Late Effects of Treatment for Childhood Cancer

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the late effects of treatment for childhood cancer. Monitoring issues are also discussed.

Late Effects of Treatment for Childhood Cancer

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 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 radiation therapy or chemotherapy.
  • Premorbid state.

Several comprehensive reviews and books that address late effects of childhood cancer and its therapy have been published.^{2,3,4,5,6,7,8,9} 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.

Table 1. Common Agents Associated With Therapy Late Effects

Agent/Agent Class/ModalityAffected Body SystemAnthracyclinesCirculatory (Cardiac) Respiratory (Pulmonary) Alkylating agentsReproductive (Gonadal) Second malignant neoplasmsTopoisomerase II inhibitorsSecond malignant neoplasmsPlatinumsUrinary (Renal) Special senses (Hearing) Second malignant neoplasmsCorticosteroidsCentral nervous systemMusculoskeletal (Bone and body composition) Musculoskeletal (Obesity) Intrathecal chemotherapyCentral nervous systemBleomycinRespiratory (Pulmonary) MethotrexateCentral nervous systemVincristineDigestive (Dental) ThioguanineDigestive (Hepatic)

Information concerning late effects is summarized in tables throughout the summary. Tables in the Common Late Effects of Childhood Cancer by Body System section of the summary have been modified from another review, with author permission.^5,

¹ Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed April 19, 2007.

² Oeffinger KC, Hudson MM: Long-term complications following childhood and adolescent cancer: foundations for providing risk-based health care for survivors. CA Cancer J Clin 54 (4): 208-36, 2004 Jul-Aug.

³ Meister LA, Meadows AT: Late effects of childhood cancer therapy. Curr Probl Pediatr 23 (3): 102-31, 1993.

⁴ Schwartz CL: Long-term survivors of childhood cancer: the late effects of therapy. Oncologist 4 (1): 45-54, 1999.

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.

⁹ Smith M, Hare ML: An overview of progress in childhood cancer survival. J Pediatr Oncol Nurs 21 (3): 160-4, 2004 May-Jun.

Common Late Effects of Childhood Cancer by Body System

Central Nervous System

Neurocognitive

Neurocognitive late effects most commonly follow treatment of malignancies that require central nervous system (CNS)-directed therapies, such as cranial radiation or intraventricular/intrathecal (IT) chemotherapy; thus, children with CNS tumors, head and neck sarcomas, and acute lymphoblastic leukemia (ALL) are most commonly affected. Deficits occur in a variety of areas that include the following:^1,2,3,4,5,6,

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

For both CNS tumors and ALL, younger age at time of treatment is associated with an increased neurocognitive deficit.^7,8,9,10,11,

Some studies of children treated with cranial or craniospinal radiation therapy for CNS tumors demonstrated a significant adverse neurocognitive effect of therapy.⁴ Other studies using lower doses and more targeted volumes, however, have demonstrated improved results.^12,13,14 One study supports the hypothesis that medulloblastoma patients demonstrate a decline in intelligence quotient (IQ) values because of an inability to acquire new skills and information at a rate comparable to their healthy same-age peers, not because of a loss of previously acquired information and skills.¹⁵ In a Danish study of 133 children treated for brain tumors, younger age at diagnosis, tumor site in the cerebral hemisphere, hydrocephalus treatment with shunt, and radiation therapy were predictors of lower cognitive functions.¹⁶ Another study evaluated quantitative tissue volumes from magnetic resonance imaging scans, correlating these results with neurocognitive assessments for 40 long-term survivors of pediatric brain tumors treated with radiation therapy with or without chemotherapy 2.6 to 15.3 years earlier (median, 5.7 years) at an age of 1.7 to 14.8 years (median, 6.5 years). Analyses revealed significant impairments in patients’ neurocognitive test performance on all measures. After statistically controlling for age at time of radiation therapy and time from radiation therapy, significant associations were found between normal-appearing white matter volumes and both attentional abilities and IQ, and between attentional abilities and IQ. These associations were also correlated with deficiencies in academic skills such as reading, spelling, and math.^17,

For 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.^{11,19,20,21,22,}

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 because of direct invasion of the brain, seizures, and hydrocephalus must be recognized. Studies on CNS prophylaxis for ALL comparing craniospinal radiation therapy with cranial radiation therapy combined with IT methotrexate showed that children who were younger than 5 years at time of treatment and had received radiation therapy and intrathecal chemotherapy had lower IQ scores than those who received craniospinal radiation therapy alone.²³ Similarly, another study found a significant IQ deficit in children treated with 24 Gy of cranial radiation combined with IT methotrexate, as compared with childhood cancer survivors who received no CNS-directed therapy, with the effect greatest among those younger than 5 years.¹⁸ A similar effect on cognition with the addition of intrathecal methotrexate has been found in children treated for medulloblastoma.^24,

Systemic methotrexate in high doses and combined with radiation therapy can lead to a well-described leukoencephalopathy, in which severe neurocognitive deficits are obvious.^2,25,26 Because of its penetrance into the CNS, systemic methotrexate has been used in a variety of low-dose and high-dose regimens for leukemia CNS prophylaxis. The deleterious effects of systemic methotrexate, especially at doses above 1 g/m2 may be no different or worse than those of 18 Gy of cranial radiation therapy.^27,28 At lower methotrexate 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 methotrexate combined with intrathecal cytarabine and methotrexate for CNS leukemia prophylaxis and who were tested 3 to 9 years posttreatment showed that cognitive function was in the average range.³⁰

Chemotherapy alone for ALL may result in cognitive dysfunction. One study examined 48 children treated for leukemia without cranial radiation therapy and found impairment in tasks of higher-order cognitive functioning and learning disabilities in the area of mathematics.²⁷ Another study showed that children, particularly females, treated with systemic and IT methotrexate 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 radiation therapy and found no significant neurocognitive deficits, even when patients were exposed to either IT or high-dose intravenous (IV) methotrexate.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, because of absences from school and interruption of studies.³²

Table 2. CNS Late Effects*

Late Effect Causative TreatmentSigns and Symptoms Screening and Diagnostic Tests Management and Intervention *Adapted from Schwartz et al. ³³ Neurocognitive deficit Chemotherapy: High-dose IV methotrexate, IT methotrexateDifficulty with: reading, language, verbal and nonverbal memory, arithmetic, receptive and expressive language, decreased mental processing speed, attention deficit, decreased IQ, behavior problems, poor school attendance, poor hand-eye coordinationNeurocognitive testing: psycho-educational, neuropsychologicPsychoeducation assistance Radiation: >18 GySurgery: Resection of CNS tumorLeuko-encephalopathy Chemotherapy: methotrexate: IT or IV, IT cytarabine Seizures, neurologic impairment, compare with premorbid status Computed tomography (CT)/magnetic resonance imaging (MRI) scan baseline and symptoms Symptom management: muscle relaxants, anticonvulsants, physical therapy, occupational therapyRadiation: >18 Gy (with methotrexate) Focal necrosis Chemotherapy: methotrexate: IT or high-dose IV carmustine (BCNU), cisplatin Headaches, nausea, seizures, papilledema, hemiparesis/other focal findings, speech, learning, and memory deficits CT/MRI scan baseline, as needed for symptoms, positron emission tomography or single photon emission computed tomography scanSteroid therapy, debulking of necrotic tissueRadiation: >50 Gy (especially with >2 Gy daily fraction) Surgery: Resection of tumor Large-vessel stroke Radiation: >60 Gy Headache, seizures, hemiparesis, aphasia, focal neurologic findingsCT/MRI, arteriogramDetermined by specific neurologic impairment Vision loss Chemotherapy: Intra-arterial BCNU, cisplatinProgressive visual loss Ophthalmic evaluation, visual-evoked response Visual aids Radiation: >50 Gy (optic nerve chiasm, occipital lobe) Surgery: Resection of tumor OtotoxicityChemotherapy: CDDP, carboplatin Abnormal speech development, hearing Audiogram baseline, as needed for symptoms Speech therapy, hearing aidRadiation: >35 Gy (middle/inner ear) Surgery: Surgery, cerebrospinal fluid (CSF) shunting Myelitis Radiation: >45-50 Gy Paresis, spasticity, altered sensation, loss of sphincter control MRISteroids, physical therapy, occupational therapy Surgery: Spinal cord surgery

Psychosocial

Many childhood cancer survivors have adverse quality of life or other adverse psychologic outcomes. Incorporation of psychological screening into clinical visits for childhood cancer survivors may be valuable; however, limiting such evaluations to those returning to long-term follow-up clinics may result in a biased subsample of those with more difficulties, and precise prevalence rates may be difficult to establish. A review of behavioral, emotional, and social adjustment among survivors of childhood brain tumors illustrates this point, in whom rates of psychological maladjustment range from 25% to 93%.³⁴

Studies in the early 1990s described childhood cancer survivors as generally well adjusted, though a subset had psychological difficulties that resulted in functional impairment.^35,36,37 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 PTSD 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.^{39,40,41,42,43,44} 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 For more information about PTSD in cancer patients, please see the PDQ summary on Post-traumatic Stress Disorder.

In a study of 101 adult cancer survivors of childhood cancer, psychologic screening was performed during a routine annual evaluation at the survivorship clinic at the Dana Farber Cancer Institute. On the Symptom Checklist 90 Revised, 32 subjects had a positive screen (indicating psychological distress), and 14 subjects reported at least 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 For more information about psychological distress and cancer patients, please see the PDQ summary on Normal Adjustment and the Adjustment Disorders.

Special Senses

Hearing

Hearing loss is a common late effect of survivors of CNS cancers and cancers of the head and neck who received high doses of radiation therapy and platinum chemotherapy. Hearing loss in the speech range (0.5 kHz to 3 kHz), which may compromise language reception and expression, is reported with cumulative doses of cisplatin greater than 360mg/m2, and 25% prevalence of hearing loss is reported with doses greater than 720 mg/m2. Fifty percent of children treated with cisplatin doses greater than 450 mg/m2 have sensorineural hearing loss (SNHL) in the high frequencies (6 kHz to 8 kHz). Younger age at time of administration increases risk.^{47,48,49,50,51} 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 600 mg/m2, and 22% at 601 mg/m2 to 800 mg/m2. There was an additional effect of carboplatin when given in high-dose therapy with autologous stem cell infusion, in which 40% of patients developed hearing loss following a dose of 1,500 mg/m2.⁵² Radiation therapy can result in cochlear damage, with SNHL occurring in about 25% of patients treated with doses approaching 60 Gy, but SNHL is less frequent with lower doses of radiation therapy if cisplatin is not included in the chemotherapy regimen. Data suggest that cochlear doses of 30 Gy to 50 Gy can cause intermediate-frequency SNHL, and that CSF shunting procedures increase the risk.^50,53,54,55 Cisplatin, at doses as low as 270 mg/m2, can result in hearing loss when combined with cranial radiation therapy doses of 40 Gy to 50 Gy.^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,

Table 3. Ear Late Effects*

Late EffectsCausative Treatment Signs and SymptomsScreening and Diagnostic TestsManagement and Intervention*Adapted from Schwartz et al. ³³ Chronic otitisRadiation: >35 GyDryness and thickening of canal and tympanic membrane, conductive hearing loss, perforation of tympanic membraneOtoscopic exam, audiometryAntibiotic therapy, decongestants, myringotomy, pressure equalizer tubes, preferential seating in school, amplificationSensorineural hearing lossChemotherapy: Cisplatin, carboplatinHigh frequency hearing loss (bilateral), tinnitus, vertigoConventional pure tone audiogram baseline and then every 2-3 years; bilateral, symmetrical, irreversiblePreferential seating in school, amplificationRadiation: 40-50 Gy, cranial radiation enhances the platinum effectDecreased production of cerumenRadiation: 30-40 GyHard and encrusted cerumen in canal, hearing impairment, otitis externaExamination of canalPeriodic cleaning of ear canal, cerumen-loosening agents, otic drops for otitis externa; keep ear dry: ear plugs, drying solutionChondritisRadiation: 50 GyCauliflower earInspection of auricleAntibiotics, surgical repair (reconstruction may be hampered by poor blood supply)ChondronecrosisRadiation: 60 Gy—— Antibiotics, surgical repair (reconstruction may be hampered by poor blood supply)

Optic and Orbital

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

For survivors of retinoblastoma, a small orbital volume may result from either enucleation or radiation therapy. Age younger than 1 year may increase risk, but this is not consistent across studies.^56,57 Better management of prosthetic implants and newer methods of delivering radiation therapy 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.^{58,59,60,61,62,63,}

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 doses of 30 Gy to 65 Gy. The higher dose ranges (>50 Gy) are associated with lid epitheliomas, keratoconjunctivitis, lacrimal duct atrophy, and severe dry eye. Retinitis and optic neuropathy may also result from doses of 50 Gy to 65 Gy and even at lower total doses if the individual fraction size is greater than 2 Gy.⁶⁴ Cataracts are reported following lower doses of 10 Gy to 18 Gy.^{50,55,65,66,67,68,}

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.^{69,70,71,72,73,74,}

Table 4. Eye Late Effects*

Late EffectCausative Treatment Signs and SymptomsScreening and Diagnostic TestsManagement and Intervention*Adapted from Schwartz et al. ³³ Lacrimal glands: decreased tear productionChemotherapy: fluorouracil (5-FU)Dry, irritated red eye, foreign-body sensation, positive fluorescein stainingPenlight/slit lamp exam, fluorescein stainingTear replacement, occlude lacrimal puncta, education regarding avoiding rubbing lids when puncta plug is intactRadiation: >50 GyLacrimal duct: fibrosisChemotherapy: 5-FUTearingOphthalmic examDilation of ductRadiation: >50 GyEyelids:UlcerationRadiation: >50 GyBlepharitis, bleeding/crusted lesion, previous infectionsPhysical examTopical/oral steroids, skin balm; teach: lid hygiene, radiosensitizing drugs, UV protection; avoid trauma, harsh soaps and lotionsTelangiectasiaRadiation: >50 GyEnlarged, tortuous blood vessels, pigmentary changesSlit lamp/penlight exam, open and closed eyelid examTopical/oral steroids, skin balm; teach: lid hygiene, radiosensitizing drugs, UV protection; avoid trauma, harsh soaps and lotionsConjunctiva:NecrosisRadiation: Radioactive plaque therapyDry, irritated eye, foreign-body sensation Slit lamp/penlight exam, fluorescein stainSteroids/antibiotic dropsScarringRadiation: >50 GyIrregular, rough conjunctival surface, telangiectasia— Tear replacement (resolves spontaneously)Subconjunctival hemorrhageRadiation: >45 GyIrritated eye, foreign-body sensation, dry, irregular conjunctival surface— Patching, tear replacement Sclera: thinningRadiation: >50 GyMay be asymptomatic, dry eyes, foreign-body sensation; grey, charred, blue scleraSlit lamp/penlight examAntibiotic drops, avoid trauma, protective glassesCornea: ulcerationRadiation: >45 GyPain, foreign-body sensation, decreased visual acuity, photosensitivitySlit lamp/penlight exam, fluorescein stainingTear replacement, antibiotics, soft bandages, soft contact lens, surgery, ophthalmologyNeovascularizationRadiation: >50 GyIncreased tearing, increased vessels surrounding edge of corneaSlit lamp examTear replacement, antibiotics, soft bandages, soft contact lens, surgery, ophthalmologyKeratinizationRadiation: >50 GyDecreased corneal sensation, photosensitivity, fluorescein stainingSlit lamp exam, fluorescein staining—EdemaRadiation: >40 GyDecreased visual acuity, hazy corneaPenlight/slit lamp exam: white, opaque cornea—Lens: cataractChemotherapy: Steroids (incidence varies with dose)Decreased visual acuity, opaque lensDirect ophthalmoscopic exam, decreased red reflex, slit lamp/penlight exam: opaque lensPrevention by shielding during treatment, surgical removal, educate regarding UV protectionRadiation: >8 Gy (single dose), >10-15 Gy (fractionated)Iris:NeovascularizationRadiation: >50 GyMay be asymptomatic, new blood vessels in iris (rubeosis), blood in anterior chamber, different colored irisesSlit lamp/penlight examSteroid dropsSecondary glaucoma—Eye pain, headache, nausea/vomiting, decreased peripheral vision, increased intraocular pressure Measure ocular pressureBeta blocker drops, atropine, acetazolamide (Diamox)AtrophyRadiation: >50 GyDecreased iris stroma at pupillary marginSlit lamp/penlight examPhotocoagulationRetina:InfarctionRadiation: >50 GyBlanched white cotton specks, decreased visual acuity, decreased visual field, blurred vision (central or peripheral), blood vessels: yellow fluid, bleeding, thin, incompetent vessels, tortuous, enlarged vesselsVisual acuity, visual field (confrontation computerized or Amsler grid), direct and indirect ophthalmoscope exam, fundus photographySteroids, photocoagulation, education regarding avoiding aspirin and bleeding precautionsExudatesRadiation: >50 Gy—Visual acuity, visual field (confrontation computerized or Amsler grid), direct and indirect ophthalmoscope exam, fundus photography Steroids, photocoagulation, education regarding avoiding aspirin and bleeding precautionsHemorrhageRadiation: >50 Gy—Visual acuity, visual field (confrontation computerized or Amsler grid), direct and indirect ophthalmoscope exam, fundus photographySteroids, photocoagulation, education regarding avoiding aspirin and bleeding precautionsTelangiectasiaRadiation: >50 Gy—Visual acuity, visual field (confrontation computerized or Amsler grid), direct and indirect ophthalmoscope exam, fundus photographySteroids, photocoagulation, education regarding avoiding aspirin and bleeding precautionsNeovascularizationRadiation: >50 Gy—Visual acuity, visual field (confrontation computerized or Amsler grid), direct and indirect ophthalmoscope exam, fundus photographySteroids, photocoagulation, education regarding avoiding aspirin and bleeding precautionsMacular edema visual acuity and visual field —Blister of fluid in the maculaVisual acuity, visual field (confrontation computerized or Amsler grid), direct and indirect ophthalmoscope exam, fundus photographySteroids, photocoagulation, education regarding avoiding aspirin and bleeding precautionsOptic neuropathyRadiation: >50 GyPale optic disc, abnormal pupillary responsesVisual evaluationVisual aidsSurgery: Tumor resection

Digestive System

Dental

Both chemotherapy and radiation therapy can cause multiple cosmetic and functional abnormalities of dentition, most predominantly in children treated before age 3 years who have not yet developed deciduous dentition. However, even older prepubertal children are at risk. Developing teeth are irradiated in the course of treating head and neck sarcomas, Hodgkin’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 greater than 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.^76,77,78 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 less than 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.^82,83,84

It has been reported that the incidence of dental visits for childhood cancer survivors falls below the American Dental Association's recommendation that all adults visit the dentist annually.⁸⁵ These findings give health care providers further impetus to encourage routine dental and dental hygiene evaluations for survivors of childhood treatment. For more information about oral complications and cancer patients, please see the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation.

Table 5. Dental Late Effects*

Late EffectsCausative Treatment Signs and SymptomsScreening and Diagnostic TestsManagement and Intervention*Adapted from Schwartz et al. ³³ Xerostomia (decreased salivary gland function)Radiation: >40 Gy and >50% of gland irradiatedDecreased salivary flow, dry mouth, altered taste perception, dental decay, Candida (thrush) Dental examination, salivary flow studies, attention to early caries, periodontal diseaseEncourage meticulous oral hygiene, saliva substitution, prophylactic fluoride, dietary counseling regarding avoiding fermentable carbohydrates, nystatin for oral candidiasis, pilocarpineAbnormal tooth and root developmentChemotherapy: vincristine, actinomycin D, cyclophosphamide, 6-mercaptopurine (6-MP), procarbazine, nitrogen mustard (HN2)Enamel appears pale, teeth appear small, uneven; malocclusionDental examination every 6 months with, attention to early caries, periodontal disease, and gingivitis, Panorex/bite/wing radiographs baseline (age 5-6 years) Careful evaluation before tooth extraction, endodontics and orthodontics, fluoride, antibiotics as needed for risk of infection (e.g., trauma)Radiation: Generally 10 Gy can destroy developing roots

Hepatic

Most chemotherapy agents employed in childhood cancer therapy can have acute hepatotoxic effects. In the modern era, long-term hepatic effects following chemotherapy alone are uncommon. Attention to baseline hepatic function and monitoring during therapy can prevent significant acute effects that may result in chronic hepatic dysfunction.⁸⁶ Veno-occlusive disease, which most commonly occurs in the setting of radiation therapy and chemotherapy administered for marrow transplantation, is the most critical hepatic toxicity and occurs acutely. This is characterized by occlusion and obliteration of the central veins of the hepatic lobules, with retrograde congestion and secondary necrosis of hepatocytes. Although there may be a dose effect of radiation therapy, this complication is also reported following conditioning regimens with cyclophosphamide and busulfan alone. Pre-existing hepatic disease, including infection, and GVHD may increase the risk. Long-term complications of veno-occlusive disease depend on severity but can include hepatic insufficiency or failure and portal hypertension.^87,88,89

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.⁹⁰ Lower doses can be associated with hepatopathy if the child is also receiving sensitizing chemotherapy. This is evident in a series of children treated for Wilms’ tumor, neuroblastoma, or hepatoma with radiation therapy to the liver and chemotherapy. Fractionated doses of 12 Gy to 25 Gy caused abnormal results in liver function tests and radionuclide scans in 50% of patients; 25 Gy to 35 Gy caused abnormalities in 63%, and >35 Gy was toxic in 86% of patients.⁹¹ In the National Wilms’ Tumor Study (NWTS), 16 of 303 patients (5.3%) had liver toxicity. The doses of radiation to portions of the liver ranged from less than 15 Gy to greater than 30 Gy, with right flank or whole abdominal radiation increasing risk significantly more than isolated left flank radiation. All the patients received chemotherapy, including vincristine and dactinomycin, and some received doxorubicin.⁹²

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.^{93,94,95,96,97,98,99,100} Therefore, all children who received blood transfusions before 1992 should be screened for hepatitis C virus. Those found to be positive should be referred to gastroenterologists for consideration of therapy in ongoing studies.

New data suggest an association between thioguanine exposure and hepatotoxicity. In a phase III trial for ALL, 1,011 patients were randomized to treatment with thioguanine compared with mercaptopurine. There were 200 reports of hepatic veno-occlusive disease, but no fatalities were directly attributed to the syndrome. An additional 32 patients did not have full clinical features of veno-occlusive disease, but did have episodes of thrombocytopenia out of proportion to neutropenia and were felt to have a subclinical form of veno-occlusive disease. An additional 51 patients have developed persistent splenomegaly identified during the end of maintenance or during the first year off therapy, and 25% have documented portal hypertension.¹⁰¹ Similar results were reported by the United Kingdom Children’s Cooperative Group for their ALL study employing the use of thioguanine.¹⁰²

Table 6. Hepatic Late Effects*

Late EffectsCausative Treatment Signs and SymptomsScreening and Diagnostic TestsManagement and Intervention*Adapted from Schwartz et al.³³ Hepatic fibrosis/cirrhosisChemotherapy: methotrexate, actinomycin D, 6-MP, 6-thioguanine (6-TG) Itching, jaundice, spider nevi, bruising, portal hypertension, esophageal varices, hemorrhoids, hematemesis, encephalopathyHeight and weight each year, CBC, reticulocytes, platelets, each year; liver function studies every 2-5 years (hepatic screen, liver biopsy, endoscopy)Hepatitis screen (hepatitis A, B, C/ cytomegalovirus [CMV]), diuretics, liver transplant, varices, sclerosis, vascular shuntingRadiation: >30 GySurgery: Massive resection

Digestive Tract

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

In a report of 42 survivors of Wilms’ tumor treated from 1968 to 1994 with megavoltage radiation therapy, dactinomycin and vincristine, with or without doxorubicin, the actuarial incidence of bowel obstruction at 5, 10, and 15 years was 9.5 ± 4.5%, 13.0 ± 5.6%, and 17.0 ± 6.5%, respectively. Of 23 patients, 5 irradiated within 10 days of surgery and 1 of 19 irradiated after 10 days developed bowel obstruction.¹⁰⁶ In a report from the Intergroup Rhabdomyosarcoma Study Committee, extended follow-up of 86 children and adolescents who were treated for paratesticular rhabdomyosarcoma on the Intergroup Rhabdomyosarcoma Studies I and II (IRS I-II) revealed that 4 patients who had abdominal radiation therapy had chronic diarrhea.¹⁰⁷

Table 7. Gastrointestinal (GI) Late Effects*

Late EffectsCausative TreatmentSigns and SymptomsScreening and Diagnostic TestsManagement and Intervention*Adapted from Schwartz et al. ³³ EnteritisChemotherapy: actinomycin D and doxorubicin (enhance radiation therapy effect)Abdominal pain, diarrhea, decreased stool bulk, emesis, weight loss, poor linear growthHeight and weight every year, stool guaiac every year, complete blood count (CBC) with mean corpuscle volume (MCV) every year, total protein & albumin every 3-5 years (absorption tests, vitamin B12 level, and contrast studies)Dietary management, refer to gastroenterologistRadiation: >40 GySurgery: Abdominal surgery enhances RT effectAdhesionsRadiation: Radiation enhances effectAbdominal pain, bilious vomiting, hyperactive bowel soundsAbdominal radiographNothing by mouth, gastric suction, adhesion lysisSurgery: LaparotomyFibrosis: esophagus (stricture)Chemotherapy: actinomycin D and doxorubicin (radiation therapy enhancers) Weight loss, dysphagia, poor linear growthHeight and weight every year, CBC every year, (barium swallow/endoscopy as needed)Esophageal dilation, antireflux surgeryRadiation: >40-50 GySurgery: Abdominal surgeryFibrosis: small intestinesRadiation: >40 Gy Diarrhea, weight loss, obstruction, abdominal pain, constipationHeight and weight every year, CBC with MCV every year, serum protein & albumin every 3-5 years (upper GI, small bowel biopsy)High-fiber diet, decompression, resection, balloon dilationSurgery: Abdominal surgeryFibrosis: large intestine, colonRadiation: >40 Gy Abdominal colic, rectal pain, constipation, melena, weight loss, obstruction Height and weight every year, rectal exam, stool guaiac every year, lower GI, colonoscopy, sigmoidoscopyStool softeners, high-fiber dietSurgery: Abdominal surgery

Immune System

Spleen

Splenectomy increases risk of life-threatening invasive bacterial infection.¹⁰⁸ 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.^109,110 Children may be rendered asplenic by radiation therapy to the spleen in doses greater than 30 Gy, however, given as involved-field irradiation or as part of nodal irradiation.^111,112 Low-dose involved-field radiation (21 Gy) combined with multiagent chemotherapy does not appear to adversely affect splenic function.¹¹²

For patients with surgical or functional asplenia, prophylactic antibiotics (generally penicillin) are recommended as daily lifelong treatment. No randomized studies that address the benefit of antibiotics have been conducted in a pediatric oncology population; thus, these recommendations are based on any pediatric population with asplenia.^{113,114,115,116} As a result, some patients, over time, discontinue use of antibiotics. In these cases, antibiotics—generally penicillin—should be taken at the first onset of febrile illness if the patient is not on daily prophylaxis. Medical care should be sought promptly for fevers higher than 38.5° C. Patients should receive antibiotic prophylaxis for dental work and should be immunized against meningococcus, hemophilus influenzae type B, and Streptococcus pneumoniae.^108,

Table 8. Spleen Late Effects*

Late EffectsCausative TreatmentSigns and SymptomsManagement and Intervention*Adapted from Schwartz et al. ³³ SepsisRadiation: >30 GyFever, bacteremia, localizing signs of infection, rigors, hypotension, shockDaily antibiotic prophylaxis, immunizations for encapsulated organisms and influenza, antibiotic prophylaxis for dental work, prompt medical attention for infections associated with feverSurgery: Splenectomy

Circulatory System

Cardiovascular

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

The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. The pathogenesis of injury differs, however, with radiation primarily affecting the fine vasculature of the heart and anthracyclines directly damaging myocytes.¹¹⁷ Late effects of radiation to the heart include:^118,119,120

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

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

Increased risk of doxorubicin-related cardiomyopathy is associated with female sex, cumulative doses greater than 200 mg/m2 to 300 mg/m2, younger age at time of exposure, and increased time from exposure.^{123,124,125,126,127,128,129,130,131,132,133,134,135,136,137} Route of administration of doxorubicin may influence risk of cardiomyopathy. One study looked at the effect of continuous (48-hour) versus bolus (1-hour) infusions of doxorubicin in 121 children who received a cumulative dose of 360 mg/m2 for treatment of ALL and found no difference in the degree or spectrum of cardiotoxicity in the 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.¹³⁰ Another study compared cardiac dysfunction in 113 children who received doxorubicin either by single-dose infusion or by a consecutive divided daily-dose schedule. The divided-dose patients received one third of the total cycle dose over 20 minutes for 3 consecutive days. Patients treated according to a single-dose schedule received the cycle dose as a 20-minute infusion. There was no significant difference in the incidence of cardiac dysfunction between the divided-dose and single-dose infusion groups.¹²³ Earlier studies in adults have shown decreased cardiotoxicity with prolonged infusion; thus, further evaluation of this question is warranted.^{138,139,140,141}

Prevention or amelioration of anthracycline-induced cardiomyopathy is clearly important because the continued use of anthracyclines is required in cancer therapy. Dexrazoxane (DZR) is a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent. Evidence supports its capacity to mitigate cardiac toxicity in patients treated with anthracyclines.^{121,142,143,144,145}

In 2 closed Pediatric Oncology Group therapeutic phase III studies for Hodgkin’s lymphoma,^146,147 myocardial toxicity is being measured clinically and sequentially over time by echocardiography and electrocardiography, as well as by the determination of levels of cardiac troponin T (cTnT), a protein that is elevated after myocardial damage.^{144,148,149,150,151,152}

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.¹⁴³ For this reason, studies to date in anthracycline-treated cancer survivors have not demonstrated a benefit of enalapril in preventing progressive cardiac toxicity.^142,143

Rhythm disturbances are also reported after doxorubicin exposure. One study looked at electrocardiograms (ECGs) in 52 long-term survivors of childhood cancer who had been treated with anthracyclines. Prolongation of corrected QT interval (QTc) of more than 0.43 was noted in 6 of 22 patients who had received cumulative anthracycline doses greater than 300 mg/m2, as compared with 0 of 15 patients who had received lower anthracycline doses. Thoracic radiation therapy increased the risk in both groups, though the higher anthracycline dose group still demonstrated a higher frequency of prolongation of QTc. Exercise further prolonged the QTc in 6 of 10 patients evaluated.¹⁵³

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.¹⁵⁴ 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.¹⁵⁵ 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 greater than 20 Gy, left-sided abdominal irradiation, and doxorubicin dose greater than 300 mg/m2.¹²⁵ Children who require hematopoietic stem cell transplantation (HSCT) are at especially high risk of cardiac toxicity. They may have received anthracyclines or radiation therapy with the heart in the field as part of their initial cancer therapy, and they are subsequently exposed to conditioning regimens that may include high-dose cyclophosphamide and TBI.^{156,157,158,159,160}

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.^{153,159,160,161,162,163,164} Specific abnormalities of cardiac function may progress over time after therapy, as suggested by a report targeting parameters of LV contractility.¹⁶⁵ It remains unclear whether these abnormalities will have clinical impact; however, additional follow-up of these findings is required.

More time is needed before the effects of reduction in the dose of anthracyclines or thoracic radiation therapy are known.

Table 9. Cardiac Late Effects*

Late EffectsCausative TreatmentSigns and SymptomsScreening and Diagnostic TestsManagement and Intervention*Adapted from Schwartz et al. ³³ CardiomyopathyChemotherapy: anthracycline >300 mg/m2, >200 mg/m2 and radiation therapy to mediastinum, high-dose cyclophosphamide, (bone marrow transplant [BMT]) (possibly ifosfamide) Fatigue, cough, dyspnea on exertion, peripheral edema, hypertension, tachypnea/rales, tachycardia, cardiomegaly (S3/S4), hepatomegaly, syncope, palpitations, arrhythmiasECG, echocardiogram/ radionuclear angiography and chest x-ray baselines, every 2-5 years (depending on risk factors), Holter monitor and exercise testing baseline, as needed for symptoms and after high cumulative anthracycline dose (>300 mg/m2)Diuretics, digoxin, afterload reduction, antiarrhythmics, cardiac transplant, education regarding risks of: isometric exercises, alcohol consumption, drug use, smoking, pregnancy, anesthesiaRadiation: >35 GyChemotherapy and Radiation: >25 Gy and anthracyclinesValvular damage (mitral/tricuspid aortic)Radiation: >40 GyWeakness, cough, dyspnea on exertion, new murmur, pulsating liverEchocardiogram and chest x-ray (baseline), every 3-5 years then as needed for symptomsPenicillin prophylaxis for surgery/dental proceduresPericardial damageRadiation: >35 GyFatigue, dyspnea on exertion, chest pain, cyanosis, ascites, peripheral edema, hypotension, friction rub, muffled heart sounds, venous distension, pulsus paradoxusECG (ST-T changes, decreased voltage), echocardiogram, chest x-ray baseline, every 3-5 yearsPericardial strippingCoronary artery diseaseRadiation: >30 GyChest pain on exertion (radiates to arm/neck), dyspnea, diaphoresis, pallor, hypotension, arrhythmiasECG every 3 years, stress test (consider thallium scintigraphy) baseline, every 3-5 years or as needed for symptomsDiuretics, cardiac medications, low-sodium, low-fat diet, conditioning regimens

Respiratory System

Pulmonary

Pulmonary fibrotic disease is seen as a late complication of radiation therapy. In the modern management of pediatric malignancies, radiation therapy is often given in combination with chemotherapy. Many chemotherapeutic agents induce lung damage on their own or potentiate the damaging effects of radiation to the lung. Thus, the potential for acute or chronic pulmonary sequelae must be considered in the context of the specific chemotherapeutic agents and the radiation dose administered, as well as the volume of lung irradiated and the fractional radiation therapy doses. Acute pneumonitis manifested by fever, congestion, cough, and dyspnea can follow radiation therapy alone at doses greater than 40 Gy to focal lung volumes, or after lower doses when combined with dactinomycin or anthracyclines. Fatal pneumonitis is possible after radiation therapy alone at doses to the whole lung greater than 20 Gy, but is possible after lower doses when combined with chemotherapy. Infection, GVHD in the setting of BMT, and pre-existing pulmonary compromise (e.g., asthma) all may influence this risk. Changes in lung function have been reported in children treated with whole-lung radiation therapy for metastatic Wilms’ tumor. A dose of 12 Gy to 14 Gy reduced total lung capacity and vital capacity to about 70% of predicted values, and even lower if the patient had undergone thoracotomy. Fractionation of dose decreases this risk.^166,167 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.^166,167,168

The development of bleomycin-associated pulmonary fibrosis with permanent restrictive disease is dose dependent, usually occurring at doses greater than 200 U/m2 to 400 U/m2, higher than those used in pediatric malignancies.^168,169,170 One study evaluated lung function in 20 pediatric Hodgkin’s lymphoma patients treated with MOPP (mechlorethamine [HN 2], vincristine [Oncovin], prednisone, and procarbazine)/ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) and 15 Gy to 25 Gy mantle radiation and found 55% to have abnormal diffusing capacity.¹⁷¹ Another study evaluated serial pulmonary function in children treated with COP (cyclophosphamide, vincristine, and prednisone)/ABVD and mantle radiation therapy and found 65% to 73% to have only mildly decreased or normal diffusing capacity.¹⁷² 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.^173,174 clinical symptoms were uncommon and generally did not correlate with pulmonary function test results in these studies.

Patients who are treated with HSCT are at increased risk of pulmonary toxicity, related to preexisting pulmonary dysfunction (e.g., asthma, pretransplant therapy), the preparative regimen that may include cyclophosphamide, busulfan, carmustine, TBI, and the presence of GVHD.^{175,176,177,178,179,180,181} Although most survivors of transplant are not clinically compromised, restrictive lung disease may occur. Obstructive disease is less common, as is Late Onset Pulmonary Syndrome, which includes the spectrum of restrictive and obstructive disease. Bronchiolitis obliterans with or without organizing pneumonia, diffuse alveolar damage, and interstitial pneumonia may occur as a component of this syndrome, generally between 6 and 12 months posttransplant. Cough, dyspnea, or wheezing may occur with either normal chest x-ray or diffuse/patchy infiltrates; however, most patients are symptom free.^179,180

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 (RR) of lung fibrosis, recurrent pneumonia, chronic cough, pleurisy, use of supplemental oxygen therapy, abnormal chest wall, exercise-induced shortness of breath and bronchitis, with RRs ranging from 1.2 to 13.0 (highest for lung fibrosis and lowest for bronchitis). The 25-year cumulative incidence of lung fibrosis was 5% for those who received chest radiation therapy and less than 1% for those who received pulmonary toxic chemotherapy. For more subjective complaints, the 25-year cumulative incidences were higher, as follows: chronic cough, 15% for combined chest radiation therapy and pulmonary toxic chemotherapy, 12% chest radiation therapy alone, 6% pulmonary toxic chemotherapy alone; exercise-induced shortness of breath, 20% chest radiation therapy and pulmonary toxic chemotherapy, 15% chest radiation therapy alone, 6% pulmonary toxic chemotherapy alone. Treatment-related risk factors included chest radiation for lung fibrosis, supplemental oxygen therapy, recurrent pneumonia, exercise-induced shortness of breath, and chronic cough. Cyclophosphamide increased risk for exercise-induced shortness of breath, supplemental oxygen therapy, chronic cough, bronchitis, and recurrent pneumonia. Bleomycin increased risk for supplemental oxygen therapy, bronchitis, and chronic cough. Busulfan increased risk of chronic cough and pleurisy. Doxorubicin was associated with an increased risk of emphysema, supplemental oxygen therapy, chronic cough, and shortness of breath. Nitrosoureas were associated with an increased risk of supplemental oxygen therapy. Three survivors had undergone a lung transplant, and another 3 survivors developed adenocarcinoma of the lung as a second malignancy. Risk continues to increase with time since diagnosis.¹⁸² With changes in the doses of radiation therapy employed since the late 1980s, the incidence of these abnormalities is likely to decrease.

Table 10. Pulmonary Late Effects*

Late EffectsCausative treatmentSigns and SymptomsScreening and Diagnostic TestsManagement and Intervention*Adapted from Schwartz et al. ³³ Pulmonary fibrosisChemotherapy: bleomycin (Blenoxane), lomustine (CCNU), carmustine (BCNU), cyclophosphamide, methotrexate, mitomycin, vinca alkaloidsFatigue, cough, dyspnea on exertion, reduced exercise tolerance, orthopnea, cyanosis, finger clubbing, rales, cor pulmonaleBaseline chest x-ray and O2 saturation, pulmonary function test including diffusing capacity for carbon monoxide, then every 3-5 years or as neededConsider pulmonary evaluation, steroid therapy; prevention: avoidance of smoking. Avoidance of infections: influenza vaccine, Pneumovax. after bleomycin: avoid fractional inspired oxygen (FiO2) >30% intraoperatively and postoperatively avoid excessive hydrationRadiation: Pulmonary radiation therapy >15-20 Gy, risk increases with dose, larger volume irradiated, and younger age

Urinary System

Renal

Cisplatin at doses greater than 200 mg/m2 can result in glomerular or tubular injury and renal insufficiency. Other nephrotoxic agents such as aminoglycosides, amphotericin, and ifosfamide may further increase risk. Effects can be seen acutely and may progress after completion of therapy.^{49,183,184,185} Studies in the early 1990s have shown that carboplatin has less acute nephrotoxicity than cisplatin.^186,187,188 Only a few small studies examining children treated with carboplatin, however, have evaluated short-term and long-term nephrotoxicity, finding nothing significant to date.^189,190 As with ototoxicity, however, additional follow-up in larger numbers of survivors treated with carboplatin must be evaluated before potential renal toxicity can be better defined.

Ifosfamide can also cause glomerular and tubular toxicity, with renal tubular acidosis, and Fanconi’s syndrome. Doses greater than 60 g/m2 to 100 g/m2, age younger than 5 years at time of treatment, and combination with cisplatin and carboplatin increase risk. Abnormalities in glomerular filtration are less common, and when found are usually not clinically significant. More common are abnormalities with proximal tubular function greater than distal tubular function, though the prevalence of these findings is uncertain and further study of larger cohorts with longer follow-up is required.^{191,192,193,194,195}

Radiation nephropathy is dose-related. Doses greater than 25 Gy to both kidneys can cause renal failure at delayed intervals of more than 6 months.^196,197 The effect of radiation therapy on the kidney has best been examined in survivors of pediatric Wilms’ tumor, where unilateral nephrectomy is also common. Unilateral irradiation to doses of 14 Gy to 20 Gy may reduce the ability of the contralateral (untreated) kidney to undergo compensatory hypertrophy.¹⁹⁸ One study examined the spectrum of renal failure in 55 patients among the 5,823 patients treated for Wilms’ tumor. The incidence of renal failure at 16 years postdiagnosis was 0.6% for patients with unilateral disease and 13% for patients with bilateral disease. The most common etiologies of renal failure were bilateral nephrectomy for persistent or recurrent tumor, progressive tumor in the remaining kidney without nephrectomy, Denys-Drash syndrome (DDS), and radiation nephritis.¹⁹⁹ 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.²⁰⁰ In another study from the National Wilms’ Tumor Group of children treated from 1969 to 1995, 58 of 5,976 developed renal failure with a median follow-up of 11 years. Patients with bilateral disease and unilateral disease had a 20-year renal failure incidence of 5.5% and 1.0%, respectively. Treatment for Wilms' tumor without flank or abdominal radiation therapy was not associated with significant nephrotoxicity in a study of 40 Wilms' tumor survivors treated in England.²⁰¹ Patients with predisposition syndromes such as DDS, WAGR (Wilms’ tumor, Aniridia, Genitourinary abnormalities, Mental retardation) syndrome, or male genitourinary anomalies had much higher incidence of renal failure at 20 years 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.²⁰²

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.¹⁷⁹

Table 11. Kidney and Bladder Late Effects*

Late EffectsCausative TreatmentSigns and SymptomsScreening and Diagnostic Tests Management and Intervention*Adapted from Schwartz et al. ³³ Glomerular dysfunction Chemotherapy: cisplatin, carboplatinAsymptomatic or fatigue, poor linear growth, anemia, oliguriaAnnual: blood pressure, height, weight, hemoglobin/ hematocrit, urinalysis, creatinine, BUN; creatinine clearance baseline and every 3 yearsLow-protein diet, dialysis, renal transplantHypoplastic kidney/renal arteriosclerosisRadiation: 20-30 Gy; 10-15 Gy with chemotherapy Fatigue, poor linear growth, hypertension, headache, edema (ankle, pulmonary), albuminuria, urinary casts, hepatomegalyAnnual: blood pressure, height, weight, hemoglobin/ hematocrit, urinalysis, creatinine, BUN; creatinine clearance baseline and every 3 yearsLow-protein diet, dialysis, renal transplantTubular dysfunctionChemotherapy: cisplatin, carboplatin, ifosfamide Seizures (↓magnesium [Mg]), weakness (↓phosphate [PO4]), glycosuria, poor linear growthAnnual: blood pressure, height, weight, hemoglobin/ hematocrit, urinalysis, creatinine, BUN; creatinine clearance baseline and every 3 years and Mg, PO4 (24-hour urine for calcium, PO4)Mg supplement, PO4 supplementNephrotic syndromeRadiation: 20-30 GyProteinuria, edemaUrinalysis every year, blood pressure every year, (serum protein, albumin, creatinine [Cr], BUN) (24-hour urine for protein, Cr)Low-salt diet, diureticsBladder: fibrosis or hypoplasia (reduced bladder capacity)Chemotherapy: cyclophosphamide, ifosfamide Urgency, frequency, dysuria, incontinence (nocturia), pelvic hypoplasiaUrinalysis every year (cystoscopy, intravenous pyelogram/ ultrasound [US] : volumetrics)Exercises to increase bladder capacity, surgical referralRadiation: >30 Gy prepubertal, >50 Gy postpubertalHemorrhagic cystitisChemotherapy: cyclophosphamide, ifosfamide Hematuria, frequency, urgency, dysuria, bladder tendernessUrinalysis every year to rule out urinary tract infection (UTI), renal calculi (cystoscopy if hematuria on 2 exams)Transfusion, antispasmodics, formalin, counsel regarding risk of bladder cancerRadiation: (Radiation enhances chemotherapy effect)

Endocrine System

Thyroid Gland

Thyroid dysfunction, manifested by primary hypothyroidism, hyperthyroidism, goiter, or nodules, is a common delayed effect of radiation therapy fields that include the thyroid gland incidental to treating Hodgkin’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.²⁰³ For example, criteria for diagnosis of hypothyroidism, the most frequently reported abnormality, include elevated thyroid-stimulating hormone (TSH), depressed thyroxine (T4), or both.^{204,205,206,207} Compensated hypothyroidism includes an elevated TSH with a normal T4 and is asymptomatic. The natural history is unclear, but most endocrinologists support treatment. Uncompensated hypothyroidism includes both an elevated TSH and a depressed T4. Thyroid hormone replacement is beneficial for correction of the metabolic abnormality, and has positive implications for cardiac, gastrointestinal, and neurocognitive function.

The incidence of hypothyroidism should decrease with lower cumulative doses of radiation therapy employed in newer protocols. In a study of 1,677 children and adults with Hodgkin’s lymphoma who were treated with radiation therapy between 1961 and 1989, the actuarial risk at 26 years posttreatment for overt or subclinical hypothyroidism was 47%, with a peak incidence at 2-3 years posttreatment.²⁰⁸ In a study of Hodgkin’s lymphoma patients treated between 1962 and 1979, hypothyroidism occurred in 4 of 24 patients who received mantle doses less than 26 Gy but in 74 of 95 patients who received greater than 26 Gy. The peak incidence occurred at 3 to 5 years posttreatment, with a median of 4.6 years.²⁰⁹ 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 less than 35 Gy, 30% for those who received 35 Gy to 44.9 Gy, and 50% for those who received greater than 45 Gy to the thyroid gland. The RR for hypothyroidism was 17.1; for hyperthyroidism 8.0; and for thyroid nodules, 27.0. Elapsed time since diagnosis was a risk factor for both hypothyroidism and hyperthyroidism, where the risk increased in the first 3 to 5 years after diagnosis. For nodules, the risk increased beginning at 10 years after diagnosis. Females were at increased risk for hypothyroidism and thyroid nodules.²¹⁰ 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.^211,212

Table 12. Thyroid Late Effects*

Late EffectsCausative TreatmentSigns and SymptomsScreening and Diagnostic TestsManagement and Intervention*Adapted from Schwartz et al. ³³ Overt hypothyroidism (elevated TSH, decreased T4)Radiation: >20 Gy to the neck, cervical spine Hoarseness, fatigue, weight gain, dry skin, cold intolerance, dry brittle hair, alopecia, constipation, lethargy, poor linear growth, menstrual irregularities, pubertal delay, bradycardia, hypotensionFree T4, TSH annually up to 10 years postradiation or if symptomatic, plot on growth chartRefer to endocrinologist, thyroxine replacement, anticipatory guidance regarding symptoms of hyperthyroidism/ hypothyroidismRadiation: >7.5 Gy TBI Surgery: Partial or complete thyroidectomyCompensated hypothyroidism (elevated TSH, normal T4)Same as overt hypothyroidism with regard to radiation and surgery AsymptomaticFree T4, TSH annually up to 10 years postradiation or if symptomatic, plot on growth chartRefer to endocrinologist, thyroxine to suppress gland activityThyroid nodulesAny dose radiationHoarseness, fatigue, weight gain, dry skin, cold intolerance, dry brittle hair, alopecia, constipation, lethargy, poor linear growth, menstrual irregularities, pubertal delay, bradycardia, hypotensionFree T4, TSH annually up to 10 years postradiation or if symptomatic, plot on growth chart, physical exam; ultrasound for technetium99m scan baseline and then as needed for symptomsRefer to endocrinologist, thyroid scan, biopsy/resectionHyperthyroidism decreased TSH, elevated T4 Same as overt hypothyroidism with regard to radiation Nervousness, tremors, heat intolerance, weight loss, insomnia, increased appetite, diarrhea, moist skin, tachycardia, exophthalmus, goiterFree T4, TSH annually up to 10 years postradiation or if symptomatic, plot on growth chart physical exam; ultrasound for technetium99m scan baseline and then as needed for symptoms, triiodothyronine (T3), antithyroglobulin, antimicrosomal antibody baseline, then as needed for symptomsRefer to endocrinologist, propylthiouracil (PTU), propanol 131I, thyroidectomy

Neuroendocrine System

Other endocrine abnormalities can occur after cranial irradiation, including growth hormone (GH) deficiency, delayed or precocious puberty, and hypopituitarism. Hypothalamic dysfunction is most common, though pituitary insufficiency may occur.^{155,204,213,214,215,216,}

The potential for neuroendocrine damage is likely to decrease because of the use of more focused radiation therapy and a decrease in dose for some conditions such as medulloblastoma. Approximately 60% to 80% of irradiated pediatric brain tumor patients who have received doses greater than 30 Gy will have impaired serum GH response to provocative stimulation, usually within 5 years of treatment. The dose-response relationship has a threshold of 18 Gy to 20 Gy; the higher the radiation dose, the earlier the GH deficiency will occur after treatment. A study of conformal radiation therapy in children with CNS tumors indicates that GH insufficiency can usually be demonstrated within 12 months of radiation therapy, depending on hypothalamic dose-volume effects.²¹⁷ Children treated with CNS irradiation for leukemia are also at increased risk of GH deficiency. One study evaluated 127 patients with ALL treated with 24 Gy, 18 Gy, or no cranial irradiation. The change in height, compared with population norms expressed as the standard deviation score (SDS), was significant for all 3 groups with a dose-response of -0.49 ± 0.14 for the no radiation therapy group, -0.65 ± 0.15 for the 18 Gy radiation therapy group, and -1.38 ± 0.16 for the 24 Gy group.²¹⁸ Another study found similar results in 118 ALL survivors treated with 24 Gy cranial irradiation, in which 74% had SDS score of ≥-1 and the remainder ≥-2.²¹⁹

Children who receive HSCT with TBI have a significant risk of GH deficiency. Risk is increased with single-dose as opposed to fractionated radiation, pretransplant cranial irradiation, female gender, and posttreatment complications such as GVHD.^{220,221,222,223} Regimens containing busulfan and cyclophosphamide also increase risk.²²³ Hyperfractionation of the TBI dose markedly reduces risk, without pretransplant cranial radiation.²²⁴ 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.²²⁵ In a report from the European Group for Blood and Marrow Transplantation, among 181 patients with aplastic anemia, leukemias, and lymphomas who underwent HSCT before puberty, an overall decrease in final height-SDS value was found compared with height at transplant and genetic height. The type of transplantation, GVHD, GH, or steroid treatment did not influence final height. TBI (single dose radiation therapy more than fractionated dose radiation therapy), male gender, and young age at transplant, were found to be major factors for long-term height loss. Most patients (140/181) reached adult height within the normal range of the general population.^226,

GH deficiency should be treated with replacement therapy. Some controversy surrounds this, with a concern over increased risk of recurrence and second malignancies. Most studies, however, are limited by selection bias and small sample size. One study evaluated 361 GH-treated cancer survivors enrolled in the CCSS and compared risk of recurrence, risk of secondary neoplasm, and risk of death among survivors who did and did not receive treatment with GH. The RR of disease recurrence was 0.83 (95% CI, 0.37-1.86) for GH-treated survivors. GH-treated subjects were diagnosed with 15 second malignant neoplasms, all solid tumors, for an overall RR of 3.21 (95% CI, 1.88-5.46), mainly because of a small excess number of second neoplasms observed in survivors of acute leukemia. The data surrounding second malignancies need to be interpreted with caution given the small number of events.^227,228

Pubertal growth can be adversely affected by cranial radiation. Doses greater than 50 Gy may result in gonadotrophin deficiency, while doses in the range of 18 Gy to 47 Gy can result in precocious puberty. Precocious puberty has been reported in some children receiving cranial irradiation, mostly in girls who receive doses greater than 24 Gy cranial radiation. Earlier puberty and earlier peak height velocity, however, are seen in girls treated with 18 Gy cranial radiation.^229,230 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.²³¹ 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.²³² One other study documented non-GH abnormalities in 20 children treated with irradiation for brain tumors not involving the hypothalamic-pituitary (H-P) region, including low free T4 levels because of hypothalamic or pituitary injury and low luteinizing hormone (LH) and estradiol with oligomenorrhea.²¹³ Adrenocorticotropin deficiencies and hyperprolactinemia are relatively rare in children because these conditions develop only with doses greater than 50 Gy.^213,233

Table 13. Neuroendocrine Late Effects*

Late EffectsCausative TreatmentSigns and SymptomsScreening and Diagnostic TestsManagement and Intervention*Adapted from Schwartz et al. ³³ GH deficiencyRadiation: >18 Gy to H-P axisFalling off of growth curve, inadequate growth velocity, inadequate pubertal growth spurtAnnual stadiometer height (every 6 months at age 9-12 years), growth curve, bone age at 9 years, then every year to puberty (insulin stimulation test and pulsatile GH analysis)GH therapy, delay puberty with gonadotropin releasing hormone (GnRH) agonistSurgery: Tumor in region of H-P axisAdrenocorticotropic hormone (ACTH) deficiencyRadiation: >40 Gy to H-P axisMuscular weakness, anorexia, nausea, weight loss, dehydration, hypotension, abdominal pain, increased pigmentation (skin, buccal mucosa)Cortisol (a.m.) baseline, prn symptoms (insulin–hypoglycemia; metapyrone stimulation tests)HydrocortisoneSurgery: Tumor in region of H-P axisThyrotropin-releasing hormone (TRH) deficiencyRadiation: >40 Gy H-P axisHoarseness, fatigue, weight gain, dry skin, cold intolerance, dry brittle hair, alopecia, constipation, lethargy, poor linear growth, menstrual irregularities, pubertal delay, bradycardia, hypotensionFree T4, T3, TSH baseline, every 3-5 yearsHormone replacement with thyroxine, anticipatory guidance regarding symptoms of hypothyroidismSurgery: Tumor in region of H-P axisPrecocious puberty (especially females)Radiation: >20 Gy to H-P axisEarly growth spurt, false catch-up, premature sexual maturation; female: breast development and pubic hair before 8 years and menses before 9 years; male: testicular/penile growth and pubic hair before 9-9.5 yearsHeight, growth curve every year, bone age every 2 years until mature, (LH, follicle- stimulating hormone [FSH], estradiol or testosterone)(pelvic ultrasound, GnRH-stimulation testing)GnRH agonistSurgery: Tumor in region of H-P axisGonadotropin deficiency:MaleRadiation: >40 Gy to hypothalamic regionDelayed/ arrested/absent pubertal development: lack of or diminished pubic and axillary hair, penile and testicular enlargement, voice change, body odor, acne; testicular atrophy (softer and smaller); failure to impregnate Tanner stage, LH, FSH, estradiol every 3-5 years, (GnRH testing)Anticipatory guidance regarding symptoms of estrogen deficiency, hormone replacement, early intervention may prevent osteoporosis, and atherosclerosisSurgery: Tumor in region of hypothalamus FemaleRadiation: >40 Gy to hypothalamic regionDelayed/ arrested/ absent pubertal development including: breasts, female escutcheon, female habitus, vaginal estrogen effect, body odor, acne; changes in duration, frequency, and character of menstruation (less cramping) estrogen deficiency: hot flashes, vaginal dryness, dyspareunia, low libido; infertility (if not on birth control pills)Tanner stage, LH, FSH, estradiol every 3-5 years, GnRH-stimulation testsAnticipatory guidance regarding symptoms of estrogen deficiency, hormone replacement, early intervention may prevent osteoporosis, and atherosclerosisSurgery: Tumor in region of hypothalamusHyper-prolactinemiaRadiation: >40 Gy H-P axisFemale: menstrual irregularities, loss of libido, infertility, galactorrhea, hot flashes, osteopenia; male: loss of libido, impotence, infertilityProlactin-level baseline, then as needed for symptomsDopamine agonist (bromocriptine)Surgery: Tumor in region of hypothalamusMetabolic syndromeChemotherapy: SteroidsObesity, hypertension, hyperlipidemia, hyperglycemia, insulin resistance with hyperinsulinemiasFasting lipids, glucose, insulin levels, body mass index (BMI) evaluationRefer to endocrinologyRadiation: Questionable ≥18 Gy (dose not well established)

Musculoskeletal System

Bone and Body Composition

Chondroblasts and chondrocytes are affected by radiation therapy in growing children, which can result in soft tissue hypoplasia and diminution of bone growth. These effects are associated with the total and fractional radiation dose, and the inclusion of the epiphyses in the radiation field.^234,235,236 Craniospinal radiation results in both abnormal GH secretion and effects on the vertebral bodies.²³⁷

Avascular necrosis has been reported in survivors of ALL who were treated by conventional therapy or by HSCT, with corticosteroids representing a significant risk factor.^{238,239,240,241,242,243} 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 74.²⁴⁴

Bone mineral density in childhood cancer survivors may be reduced, especially in children treated for ALL, in whom it has been best studied. An increased incidence of fractures and osteonecrosis also occurs in these patients. Risk factors include increased age at time of exposure, estrogen deficiency, female gender, corticosteroid use and type, GH deficiency and cranial radiation. Prevalence, chronicity, and severity are not consistent across studies; therefore, the risk remains poorly defined.^{245,246,247,248,249,250,251,252,253} Decreased bone mineral density has also been reported in patients treated for osteosarcoma,^254,255 Wilms’ tumor,²⁵⁶ and CNS tumors.²⁵⁷ For survivors of HSCT, again there is a lack of consensus regarding the risk and incidence of decreased bone mineral density posttransplant.^{258,259,260,261,262} 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.^263,264

Obesity

Abnormal body composition is also reported in excess in survivors of pediatric ALL. One study evaluated obesity in 1,764 ALL survivors followed in the CCSS, and compared them with a cohort of 2,565 siblings. The odds ratio for being obese was 2.6 for female survivors and 1.9 for male survivors who received doses of radiation greater than 20 Gy. The highest risk was for females treated at 4 years and younger with cranial radiation doses of greater than 20 Gy. Risk of obesity was not increased among ALL survivors treated with chemotherapy alone or with doses of cranial radiation of 10 Gy to 19 Gy.²⁶⁵ Genetic predisposition may be an important factor in risk for obesity in these ALL survivors. The CCSS has found higher BMI to be associated with a polymorphism in the leptin receptor gene.²⁶⁶ Similar findings were reported by 1 group in which 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.²⁶⁷ 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.^268,269 A study from Denmark reports reduced lean body mass among survivors of childhood non-Hodgkin’s lymphoma and Hodgkin’s lymphoma.²⁷⁰ Children treated for brain tumors are at risk for development of obesity because of hypothalamic dysfunction resulting from the tumor, surgery, or irradiation.²⁷¹

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, because of disturbances of the H-P axis, but more research is required to better understand all of the presentations of the syndrome, its incidence, and its prevalence in survivors of childhood cancer.^272,273,274,

Table 14. Musculoskeletal Late Effects*

Late EffectsCausative TreatmentSigns and SymptomsScreening and Diagnostic TestsManagement and Intervention*Adapted from Schwartz et al. ³³ Muscular hypoplasiaRadiation: >20 Gy (growing child); younger children more sensitiveAsymmetry of muscle mass when compared with untreated area, decreased range of motion, stiffness and pain in affected area (uncommon)Careful comparison and measurement of irradiated and unirradiated areas, range of motionPrevention: good exercise program, range of motion, muscle strengtheningSurgery: Muscle loss or resectionSpinal abnormalities: scoliosis, kyphosis, lordosis, decreased sitting heightRadiation: For young children, radiation therapy to hemiabdomen or spine (especially hemivertebral); 10 Gy (minimal effect), >20 Gy (clinically notable defect)Back pain, hip pain, uneven shoulder height, rib humps or flares, deviation from vertical curve, gait abnormalitiesStanding and sitting height at each visit and plot on chart (stadiometer), during puberty examine spine every 3-6 months until growth is completed and then every 1-2 years, spinal films baseline during puberty, then as needed for curvature (COBB technique to measure curvature)Refer to orthopedist if any curvature is noted, especially during a period of rapid growthSurgery: LaminectomyLength discrepancyRadiation: >20 GyLower back pain, limp, hip pain, discrepancy in muscle mass and length when compared with untreated extremity, scoliosisAnnual measurement of treated and untreated limb (completely undressed patient to assure accurate measurements); radiograph baseline to assess remaining epiphyseal growth, radiographs annually during periods of rapid growthContralateral epiphysiodesis; limb-shortening proceduresPathological fractureRadiation: >40 GyPain, edema, ecchymosisBaseline radiograph of treated area to assess bone integrity, then as needed for symptomsPrevention: consider limitation of activities (e.g., contact sports) surgical repair of fracture; may require internal fixationSurgery: BiopsyOsteonecrosisChemotherapy: SteroidsPain in affected joint, limpRadiograph, CT scan as needed for symptomsSymptomatic care; joint replacementRadiation: >40-50 Gy (more common in adults)Osteocartilaginous exostosesRadiation therapyPainless lump/mass noted in the field of radiationRadiograph baseline and as needed for growth of lesionResection for cosmetic/functional reasons, counsel regarding 10% incidence of malignant degenerationOsteopenia/ osteoporosisChemotherapy: SteroidsFractures, painDEXA — intervals of testing unclear. Pediatric norms not well established. Best data are in adultsCalcium supplementation, increase weight bearing exercise; refer to endocrinology for possible bisphosphonate therapyRadiation: >18 Gy cranial radiation therapy Slipped capitofemoral epiphysisChemotherapy: High-dose steroidsPain in affected hip, limp, abnormal gaitRadiograph baseline to assess integrity of the treated joint(s), then as needed for symptomsRefer to orthopedist for surgical interventionRadiation: >25 Gy (at young age)

Reproductive System

Gonadal Function

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

Male Gonadal Function

Spermatogenesis is highly sensitive to cyclophosphamide, with a dose-effect exhibited that is exacerbated by coadministration of other alkylating agents, such as procarbazine.^{275,276,277,278,279,280,281} 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 FSH had received higher doses of cyclophosphamide than the mean.²⁸² 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.^107,283,284 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.²⁷⁶ Reduction of alkylating agent therapy in multiagent protocols has resulted in reduction in the risk for male infertility.^{278,279,280,285,286} Review of the available studies has led to the consensus that males who receive less than 4 gm/m2 of cyclophosphamide without any other alkylating agents and without either testicular or cranial radiation are likely to retain their fertility. Doses greater than 9 gm/m2 are unlikely to result in any conservation of fertility.

Ifosfamide has been used as part of multimodality therapy for a variety of childhood cancers, often in combination with cyclophosphamide and/or abdominopelvic radiation therapy. Little is known about its long-term gonadal toxicity. A study was performed to evaluate fertility in 96 male patients treated with ifosfamide and no other alkylating agents for osteosarcoma. Eleven patients were prepubertal and 85 were postpubertal at the time of chemotherapy. Of the 96 patients, 26 underwent sperm analysis, and 20 showed oligospermia or azoospermia. Patients who received high-dose ifosfamide showed a higher incidence of azoospermia. Six patients were normospermic and had received either no ifosfamide or lower doses of ifosfamide. Eight patients fathered a total of 12 children.^287,

The degree and permanency of radiation therapy-induced damage to the male reproductive system are dose, field and schedule, and age dependent. The germinal epithelium is damaged by much lower doses (<1 Gy) of radiation therapy than are Leydig cells (20 Gy-30 Gy).²⁸⁸ Although temporary oligospermia can occur after these very low radiation doses, permanent azoospermia results from higher doses of greater than 3 Gy to 4 Gy. The potential for a return of spermatogenesis in the intermediate dose range of 1 Gy to 3 Gy is variable.^289,290 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.²⁹¹ Scatter from abdominal radiation with doses greater than 20 Gy for Hodgkin’s disease can cause transient elevation in FSH and oligospermia but not with lower doses.²⁹²

Table 15. Male Gonadal Late Effects*

Late EffectsCausative TreatmentSigns and SymptomsScreening and Diagnostic TestsManagement and Intervention*Adapted from Schwartz et al. ³³ Germ cell damage: oligospermia/ azoospermiaChemotherapy: cyclophosphamide, mechlorethamine, lomustine (CCNU)/carmustine (BCNU), procarbazine, ifosfamide, busulfan, melphalan, dacarbazine (DTIC)Testicular atrophy (softer and smaller), failure to impregnateTanner stage, inquire regarding previous sperm banking, determine testicular size and consistency, LH, FSH, testosterone: (1) for failure of pubertal development, (2) baseline when sexually mature, (3) for failure to impregnate (repeat every 3 years for possible recovery), analysis of sperm at maturity, or for failure to impregnate (repeat every 3-5 years to assess recovery)Instruct on testicular self-examination, anticipatory guidance regarding germ-cell damage, referral to reproductive endocrinology, infertility counseling, and alternate strategies for fatheringRadiation: >1-6 GySurgery: Orchiectomy or surgical manipulationLeydig cell damage: testosterone deficiencyChemotherapy: cyclophosphamide/etoposide Delayed/ arrested/ absent pubertal development, pubic and axillary hair (female hair pattern), lack of penile and testicular enlargement, voice change, body odor and acne, testicular atrophy (softer and smaller)