Abstract]
     
     
109. Jockovich M, Mendenhall NP, Sombeck MD, et al.: Long-term complications of laparotomy in Hodgkin's disease. Ann Surg 219 (6): 615-21; discussion 621-4, 1994.  [PUBMED Abstract]
     
     
110. Coleman CN, McDougall IR, Dailey MO, et al.: Functional hyposplenia after splenic irradiation for Hodgkin's disease. Ann Intern Med 96 (1): 44-7, 1982.  [PUBMED Abstract]
     
     
111. Weiner MA, Landmann RG, DeParedes L, et al.: Vesiculated erythrocytes as a determination of splenic reticuloendothelial function in pediatric patients with Hodgkin's disease. J Pediatr Hematol Oncol 17 (4): 338-41, 1995.  [PUBMED Abstract]
     
     
112. Waghorn DJ, Mayon-White RT: A study of 42 episodes of overwhelming post-splenectomy infection: is current guidance for asplenic individuals being followed? J Infect 35 (3): 289-94, 1997.  [PUBMED Abstract]
     
     
113. Ejstrud P, Kristensen B, Hansen JB, et al.: Risk and patterns of bacteraemia after splenectomy: a population-based study. Scand J Infect Dis 32 (5): 521-5, 2000.  [PUBMED Abstract]
     
     
114. Bisharat N, Omari H, Lavi I, et al.: Risk of infection and death among post-splenectomy patients. J Infect 43 (3): 182-6, 2001.  [PUBMED Abstract]
     
     
115. Davidson RN, Wall RA: Prevention and management of infections in patients without a spleen. Clin Microbiol Infect 7 (12): 657-60, 2001.  [PUBMED Abstract]
     
     
116. Fajardo LF, Eltringham JR, Steward JR: Combined cardiotoxicity of adriamycin and x-radiation. Lab Invest 34 (1): 86-96, 1976.  [PUBMED Abstract]
     
     
117. Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA 270 (16): 1949-55, 1993.  [PUBMED Abstract]
     
     
118. King V, Constine LS, Clark D, et al.: Symptomatic coronary artery disease after mantle irradiation for Hodgkin's disease. Int J Radiat Oncol Biol Phys 36 (4): 881-9, 1996.  [PUBMED Abstract]
     
     
119. Adams MJ, Lipshultz SE, Schwartz C, et al.: Radiation-associated cardiovascular disease: manifestations and management. Semin Radiat Oncol 13 (3): 346-56, 2003.  [PUBMED Abstract]
     
     
120. Hancock SL, Donaldson SS, Hoppe RT: Cardiac disease following treatment of Hodgkin's disease in children and adolescents. J Clin Oncol 11 (7): 1208-15, 1993.  [PUBMED Abstract]
     
     
121. Ewer MS, Jaffe N, Ried H, et al.: Doxorubicin cardiotoxicity in children: comparison of a consecutive divided daily dose administration schedule with single dose (rapid) infusion administration. Med Pediatr Oncol 31 (6): 512-5, 1998.  [PUBMED Abstract]
     
     
122. Giantris A, Abdurrahman L, Hinkle A, et al.: Anthracycline-induced cardiotoxicity in children and young adults. Crit Rev Oncol Hematol 27 (1): 53-68, 1998.  [PUBMED Abstract]
     
     
123. Green DM, Grigoriev YA, Nan B, et al.: Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study group. J Clin Oncol 19 (7): 1926-34, 2001.  [PUBMED Abstract]
     
     
124. Krischer JP, Epstein S, Cuthbertson DD, et al.: Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol 15 (4): 1544-52, 1997.  [PUBMED Abstract]
     
     
125. Lipshultz SE, Sanders SP, Goorin AM, et al.: Monitoring for anthracycline cardiotoxicity. Pediatrics 93 (3): 433-7, 1994.  [PUBMED Abstract]
     
     
126. Lipshultz SE, Lipsitz SR, Mone SM, et al.: Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 332 (26): 1738-43, 1995.  [PUBMED Abstract]
     
     
127. Lipshultz S, Lipsitz S, Sallan S, et al.: Chronic progressive left ventricular systolic dysfunction and afterload excess years after doxorubicin therapy for childhood acute lymphoblastic leukemia. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A-2281, 580a, 2000. 
     
     
128. Lipshultz SE, Giantris AL, Lipsitz SR, et al.: Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol. J Clin Oncol 20 (6): 1677-82, 2002.  [PUBMED Abstract]
     
     
129. Nysom K, Holm K, Lipsitz SR, et al.: Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol 16 (2): 545-50, 1998.  [PUBMED Abstract]
     
     
130. Silber JH, Jakacki RI, Larsen RL, et al.: Increased risk of cardiac dysfunction after anthracyclines in girls. Med Pediatr Oncol 21 (7): 477-9, 1993.  [PUBMED Abstract]
     
     
131. Steinherz LJ, Graham T, Hurwitz R, et al.: Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics 89 (5 Pt 1): 942-9, 1992.  [PUBMED Abstract]
     
     
132. Steinherz LJ, Steinherz PG, Tan C: Cardiac failure and dysrhythmias 6-19 years after anthracycline therapy: a series of 15 patients. Med Pediatr Oncol 24 (6): 352-61, 1995.  [PUBMED Abstract]
     
     
133. Grenier MA, Lipshultz SE: Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol 25 (4 Suppl 10): 72-85, 1998.  [PUBMED Abstract]
     
     
134. Zinzani PL, Gherlinzoni F, Piovaccari G, et al.: Cardiac injury as late toxicity of mediastinal radiation therapy for Hodgkin's disease patients. Haematologica 81 (2): 132-7, 1996 Mar-Apr.  [PUBMED Abstract]
     
     
135. de Valeriola D: Dose optimization of anthracyclines. Anticancer Res 14 (6A): 2307-13, 1994 Nov-Dec.  [PUBMED Abstract]
     
     
136. Shapira J, Gotfried M, Lishner M, et al.: Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen. A prospective randomized evaluation. Cancer 65 (4): 870-3, 1990.  [PUBMED Abstract]
     
     
137. Storm G, van Hoesel QG, de Groot G, et al.: A comparative study on the antitumor effect, cardiotoxicity and nephrotoxicity of doxorubicin given as a bolus, continuous infusion or entrapped in liposomes in the Lou/M Wsl rat. Cancer Chemother Pharmacol 24 (6): 341-8, 1989.  [PUBMED Abstract]
     
     
138. Legha SS, Benjamin RS, Mackay B, et al.: Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96 (2): 133-9, 1982.  [PUBMED Abstract]
     
     
139. Herman EH, Zhang J, Rifai N, et al.: The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity. Cancer Chemother Pharmacol 48 (4): 297-304, 2001.  [PUBMED Abstract]
     
     
140. Lipshultz SE: Dexrazoxane for protection against cardiotoxic effects of anthracyclines in children. J Clin Oncol 14 (2): 328-31, 1996.  [PUBMED Abstract]
     
     
141. Swain SM, Whaley FS, Gerber MC, et al.: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15 (4): 1318-32, 1997.  [PUBMED Abstract]
     
     
142. Venturini M, Michelotti A, Del Mastro L, et al.: Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 14 (12): 3112-20, 1996.  [PUBMED Abstract]
     
     
143. Wexler LH: Ameliorating anthracycline cardiotoxicity in children with cancer: clinical trials with dexrazoxane. Semin Oncol 25 (4 Suppl 10): 86-92, 1998.  [PUBMED Abstract]
     
     
144. Schwartz CL, Constine LS, London W, et al.: POG 9425: response-based, intensively timed therapy for intermediate/high stage (IS/HS) pediatric Hodgkin's disease. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1555, 2002. 
     
     
145. Tebbi CK, Mendenhall N, Schwartz C, et al.: Response dependent treatment of stages IA, IIA, and IIIA1micro Hodgkin's disease with DBVE and low dose involved field irradiation with or without dexrazoxane. [Abstract] Leuk Lymphoma 42 (Suppl 1): P-100, 56, 2001. 
     
     
146. Hamm CW: Cardiac biomarkers for rapid evaluation of chest pain. Circulation 104 (13): 1454-6, 2001.  [PUBMED Abstract]
     
     
147. Heeschen C, Goldmann BU, Terres W, et al.: Cardiovascular risk and therapeutic benefit of coronary interventions for patients with unstable angina according to the troponin T status. Eur Heart J 21 (14): 1159-66, 2000.  [PUBMED Abstract]
     
     
148. Herman EH, Zhang J, Lipshultz SE, et al.: Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. J Clin Oncol 17 (7): 2237-43, 1999.  [PUBMED Abstract]
     
     
149. Lipshultz SE, Rifai N, Sallan SE, et al.: Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 96 (8): 2641-8, 1997.  [PUBMED Abstract]
     
     
150. Mathew P, Suarez W, Kip K, et al.: Is there a potential role for serum cardiac troponin I as a marker for myocardial dysfunction in pediatric patients receiving anthracycline-based therapy? A pilot study. Cancer Invest 19 (4): 352-9, 2001.  [PUBMED Abstract]
     
     
151. Lipshultz SE, Lipsitz SR, Sallan SE, et al.: Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood cancer. J Clin Oncol 20 (23): 4517-22, 2002.  [PUBMED Abstract]
     
     
152. Schwartz CL, Hobbie WL, Truesdell S, et al.: Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer. J Clin Oncol 11 (10): 1906-10, 1993.  [PUBMED Abstract]
     
     
153. Jakacki RI, Goldwein JW, Larsen RL, et al.: Cardiac dysfunction following spinal irradiation during childhood. J Clin Oncol 11 (6): 1033-8, 1993.  [PUBMED Abstract]
     
     
154. Gurney JG, Kadan-Lottick NS, Packer RJ, et al.: Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study. Cancer 97 (3): 663-73, 2003.  [PUBMED Abstract]
     
     
155. Carlson K, Smedmyr B, Bäcklund L, et al.: Subclinical disturbances in cardiac function at rest and in gas exchange during exercise are common findings after autologous bone marrow transplantation. Bone Marrow Transplant 14 (6): 949-54, 1994.  [PUBMED Abstract]
     
     
156. Eames GM, Crosson J, Steinberger J, et al.: Cardiovascular function in children following bone marrow transplant: a cross-sectional study. Bone Marrow Transplant 19 (1): 61-6, 1997.  [PUBMED Abstract]
     
     
157. Hertenstein B, Stefanic M, Schmeiser T, et al.: Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant. J Clin Oncol 12 (5): 998-1004, 1994.  [PUBMED Abstract]
     
     
158. Hogarty AN, Leahey A, Zhao H, et al.: Longitudinal evaluation of cardiopulmonary performance during exercise after bone marrow transplantation in children. J Pediatr 136 (3): 311-7, 2000.  [PUBMED Abstract]
     
     
159. Pihkala J, Happonen JM, Virtanen K, et al.: Cardiopulmonary evaluation of exercise tolerance after chest irradiation and anticancer chemotherapy in children and adolescents. Pediatrics 95 (5): 722-6, 1995.  [PUBMED Abstract]
     
     
160. De Wolf D, Suys B, Matthys D: Stress echocardiography in the evaluation of late cardiac toxicity after moderate dose of antyracycline therapy in childhood. International Journal of Pediatric Hematology/Oncology 1: 399-404, 1994. 
     
     
161. Jakacki RI, Larsen RL, Barber G, et al.: Comparison of cardiac function tests after anthracycline therapy in childhood. Implications for screening. Cancer 72 (9): 2739-45, 1993.  [PUBMED Abstract]
     
     
162. Jenney ME, Faragher EB, Jones PH, et al.: Lung function and exercise capacity in survivors of childhood leukaemia. Med Pediatr Oncol 24 (4): 222-30, 1995.  [PUBMED Abstract]
     
     
163. Turner-Gomes SO, Lands LC, Halton J, et al.: Cardiorespiratory status after treatment for acute lymphoblastic leukemia. Med Pediatr Oncol 26 (3): 160-5, 1996.  [PUBMED Abstract]
     
     
164. Poutanen T, Tikanoja T, Riikonen P, et al.: Long-term prospective follow-up study of cardiac function after cardiotoxic therapy for malignancy in children. J Clin Oncol 21 (12): 2349-56, 2003.  [PUBMED Abstract]
     
     
165. McDonald S, Rubin P, Maasilta P: Response of normal lung to irradiation. Tolerance doses/tolerance volumes in pulmonary radiation syndromes. Front Radiat Ther Oncol 23: 255-76; discussion 299-301, 1989.  [PUBMED Abstract]
     
     
166. McDonald S, Rubin P, Phillips TL, et al.: Injury to the lung from cancer therapy: clinical syndromes, measurable endpoints, and potential scoring systems. Int J Radiat Oncol Biol Phys 31 (5): 1187-203, 1995.  [PUBMED Abstract]
     
     
167. Kreisman H, Wolkove N: Pulmonary toxicity of antineoplastic therapy. Semin Oncol 19 (5): 508-20, 1992.  [PUBMED Abstract]
     
     
168. Bossi G, Cerveri I, Volpini E, et al.: Long-term pulmonary sequelae after treatment of childhood Hodgkin's disease. Ann Oncol 8 (Suppl 1): 19-24, 1997.  [PUBMED Abstract]
     
     
169. Fryer CJ, Hutchinson RJ, Krailo M, et al.: Efficacy and toxicity of 12 courses of ABVD chemotherapy followed by low-dose regional radiation in advanced Hodgkin's disease in children: a report from the Children's Cancer Study Group. J Clin Oncol 8 (12): 1971-80, 1990.  [PUBMED Abstract]
     
     
170. Mefferd JM, Donaldson SS, Link MP: Pediatric Hodgkin's disease: pulmonary, cardiac, and thyroid function following combined modality therapy. Int J Radiat Oncol Biol Phys 16 (3): 679-85, 1989.  [PUBMED Abstract]
     
     
171. Marina NM, Greenwald CA, Fairclough DL, et al.: Serial pulmonary function studies in children treated for newly diagnosed Hodgkin's disease with mantle radiotherapy plus cycles of cyclophosphamide, vincristine, and procarbazine alternating with cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Cancer 75 (7): 1706-11, 1995.  [PUBMED Abstract]
     
     
172. Nysom K, Holm K, Hertz H, et al.: Risk factors for reduced pulmonary function after malignant lymphoma in childhood. Med Pediatr Oncol 30 (4): 240-8, 1998.  [PUBMED Abstract]
     
     
173. Nysom K, Holm K, Olsen JH, et al.: Pulmonary function after treatment for acute lymphoblastic leukaemia in childhood. Br J Cancer 78 (1): 21-7, 1998.  [PUBMED Abstract]
     
     
174. Cerveri I, Fulgoni P, Giorgiani G, et al.: Lung function abnormalities after bone marrow transplantation in children: has the trend recently changed? Chest 120 (6): 1900-6, 2001.  [PUBMED Abstract]
     
     
175. Kaplan EB, Wodell RA, Wilmott RW, et al.: Late effects of bone marrow transplantation on pulmonary function in children. Bone Marrow Transplant 14 (4): 613-21, 1994.  [PUBMED Abstract]
     
     
176. Nenadov Beck M, Meresse V, Hartmann O, et al.: Long-term pulmonary sequelae after autologous bone marrow transplantation in children without total body irradiation. Bone Marrow Transplant 16 (6): 771-5, 1995.  [PUBMED Abstract]
     
     
177. Nysom K, Holm K, Hesse B, et al.: Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma. Arch Dis Child 74 (5): 432-6, 1996.  [PUBMED Abstract]
     
     
178. Leiper AD: Non-endocrine late complications of bone marrow transplantation in childhood: part II. Br J Haematol 118 (1): 23-43, 2002.  [PUBMED Abstract]
     
     
179. Schultz KR, Green GJ, Wensley D, et al.: Obstructive lung disease in children after allogeneic bone marrow transplantation. Blood 84 (9): 3212-20, 1994.  [PUBMED Abstract]
     
     
180. Mertens AC, Yasui Y, Liu Y, et al.: Pulmonary complications in survivors of childhood and adolescent cancer. A report from the Childhood Cancer Survivor Study. Cancer 95 (11): 2431-41, 2002.  [PUBMED Abstract]
     
     
181. Bianchetti MG, Kanaka C, Ridolfi-Lüthy A, et al.: Persisting renotubular sequelae after cisplatin in children and adolescents. Am J Nephrol 11 (2): 127-30, 1991.  [PUBMED Abstract]
     
     
182. Cvitkovic E: Cumulative toxicities from cisplatin therapy and current cytoprotective measures. Cancer Treat Rev 24 (4): 265-81, 1998.  [PUBMED Abstract]
     
     
183. Hutchison FN, Perez EA, Gandara DR, et al.: Renal salt wasting in patients treated with cisplatin. Ann Intern Med 108 (1): 21-5, 1988.  [PUBMED Abstract]
     
     
184. Ettinger LJ, Krailo MD, Gaynon PS, et al.: A phase I study of carboplatin in children with acute leukemia in bone marrow relapse. A report from the Childrens Cancer Group. Cancer 72 (3): 917-22, 1993.  [PUBMED Abstract]
     
     
185. Ettinger LJ, Gaynon PS, Krailo MD, et al.: A phase II study of carboplatin in children with recurrent or progressive solid tumors. A report from the Childrens Cancer Group. Cancer 73 (4): 1297-301, 1994.  [PUBMED Abstract]
     
     
186. Gaynon PS, Ettinger LJ, Baum ES, et al.: Carboplatin in childhood brain tumors. A Children's Cancer Study Group Phase II trial. Cancer 66 (12): 2465-9, 1990.  [PUBMED Abstract]
     
     
187. Meyer WH, Pratt CB, Poquette CA, et al.: Carboplatin/ifosfamide window therapy for osteosarcoma: results of the St Jude Children's Research Hospital OS-91 trial. J Clin Oncol 19 (1): 171-82, 2001.  [PUBMED Abstract]
     
     
188. Stern JW, Bunin N: Prospective study of carboplatin-based chemotherapy for pediatric germ cell tumors. Med Pediatr Oncol 39 (3): 163-7, 2002.  [PUBMED Abstract]
     
     
189. Arndt C, Morgenstern B, Wilson D, et al.: Renal function in children and adolescents following 72 g/m2 of ifosfamide. Cancer Chemother Pharmacol 34 (5): 431-3, 1994.  [PUBMED Abstract]
     
     
190. Arndt C, Morgenstern B, Hawkins D, et al.: Renal function following combination chemotherapy with ifosfamide and cisplatin in patients with osteogenic sarcoma. Med Pediatr Oncol 32 (2): 93-6, 1999.  [PUBMED Abstract]
     
     
191. Loebstein R, Koren G: Ifosfamide-induced nephrotoxicity in children: critical review of predictive risk factors. Pediatrics 101 (6): E8, 1998.  [PUBMED Abstract]
     
     
192. Prasad VK, Lewis IJ, Aparicio SR, et al.: Progressive glomerular toxicity of ifosfamide in children. Med Pediatr Oncol 27 (3): 149-55, 1996.  [PUBMED Abstract]
     
     
193. Skinner R, Pearson AD, English MW, et al.: Risk factors for ifosfamide nephrotoxicity in children. Lancet 348 (9027): 578-80, 1996.  [PUBMED Abstract]
     
     
194. Cassady JR: Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys 31 (5): 1249-56, 1995.  [PUBMED Abstract]
     
     
195. Irwin C, Fyles A, Wong CS, et al.: Late renal function following whole abdominal irradiation. Radiother Oncol 38 (3): 257-61, 1996.  [PUBMED Abstract]
     
     
196. Cassady JR, Lebowitz RL, Jaffe N, et al.: Effect of low dose irradiation on renal enlargement in children following nephrectomy for Wilms' tumor. Acta Radiol Oncol 20 (1): 5-8, 1981.  [PUBMED Abstract]
     
     
197. Ritchey ML, Green DM, Thomas PR, et al.: Renal failure in Wilms' tumor patients: a report from the National Wilms' Tumor Study Group. Med Pediatr Oncol 26 (2): 75-80, 1996.  [PUBMED Abstract]
     
     
198. Smith GR, Thomas PR, Ritchey M, et al.: Long-term renal function in patients with irradiated bilateral Wilms tumor. National Wilms' Tumor Study Group. Am J Clin Oncol 21 (1): 58-63, 1998.  [PUBMED Abstract]
     
     
199. Bailey S, Roberts A, Brock C, et al.: Nephrotoxicity in survivors of Wilms' tumours in the North of England. Br J Cancer 87 (10): 1092-8, 2002.  [PUBMED Abstract]
     
     
200. Breslow NE, Takashima JR, Ritchey ML, et al.: Renal failure in the Denys-Drash and Wilms' tumor-aniridia syndromes. Cancer Res 60 (15): 4030-2, 2000.  [PUBMED Abstract]
     
     
201. Gleeson HK, Darzy K, Shalet SM: Late endocrine, metabolic and skeletal sequelae following treatment of childhood cancer. Best Pract Res Clin Endocrinol Metab 16 (2): 335-48, 2002.  [PUBMED Abstract]
     
     
202. Sklar CA: Overview of the effects of cancer therapies: the nature, scale and breadth of the problem. Acta Paediatr Suppl 88 (433): 1-4, 1999.  [PUBMED Abstract]
     
     
203. Shalet SM: Endocrine sequelae of cancer therapy. Eur J Endocrinol 135 (2): 135-43, 1996.  [PUBMED Abstract]
     
     
204. Oberfield SE, Chin D, Uli N, et al.: Endocrine late effects of childhood cancers. J Pediatr 131 (1 Pt 2): S37-41, 1997.  [PUBMED Abstract]
     
     
205. Hancock SL, McDougall IR, Constine LS: Thyroid abnormalities after therapeutic external radiation. Int J Radiat Oncol Biol Phys 31 (5): 1165-70, 1995.  [PUBMED Abstract]
     
     
206. Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 325 (9): 599-605, 1991.  [PUBMED Abstract]
     
     
207. Constine LS, Donaldson SS, McDougall IR, et al.: Thyroid dysfunction after radiotherapy in children with Hodgkin's disease. Cancer 53 (4): 878-83, 1984.  [PUBMED Abstract]
     
     
208. Sklar C, Whitton J, Mertens A, et al.: Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85 (9): 3227-32, 2000.  [PUBMED Abstract]
     
     
209. Sanders JE: The impact of marrow transplant preparative regimens on subsequent growth and development. The Seattle Marrow Transplant Team. Semin Hematol 28 (3): 244-9, 1991.  [PUBMED Abstract]
     
     
210. Borgström B, Bolme P: Thyroid function in children after allogeneic bone marrow transplantation. Bone Marrow Transplant 13 (1): 59-64, 1994.  [PUBMED Abstract]
     
     
211. Constine LS, Woolf PD, Cann D, et al.: Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 328 (2): 87-94, 1993.  [PUBMED Abstract]
     
     
212. Ogilvy-Stuart AL, Wallace WH, Shalet SM: Radiation and neuroregulatory control of growth hormone secretion. Clin Endocrinol (Oxf) 41 (2): 163-8, 1994.  [PUBMED Abstract]
     
     
213. Rapaport R, Oberfield SE, Robison L, et al.: Relationship of growth hormone deficiency and leukemia. J Pediatr 126 (5 Pt 1): 759-61, 1995.  [PUBMED Abstract]
     
     
214. Sklar CA: Growth and neuroendocrine dysfunction following therapy for childhood cancer. Pediatr Clin North Am 44 (2): 489-503, 1997.  [PUBMED Abstract]
     
     
215. Merchant TE, Goloubeva O, Pritchard DL, et al.: Radiation dose-volume effects on growth hormone secretion. Int J Radiat Oncol Biol Phys 52 (5): 1264-70, 2002.  [PUBMED Abstract]
     
     
216. Sklar C, Mertens A, Walter A, et al.: Final height after treatment for childhood acute lymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400 centigrays of cranial irradiation. J Pediatr 123 (1): 59-64, 1993.  [PUBMED Abstract]
     
     
217. Schriock EA, Schell MJ, Carter M, et al.: Abnormal growth patterns and adult short stature in 115 long-term survivors of childhood leukemia. J Clin Oncol 9 (3): 400-5, 1991.  [PUBMED Abstract]
     
     
218. Sanders JE: Endocrine problems in children after bone marrow transplant for hematologic malignancies. The Long-term Follow-up Team. Bone Marrow Transplant 8 (Suppl 1): 2-4, 1991.  [PUBMED Abstract]
     
     
219. Ogilvy-Stuart AL, Clark DJ, Wallace WH, et al.: Endocrine deficit after fractionated total body irradiation. Arch Dis Child 67 (9): 1107-10, 1992.  [PUBMED Abstract]
     
     
220. Willi SM, Cooke K, Goldwein J, et al.: Growth in children after bone marrow transplantation for advanced neuroblastoma compared with growth after transplantation for leukemia or aplastic anemia. J Pediatr 120 (5): 726-32, 1992.  [PUBMED Abstract]
     
     
221. Wingard JR, Plotnick LP, Freemer CS, et al.: Growth in children after bone marrow transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body irradiation. Blood 79 (4): 1068-73, 1992.  [PUBMED Abstract]
     
     
222. Huma Z, Boulad F, Black P, et al.: Growth in children after bone marrow transplantation for acute leukemia. Blood 86 (2): 819-24, 1995.  [PUBMED Abstract]
     
     
223. Socié G, Salooja N, Cohen A, et al.: Nonmalignant late effects after allogeneic stem cell transplantation. Blood 101 (9): 3373-85, 2003.  [PUBMED Abstract]
     
     
224. Cohen A, Rovelli A, Bakker B, et al.: Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT. Blood 93 (12): 4109-15, 1999.  [PUBMED Abstract]
     
     
225. Sklar CA, Mertens AC, Mitby P, et al.: Risk of disease recurrence and second neoplasms in survivors of childhood cancer treated with growth hormone: a report from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 87 (7): 3136-41, 2002.  [PUBMED Abstract]
     
     
226. Didcock E, Davies HA, Didi M, et al.: Pubertal growth in young adult survivors of childhood leukemia. J Clin Oncol 13 (10): 2503-7, 1995.  [PUBMED Abstract]
     
     
227. Shalet SM, Brennan BM: Puberty in children with cancer. Horm Res 57 (Suppl 2): 39-42, 2002.  [PUBMED Abstract]
     
     
228. Shalet SM, Crowne EC, Didi MA, et al.: Irradiation-induced growth failure. Baillieres Clin Endocrinol Metab 6 (3): 513-26, 1992.  [PUBMED Abstract]
     
     
229. Rappaport R, Brauner R, Czernichow P, et al.: Effect of hypothalamic and pituitary irradiation on pubertal development in children with cranial tumors. J Clin Endocrinol Metab 54 (6): 1164-8, 1982.  [PUBMED Abstract]
     
     
230. Constine LS, Rubin P, Woolf PD, et al.: Hyperprolactinemia and hypothyroidism following cytotoxic therapy for central nervous system malignancies. J Clin Oncol 5 (11): 1841-51, 1987.  [PUBMED Abstract]
     
     
231. Willman KY, Cox RS, Donaldson SS: Radiation induced height impairment in pediatric Hodgkin's disease. Int J Radiat Oncol Biol Phys 28 (1): 85-92, 1994.  [PUBMED Abstract]
     
     
232. Hogeboom CJ, Grosser SC, Guthrie KA, et al.: Stature loss following treatment for Wilms tumor. Med Pediatr Oncol 36 (2): 295-304, 2001.  [PUBMED Abstract]
     
     
233. Silber JH, Littman PS, Meadows AT: Stature loss following skeletal irradiation for childhood cancer. J Clin Oncol 8 (2): 304-12, 1990.  [PUBMED Abstract]
     
     
234. Sklar CA: Growth following therapy for childhood cancer. Cancer Invest 13 (5): 511-6, 1995.  [PUBMED Abstract]
     
     
235. Hoelzer D, Gökbuget N, Ottmann O, et al.: Acute lymphoblastic leukemia. Hematology (Am Soc Hematol Educ Program) : 162-92, 2002.  [PUBMED Abstract]
     
     
236. Gaynon PS, Carrel AL: Glucocorticosteroid therapy in childhood acute lymphoblastic leukemia. Adv Exp Med Biol 457: 593-605, 1999.  [PUBMED Abstract]
     
     
237. Shusterman S, Meadows AT: Long term survivors of childhood leukemia. Curr Opin Hematol 7 (4): 217-22, 2000.  [PUBMED Abstract]
     
     
238. Fletcher BD, Crom DB, Krance RA, et al.: Radiation-induced bone abnormalities after bone marrow transplantation for childhood leukemia. Radiology 191 (1): 231-5, 1994.  [PUBMED Abstract]
     
     
239. Gaynon PS, Lustig RH: The use of glucocorticoids in acute lymphoblastic leukemia of childhood. Molecular, cellular, and clinical considerations. J Pediatr Hematol Oncol 17 (1): 1-12, 1995.  [PUBMED Abstract]
     
     
240. Seibel NL, Steinherz P, Sather H, et al.: Early treatment intensification improves outcome in children and adolescents with acute lymphoblastic leukemia (ALL) presenting with unfavorable features who show a rapid early response (RER) to induction chemotherapy: a report of CCG-1961. [Abstract] Blood 102 (11): A-787, 2003. 
     
     
241. Kaste SC, Jones-Wallace D, Rose SR, et al.: Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development. Leukemia 15 (5): 728-34, 2001.  [PUBMED Abstract]
     
     
242. Brennan B, Shalet SM: Reduced bone mineral density at completion of chemotherapy for a malignancy. Arch Dis Child 81 (4): 372, 1999.  [PUBMED Abstract]
     
     
243. Arikoski P, Komulainen J, Voutilainen R, et al.: Reduced bone mineral density in long-term survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 20 (3): 234-40, 1998 May-Jun.  [PUBMED Abstract]
     
     
244. Kadan-Lottick N, Marshall JA, Barón AE, et al.: Normal bone mineral density after treatment for childhood acute lymphoblastic leukemia diagnosed between 1991 and 1998. J Pediatr 138 (6): 898-904, 2001.  [PUBMED Abstract]
     
     
245. Aisenberg J, Hsieh K, Kalaitzoglou G, et al.: Bone mineral density in young adult survivors of childhood cancer. J Pediatr Hematol Oncol 20 (3): 241-5, 1998 May-Jun.  [PUBMED Abstract]
     
     
246. Strauss AJ, Su JT, Dalton VM, et al.: Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol 19 (12): 3066-72, 2001.  [PUBMED Abstract]
     
     
247. Vassilopoulou-Sellin R, Brosnan P, Delpassand A, et al.: Osteopenia in young adult survivors of childhood cancer. Med Pediatr Oncol 32 (4): 272-8, 1999.  [PUBMED Abstract]
     
     
248. van Leeuwen BL, Kamps WA, Jansen HW, et al.: The effect of chemotherapy on the growing skeleton. Cancer Treat Rev 26 (5): 363-76, 2000.  [PUBMED Abstract]
     
     
249. van der Sluis IM, van den Heuvel-Eibrink MM, Hählen K, et al.: Altered bone mineral density and body composition, and increased fracture risk in childhood acute lymphoblastic leukemia. J Pediatr 141 (2): 204-10, 2002.  [PUBMED Abstract]
     
     
250. Azcona C, Burghard E, Ruza E, et al.: Reduced bone mineralization in adolescent survivors of malignant bone tumors: comparison of quantitative ultrasound and dual-energy x-ray absorptiometry. J Pediatr Hematol Oncol 25 (4): 297-302, 2003.  [PUBMED Abstract]
     
     
251. Holzer G, Krepler P, Koschat MA, et al.: Bone mineral density in long-term survivors of highly malignant osteosarcoma. J Bone Joint Surg Br 85 (2): 231-7, 2003.  [PUBMED Abstract]
     
     
252. Othman F, Guo CY, Webber C, et al.: Osteopenia in survivors of Wilms tumor. Int J Oncol 20 (4): 827-33, 2002.  [PUBMED Abstract]
     
     
253. Barr RD, Simpson T, Webber CE, et al.: Osteopenia in children surviving brain tumours. Eur J Cancer 34 (6): 873-7, 1998.  [PUBMED Abstract]
     
     
254. Välimäki MJ, Kinnunen K, Volin L, et al.: A prospective study of bone loss and turnover after allogeneic bone marrow transplantation: effect of calcium supplementation with or without calcitonin. Bone Marrow Transplant 23 (4): 355-61, 1999.  [PUBMED Abstract]
     
     
255. Kauppila M, Irjala K, Koskinen P, et al.: Bone mineral density after allogeneic bone marrow transplantation. Bone Marrow Transplant 24 (8): 885-9, 1999.  [PUBMED Abstract]
     
     
256. Bhatia S, Ramsay NK, Weisdorf D, et al.: Bone mineral density in patients undergoing bone marrow transplantation for myeloid malignancies. Bone Marrow Transplant 22 (1): 87-90, 1998.  [PUBMED Abstract]
     
     
257. Nysom K, Holm K, Michaelsen KF, et al.: Bone mass after allogeneic BMT for childhood leukaemia or lymphoma. Bone Marrow Transplant 25 (2): 191-6, 2000.  [PUBMED Abstract]
     
     
258. Greenspan SL, Harris ST, Bone H, et al.: Bisphosphonates: safety and efficacy in the treatment and prevention of osteoporosis. Am Fam Physician 61 (9): 2731-6, 2000.  [PUBMED Abstract]
     
     
259. Sherman S: Preventing and treating osteoporosis: strategies at the millennium. Ann N Y Acad Sci 949: 188-97, 2001.  [PUBMED Abstract]
     
     
260. Oeffinger KC, Mertens AC, Sklar CA, et al.: Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 21 (7): 1359-65, 2003.  [PUBMED Abstract]
     
     
261. Warner JT, Evans WD, Webb DK, et al.: Body composition of long-term survivors of acute lymphoblastic leukaemia. Med Pediatr Oncol 38 (3): 165-72, 2002.  [PUBMED Abstract]
     
     
262. Reilly JJ, Ventham JC, Newell J, et al.: Risk factors for excess weight gain in children treated for acute lymphoblastic leukaemia. Int J Obes Relat Metab Disord 24 (11): 1537-41, 2000.  [PUBMED Abstract]
     
     
263. Reilly JJ, Kelly A, Ness P, et al.: Premature adiposity rebound in children treated for acute lymphoblastic leukemia. J Clin Endocrinol Metab 86 (6): 2775-8, 2001.  [PUBMED Abstract]
     
     
264. Nysom K, Holm K, Michaelsen KF, et al.: Degree of fatness after treatment of malignant lymphoma in childhood. Med Pediatr Oncol 40 (4): 239-43, 2003.  [PUBMED Abstract]
     
     
265. Lustig RH, Post SR, Srivannaboon K, et al.: Risk factors for the development of obesity in children surviving brain tumors. J Clin Endocrinol Metab 88 (2): 611-6, 2003.  [PUBMED Abstract]
     
     
266. Talvensaari KK, Lanning M, Tapanainen P, et al.: Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome. J Clin Endocrinol Metab 81 (8): 3051-5, 1996.  [PUBMED Abstract]
     
     
267. Nuver J, Smit AJ, Postma A, et al.: The metabolic syndrome in long-term cancer survivors, an important target for secondary preventive measures. Cancer Treat Rev 28 (4): 195-214, 2002.  [PUBMED Abstract]
     
     
268. Ben Arush MW, Solt I, Lightman A, et al.: Male gonadal function in survivors of childhood Hodgkin and non-Hodgkin lymphoma. Pediatr Hematol Oncol 17 (3): 239-45, 2000 Apr-May.  [PUBMED Abstract]
     
     
269. Dhabhar BN, Malhotra H, Joseph R, et al.: Gonadal function in prepubertal boys following treatment for Hodgkin's disease. Am J Pediatr Hematol Oncol 15 (3): 306-10, 1993.  [PUBMED Abstract]
     
     
270. Gerres L, Brämswig JH, Schlegel W, et al.: The effects of etoposide on testicular function in boys treated for Hodgkin's disease. Cancer 83 (10): 2217-22, 1998.  [PUBMED Abstract]
     
     
271. Hill M, Milan S, Cunningham D, et al.: Evaluation of the efficacy of the VEEP regimen in adult Hodgkin's disease with assessment of gonadal and cardiac toxicity. J Clin Oncol 13 (2): 387-95, 1995.  [PUBMED Abstract]
     
     
272. Kulkarni SS, Sastry PS, Saikia TK, et al.: Gonadal function following ABVD therapy for Hodgkin's disease. Am J Clin Oncol 20 (4): 354-7, 1997.  [PUBMED Abstract]
     
     
273. Müller U, Stahel RA: Gonadal function after MACOP-B or VACOP-B with or without dose intensification and ABMT in young patients with aggressive non-Hodgkin's lymphoma. Ann Oncol 4 (5): 399-402, 1993.  [PUBMED Abstract]
     
     
274. Pryzant RM, Meistrich ML, Wilson G, et al.: Long-term reduction in sperm count after chemotherapy with and without radiation therapy for non-Hodgkin's lymphomas. J Clin Oncol 11 (2): 239-47, 1993.  [PUBMED Abstract]
     
     
275. Bokemeyer C, Schmoll HJ, van Rhee J, et al.: Long-term gonadal toxicity after therapy for Hodgkin's and non-Hodgkin's lymphoma. Ann Hematol 68 (3): 105-10, 1994.  [PUBMED Abstract]
     
     
276. Kenney LB, Laufer MR, Grant FD, et al.: High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer 91 (3): 613-21, 2001.  [PUBMED Abstract]
     
     
277. Meistrich ML, Wilson G, Brown BW, et al.: Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Cancer 70 (11): 2703-12, 1992.  [PUBMED Abstract]
     
     
278. Relander T, Cavallin-Ståhl E, Garwicz S, et al.: Gonadal and sexual function in men treated for childhood cancer. Med Pediatr Oncol 35 (1): 52-63, 2000.  [PUBMED Abstract]
     
     
279. Schellong G, Pötter R, Brämswig J, et al.: High cure rates and reduced long-term toxicity in pediatric Hodgkin's disease: the German-Austrian multicenter trial DAL-HD-90. The German-Austrian Pediatric Hodgkin's Disease Study Group. J Clin Oncol 17 (12): 3736-44, 1999.  [PUBMED Abstract]
     
     
280. Longhi A, Macchiagodena M, Vitali G, et al.: Fertility in male patients treated with neoadjuvant chemotherapy for osteosarcoma. J Pediatr Hematol Oncol 25 (4): 292-6, 2003.  [PUBMED Abstract]
     
     
281. Thomson AB, Critchley HO, Kelnar CJ, et al.: Late reproductive sequelae following treatment of childhood cancer and options for fertility preservation. Best Pract Res Clin Endocrinol Metab 16 (2): 311-34, 2002.  [PUBMED Abstract]
     
     
282. Ash P: The influence of radiation on fertility in man. Br J Radiol 53 (628): 271-8, 1980.  [PUBMED Abstract]
     
     
283. Lushbaugh CC, Casarett GW: The effects of gonadal irradiation in clinical radiation therapy: a review. Cancer 37 (2 Suppl): 1111-25, 1976.  [PUBMED Abstract]
     
     
284. Sklar CA, Robison LL, Nesbit ME, et al.: Effects of radiation on testicular function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Children Cancer Study Group. J Clin Oncol 8 (12): 1981-7, 1990.  [PUBMED Abstract]
     
     
285. Kinsella TJ, Fraass BA, Glatstein E: Late effects of radiation therapy in the treatment of Hodgkin's disease. Cancer Treat Rep 66 (4): 991-1001, 1982.  [PUBMED Abstract]
     
     
286. Bath LE, Wallace WH, Critchley HO: Late effects of the treatment of childhood cancer on the female reproductive system and the potential for fertility preservation. BJOG 109 (2): 107-14, 2002.  [PUBMED Abstract]
     
     
287. Damewood MD, Grochow LB: Prospects for fertility after chemotherapy or radiation for neoplastic disease. Fertil Steril 45 (4): 443-59, 1986.  [PUBMED Abstract]
     
     
288. Mayer EI, Dopfer RE, Klingebiel T, et al.: Longitudinal gonadal function after bone marrow transplantation for acute lymphoblastic leukemia during childhood. Pediatr Transplant 3 (1): 38-44, 1999.  [PUBMED Abstract]
     
     
289. Nicosia SV, Matus-Ridley M, Meadows AT: Gonadal effects of cancer therapy in girls. Cancer 55 (10): 2364-72, 1985.  [PUBMED Abstract]
     
     
290. Kreuser ED, Felsenberg D, Behles C, et al.: Long-term gonadal dysfunction and its impact on bone mineralization in patients following COPP/ABVD chemotherapy for Hodgkin's disease. Ann Oncol 3 (Suppl 4): 105-10, 1992.  [PUBMED Abstract]
     
     
291. Byrne J, Mulvihill JJ, Myers MH, et al.: Effects of treatment on fertility in long-term survivors of childhood or adolescent cancer. N Engl J Med 317 (21): 1315-21, 1987.  [PUBMED Abstract]
     
     
292. Chiarelli AM, Marrett LD, Darlington G: Early menopause and infertility in females after treatment for childhood cancer diagnosed in 1964-1988 in Ontario, Canada. Am J Epidemiol 150 (3): 245-54, 1999.  [PUBMED Abstract]
     
     
293. Santoro A, Valagussa P: Advances in the treatment of Hodgkin's disease. Curr Opin Oncol 4 (5): 821-8, 1992.  [PUBMED Abstract]
     
     
294. Longhi A, Pignotti E, Versari M, et al.: Effect of oral contraceptive on ovarian function in young females undergoing neoadjuvant chemotherapy treatment for osteosarcoma. Oncol Rep 10 (1): 151-5, 2003 Jan-Feb.  [PUBMED Abstract]
     
     
295. Wallace WH, Shalet SM, Hendry JH, et al.: Ovarian failure following abdominal irradiation in childhood: the radiosensitivity of the human oocyte. Br J Radiol 62 (743): 995-8, 1989.  [PUBMED Abstract]
     
     
296. Critchley HO, Bath LE, Wallace WH: Radiation damage to the uterus -- review of the effects of treatment of childhood cancer. Hum Fertil (Camb) 5 (2): 61-6, 2002.  [PUBMED Abstract]
     
     
297. Green DM, Whitton JA, Stovall M, et al.: Pregnancy outcome of female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Am J Obstet Gynecol 187 (4): 1070-80, 2002.  [PUBMED Abstract]
     
     
298. Green DM, Whitton JA, Stovall M, et al.: Pregnancy outcome of partners of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 21 (4): 716-21, 2003.  [PUBMED Abstract]
     
     
299. Green DM, Peabody EM, Nan B, et al.: Pregnancy outcome after treatment for Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 20 (10): 2506-13, 2002.  [PUBMED Abstract]
     
     
300. Teinturier C, Hartmann O, Valteau-Couanet D, et al.: Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure. Bone Marrow Transplant 22 (10): 989-94, 1998.  [PUBMED Abstract]
     
     
301. Sanders JE, Hawley J, Levy W, et al.: Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 87 (7): 3045-52, 1996.  [PUBMED Abstract]
     
     
302. Agarwa A: Semen banking in patients with cancer: 20-year experience. Int J Androl 23 (Suppl 2): 16-9, 2000.  [PUBMED Abstract]
     
     
303. Hallak J, Hendin BN, Thomas AJ Jr, et al.: Investigation of fertilizing capacity of cryopreserved spermatozoa from patients with cancer. J Urol 159 (4): 1217-20, 1998.  [PUBMED Abstract]
     
     
304. Khalifa E, Oehninger S, Acosta AA, et al.: Successful fertilization and pregnancy outcome in in-vitro fertilization using cryopreserved/thawed spermatozoa from patients with malignant diseases. Hum Reprod 7 (1): 105-8, 1992.  [PUBMED Abstract]
     
     
305. Müller J, Sønksen J, Sommer P, et al.: Cryopreservation of semen from pubertal boys with cancer. Med Pediatr Oncol 34 (3): 191-4, 2000.  [PUBMED Abstract]
     
     
306. Damani MN, Master V, Meng MV, et al.: Postchemotherapy ejaculatory azoospermia: fatherhood with sperm from testis tissue with intracytoplasmic sperm injection. J Clin Oncol 20 (4): 930-6, 2002.  [PUBMED Abstract]
     
     
307. Pfeifer SM, Coutifaris C: Reproductive technologies 1998: options available for the cancer patient. Med Pediatr Oncol 33 (1): 34-40, 1999.  [PUBMED Abstract]
     
     
308. Bahadur G, Steele SJ: Ovarian tissue cryopreservation for patients. Hum Reprod 11 (10): 2215-6, 1996.  [PUBMED Abstract]
     
     
309. Donnez J, Godin PA, Qu J, et al.: Gonadal cryopreservation in the young patient with gynaecological malignancy. Curr Opin Obstet Gynecol 12 (1): 1-9, 2000.  [PUBMED Abstract]
     
     
310. Newton H: The cryopreservation of ovarian tissue as a strategy for preserving the fertility of cancer patients. Hum Reprod Update 4 (3): 237-47, 1998 May-Jun.  [PUBMED Abstract]
     
     
311. Byrne J, Rasmussen SA, Steinhorn SC, et al.: Genetic disease in offspring of long-term survivors of childhood and adolescent cancer. Am J Hum Genet 62 (1): 45-52, 1998.  [PUBMED Abstract]
     
     
312. Green DM, Fiorello A, Zevon MA, et al.: Birth defects and childhood cancer in offspring of survivors of childhood cancer. Arch Pediatr Adolesc Med 151 (4): 379-83, 1997.  [PUBMED Abstract]
     
     
313. Hansen M, Kurinczuk JJ, Bower C, et al.: The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 346 (10): 725-30, 2002.  [PUBMED Abstract]
     
     
314. Bonduelle M, Liebaers I, Deketelaere V, et al.: Neonatal data on a cohort of 2889 infants born after ICSI (1991-1999) and of 2995 infants born after IVF (1983-1999). Hum Reprod 17 (3): 671-94, 2002.  [PUBMED Abstract]
     
     
315. Simpson JL, Lamb DJ: Genetic effects of intracytoplasmic sperm injection. Semin Reprod Med 19 (3): 239-49, 2001.  [PUBMED Abstract]
     
     
316. Serafini P: Outcome and follow-up of children born after IVF-surrogacy. Hum Reprod Update 7 (1): 23-7, 2001 Jan-Feb.  [PUBMED Abstract]
     
     
317. Ericson A, Källén B: Congenital malformations in infants born after IVF: a population-based study. Hum Reprod 16 (3): 504-9, 2001.  [PUBMED Abstract]
     
     
318. Sankila R, Olsen JH, Anderson H, et al.: Risk of cancer among offspring of childhood-cancer survivors. Association of the Nordic Cancer Registries and the Nordic Society of Paediatric Haematology and Oncology. N Engl J Med 338 (19): 1339-44, 1998.  [PUBMED Abstract]
     
     
319. Friedman DL, Kadan-Lottick N, Liu Y, et al.: History of cancer among first-degree relatives of childhood cancer survivors: a report from the Childhood Cancer Survivor Study. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-1728, 433a, 2001. 
     
     

Second Malignant Neoplasms

Several large studies have examined the incidence and spectrum of second malignant neoplasms (SMNs) in childhood cancer survivors, where the cumulative risk at 20 years posttreatment varies from 3% to 10% and is 3 to 20 times greater than that expected in the general population. 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. Alkylating agents, platinums, and topoisomerase II inhibitors are associated with the development of leukemia.[1-12] Epipodophyllotoxins are known to increase the risk for secondary leukemia, and anthracyclines may also increase this risk after treatment for solid tumors.[13] 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’s lymphoma (3.2) and the highest for Hodgkin’s lymphoma (9.7). Risk was elevated for secondary leukemia, lymphoma, central nervous system (CNS) tumors, soft tissue and bone sarcomas, melanoma, 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’s lymphoma or soft tissue sarcoma and exposure to alkylating agents.[3] 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.[3,4,11] Several studies have examined the risk of SMNs in survivors of Hodgkin’s lymphoma, where the incidence of secondary breast and thyroid cancer is particularly high. Survivors of Hodgkin’s lymphoma are also at increased risk of second leukemia, sarcoma, melanoma, and lung, thyroid, and gastrointestinal cancer. Although data exist that suggest an increased risk in female survivors, even accounting for breast cancer, these results are not consistent. While the gender effect is not consistent among studies, diagnosis at younger age and therapy for relapsed disease are associated with increased risk.[1-4,7,8,11,14-17] 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.[18]

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.[19] 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 without previous radiation therapy treatment.[20] Neurofibromatosis also increases the risk of additional neoplasms, some not associated with therapy.[21,22] Breast cancer at an early age, sarcoma, and other cancers can be expected in children with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome.[23,24] 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.[25,26]

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. Currently, Children’s Oncology Group studies of Hodgkin’s disease are addressing such issues.[27]

References

1. 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.  [PUBMED Abstract]
   
   
2. 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.  [PUBMED Abstract]
   
   
3. 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.  [PUBMED Abstract]
   
   
4. 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.  [PUBMED Abstract]
   
   
5. 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.  [PUBMED Abstract]
   
   
6. 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.  [PUBMED Abstract]
   
   
7. 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.  [PUBMED Abstract]
   
   
8. 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.  [PUBMED Abstract]
   
   
9. 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.  [PUBMED Abstract]
   
   
10. Inskip PD: Thyroid cancer after radiotherapy for childhood cancer. Med Pediatr Oncol 36 (5): 568-73, 2001.  [PUBMED Abstract]
    
    
11. Wolden SL, Lamborn KR, Cleary SF, et al.: Second cancers following pediatric Hodgkin's disease. J Clin Oncol 16 (2): 536-44, 1998.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. 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.  [PUBMED Abstract]
    
    
14. 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.  [PUBMED Abstract]
    
    
15. Bhatia S, Ramsay NK, Steinbuch M, et al.: Malignant neoplasms following bone marrow transplantation. Blood 87 (9): 3633-9, 1996.  [PUBMED Abstract]
    
    
16. 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.  [PUBMED Abstract]
    
    
17. 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.  [PUBMED Abstract]
    
    
18. 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.  [PUBMED Abstract]
    
    
19. 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. 
    
    
20. Wong FL, Boice JD Jr, Abramson DH, et al.: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 278 (15): 1262-7, 1997.  [PUBMED Abstract]
    
    
21. Meadows AT, Baum E, Fossati-Bellani F, et al.: Second malignant neoplasms in children: an update from the Late Effects Study Group. J Clin Oncol 3 (4): 532-8, 1985.  [PUBMED Abstract]
    
    
22. Maris JM, Wiersma SR, Mahgoub N, et al.: Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1. Cancer 79 (7): 1438-46, 1997.  [PUBMED Abstract]
    
    
23. Birch JM, Alston RD, McNally RJ, et al.: Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20 (34): 4621-8, 2001.  [PUBMED Abstract]
    
    
24. Malkin D, Jolly KW, Barbier N, et al.: Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med 326 (20): 1309-15, 1992.  [PUBMED Abstract]
    
    
25. Garber JE, Li FP, Kingston JE, et al.: Hepatoblastoma and familial adenomatous polyposis. J Natl Cancer Inst 80 (20): 1626-8, 1988.  [PUBMED Abstract]
    
    
26. Li FP, Thurber WA, Seddon J, et al.: Hepatoblastoma in families with polyposis coli. JAMA 257 (18): 2475-7, 1987.  [PUBMED Abstract]
    
    
27. Kelly KM, Perentesis JP; Children's Oncology Group.: Polymorphisms of drug metabolizing enzymes and markers of genotoxicity to identify patients with Hodgkin's lymphoma at risk of treatment-related complications. Ann Oncol 13 (Suppl 1): 34-9, 2002.  [PUBMED Abstract]
    
    

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, there has been an overall decrease in mortality over time. This decrease 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 as a consequence of the study of 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 fact that many of the long-term sequelae 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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   

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.[1-5] Comprehensive monitoring guidelines for late effects has 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. 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, health-care, educational, vocational, and social-service systems.[3,7,8]

Health-promoting behaviors should be stressed for survivors of childhood cancer, and targeted educational efforts are worthwhile.[9] 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 (CCSS) 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’s disease at greatest risk. Similarly, survivors of CNS tumors, leukemia, neuroblastoma, and non-Hodgkin’s lymphoma were less likely than their siblings to complete high school or college.[10] 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% CI 6.32, 13.11). Compared to 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 >30 Gy of cranial radiotherapy (95% confidence interval [CI] 4.18-6.97). The risk was similarly increased for those who were treated with >30 Gy of cranial radiotherapy 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 <30 Gy of cranial radiotherapy (OR 2.14, 95% CI 1.36-3.24).[11]

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.[12-16]

References

1. Arceci RJ: Comprehensive pediatric hematology/oncology programs: standard requirements for children and adolescents with cancer and blood disorders. The American Society of Pediatric Hematology/Oncology News 1(2): 6-9, 1996. 
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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. ³ Last accessed April 19, 2004. 
   
   
7. Hobbie WL, Hollen PJ: Pediatric nurse practitioners specializing with survivors of childhood cancer. J Pediatr Health Care 7 (1): 24-30, 1993 Jan-Feb.  [PUBMED Abstract]
   
   
8. Blum RW: Transition to adult health care: setting the stage. J Adolesc Health 17 (1): 3-5, 1995.  [PUBMED Abstract]
   
   
9. 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.  [PUBMED Abstract]
   
   
10. 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.  [PUBMED Abstract]
    
    
11. 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. 
    
    
12. 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.  [PUBMED Abstract]
    
    
13. Hays DM: Adult survivors of childhood cancer. Employment and insurance issues in different age groups. Cancer 71 (10 Suppl): 3306-9, 1993.  [PUBMED Abstract]
    
    
14. Monaco GP, Fiduccia D, Smith G: Legal and societal issues facing survivors of childhood cancer. Pediatr Clin North Am 44 (4): 1043-58, 1997.  [PUBMED Abstract]
    
    
15. 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.  [PUBMED Abstract]
    
    
16. 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.  [PUBMED Abstract]
    
    

Changes to This Summary (07/22/04)

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

Tables that summarize information concerning late effects were added to this section.

More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database ⁴.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment ⁵

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment ⁶

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive Care ⁷

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer) ⁸

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention ⁹

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics ¹⁰

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine ¹¹

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).