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Late Effects of Treatment for Childhood Cancer (PDQ®)

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General Information About Late Effects of Treatment for Childhood Cancer
Subsequent Neoplasms
Late Effects of the Cardiovascular System
Late Effects of the Central Nervous System
Late Effects of the Digestive System
Late Effects of the Endocrine System
Late Effects of the Immune System
Late Effects of the Musculoskeletal System
Late Effects of the Reproductive System
Late Effects of the Respiratory System
Late Effects of the Special Senses
Late Effects of the Urinary System
Changes to This Summary (09/28/2017)
About This PDQ Summary

General Information About Late Effects of Treatment for Childhood Cancer

During the past five decades, dramatic progress has been made in the development of curative therapy for pediatric malignancies. Long-term survival into adulthood is the expectation for more than 80% of children with access to contemporary therapies for pediatric malignancies. [1] [2] The therapy responsible for this survival can also produce adverse long-term health-related outcomes, referred to as late effects, which manifest months to years after completion of cancer treatment.

A variety of approaches have been used to advance knowledge about the very long-term morbidity associated with childhood cancer and its contribution to early mortality. These initiatives have utilized a spectrum of resources including investigation of data from the following:

Studies reporting outcomes in survivors who have been well characterized in regards to clinical status and treatment exposures, and comprehensively ascertained for specific effects through medical assessments, typically provide the highest quality of data to establish the occurrence and risk profiles for late cancer treatment–related toxicity. Regardless of study methodology, it is important to consider selection and participation bias of the cohort studies in the context of the findings reported.

Prevalence of Late Effects in Childhood Cancer Survivors

Late effects are commonly experienced by adults who have survived childhood cancer; the prevalence of late effects increases as time from cancer diagnosis elapses. Population-based studies support excess hospital-related morbidity among childhood and young adult cancer survivors compared with age- and sex-matched controls. [3] [4] [5] [10] [11] [12]

Research has demonstrated that among adults treated for cancer during childhood, late effects contribute to a high burden of morbidity, including the following: [6] [8] [9] [13] [14]

The variability in prevalence is related to differences in the following:

Childhood Cancer Survivor Study (CCSS) investigators demonstrated that the elevated risk of morbidity and mortality among aging survivors in the cohort increases beyond the fourth decade of life. By age 50 years, the cumulative incidence of a self-reported severe, disabling, life-threatening, or fatal health condition was 53.6% among survivors, compared with 19.8% among a sibling control group. Among survivors who reached age 35 years without a previous severe, disabling, life-threatening, or fatal health condition, 25.9% experienced a new grade 3 to grade 5 health condition within 10 years, compared with 6.0% of healthy siblings (refer to Figure 1). [6]

The presence of serious, disabling, and life-threatening chronic health conditions adversely affects the health status of aging survivors, with the greatest impact on functional impairment and activity limitations. Predictably, chronic health conditions have been reported to contribute to a higher prevalence of emotional distress symptoms in adult survivors than in population controls. [15] Female survivors demonstrate a steeper trajectory of age-dependent decline in health status than do male survivors. [16] The even-higher prevalence of late effects among clinically ascertained cohorts is related to the subclinical and undiagnosed conditions detected by screening and surveillance measures. [9]

Charts showing the cumulative incidence of chronic health conditions by age among survivors and siblings.Figure 1. Cumulative incidence of chronic health conditions for (A) grades 3 to 5 chronic health conditions, (B) multiple grade 3 to 5 conditions in survivors, (C) multiple grade 3 to 5 conditions in siblings, (D) conditioned based on no previous grade 3 to 5 conditions among survivors by ages 25, 35, or 45, and (E) conditioned based on no previous grade 3 to 5 conditions among siblings by ages 25, 35, or 45. Gregory T. Armstrong, Toana Kawashima, Wendy Leisenring, Kayla Stratton, Marilyn Stovall, Melissa M. Hudson, Charles A. Sklar, Leslie L Robison, Kevin C. Oeffinger; Aging and Risk of Severe, Disabling, Life-Threatening, and Fatal Events in the Childhood Cancer Survivor Study; Journal of Clinical Oncology, volume 32, issue 12, pages 1218-1227. Reprinted with permission. © (2014) American Society of Clinical Oncology. All rights reserved.

CCSS investigators also evaluated the impact of race and ethnicity on late outcomes by comparing late mortality, subsequent neoplasms, and chronic health conditions in Hispanic (n = 750) and non-Hispanic black (n = 694) participants with non-Hispanic white participants (n = 12,397). [17] The following results were observed:

Recognition of late effects, concurrent with advances in cancer biology, radiological sciences, and supportive care, has resulted in a change in the prevalence and spectrum of treatment effects. In an effort to reduce and prevent late effects, contemporary therapy for most pediatric malignancies has evolved to a risk-adapted approach that is assigned based on a variety of clinical, biological, and sometimes genetic factors. The CCSS reported that with decreased cumulative dose and frequency of therapeutic radiation use over treatment decades from 1970 to 1999, survivors have experienced a significant decrease in risk of subsequent neoplasms. [19] With the exception of survivors requiring intensive multimodality therapy, sometimes including hematopoietic cell transplantation, for aggressive or refractory/relapsed malignancies, life-threatening treatment effects are relatively uncommon after contemporary therapy in early follow-up (up to 10 years after diagnosis). However, survivors still frequently experience life-altering morbidity related to effects of cancer treatment on endocrine, reproductive, musculoskeletal, and neurologic function.

Mortality

Late effects also contribute to an excess risk of premature death among long-term survivors of childhood cancer as observed in the following:

Despite high premature morbidity rates, overall mortality has decreased over time. [20] [28] [29] [30] This reduction is related to a decrease in deaths from the primary cancer without an associated increase in mortality from subsequent cancers or treatment-related toxicities. The former reflects improvements in therapeutic efficacy, and the latter reflects changes in therapy made subsequent to studying the causes of late effects. The expectation that mortality rates in survivors will continue to exceed those in the general population is based on the long-term sequelae that are likely to increase with attained age. If patients treated on therapeutic protocols are followed up for long periods into adulthood, it will be possible to evaluate the excess lifetime mortality in relation to specific therapeutic interventions.

Monitoring for Late Effects

Recognition of both acute and late modality–specific toxicity has motivated investigations evaluating the pathophysiology and prognostic factors for cancer treatment–related effects. The results of these studies have played an important role in the following areas: [20] [28]

The common late effects of pediatric cancer encompass several broad domains, including the following:

Late sequelae of therapy for childhood cancer can be anticipated based on therapeutic exposures, but the magnitude of risk and the manifestations in an individual patient are influenced by numerous factors. Factors that should be considered in the risk assessment for a given late effect include the following:

Resources to Support Survivor Care

Risk-based screening

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, the American Academy of Pediatrics, the Children’s Oncology Group (COG), and the Institute of Medicine. A risk-based medical follow-up is recommended, which includes a systematic plan for lifelong screening, surveillance, and prevention that incorporates risk estimates based on the following: [31]

Part of long-term follow-up is also focused on appropriate screening of educational and vocational progress. Specific treatments for childhood cancer, especially those that directly impact nervous system structures, may result in sensory, motor, and neurocognitive deficits that may have adverse consequences on functional status, educational attainment, and future vocational opportunities. [32] In support of this, a CCSS investigation observed the following: [33]

These data emphasize the importance of facilitating survivor access to remedial services, which has been demonstrated to have a positive impact on education achievement, [34] which may in turn enhance vocational opportunities.

In addition to risk-based screening for medical late effects, the impact of health behaviors on cancer-related health risks is also emphasized. Health-promoting behaviors are stressed for survivors of childhood cancer. Targeted educational efforts appear to be worthwhile in the following areas: [35]

Proactively addressing unhealthy and risky behaviors is pertinent, as several research investigations confirm that long-term survivors use tobacco and alcohol and have inactive lifestyles at higher rates than is ideal given their increased risk of cardiac, pulmonary, and metabolic late effects. [35] [36] [37]

Access to risk-based survivor care

Most childhood cancer survivors do not receive recommended risk-based care. The CCSS observed the following:

Access to health insurance appears to play an important role in risk-based survivor care. [41] [42] Lack of access to health insurance affects the following:

Overall, lack of health insurance remains a significant concern for survivors of childhood cancer because of health issues, unemployment, and other societal factors. [44] [45] Legislation, including the Health Insurance Portability and Accountability Act, [46] [47] has improved access and retention of health insurance among survivors, although the quality and limitations associated with these policies have not been well studied.

Transition of Survivor Care

Long-term follow-up programs

Transition of care from the pediatric to adult health care setting is necessary for most childhood cancer survivors in the United States.

When available, multidisciplinary long-term follow-up programs in the pediatric cancer center work collaboratively with community physicians to provide care for childhood cancer survivors. This type of shared care has been proposed as the optimal model to facilitate coordination between the cancer center oncology team and community physician groups providing survivor care. [48]

An essential service of long-term follow-up programs is the organization of an individualized survivorship care plan that includes the following:

For survivors who have not been provided with this information, the COG offers a template that can be used by survivors to organize a personal treatment summary (refer to the COG Survivorship Guidelines, Appendix 1).

COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers

To facilitate survivor and provider access to succinct information to guide risk-based care, COG investigators have organized a compendium of exposure- and risk-based health surveillance recommendations, with the goal of standardizing the care of childhood cancer survivors. [49]

The compendium of resources includes the following:

Information concerning late effects is summarized in tables throughout this summary.

Several groups have undertaken research to evaluate the yield from risk-based screening as recommended by the COG and other pediatric oncology cooperative groups. [9] [64] [65] Pertinent considerations in interpreting the results of these studies include:

Collectively, these studies demonstrate that screening identifies a substantial proportion of individuals with previously unrecognized, treatment-related health complications of varying degrees of severity. Study results have also identified low-yield evaluations that have encouraged revisions of screening recommendations. Ongoing research is evaluating cost effectiveness of screening in the context of consideration of benefits, risks, and harms.

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Subsequent Neoplasms

Subsequent neoplasms (SNs), which may be benign or malignant, are defined as histologically distinct neoplasms developing at least 2 months after completion of treatment for the primary malignancy. Childhood cancer survivors have an increased risk of developing SNs that varies according to the following:

SNs are the leading cause of nonrelapse late mortality (standardized mortality ratio, 15.2; 95% confidence interval [CI], 13.9–16.6). [1] The Childhood Cancer Survivor Study (CCSS) reported the following 30-year cumulative incidence rates: [2]

This represents a sixfold increased risk of SNs among cancer survivors, compared with the general population. [2]

The excess risk of SNs persists even after the age of 40 years, as seen in the following studies: [3]

The development of an SN is likely multifactorial in etiology and results from a combination of influences including gene-environment and gene-gene interactions. Outcome after the diagnosis of an SN is variable, as treatment for some histological subtypes may be compromised if childhood cancer therapy included cumulative doses of agents and modalities at the threshold of tissue tolerance. [8]

The incidence and type of SNs depend on the following:

Unique associations with specific therapeutic exposures have resulted in the classification of SNs into the following two distinct groups:

Therapy-Related Myelodysplastic Syndrome and Leukemia

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) has been reported after treatment of Hodgkin lymphoma (HL), acute lymphoblastic leukemia (ALL), and sarcomas, with the cumulative incidence approaching 2% at 15 years after therapy. [9] [10] [11] [12]

Characteristics of t-MDS/AML include the following: [9] [13] [14]

t-MDS/AML is a clonal disorder characterized by distinct chromosomal changes. The following two types of t-MDS/AML are recognized by the World Health Organization classification: [15]

Therapy-Related Solid Neoplasms

Therapy-related solid SNs represent 80% of all SNs and demonstrate a strong relationship with radiation exposure and are characterized by a latency that exceeds 10 years. The risk of solid SNs continues to increase with longer follow-up. The risk of solid SNs is highest when the following occur: [2]

The histological subtypes of solid SNs encompass a neoplastic spectrum ranging from benign and low-grade malignant lesions (e.g., NMSC, meningiomas) to high-grade malignancies (e.g., breast cancers, glioblastomas). [2] [11] [18] [19] [20] [21] [22]

Solid SNs in childhood cancer survivors most commonly involve the following: [2] [9] [11] [19] [23] [24]

With more prolonged follow-up of adult survivors of childhood cancer cohorts, epithelial neoplasms have been observed in the following: [2] [9] [18] [25]

Benign and low-grade SNs, including NMSCs and meningiomas, have also been observed with increasing prevalence in survivors who were treated with radiation therapy for childhood cancer. [2] [19] [20]

In addition to radiation exposure, exposure to certain anticancer agents may result in solid SNs. In recipients of a hematopoietic cell transplant conditioned with high-dose busulfan and cyclophosphamide (Bu-Cy), the cumulative incidence of new solid cancers appears to be similar regardless of exposure to radiation. In a registry-based, retrospective, cohort study, Bu-Cy conditioning without TBI was associated with higher risks of solid SNs than in the general population. Chronic graft-versus-host disease increased the risk of SNs, especially those involving the oral cavity. [26]

Some well-established solid SNs include the following: [27]

Subsequent Neoplasms and Genetic Susceptibility

Literature clearly supports the role of chemotherapy and radiation therapy in the development of SNs. However, interindividual variability exists, suggesting that genetic variation has a role in susceptibility to genotoxic exposures, or that genetic susceptibility syndrome confers an increased risk of cancer, such as Li-Fraumeni syndrome. [78] Previous studies have demonstrated that childhood cancer survivors with a family history of Li-Fraumeni syndrome in particular, or a family history of cancer, carry an increased risk of developing an SN. [79] [80]

The risk of SNs could potentially be modified by mutations in high-penetrance genes that lead to these serious genetic diseases (e.g., Li-Fraumeni syndrome). [80] However, the attributable risk is expected to be very small because of the extremely low prevalence of mutations in high-penetrance genes.

Table 1 summarizes the spectrum of neoplasms, affected genes, and Mendelian mode of inheritance of selected syndromes of inherited cancer predisposition.

Table 1. Selected Syndromes of Inherited Cancer Predispositiona

SyndromeMajor Tumor TypesAffected GeneMode of Inheritance
Adenomatous polyposis of the colonColon, hepatoblastoma, intestinal cancers, stomach, thyroid cancer APCDominant
Ataxia-telangiectasiaLeukemia, lymphomaATMRecessive
Beckwith-Wiedemann syndromeAdrenal carcinoma, hepatoblastoma, rhabdomyosarcoma, Wilms tumorCDKN1C/NSD1Dominant
Bloom syndromeLeukemia, lymphoma, skin cancerBLMRecessive
Diamond-Blackfan anemiaColon cancer, osteogenic sarcoma, AML/MDSRPS19 and other RP genesDominant, spontaneousb
Fanconi anemiaGynecological tumors, leukemia, squamous cell carcinomaFANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCGRecessive
Juvenile polyposis syndromeGastrointestinal tumorsSMAD4/DPC4Dominant
Li-Fraumeni syndromeAdrenocortical carcinoma, brain tumor, breast carcinoma, leukemia, osteosarcoma, soft tissue sarcomaTP53Dominant
Multiple endocrine neoplasia 1Pancreatic islet cell tumor, parathyroid adenoma, pituitary adenomaMEN1Dominant
Multiple endocrine neoplasia 2Medullary thyroid carcinoma, pheochromocytomaRETDominant
Neurofibromatosis type 1Neurofibroma, optic pathway glioma, peripheral nerve sheath tumorNF1Dominant
Neurofibromatosis type 2Vestibular schwannomaNF2Dominant
Nevoid basal cell carcinoma syndromeBasal cell carcinoma, medulloblastomaPTCHDominant
Peutz-Jeghers syndromeIntestinal cancers, ovarian carcinoma, pancreatic carcinomaSTK11Dominant
RetinoblastomaOsteosarcoma, retinoblastoma RB1Dominant
Tuberous sclerosisHamartoma, renal angiomyolipoma, renal cell carcinomaTSC1/TSC2Dominant
von Hippel-Lindau syndromeHemangioblastoma, pheochromocytoma, renal cell carcinoma, retinal and central nervous system tumors VHLDominant
WAGR syndromeGonadoblastoma, Wilms tumor WT1Dominant
Wilms tumor syndromeWilms tumorWT1Dominant
Xeroderma pigmentosumLeukemia, melanoma XPA, XPB, XPC, XPD, XPE, XPF, XPG, POLHRecessive
AML = acute myeloid leukemia; MDS = myelodysplastic syndromes; WAGR = Wilms tumor, aniridia, genitourinary anomalies, mental retardation.
aAdapted from Strahm et al. [81]
bDominant in a fraction of patients, spontaneous mutations can occur.

Drug-metabolizing enzymes and DNA repair polymorphisms

The interindividual variability in risk of SNs is more likely related to common polymorphisms in low-penetrance genes that regulate the availability of active drug metabolites or are responsible for DNA repair. Gene-environment interactions may magnify subtle functional differences resulting from genetic variations.

Drug-metabolizing enzymes

Metabolism of genotoxic agents occurs in two phases.

  1. Phase I involves activation of substrates into highly reactive electrophilic intermediates that can damage DNA, a reaction principally performed by the cytochrome p450 (CYP) family of enzymes.
  2. Phase II enzymes (conjugation) function to inactivate genotoxic substrates. The phase II proteins comprise the glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase-1 (NQO1), and others.

The balance between the two sets of enzymes is critical to the cellular response to xenobiotics; for example, high activity of a phase I enzyme and low activity of a phase II enzyme can result in DNA damage.

DNA repair polymorphisms

DNA repair mechanisms protect somatic cells from mutations in tumor suppressor genes and oncogenes that can lead to cancer initiation and progression. An individual’s DNA repair capacity appears to be genetically determined. [82] A number of DNA repair genes contain polymorphic variants, resulting in large interindividual variations in DNA repair capacity. [82] Evaluation of the contribution of polymorphisms influencing DNA repair to the risk of SN represents an active area of research.

Screening and Follow-up for Subsequent Neoplasms

Vigilant screening is important for childhood cancer survivors at risk. [83] Because of the relatively small size of the pediatric cancer survivor population and the prevalence and time to onset of therapy-related complications, undertaking clinical studies to assess the impact of screening recommendations on the morbidity and mortality associated with the late effect is not feasible.

Well-conducted studies on large populations of childhood cancer survivors have provided compelling evidence linking specific therapeutic exposures and late effects. This evidence has been used by several national and international cooperative groups (Scottish Collegiate Guidelines Network, Children’s Cancer and Leukaemia Group, Children's Oncology Group [COG], Dutch Children's Oncology Group) to develop consensus-based clinical practice guidelines to increase awareness and standardize the immediate care needs of medically vulnerable childhood cancer survivors. [84]

All pediatric cancer survivor health screening guidelines employ a hybrid approach that is both evidence-based (utilizing established associations between therapeutic exposures and late effects to identify high-risk categories) and grounded in the collective clinical experience of experts (matching the magnitude of the risk with the intensity of the screening recommendations). The screening recommendations in these guidelines represent a statement of consensus from a panel of experts in the late effects of pediatric cancer treatment. [83] [84]

The COG Guidelines for malignant SNs indicate that certain high-risk populations of childhood cancer survivors merit heightened surveillance because of predisposing host, behavioral, or therapeutic factors. [83]

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Late Effects of the Cardiovascular System

Cardiovascular disease, after recurrence of the original cancer and development of second primary cancers, has been reported to be the leading cause of premature mortality among long-term childhood cancer survivors. [1] [2] [3] [4] [5]

Evidence (excess risk of premature cardiovascular mortality):

  1. Among more than 20,000 North American 5-year survivors of childhood cancer (in the Childhood Cancer Survivor Study [CCSS]) treated from 1970 to 1986, participants had a standardized mortality ratio of 7.0 (95% confidence interval [CI], 5.9–8.2) for cardiac mortality, which translated to 0.36 excess deaths per 1,000 person-years. [1]
  2. All-cause circulatory disease was associated with an absolute excess risk of 3.4% (95% CI, 2.8%–4.2%) among nearly 18,000 5-year survivors in the British CCSS who were diagnosed with cancer between 1950 and 1991. Individual standardized mortality ratios for cardiac, cerebrovascular, and other circulatory diseases ranged from 3.5 to 5.2. [2]

By age 45 years, the overall cumulative incidence of severe, life-threatening, or fatal cardiac events has been reported to be approximately 5% for coronary artery disease and heart failure separately and 1% to 2% for valve disorders and arrhythmias. [6] Compared with siblings, 5-year survivors had relative risks (RRs) approaching, if not exceeding, tenfold for heart failure, coronary artery disease, and cerebrovascular disease. [7] The burden of subclinical disease is likely much greater. [8]

The specific late effects covered in this section include the following:

The section will also briefly discuss the influence of related conditions such as hypertension, dyslipidemia, and diabetes in relation to these late effects, but not directly review in detail those conditions as a consequence of childhood cancer treatment. A comprehensive review on long-term cardiovascular toxicity in childhood and young adult survivors of cancer, issued by the American Heart Association, has been published. [5]

Overall, there has been a wealth of studies focused on the topic of cardiac events among childhood cancer survivors. In addition to many smaller studies not covered in detail here, the literature includes very large cohort studies that are either hospital based, [6] [8] [9] [10] [11] [12] clinical trial based, [13] [14] or population based, [2] [4] many with up to several decades of follow-up. However, even with decades of follow-up, the average age of these populations may still be relatively young (young or middle adulthood). And while the risk of serious cardiovascular outcomes may be very high relative to the age-matched general population, the absolute risk often remains low, limiting the power of many studies. Among the very large studies featuring thousands of survivors, the main limitation has been inadequate ability to clinically ascertain late cardiovascular complications, with a greater reliance on either administrative records (e.g., death registries) and/or self-report or proxy-report.

While each study design has some inherent biases, the overall literature, based on a combination of self-reported outcomes, clinical ascertainment, and administrative data sources, is robust in concluding that certain cancer-related exposures predispose survivors toward a significantly greater risk of cardiovascular morbidity and mortality. Although late effects research often lags behind changes in contemporary therapy, many therapies linked to cardiovascular late effects remain in common use today. [15] [16] Ongoing research will be important to ensure that newer targeted agents being introduced today do not result in unexpected cardiovascular effects. [17]

Evidence (selected cohort studies describing the rates of cardiovascular outcomes):

  1. A multicenter French cohort of 3,162 5-year survivors treated between 1942 and 1986 were monitored for a median of 26 years. [12]
  2. A Dutch hospital-based cohort of 1,362 5-year childhood cancer survivors (median attained age, 29.1 years) were monitored from diagnosis for a median of 22.2 years. [11]
  3. A report from the CCSS that featured over 14,000 5-year survivors examined detailed dose-response to both radiation therapy and chemotherapy (anthracycline) in relation to self-reported (or death caused by) myocardial infarction, congestive heart failure, pericardial disease, and valvular abnormalities. [10]
  4. A follow-up study from the CCSS demonstrated that the cumulative incidence of these serious cardiac events continued to increase beyond age 45 years. [6]
  5. Of 670 survivors of Hodgkin lymphoma (HL) who were treated at St. Jude Children’s Research Hospital (SJCRH) and have lived 10 or more years, 348 patients were clinically assessed in the St. Jude Lifetime Cohort Study. [18]

Using data from four large, well-annotated childhood cancer survivor cohorts (CCSS, National Wilms Tumor Study Group, the Netherlands, and SJCRH), a heart failure risk calculator based on readily available demographic and treatment characteristics has been created and validated, which may provide more individualized clinical heart failure risk estimation for 5-year survivors of childhood cancer who have recently completed therapy and up through age 40 years. One limitation of this estimator is that because of the young age of participants at the time of baseline prediction (5-year survival), information on conventional cardiovascular conditions such as hypertension, dyslipidemia, or diabetes could not be incorporated. [19]

Treatment Risk Factors

Chemotherapy (in particular, anthracyclines and anthraquinones) along with radiation therapy both independently and in combination, increase the risk of cardiovascular disease in survivors of childhood cancer and are considered to be the most important risk factors contributing to premature cardiovascular disease in this population (refer to Figure 2). [11]

Five charts showing marginal and cause-specific cumulative incidence of cardiac events among childhood cancer survivors according to different treatment groups. Figure 2. (A, B) Marginal (Kaplan-Meier) and (C–E) cause-specific (competing risk) cumulative incidence of cardiac events (CEs) in childhood cancer survivors stratified according to different treatment groups. (A) Marginal cumulative incidence for all CEs, stratified according to potential cardiotoxic (CTX) therapy or no CTX therapy, log-rank P < .001. (B) Marginal cumulative incidence for all CEs, stratified according to different CTX therapies, log-rank P < .001. (C) Cause-specific cumulative incidence for congestive heart failure, stratified according to different treatment groups, log-rank P < .001. (D) Cause-specific cumulative incidence for cardiac ischemia, stratified according to cardiac irradiation (RTX) or no RTX, log-rank P = .01. (E) Cause-specific cumulative incidence for valvular disease, stratified according to RTX or no RTX, log-rank P < .001. The shaded colorized background areas refer to the 95% CIs. Ant, anthracycline. Helena J. van der Pal, Elvira C. van Dalen, Evelien van Delden, Irma W. van Dijk, Wouter E. Kok, Ronald B. Geskus, Elske Sieswerda, Foppe Oldenburger, Caro C. Koning, Flora E. van Leeuwen, Huib N. Caron, Leontien C. Kremer, High Risk of Symptomatic Cardiac Events in Childhood Cancer Survivors, Journal of Clinical Oncology, volume 30, issue 13, pages 1429-1437. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.

Anthracyclines and related agents

Anthracyclines (e.g., doxorubicin, daunorubicin, idarubicin, and epirubicin) and anthraquinones (e.g., mitoxantrone) are known to directly injure cardiomyocytes through the formation of reactive oxygen species and inducing mitochondrial apoptosis. [5] [20] The downstream results of cell death are changes in heart structure, including wall thinning, which leads to ventricular overload and pathologic remodeling that, over time, leads to dysfunction and eventual clinical heart failure. [21] [22] [23] [24]

Risk factors for anthracycline-related cardiomyopathy include the following: [25]

Among these factors, cumulative dose appears to be the most significant (refer to Figure 3). [9] While it is not completely certain whether there is a truly safe lower dose threshold, doses in excess of 250 mg/m2 to 300 mg/m2 have been associated with a substantially increased risk of cardiomyopathy, with cumulative incidences exceeding 5% after 20 years of follow-up, and in some subgroups, reaching or exceeding 10% cumulative incidence by age 40 years. [9] [10] [19] [22] [24] Concurrent chest or heart radiation therapy also further increases risk of cardiomyopathy, [11] [12] [19] as does the presence of other cardiometabolic traits such as hypertension. [6] [26] While development of clinical heart failure can occur within a few years after anthracycline exposure, in most survivors, even those who received very high doses, clinical manifestations may not occur for decades.

Chart showing risk of anthracycline-induced clinical heart failure (A-CHF) according to cumulative anthracycline dose.Figure 3. Risk of anthracycline-induced clinical heart failure (A-CHF) according to cumulative anthracycline dose. Reprinted from European Journal of Cancer, Volume 42, Elvira C. van Dalen, Helena J.H. van der Pal, Wouter E.M. Kok, Huib N. Caron, Leontien C.M. Kremer, Clinical heart failure in a cohort of children treated with anthracyclines: A long-term follow-up study, Pages 3191-3198, Copyright (2006), with permission from Elsevier.

Anthracycline Dose Equivalency

It remains unclear how best to add together doses of different anthracycline agents. A variety of anthracycline equivalence formulas (in relation to doxorubicin) have been used; however, they are largely based on hematologic toxicity equivalence, and may not necessarily be the same for cardiac toxicity. [19] [27] [28] Most pediatric professional societies and groups have generally considered daunorubicin equivalent, or near equivalent, to doxorubicin, although historically lower ratios have been proposed as well. [29] A large analysis of over 15,000 childhood cancer survivors who were monitored to age 40 years found that daunorubicin may be significantly less cardiotoxic than doxorubicin (equivalence ratio, 0.5 [95% CI, 0.2–0.7]). [30]

Other agents such as idarubicin, epirubicin, and mitoxantrone (an anthraquinone) were designed to reduce cardiac toxicity while maintaining similar antitumor effect, although data supporting this are primarily limited to adult cancer patients. [31] Similarly, data on whether liposomal formulations of anthracyclines reduce cardiac toxicity in children also are limited. [31]

Anthracycline Cardioprotection

Cardioprotective strategies that have been explored include the following:

Radiation therapy

While anthracyclines directly damage cardiomyocytes, radiation therapy primarily affects the fine vasculature of affected organs. [5]

Cardiovascular disease

Late effects of radiation therapy to the heart specifically include the following:

These cardiac late effects are related to the following:

Similar to anthracyclines, manifestation of these late effects may take years, if not decades, to present. Finally, patients who were exposed to both radiation therapy affecting the cardiovascular system and cardiotoxic chemotherapy agents are at even greater risk of late cardiovascular outcomes. [12]

Cerebrovascular disease

Cerebrovascular disease after radiation therapy exposure is another potential late effect for survivors. While brain tumor survivors have had traditionally the greatest risk, other survivors exposed to cranial irradiation (≥18 Gy) and neck irradiation (≥40 Gy), such as leukemia and lymphoma survivors, have also been reported to be at increased risk. [46] [47] [48] In lymphoma survivors who only received chest and/or neck radiation therapy, cerebrovascular disease is thought to be caused by large-vessel atherosclerosis and cardiac embolism. [47]

As with cardiac outcomes, risk increases with cumulative dose received. One study (N = 325) reported that the stroke hazard increased by 5% (hazard ratio [HR], 1.05; 95% CI, 1.01–1.09; P = .02), with each 1 Gy increase in the radiation dose, leading to a cumulative incidence of 2% for the first stroke after 5 years and 4% after 10 years. [49] Survivors who experienced stroke were then at significantly greater risk of experiencing recurrent strokes.

Evidence (selected studies describing prevalence of and risk factors for cerebrovascular [CVA]/vascular disease):

  1. In a multicenter retrospective Dutch study, among 2,201 5-year survivors of HL diagnosed before age 51 years (25% pediatric-aged patients), with a median follow-up of 18 years, 96 patients developed cerebrovascular disease (CVA and transient ischemic attacks [TIA]). [47]
  2. French investigators observed a significant association between radiation dose to the brain and long-term cerebrovascular mortality among 4,227 5-year childhood cancer survivors (median follow-up, 29 years). [48]
  3. A retrospective, single-center, cohort study of 325 survivors of pediatric cancer treated with cranial irradiation or cervical irradiation determined that cranial irradiation put survivors at a high risk of first and recurrent strokes. [49]
  4. CCSS investigators evaluated the rates and predictors of recurrent stroke among participants who reported a first stroke. [50]
  5. A retrospective study of 3,172 5-year survivors of childhood cancer monitored for a mean time of 26 years was constituted from the Euro2K cohort, which included eight centers in France and the United Kingdom. Radiation doses to the Circle of Willis were estimated for each of the 2,202 children who received radiation therapy. [51]

Conventional cardiovascular conditions

Various cancer treatment exposures may also directly or indirectly influence the development of hypertension, diabetes mellitus, and dyslipidemia. [5] These conditions remain important among cancer survivors, as they do in the general population, in that they are independent risk factors in the development of cardiomyopathy, ischemic heart disease, and cerebrovascular disease. [6] [47] [52] [53] [54]

Childhood cancer survivors should be closely screened for the development of these cardiovascular conditions because they represent potentially modifiable targets for intervention. This includes being aware of related conditions such as obesity and various endocrinopathies (e.g., hypothyroidism, hypogonadism, growth hormone deficiency) that may be more common among subsets of childhood cancer survivors; if these conditions are untreated/uncontrolled, they may be associated with a metabolic profile that increases cardiovascular risk. [8] [55]

Other Risk Factors

Some, but not all, studies suggest that female sex may be associated with a greater risk of anthracycline-related cardiomyopathy. [5] In addition, there is emerging evidence that genetic factors, such as single nucleotide polymorphisms in genes regulating drug metabolism and distribution, could explain the heterogeneity in susceptibility to anthracycline-mediated cardiac injury. [56] [57] [58] [59] [60] [61] However, these genetic findings still require additional validation before being incorporated into any clinical screening algorithm. [62]

Knowledge Deficits

While much knowledge has been gained over the past 20 years in better understanding the long-term burden and risk factors for cardiovascular disease among childhood cancer survivors, many areas of inquiry remain, and include the following:

Screening, Surveillance, and Counseling

Various national groups, including the National Institutes of Health–sponsored COG (refer to Table 2), have published recommendations regarding screening and surveillance for cardiovascular and other late effects among childhood cancer survivors. [65] [66] [67] [68] [69] Professional groups (both pediatric and adult) have developed evidence-based health surveillance recommendations and have identified knowledge deficits to help guide future studies. [25] [70] Adult oncology professional and national groups have also issued recommendations related to cardiac toxicity monitoring. [71]

At this point, there is no clear evidence (at least through age 50 years or 30–40 years posttreatment) that there is a plateau in risk that occurs after a certain time among survivors exposed to cancer treatments associated with cardiovascular late effects. [3] [4] [10] [11] [46] [72] Thus, some form of life-long surveillance is recommended, even if the cost-effectiveness of certain screening strategies remains unclear. [25] [73] [74] [75]

However, a growing amount of literature is beginning to establish the yield from these screening studies, which will help inform future guidelines. [8] [76] [77] [78] In these studies, for example, among adult-aged survivors of childhood cancer, evidence for cardiomyopathy on the basis of echocardiographic changes was found in approximately 6% of at-risk survivors. Overall, in a cohort of more than 1,000 survivors (median age, 32 years), nearly 60% of screened at-risk survivors had some clinically ascertained cardiac abnormality identified. [8]

Given the growing evidence that conventional cardiovascular conditions such as hypertension, dyslipidemia, and diabetes substantially increase the risk of more serious cardiovascular disease among survivors, clinicians should carefully consider baseline and follow-up screening and treatment of these comorbid conditions that impact cardiovascular health (refer to Table 2). [6] [47] [52] [53]

There is also emerging evidence that adoption of healthier lifestyle factors may decrease future cardiovascular morbidity in at-risk survivors. [79] Thus, similar to the general population, survivors are counseled about maintaining a healthy weight, participating in regular physical activity, adhering to a heart-healthy diet, and abstaining from smoking.

In addition to releasing a comprehensive, publicly available (online) set of guidelines, the COG has also put together a series of handouts on cardiovascular and related topics, including lifestyle choices written for a lay audience, available on the same website.

Table 2. Cardiovascular Late Effectsa,b

Predisposing Therapy Potential Cardiovascular EffectsHealth Screening
Any anthracycline and/or any radiation to the heartCardiac toxicity (arrhythmia, cardiomyopathy/heart failure, pericardial disease, valve disease, ischemic heart disease)Yearly medical history and physical exam
Electrocardiogram at entry into long-term follow-up  
Echocardiogram at entry into long-term follow-up, periodically repeat based on previous exposures and other risk factors  
Radiation to the area (≥40 Gy)Carotid and/or subclavian artery diseaseYearly medical history and physical exam; consider Doppler ultrasound 10 years after exposure
Radiation to the brain/cranium (≥18 Gy)Cerebrovascular disease (cavernomas, Moyamoya, occlusive cerebral vasculopathy, stroke)Yearly medical history and physical exam
Radiation to the abdomenDiabetesDiabetes screen every 2 years
Total-body irradiationDyslipidemia; diabetesFasting lipid profile and diabetes screen every 2 years
Heavy metals (carboplatin, cisplatin), ifosfamide, and methotrexate exposure; radiation to the kidneys; hematopoietic cell transplantation; nephrectomyHypertension (as a consequence of renal toxicity)Yearly blood pressure and urinalysis; renal function laboratory studies at entry into long-term follow-up
aThe Children's Oncology Group (COG) guidelines also cover other conditions that may influence cardiovascular risk also exist, such as obesity and diabetes mellitus/impaired glucose metabolism.
bAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

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Late Effects of the Central Nervous System

Neurocognitive

Neurocognitive late effects are most commonly observed after treatment of malignancies that require central nervous system (CNS)–directed therapies. While there is considerable evidence published about this outcome, its quality is often limited by small sample size, cohort selection and participation bias, cross-sectional versus longitudinal evaluations, and variable time of assessment from treatment exposures. CNS-directed therapies include the following:

Children with brain tumors or acute lymphoblastic leukemia (ALL) are most likely to be affected. Risk factors for the development of neurocognitive late effects include the following: [1] [2] [3] [4] [5] [6] [7]

It should be noted that the cognitive phenotypes observed in childhood survivors of ALL and CNS tumors may differ from traditional developmental disorders. For example, the phenotype of attention problems in ALL and brain tumor survivors appears to differ from developmental attention-deficit/hyperactivity disorder in that few survivors demonstrate significant hyperactivity/impulsivity, but instead have associated difficulties with processing speed and executive function. [8] [9]

Neurocognitive outcomes in brain tumor survivors

Survival rates have increased over recent decades for children with brain tumors; however, long-term cognitive effects caused by illness and associated treatments are a well-established morbidity in this group of survivors. In childhood and adolescent brain tumor survivors, risk factors for adverse neurocognitive effects include the following:

The negative impact of radiation treatment has been characterized by changes in IQ scores, which have been noted to drop about 2 to 5 years after diagnosis; the decline continues 5 to 10 years afterward, although less is known about potential stabilization or further decline of IQ scores several decades after diagnosis. [20] [21] [22] The decline in IQ scores over time typically reflects the child’s failure to acquire new abilities or information at a rate similar to that of his or her peers, rather than a progressive loss of skills and knowledge. [11] Affected children also may experience deficits in other cognitive areas, including academic difficulties (reading and math) and problems with attention, processing speed, memory, and visual or perceptual motor skills. [21] [23] [24]

These changes in cognitive functioning may be partially explained by radiation-induced reduction of normal-appearing white matter volume or integrity of white matter pathways, as evaluated through magnetic resonance imaging (MRI). [25] [26] [27] In fact, reduced white matter integrity has been directly linked to slowed cognitive processing speed in survivors of brain tumors, [28] while greater white matter volume has been associated with better working memory, particularly in females. [27] It should be noted that data emerging from contemporary protocols show that using lower doses of cranial radiation and more targeted treatment volumes appears to reduce the severity of neurocognitive effects of therapy. [13] [15] [29]

Data are emerging regarding cognitive outcomes after proton radiation to the CNS. [30] [31] To date, these studies largely describe IQ changes during early (less than 5 years from radiation) follow-up and are limited by retrospective analysis of cognitive outcomes among relatively small clinically heterogeneous pediatric brain tumor cohorts and use of historically treated photon patients or population standards as comparison groups. Study results demonstrating lack of difference in slopes of IQ change among photon- and proton-treated patients [30] and significant declines in cognitive processing speed among patients treated with proton radiation [31] underscore the importance of longitudinal follow-up to determine whether proton radiation provides a clinically meaningful benefit in sparing cognitive function compared with photon radiation.

In addition, studies are beginning to examine cognitive outcomes in histologically distinct subtypes of brain tumors. For example, data from a sample of 121 medulloblastoma patients demonstrated variation in cognitive outcomes by four distinct molecular subgroups and differences in patterns of change over time. [32] This study highlights the need for future research to consider neurocognitive outcomes across biologically distinct subtypes of childhood brain tumors.

Longitudinal cohort studies have provided insight into the trajectory and predictors of cognitive decline among survivors of CNS tumors.

Evidence (predictors of cognitive decline among survivors of CNS tumors):

  1. St. Jude Children’s Research Hospital (SJCRH) studied 78 children younger than 20 years (mean, 9.7 years) diagnosed with low-grade glioma. [33]
  2. A study of 126 medulloblastoma survivors treated with 23.4 Gy or 36 Gy to 39.6 Gy of cranial spinal radiation (with a conformal boost dose of 55.8 Gy to the primary tumor bed) assessed processing speed, attention, and memory performance. [34]
  3. Canadian investigators evaluated the impact of radiation (dose and boost volume) and neurologic complications on patterns of intellectual functioning in a cohort of 113 medulloblastoma survivors (mean age at diagnosis, 7.5 years; mean time from diagnosis to last assessment, 6 years). [37]

Although adverse neurocognitive outcomes observed 5 to 10 years after treatment are presumed to be pervasive, and potentially worsen over time, few empirical data are available regarding the neurocognitive functioning in very long-term survivors of CNS tumors.

The neurocognitive consequences of CNS disease and treatment may have a considerable impact on functional outcomes for brain tumor survivors.

Neurocognitive outcomes in acute lymphoblastic leukemia (ALL) survivors

The increase in cure rates for children with ALL over the past decades has resulted in greater attention to the neurocognitive morbidity and quality of life of survivors. The goal of current ALL treatment is to minimize adverse late effects while maintaining high survival rates. To minimize the risk of late sequelae, patients are stratified for treatment according to their risk of relapse. Cranial irradiation is reserved for the fewer than 20% of children who are considered at high risk for CNS relapse. [44]

Although low-risk, standard-risk, and most high-risk patients are treated with chemotherapy-only protocols, early reports of neurocognitive late effects for ALL patients were based on heterogeneously treated groups of survivors who received combinations (simultaneously or sequentially) of intrathecal chemotherapy, radiation therapy, and high-dose chemotherapy, making it difficult to differentiate the impact of the individual treatment components. However, outcome data are increasingly available regarding the risk of neurocognitive late effects in survivors of childhood ALL treated with chemotherapy only.

ALL and cranial radiation

In survivors of ALL, cranial radiation therapy may result in clinical and radiographic neurologic late sequelae, including the following:

ALL and chemotherapy-only CNS therapy

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. Systemic methotrexate in high doses with or without radiation therapy can lead to an infrequent but well-described leukoencephalopathy, which has been linked to neurocognitive impairment. [45] When neurocognitive outcomes after radiation therapy and chemotherapy-only regimens are directly compared, the evidence suggests a better outcome for those treated with chemotherapy alone, although some studies show no significant difference. [54] [55]

Compared with cranial irradiation, chemotherapy-only CNS-directed treatment produces neurocognitive deficits involving processes of attention, speed of information processing, memory, verbal comprehension, visual-spatial skills, visual-motor functioning, and executive functioning; global intellectual function is typically preserved. [48] [54] [56] [57] [58] [59] Few longitudinal studies evaluating long-term neurocognitive outcome report adequate data for a decline in global IQ after treatment with chemotherapy alone. [57] The academic achievement of ALL survivors in the long term seems to be generally average for reading and spelling, with deficits mainly affecting arithmetic performance. [54] [60] [61] Risk factors for poor neurocognitive outcome after chemotherapy-only CNS-directed treatment are younger age and female sex. [59] [62] [63]

Reduced cognitive status has been observed in association with reduced integrity in neuroanatomical regions essential in memory formation (e.g., reduced hippocampal volume with increased activation and thinner parietal cortices). However, the long-term impact of these prevalent neurocognitive and neuroimaging abnormalities on functional status in aging adults treated for childhood ALL, particularly those treated with contemporary approaches using chemotherapy alone, remains an active area of research.

Evidence (neurocognitive functioning in large pediatric cancer survivor cohorts):

  1. In the St. Jude Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed the following: [64]
  2. In a large prospective study of neurocognitive outcomes in children with newly diagnosed ALL, 555 children were randomly assigned to receive CNS-directed therapy according to risk group. [66]
    1. Low-risk group: Intrathecal methotrexate versus high-dose methotrexate.
    2. High-risk group: High-dose methotrexate versus 24 Gy of cranial radiation therapy.
  3. Persistent cognitive deficits and progressive intellectual decline have been observed in cohorts of adults treated for ALL during childhood and associated with reduced educational attainment and unemployment. [47] [50] [53] The results of a study of more than 500 adult survivors of childhood ALL (average, 26 years postdiagnosis) showed the following: [47]

ALL and steroid therapy

The type of steroid used for ALL systemic treatment may affect cognitive functioning. In a study that involved long-term neurocognitive testing (mean follow-up, 9.8 years) of 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment, no meaningful differences in mean neurocognitive and academic performance scores were observed. [67] In contrast, in a study of 567 adult survivors of childhood leukemia (mean age, 33 years; mean time since diagnosis, 26 years) dexamethasone exposure was associated with increased risk of impairment in attention (relative risk [RR], 2.12; 95% confidence interval [CI], 1.11–4.03) and executive function (RR, 2.42; 95% CI, 1.20–4.91), independent of methotrexate exposure. Intrathecal hydrocortisone also increased risk of attention problems (RR, 1.24; 95% CI, 1.05–1.46). [47]

Other cancers

Neurocognitive abnormalities have been reported in other groups of cancer survivors. In a study of adult survivors of childhood non-CNS cancers (including ALL, n = 5,937), 13% to 21% of survivors reported impairment in task efficiency, organization, memory, or emotional regulation. This rate of impairment was approximately 50% higher than that reported in the sibling comparison group. Factors such as diagnosis before age 6 years, female sex, cranial radiation therapy, and hearing impediment were associated with impairment. [49] In addition, emerging data suggest that the development of chronic health conditions in adulthood may contribute to cognitive deficits in long-term survivors of non-CNS cancers.

Neurocognitive abnormalities have been reported for the following cancers:

Stem cell transplantation

Cognitive and academic consequences of stem cell transplantation in children have also been evaluated and include, but are not limited to, the following:

  1. In a report from SJCRH in which 268 patients were treated with stem cell transplantation, minimal risk of late cognitive and academic sequelae was observed. [76]
  2. In a series of 38 patients who underwent hematopoietic stem cell transplantation (HSCT) and received intrathecal chemotherapy, significant declines in visual motor skills and memory scores were noted within the first year posttransplant. [77]

Most neurocognitive late effects after stem cell transplantation are thought to be related to white matter damage in the brain. This was investigated in children with leukemia who were treated with HSCT. In a series of 36 patients, performance on neurocognitive measures typically associated with white matter was compared with performance on measures thought to correlate with gray matter function. Composite white matter scores were significantly lower than composite gray matter scores, thereby supporting the belief that white matter damage contributes to neurocognitive late effects in this population. [78]

Neurologic Sequelae

Risk of neurologic complications may be predisposed by the following:

In children with CNS tumors, mass effect, tumor infiltration, and increased intracranial pressure may result in motor or sensory deficits, cerebellar dysfunction, and secondary effects such as seizures and cerebrovascular complications. Numerous reports describe abnormalities of CNS integrity and function, but such studies are typically limited by small sample size, cohort selection and participation bias, cross-sectional ascertainment of outcomes, and variable time of assessment from treatment exposures. In contrast, relatively few studies comprehensively or systematically ascertain outcomes related to peripheral nervous system function.

Neurologic complications that may occur in survivors of childhood cancer include the following:

Table 3 summarizes CNS late effects and the related health screenings.

Table 3. Central Nervous System Late Effectsa

Predisposing TherapyNeurologic EffectsHealth Screening
Platinum agents (carboplatin, cisplatin) Peripheral sensory neuropathyNeurologic exam
Plant alkaloid agents (vinblastine, vincristine) Peripheral sensory or motor neuropathy (areflexia, weakness, foot drop, paresthesias)Neurologic exam
Methotrexate (high dose IV or IT); cytarabine (high dose IV or IT); radiation impacting the brain Clinical leukoencephalopathy (spasticity, ataxia, dysarthria, dysphagia, hemiparesis, seizures); headaches; seizures; sensory deficitsHistory: cognitive, motor, and/or sensory deficits, seizures
Neurologic exam  
Radiation impacting cerebrovascular structures Cerebrovascular complications (stroke, moyamoya, occlusive cerebral vasculopathy)History: transient/permanent neurological events
Blood pressure  
Neurologic exam   
Neurosurgery–brain Motor and/or sensory deficits (paralysis, movement disorders, ataxia, eye problems [ocular nerve palsy, gaze paresis, nystagmus, papilledema, optic atrophy]); seizuresNeurologic exam
Neurology evaluation  
Neurosurgery–brain Hydrocephalus; shunt malfunction Abdominal x-ray
Neurosurgery evaluation  
Neurosurgery–spine Neurogenic bladder; urinary incontinence History: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary stream
Neurosurgery–spine Neurogenic bowel; fecal incontinenceHistory: chronic constipation, fecal soiling
Rectal exam   
Predisposing TherapyNeuropsychological EffectsHealth Screening
Methotrexate (high-dose IV or IT); cytarabine (high-dose IV or IT); radiation impacting the brain; neurosurgery–brain Neurocognitive deficits (executive function, memory, attention, processing speed, etc.); learning deficits; diminished IQ; behavioral change Assessment of educational and vocational progress
Formal neuropsychological evaluation   
IQ = intelligence quotient; IT = intrathecal; IV = intravenous.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Psychosocial

Many childhood cancer survivors report reduced quality of life or other adverse psychosocial outcomes. Evidence for adverse psychosocial adjustment after childhood cancer has been derived from a number of sources, ranging from patient-reported or proxy-reported outcomes to data from population-based registries. The former may be limited by small sample size, cohort selection and participation bias, and variable methods and venues (clinical vs. distance-based survey) of assessments. The latter is often not well correlated with clinical and treatment characteristics that permit the identification of survivors at high risk of psychosocial deficits.

Survivors with neurocognitive deficits are particularly vulnerable to adverse psychosocial outcomes that affect achievement of expected social outcomes during adulthood.

Childhood cancer survivors are also at risk of developing symptoms of psychological distress. In a longitudinal study of more than 4,500 survivors, subgroups of survivors were found to be at risk of developing persistent and increasing symptoms of anxiety and depression during a 16-year period. Survivors who reported pain and worsening health status were at the greatest risk of developing symptoms of anxiety, depression, and somatization over time. [90]

Adult survivors of childhood cancer are also at risk of suicide ideation compared with siblings, with survivors of CNS tumors being most likely to report thoughts of suicide. In a CCSS study that evaluated the prevalence of recurrent suicidal ideation among 9,128 adult long-term survivors of childhood cancer, survivors were more likely to report late suicidal ideation (odds ratio [OR], 1.9; 95% CI, 1.5–2.5) and recurrent suicidal ideation (OR, 2.6; 95% CI, 1.8–3.8) compared with siblings. History of seizure was associated with a twofold increased likelihood of suicide ideation in survivors. [91] In a population-based study that evaluated suicide among adults treated for cancer before age 25 years, the absolute risk of suicide was low (24 cases among 3,375 deaths), but the hazard ratio (HR) of suicide was increased among individuals treated for cancer in childhood (0–14 years; HR, 2.5; 95% CI, 1.7–3.8) and in adolescence and young adulthood (15–24 years; HR, 2.3; 95% CI, 1.2–4.6). [92]

The presence of chronic health conditions can also impact aspects of psychological health. In a study that evaluated psychological outcomes among long-term survivors treated with HSCT, 22% of survivors and 8% of sibling controls reported adverse outcomes. Somatic distress was the most prevalent condition and affected 15% of HSCT survivors, representing a threefold higher risk compared with siblings. HSCT survivors with severe or life-threatening health conditions and active chronic GVHD had a twofold increased risk of somatic distress. [93] A report from the CCSS revealed that the presence of chronic pulmonary, endocrine, and cardiac conditions was associated with increased risk of psychological distress symptoms in a sample of 5,021 adult survivors of childhood cancer. [94]

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 survivors 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, with the prevalence of psychological maladjustment ranging from 25% to 93%. [95] In a study of 101 adult cancer survivors of childhood cancer, psychological screening was performed during a routine annual evaluation at the survivorship clinic at the Dana Farber Cancer Institute. On the Symptom Checklist 90 Revised, 32 subjects had a positive screen (indicating psychological distress), and 14 subjects reported at least one suicidal symptom. Risk factors for psychological distress included subjects’ dissatisfaction with physical appearance, poor physical health, and treatment with cranial irradiation. In this study, the instrument was shown to be feasible for use in the clinic visit setting because the psychological screening was completed in less than 30 minutes. In addition, completion of the instrument itself did not appear to cause distress in the survivors in 80% of cases. [96] These data support the feasibility and importance of consistent assessment of psychosocial distress in a medical clinic setting.

(Refer to the PDQ summary on Adjustment to Cancer: Anxiety and Distress for more information about psychological distress and cancer patients.)

Post-traumatic stress after childhood cancer

Despite the many stresses associated with the diagnosis of cancer and its treatment, studies have generally shown low levels of post-traumatic stress symptoms and post-traumatic stress disorder (PTSD) in children with cancer, typically no higher than those in healthy comparison children. [97] Patient and parent adaptive style appear to be significant determinants of PTSD in the pediatric oncology setting. [98] [99]

The prevalence of PTSD and post-traumatic stress symptoms has been reported in 15% to 20% of young adult survivors of childhood cancer, with estimates varying based on criteria used to define these conditions. [100]

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 perceive 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. [104]

Psychosocial outcomes among childhood, adolescent, and young adult cancer survivors

Most research on late effects after cancer has focused on individuals with a cancer manifestation during childhood. Little is known about the specific impact of a cancer diagnosis with an onset in adolescence or the impact of childhood cancer on adolescent and young adult (AYA) psychosocial outcomes.

Evidence (psychosocial outcomes in AYA cancer survivors):

  1. Adult survivors of cancer diagnosed during adolescence (aged 15–18 years) (N = 825) were compared with an age-matched sample from the general population and a comparison group of adults without cancer. [105]
  2. A survey of 4,054 AYA cancer survivors and 345,592 respondents who had no history of cancer reported the following: [107]
  3. The CCSS evaluated outcomes of 2,979 adolescent survivors and 649 siblings of childhood cancer survivors to determine the incidence of difficulty in six behavioral and social domains (depression/anxiety, being headstrong, attention deficit, peer conflict/social withdrawal, antisocial behaviors, and social competence). [108]
  4. Another CCSS study evaluated psychological and neurocognitive function in 2,589 long-term cancer survivors who were diagnosed during adolescence and young adulthood. [109]
  5. A follow-up CCSS study evaluated profiles of symptom comorbidities in 3,993 adolescents (aged 13–17 years) treated for cancer. [110] Latent profile analysis identified four symptom profiles:

    Overall results support that behavioral, emotional, and social symptoms frequently co-occur in adolescent survivors and are associated with treatment exposures (cranial radiation, corticosteroids, and methotrexate) and late effects (obesity, cancer-related pain, and sensory impairments).

It should be noted that social withdrawal in adolescence has been associated with adult obesity and physical inactivity. [111] As a result, these psychological problems may increase future risk for chronic health conditions and support the need to routinely screen and treat psychological problems after cancer therapy.

Because of the challenges experienced by adolescents and young adults at cancer diagnosis and during long-term follow-up, this group may benefit from access to programs to address the unique psychosocial, educational, and vocational issues that impact their transition to survivorship. [112] [113]

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for CNS and psychosocial late effects information, including risk factors, evaluation, and health counseling.

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Late Effects of the Digestive System

Dental

Overview

Chemotherapy, radiation therapy, and local surgery can cause multiple cosmetic and functional abnormalities of the oral cavity and dentition. The quality of current evidence regarding this outcome is limited by retrospective data collection, small sample size, cohort selection and participation bias, and heterogeneity in treatment approach, time since treatment, and method of ascertainment.

Oral and dental complications reported in childhood cancer survivors include the following:

Abnormalities of tooth development

Abnormalities of dental development reported in childhood cancer survivors include absence of tooth development, hypodontia, microdontia, enamel hypoplasia, and root malformation. [1] [2] [3] [4] [5] [6] [7] [8] [9] The prevalence of hypodontia has varied widely in series depending on age at diagnosis, treatment modality, and method of ascertainment. Cancer treatments that have been associated with dental maldevelopment include head and neck radiation therapy, any chemotherapy, and hematopoietic stem cell transplantation (HSCT). Children younger than 5 years are at greatest risk for dental anomalies, such as root agenesis, delayed eruption, enamel defects, and/or excessive caries related to disruption of ameloblast (enamel producing) and odontoblast (dentin producing) activity early in life. [3]

Key findings related to cancer treatment effect on tooth development include the following:

Salivary gland dysfunction

Xerostomia, the sensation of dry mouth, is a potential side effect following head and neck irradiation or HSCT that can severely impact quality of life. Complications of reduced salivary secretion include increased caries, susceptibility to oral infections, sleep disturbances, and difficulties with chewing, swallowing, and speaking. [16] [17] The prevalence of salivary gland dysfunction after cancer treatment varies based on measurement techniques (patient report vs. stimulated or unstimulated salivary secretion rates). [18] In general, the prevalence of self-reported persistent posttherapy xerostomia is infrequent among childhood cancer survivors. In the CCSS, the prevalence of self-reported xerostomia in survivors was 2.8 % compared with 0.3% in siblings, with an increased risk in survivors older than 30 years. [3]

Abnormalities of craniofacial development

Craniofacial maldevelopment is a common adverse outcome among children treated with high-dose radiation therapy to the head and neck that frequently occurs in association with other oral cavity sequelae such as dental anomalies, xerostomia, and trismus. [5] [21] [22] The extent and severity of musculoskeletal disfigurement is related to age at treatment and radiation therapy volume and dose, with higher risk observed among younger patients and those who received 30 Gy or more. Remediation of cosmetic and functional abnormalities often requires multiple surgical interventions.

Posttherapy management

Some studies suggest there may be a benefit of fluoride products or chlorhexidine rinses in patients who have undergone radiation therapy. [23] Dental caries are a problematic consequence of reduced salivary quality and flow. The use of topical fluoride can dramatically reduce the frequency of caries, and saliva substitutes and sialagogues can ameliorate sequelae such as xerostomia. [17]

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. [24] The Children’s Oncology Group Long-term Follow-Up Guidelines recommend biannual dental cleaning and exams for all survivors of childhood cancer. These findings give health care providers further impetus to encourage routine dental care and dental hygiene evaluations for survivors of childhood treatment. (Refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation for more information about oral complications in cancer patients.)

Table 4 summarizes oral and dental late effects and the related health screenings.

Table 4. Oral/Dental Late Effectsa

Predisposing TherapyOral/Dental EffectsHealth Screening/Interventions
Any chemotherapy; radiation impacting oral cavity Dental developmental abnormalities; tooth/root agenesis; microdontia; root thinning/shortening; enamel dysplasia Dental evaluation and cleaning every 6 months
Regular dental care including fluoride applications   
Consultation with orthodontist experienced in management of irradiated childhood cancer survivors   
Baseline Panorex x-ray before dental procedures to evaluate root development   
Radiation impacting oral cavity Malocclusion; temporomandibular joint dysfunction Dental evaluation and cleaning every 6 months
Regular dental care including fluoride applications   
Consultation with orthodontist experienced in management of irradiated childhood cancer survivors   
Baseline Panorex x-ray before dental procedures to evaluate root development   
   
Radiation impacting oral cavity; hematopoietic cell transplantation with history of chronic GVHD Xerostomia/salivary gland dysfunction; periodontal disease; dental caries; oral cancer (squamous cell carcinoma) Dental evaluation and cleaning every 6 months
Supportive care with saliva substitutes, moistening agents, and sialogogues (pilocarpine)  
Regular dental care including fluoride applications  
   
Radiation impacting oral cavity (≥40 Gy) OsteoradionecrosisHistory: impaired or delayed healing after dental work
Exam: persistent jaw pain, swelling or trismus  
Imaging studies (x-ray, CT scan and/or MRI) may assist in making diagnosis  
Surgical biopsy may be needed to confirm diagnosis  
Consider hyperbaric oxygen treatments  
CT = computed tomography; GVHD = graft-versus-host disease; MRI = magnetic resonance imaging.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Digestive Tract

Overview

The gastrointestinal (GI) tract is sensitive to the acute toxicities of chemotherapy, radiation therapy, and surgery. However, these important treatment modalities can also result in some long-term issues in a treatment- and dose-dependent manner. Reports published about long-term GI tract outcomes are limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment.

Key concepts about GI complications observed in childhood cancer survivors include the following:

GI outcomes from selected cohort studies

GI outcomes from selected cohort studies include the following:

Impact of cancer histology on GI outcomes

Intra-abdominal tumors represent a relatively common location for several pediatric malignancies, including rhabdomyosarcoma, Wilms tumor, lymphoma, germ cell tumors, and neuroblastoma. Intra-abdominal tumors often require multimodal therapy, occasionally necessitating resection of bowel and bowel-injuring chemotherapy and/or radiation therapy. Thus, these tumors would be expected to be particularly prone to long-term digestive tract issues.

A limited number of reports describe GI complications in pediatric patients with genitourinary solid tumors treated with radiation therapy: [31] [32] [33] [34] [35]

Table 5 summarizes digestive tract late effects and the related health screenings.

Table 5. Digestive Tract Late Effectsa

Predisposing TherapyGastrointestinal EffectsHealth Screening/Interventions
Radiation impacting esophagus; hematopoietic cell transplantation with any history of chronic GVHD Esophageal stricture History: dysphagia, heart burn
Esophageal dilation, antireflux surgery  
Radiation impacting bowel Chronic enterocolitis; fistula; strictures History: nausea, vomiting, abdominal pain, diarrhea
Serum protein and albumin levels yearly in patients with chronic diarrhea or fistula  
Surgical and/or gastroenterology consultation for symptomatic patients  
Radiation impacting bowel; laparotomy Bowel obstruction History: abdominal pain, distention, vomiting, constipation
Exam: tenderness, abdominal guarding, distension (acute episode)  
Obtain KUB in patients with clinical symptoms of obstruction  
Surgical consultation in patients unresponsive to medical management  
Pelvic surgery; cystectomy Fecal incontinence History: chronic constipation, fecal soiling
Rectal exam  
GVHD = graft-versus-host disease; KUB = kidneys, ureter, bladder (plain abdominal radiograph).
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Hepatobiliary Complications

Overview

Hepatic complications resulting from childhood cancer therapy are observed primarily as acute treatment toxicities. [37] Because many chemotherapy agents and radiation are hepatotoxic, transient liver function anomalies are common during therapy. Severe acute hepatic complications occur rarely. Survivors of childhood cancer can occasionally exhibit long-standing hepatic injury. Some general concepts regarding hepatotoxicity related to childhood cancer include the following:

Certain factors, including the type of chemotherapy, the dose and extent of radiation exposure, the influence of surgical interventions, and the evolving impact of viral hepatitis and/or other infectious complication, need additional attention in future studies.

Types of hepatobiliary complications

Less commonly reported hepatobiliary complications include the following:

Treatment-related risk factors for hepatobiliary complications

The type and intensity of previous therapy influences risk for late-occurring hepatobiliary complications. In addition to the risk of treatment-related toxicity, recipients of HSCT frequently experience chronic liver dysfunction related to microvascular, immunologic, infectious, metabolic, and other toxic etiologies.

Infectious risk factors for hepatobiliary complications

Viral hepatitis B and C may complicate the treatment course of childhood cancer and result in chronic hepatic dysfunction. Hepatitis B tends to have a more aggressive acute clinical course and a lower rate of chronic infection. Hepatitis C is characterized by a mild acute infection and a high rate of chronic infection. The incidence of transfusion-related hepatitis C in childhood cancer survivors has ranged from 5% to 50% depending on the geographic location of the reporting center. [67] [68] [69] [70] [71] [72] [73]

Chronic hepatitis predisposes the childhood cancer survivor to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Concurrent infection with both viruses accelerates the progression of liver disease. Because most patients received some type of blood product during childhood cancer treatment and many are unaware of their transfusion history, screening based on date of diagnosis/treatment is recommended unless there is absolute certainty that the patient did not receive any blood or blood products. [74] Therefore, all children who received blood transfusions before 1972 should be screened for hepatitis B, and all children who received blood transfusions before 1993 should be screened for hepatitis C and referred for discussion of treatment options.

Posttherapy management

Survivors with liver dysfunction should be counseled regarding risk-reduction methods to prevent hepatic injury. Standard recommendations include maintenance of a healthy body weight, abstinence from alcohol use, and immunization against hepatitis A and B viruses. In patients with chronic hepatitis, precautions to reduce viral transmission to household and sexual contacts should also be reviewed.

Table 6 summarizes hepatobiliary late effects and the related health screenings.

Table 6. Hepatobiliary Late Effectsa

Predisposing TherapyHepatic EffectsHealth Screening/Interventions
Methotrexate; mercaptopurine/thioguanine; HSCTHepatic dysfunction Lab: ALT, AST, bilirubin levels
Ferritin in those treated with HSCT  
Mercaptopurine/thioguanine; HSCTVeno-occlusive disease/sinusoidal obstructive syndrome Exam: scleral icterus, jaundice, ascites, hepatomegaly, splenomegaly
Lab: ALT, AST, bilirubin, platelet levels   
Ferritin in those treated with HSCT  
Radiation impacting liver/biliary tract; HSCTHepatic fibrosis/cirrhosis Exam: jaundice, spider angiomas, palmar erythema, xanthomata hepatomegaly, splenomegaly
Lab: ALT, AST, bilirubin levels  
Ferritin in those treated with HSCT  
Prothrombin time for evaluation of hepatic synthetic function in patients with abnormal liver screening tests  
Screen for viral hepatitis in patients with persistently abnormal liver function or any patient transfused before 1993  
Gastroenterology/hepatology consultation in patients with persistent liver dysfunction  
Hepatitis A and B immunizations in patients lacking immunity  
Consider phlebotomy and chelation therapy for iron overload  
Radiation impacting liver/biliary tract CholelithiasisHistory: colicky abdominal pain related to fatty food intake, excessive flatulence
Exam: right upper quadrant or epigastric tenderness (acute episode)  
Consider gallbladder ultrasound in patients with chronic abdominal pain  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HSCT = hematopoietic stem cell transplantation.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Pancreas

The pancreas has been thought to be relatively radioresistant because of a paucity of information about late pancreatic-related effects. However, children and young adults treated with TBI or abdominal irradiation are known to have an increased risk of insulin resistance and diabetes mellitus. [75] [76] [77]

A summary of the results of selected cancer cohort studies supporting this association include the following:

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for digestive system late effects information including risk factors, evaluation, and health counseling.

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  64. Levitsky J, Sorrell MF: Hepatic complications of hematopoietic cell transplantation. Curr Gastroenterol Rep 9 (1): 60-5, 2007.
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Late Effects of the Endocrine System

Endocrine dysfunction is very common among childhood cancer survivors, especially those treated with surgery or radiation therapy that involves hormone-producing organs and those receiving alkylating agent chemotherapy.

Chart showing the prevalence of endocrine disorders at the last follow-up visit by gender.Figure 6. Prevalence of endocrine disorders at the last follow-up visit, by sex. Copyright © 2013, European Society of Endocrinology.

The prevalence of specific endocrine disorders is affected by the following: [1] [2] [3]

Endocrinologic late effects can be broadly categorized as those resulting from hypothalamic/pituitary injury or from peripheral glandular compromise. [4] [5] The former are most common after treatment for central nervous system (CNS) tumors, where the prevalence was reported to be 24.8% in a nationwide cohort study of 718 survivors who lived longer than 2 years and all hypothalamic/pituitary axes were effected. [3]

The following sections summarize research that characterizes the clinical features of survivors at risk of endocrine dysfunction that impacts pituitary, thyroid, adrenal, and gonadal function.

Thyroid Gland

Thyroid dysfunction is a common delayed effect of radiation therapy fields that include the thyroid gland incidental to treating Hodgkin lymphoma (HL), brain tumors, head and neck sarcomas, and acute lymphoblastic leukemia (ALL). There is considerable evidence linking radiation exposure to thyroid abnormalities, but the prevalence of specific conditions varies widely because studies are limited by cohort selection and participation bias, heterogeneity in radiation treatment approach, time since radiation exposure, and method of ascertainment (e.g., self-report vs. clinical or diagnostic imaging assessment).

Thyroid abnormalities observed in excess in childhood cancer survivors include the following:

Hypothyroidism

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. [6] The most frequently reported abnormalities include:

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 clinical benefits for cardiovascular, gastrointestinal, and neurocognitive function.

An increased risk of hypothyroidism has been reported among childhood cancer survivors treated with head and neck radiation exposing the thyroid gland, especially among survivors of HL.

Evidence (prevalence of and risk factors for hypothyroidism):

  1. The German Group of Paediatric Radiation Oncology reported on 1,086 patients treated at 62 centers, including 404 patients (median age, 10.9 years) who received radiation therapy to the thyroid and/or pituitary gland. [7] Follow-up information was available for 264 patients (60.9%; median follow-up, 40 months), with 60 patients (22.7%) showing pathologic values.
  2. In a cohort of childhood HL survivors treated between 1970 and 1986, survivors were evaluated for thyroid disease by use of a self-report questionnaire in the Childhood Cancer Survivor Study (CCSS). [8]
    1. Among 1,791 survivors, 34% reported that they had been diagnosed with at least one thyroid abnormality.
    2. For hypothyroidism, there was a clear dose response (refer to Figure 7), with a 20-year risk of:
      • 20% for those who received less than 35 Gy of radiation to the thyroid gland.
      • 30% for those who received 35 Gy to 44.9 Gy of radiation to the thyroid gland.
      • 50% for those who received more than 45 Gy of radiation to the thyroid gland.
    3. Compared to a sibling control group, the relative risk (RR) was 17.1 for hypothyroidism; 8.0 for hyperthyroidism; and 27.0 for thyroid nodules.
    4. Elapsed time since diagnosis was a risk factor for both hypothyroidism and hyperthyroidism, with the risk increasing in the first 3 to 5 years postdiagnosis. For nodules, the risk increased beginning at 10 years postdiagnosis. Females were at increased risk for hypothyroidism and thyroid nodules.

    Probability of developing hypothyroidism according to radiation dose in 5-year survivors of childhood cancer; graph shows the proportion not affected in years since diagnosis for no RT, less than 3500 cGy, 3500-4499 cGy,  and ≥4500 cGy.Figure 7. Probability of developing hypothyroidism according to radiation dose in 5-year survivors of childhood cancer. Data from the Childhood Cancer Survivor Study. Sklar C, Whitton J, Mertens A, Stovall M, Green D, Marina N, Greffe B, Wolden S, Robison L: Abnormalities of the Thyroid in Survivors of Hodgkin's Disease: Data from the Childhood Cancer Survivor Study. The Journal of Clinical Endocrinology and Metabolism 85 (9): 3227-3232, September 1, 2000. Copyright 2000, The Endocrine Society.

  3. In a more recent report from the CCSS that compared self-reported data from 14,290 survivors with data from 4,031 sibling controls. [2]

Thyroid nodules

Any radiation field that includes the thyroid is associated with an excess risk of thyroid neoplasms, which may be benign (usually adenomas) or malignant (most often differentiated papillary carcinoma). [2] [8] [9] [10] [11] [12] The clinical manifestation of thyroid neoplasia among childhood cancer survivors ranges from asymptomatic, small, solitary nodules to large, intrathoracic goiters that compress adjacent structures. CCSS investigators performed a nested case-control study to evaluate the magnitude of risk for thyroid cancer over the therapeutic radiation dose range of pediatric cancers. The risk of thyroid cancer increased with radiation doses up to 20 Gy to 29 Gy (odds ratio [OR], 9.8; 95% confidence interval [CI], 3.2–34.8), but declined at doses higher than 30 Gy, consistent with a cell-killing effect. [12]

The following factors are linked to an increased risk of thyroid nodule development:

Several investigations have demonstrated the superiority of ultrasound to clinical exam for detecting thyroid nodules and thyroid cancers and characterized ultrasonographic features of nodules that are more likely to be malignant. [16] [17] [18] However, primary screening for thyroid neoplasia (beyond physical exam with thyroid palpation) remains controversial because of the lack of data indicating a survival benefit and quality-of-life benefit associated with early detection and intervention. In fact, because these lesions tend to be indolent, are rarely life-threatening, and may clinically manifest many years after exposure to radiation, there are significant concerns regarding the costs and harms of overscreening. [19] Expert panels have refrained from specifically endorsing or discouraging the use of ultrasound as a screening tool for thyroid cancer and this continues to be an active area of investigation. [20]

(Refer to the Subsequent Neoplasms section of this summary for information about subsequent thyroid cancers.)

Posttransplant thyroid dysfunction

Survivors of pediatric hematopoietic stem cell transplantation (HSCT) are at increased risk of thyroid dysfunction, with the risk being much lower (15%–16%) after fractionated total-body irradiation (TBI), as opposed to single-dose TBI (46%–48%). Non–TBI-containing regimens historically were not associated with an increased risk. However, in a report from the Fred Hutchinson Cancer Research Center, the increased risk of thyroid dysfunction did not differ between children receiving a TBI-based or busulfan-based regimen (P = .48). [21] Other high-dose therapies have not been studied.

TSH deficiency (central hypothyroidism) is discussed with late effects that affect the pituitary gland.

Table 7 summarizes thyroid late effects and the related health screenings.

Table 7. Thyroid Late Effectsa

Predisposing Therapy Endocrine/Metabolic EffectsHealth Screening
Radiation impacting thyroid gland; thyroidectomy Primary hypothyroidismTSH level
Radiation impacting thyroid gland HyperthyroidismFree T4 level
TSH level  
Radiation impacting thyroid gland, including 131I-MIBG Thyroid nodulesThyroid exam
Thyroid ultrasound  
131I-MIBG = Iodine I 131-metaiodobenzylguanidine; T4 = thyroxine; TSH = thyroid-stimulating hormone.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Pituitary Gland

Survivors of childhood cancer are at risk of developing a spectrum of neuroendocrine abnormalities, primarily because of the effect of radiation therapy on the hypothalamus. In addition, tumor development or surgical resection close to the hypothalamus and/or pituitary gland may induce direct anatomical damage to these structures and result in hypothalamic/pituitary dysfunction. Essentially all of the hypothalamic-pituitary axes are at risk. [4] [22] [23] [24]

Although the quality of the literature regarding pituitary endocrinopathy among childhood cancer survivors is often limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment, the evidence linking this outcome with radiation therapy, surgery, and tumor infiltration is quite compelling because affected individuals typically present with metabolic and developmental abnormalities early in follow-up.

Central diabetes insipidus

Central diabetes insipidus may herald the diagnosis of craniopharyngioma, suprasellar germ cell tumor, or Langerhans cell histiocytosis. [25] [26] [27] In these conditions, diabetes insipidus may occur as an isolated pituitary deficiency, although additional pituitary hormone deficiencies may develop with tumor progression. More commonly, however, diabetes insipidus occurs in the context of panhypopituitarism caused by the presence of a tumor in close proximity to the sellar region or as a consequence of surgical procedures undertaken for local tumor control.

Central diabetes insipidus has not been reported as a late effect of cranial irradiation in childhood cancer survivors.

Anterior pituitary hormone deficiency

Deficiencies of anterior pituitary hormones and major hypothalamic regulatory factors are common late effects among survivors treated with cranial irradiation.

Evidence (prevalence of anterior pituitary hormone deficiency):

  1. In a single-institution study, 1,713 adult survivors of childhood cancers and brain tumors (median age, 32 years) were monitored for a median follow-up of 25 years. [24]
  2. A study of 748 childhood cancer survivors treated with cranial irradiation and observed for a mean of 27.3 years reported the following: [5]

The six anterior pituitary hormones and their major hypothalamic regulatory factors are outlined in Table 8.

Table 8. Anterior Pituitary Hormones and Major Hypothalamic Regulatory Factors

Pituitary Hormone Hypothalamic FactorHypothalamic Regulation of the Pituitary Hormone
Growth hormone (GH)Growth hormone–releasing hormone +
Somatostatin  
Prolactin Dopamine
Luteinizing hormone (LH)Gonadotropin-releasing hormone+
Follicle-stimulating hormone (FSH) Gonadotropin-releasing hormone+
Thyroid-stimulating hormone (TSH)Thyroid-releasing hormone +
Somatostatin  
Adrenocorticotropin (ACTH)Corticotropin-releasing hormone +
Vasopressin+ 
(–) = inhibitory; (+) = stimulatory.

Growth hormone deficiency

Growth hormone deficiency is the earliest hormonal deficiency associated with cranial radiation therapy in childhood cancer survivors. The risk increases with radiation dose and time since treatment. Growth hormone deficiency is sensitive to low doses of radiation. Other hormone deficiencies require higher doses, and their time to onset is much longer than for growth hormone deficiency. [28] The prevalence in pooled analysis was found to be approximately 35.6%. [29]

Growth hormone deficiency is commonly observed in these long-term survivors because of radiation doses used in the treatment of childhood brain tumors. Approximately 60% to 80% of irradiated pediatric brain tumor patients who received doses higher than 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 that growth hormone deficiency will occur after treatment.

Evidence (radiation-dose response relationship of growth hormone deficiency):

  1. A study of conformal radiation therapy (CRT) in children with CNS tumors indicates that growth hormone insufficiency can usually be demonstrated within 12 months of radiation therapy, depending on hypothalamic dose-volume effects. [30]
  2. In a report featuring data from 118 patients with localized brain tumors who were treated with radiation therapy, peak growth hormone was modeled as an exponential function of time after CRT and mean radiation dose to the hypothalamus. [31]

Graph shows peak growth hormone (in ng/mL) according to hypothalamic mean dose and time (in months) after start of irradiation. Figure 8. Peak growth hormone (GH) according to hypothalamic mean dose and time after start of radiation. According to equation 2, peak GH = exp{2.5947 + time × [0.0019 − (0.00079 × mean dose)]}. Thomas E. Merchant, Susan R. Rose, Christina Bosley, Shengjie Wu, Xiaoping Xiong, and Robert H. Lustig, Growth Hormone Secretion After Conformal Radiation Therapy in Pediatric Patients With Localized Brain Tumors, Journal of Clinical Oncology, volume 29, issue 36, pages 4776-4780. Reprinted with permission. © (2011) American Society of Clinical Oncology. All rights reserved.

Children treated with CNS-directed therapy for leukemia are also at increased risk of growth hormone deficiency.

Evidence (risk of growth hormone deficiency in childhood ALL survivors):

  1. One study evaluated 127 patients with ALL treated with 24 Gy, 18 Gy, or no cranial radiation therapy. [32]
  2. Another study found similar results in 118 ALL survivors treated with 24 Gy of cranial radiation, in which 74% had SDS of -1 or higher and the remainder had scores of -2 or higher. [33]
  3. Survivors of childhood ALL who are treated with chemotherapy alone are also at increased risk for adult short stature, although the risk is highest for those treated with cranial and craniospinal radiation therapy at a young age. [34] In this cross-sectional study, attained adult height was determined for 2,434 ALL survivors participating in the CCSS.
  4. The impact of chemotherapy alone on growth in 67 survivors treated with contemporary regimens for ALL was statistically significant at -0.59 SD. The loss of growth potential did not correlate with growth hormone status in this study, further highlighting the participation of other factors in the growth impairments observed in this population. [35]

Children who undergo HSCT with TBI have a significant risk of both growth hormone deficiency and the direct effects of radiation on skeletal development. The risk is increased with single-dose TBI as opposed to fractionated TBI, pretransplant cranial irradiation, female sex, and posttreatment complications such as graft-versus-host disease (GVHD). [36] [37] [38] Hyperfractionation of the TBI dose markedly reduces risk in patients who have not undergone pretransplant cranial irradiation for CNS leukemia prophylaxis or therapy. [39] Regimens containing busulfan and cyclophosphamide appear to increase risk in some studies, [38] [40] but not others. [41]

Evidence (growth hormone deficiency in childhood HSCT survivors):

  1. The late effects that occur after HSCT have been studied and reviewed by the Late Effect Working Party of the European Group for Blood and Marrow Transplantation. Among 181 patients with aplastic anemia, leukemias, and lymphomas who underwent HSCT before puberty, the following results were observed: [42] [43]

Growth hormone deficiency replacement therapy

Growth hormone deficiency replacement therapy provides the benefit of optimizing height outcomes among children who have not reached skeletal maturity. Treatment with recombinant growth hormone (rGH) replacement therapy is generally delayed until 12 months after successful completion of cancer or brain tumor treatments and after a multidisciplinary discussion involving the prescribing pediatric endocrinologist, the primary oncologist, and other providers selected by the patient or family. [44] Safety concerns pertaining to the use of rGH in childhood cancer survivors have primarily been related to the mitogenic potential of the growth hormone stimulating tumor growth in a population with an increased risk of second neoplasms. [45] Most studies that report these outcomes, however, are limited by selection bias and small sample size.

The following study results have been reported in survivors who did or did not receive treatment with growth hormone.

Evidence (growth hormone deficiency replacement therapy):

  1. One study evaluated 361 growth hormone-treated cancer survivors enrolled in the CCSS and compared risk of recurrence, risk of subsequent neoplasm, and risk of death among survivors who did and did not receive treatment with growth hormone. [46]
  2. A review of existing data suggests that treatment with growth hormone is not associated with an increased risk of CNS tumor progression or recurrence, or new or recurrent leukemia. [48]
  3. A study from the CCSS reported specifically on the risk of subsequent CNS neoplasms after a longer period of follow-up. [49]

In general, the data addressing subsequent malignancies should be interpreted with caution given the small number of events. [44] [45] [46]

Disorders of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)

Pubertal development can be adversely affected by cranial radiation therapy. Doses higher than 18 Gy can result in central precocious puberty, while doses higher than 30 Gy to 40 Gy may result in LH and FSH deficiency. [50]

Central precocious puberty

Central precocious puberty is defined by the onset of pubertal development before age 8 years in girls and 9 years in boys as a result of the premature activation of the hypothalamic-pituitary-gonadal axis. Aside from the adjustment and psychosocial challenges associated with early pubertal development, precocious puberty can lead to the rapid closure of the skeletal growth plates and short stature. This deleterious effect can be further potentiated by growth hormone deficiency. [51] [52] The increased growth velocity induced by pubertal development can mask concurrent growth hormone deficiency with seemingly normal growth velocity; this occurrence may mislead care providers. It is also important to note that the assessment of puberty cannot be performed using testicular volume measurements in boys exposed to chemotherapy or direct radiation to the testes, given the toxic effect of these treatments on germ cells and repercussions on gonadal size. The staging of puberty in males within this population relies on the presence of other signs of virilization, such as the presence of pubic hair and the measurement of plasma testosterone levels. [51]

Children who have tumors that grow near the hypothalamus/pituitary or optic pathways (including those with neurofibromatosis type 1) have the highest risk of developing central precocious puberty. [52] [53] Hydrocephalus also seems to increase the risk of this complication. [53] Central precocious puberty has been reported in some children receiving cranial irradiation in doses of 18 Gy or higher. [52] [54] [55] The impact of central precocious puberty on linear growth can be ascertained by assessing the degree of skeletal maturation (or bone age) using an x-ray of the left hand. [56]

When appropriate, delaying the progression of puberty relies on the use of various gonadotropin-releasing hormone agonist preparations, an approach that has been shown to improve growth prospects—especially when other pituitary abnormalities, including growth hormone deficiency, are concurrently treated. [57]

LH/FSH deficiency

LH/FSH deficiency (also referred to as hypogonadotropic hypogonadism) can manifest through pubertal delay, arrested puberty, or symptoms of decreased sex hormone production, depending on age and pubertal status at the time of diagnosis. The risk of LH/FSH deficiency is highest among patients treated with cranial radiation at doses greater than or equal to 30 Gy; LH/FSH deficiency following the exposure to lower doses can occur at delayed time points. [5] With higher doses of cranial radiation therapy (>35 Gy), deficiencies in LH/FSH can be seen, with a cumulative incidence of 10% to 20% at 5 to 10 years posttreatment. [58] [59]

The treatment of LH/FSH deficiency relies on sex-hormone replacement therapy adjusted to age and pubertal status.

TSH deficiency

TSH deficiency (also referred to as central hypothyroidism) in survivors of childhood cancer can have profound clinical consequences and be underappreciated. Symptoms of central hypothyroidism (e.g., asthenia, edema, drowsiness, and skin dryness) may have a gradual onset and go unrecognized until thyroid replacement therapy is initiated. In addition to delayed puberty and slow growth, hypothyroidism may cause fatigue, dry skin, constipation, increased sleep requirement, and cold intolerance. Individuals with TSH deficiency have low plasma free T4 levels and either low or inappropriately normal TSH levels.

The risk of TSH deficiency is highest among patients treated with cranial radiation at doses greater than or equal to 30 Gy; TSH deficiency following the exposure to lower doses can occur at delayed time points. [5] Radiation dose to the hypothalamus in excess of 42 Gy is associated with an increased risk of developing TSH deficiency (44% ± 19% for dose of ≥42 Gy and 11% ± 8% for dose of <42 Gy). [60] It occurs in as many as 65% of survivors of brain tumors, 43% of survivors of childhood nasopharyngeal tumors, 35% of bone marrow transplant recipients, and 10% to 15% of leukemia survivors. [61] [62]

Mixed primary and central hypothyroidism can also occur and reflects separate injuries to the thyroid gland and the hypothalamus (e.g., radiation injury to both structures). TSH values may be elevated and, in addition, the secretory dynamics of TSH are abnormal, with a blunted or absent TSH surge or a delayed peak response to TSH-releasing hormone (TRH). [63] In a study of 208 childhood cancer survivors referred for evaluation of possible hypothyroidism or hypopituitarism, mixed hypothyroidism was present in 15 patients (7%). [63] Among patients who received TBI (fractionated total doses of 12–14.4 Gy) or craniospinal radiation therapy (fractionated total cranial doses higher than 30 Gy), 15% had mixed hypothyroidism. In one study of 32 children treated for medulloblastoma, 56% developed hypothyroidism, including 38% with primary hypothyroidism and 19% with central hypothyroidism. [64]

Thyroid hormone replacement therapy using levothyroxine represents the mainstay of treatment of TSH deficiency. The dose of levothyroxine needs to be adjusted solely using plasma free T4 levels; the levels of TSH are expected to remain low during therapy, given the central nature of this deficiency.

Adrenal-corticotropin (ACTH) deficiency

ACTH deficiency is less common than other neuroendocrine deficits but should be suspected in patients who have a history of brain tumor (regardless of therapy modality), cranial radiation therapy, growth hormone deficiency, or central hypothyroidism. [28] [60] [65] [66] [67] Although uncommon, ACTH deficiency can occur in patients treated with intracranial radiation doses of less than 24 Gy and has been reported to occur in fewer than 3% of patients after chemotherapy alone. [67]

The diagnosis should be suspected when low plasma levels of morning cortisol are measured (a screening cortisol level collected at 8 a.m. that is 10 µg/dL or more is reassuring for ACTH sufficiency, whereas a value of 5 µg/dL or lower is suspicious for insufficiency). Confirmation is necessary using dynamic testing such as the low-dose ACTH stimulation test. [66] Because of the substantial risk of central adrenal insufficiency among survivors treated with cranial radiation doses exceeding 30 Gy to the hypothalamic-pituitary axis, endocrine monitoring with periodic dynamic testing as clinically indicated is recommended for this high-risk group.

Patients with partial ACTH deficiency may have only subtle symptoms unless they become ill. Illness can disrupt these patients’ usual homeostasis and cause a more severe, prolonged, or complicated course than expected. As in complete ACTH deficiency, incomplete or unrecognized ACTH deficiency can be life-threatening during concurrent illness.

The treatment of ACTH deficiency relies on replacement with hydrocortisone, including stress dosing in situations of illness to adjust to the body’s physiologically increased need for glucocorticoids.

Hyperprolactinemia

Hyperprolactinemia has been described in patients who received radiation therapy to the hypothalamus in doses higher than 50 Gy or who underwent surgery that disrupted the integrity of the pituitary stalk. Primary hypothyroidism may lead to hyperprolactinemia as a result of hyperplasia of thyrotrophs and lactotrophs, presumably due to TRH hypersecretion. The prolactin response to TRH is usually exaggerated in these patients. [28] [68]

In general, hyperprolactinemia may result in delayed puberty, galactorrhea, menstrual irregularities, loss of libido, hot flashes, infertility, and osteopenia. However, hyperprolactinemia resulting from cranial radiation therapy is rarely symptomatic and, given its frequent associations with hypogonadism (both central and primary).

Hyperprolactinemia rarely requires treatment.

Table 9 summarizes pituitary gland late effects and the related health screenings.

Table 9. Pituitary Gland Late Effectsa

Predisposing Therapy Endocrine/Metabolic Effects Health Screening
Tumor or surgery affecting hypothalamus/pituitary. Radiation impacting hypothalamic-pituitary axis.Growth hormone deficiencyAssessment of nutritional status
Height, weight, BMI, Tanner stageb   
Tumor or surgery affecting hypothalamus/pituitary or optic pathways; hydrocephalus. Radiation impacting hypothalamic-pituitary axis.Precocious puberty Height, weight, BMI, Tanner stageb
FSH, LH, estradiol, or testosterone levels  
Tumor or surgery affecting hypothalamus/pituitary. Radiation impacting hypothalamic-pituitary axis. Gonadotropin deficiencyHistory: puberty, sexual function
Exam: Tanner stageb  
FSH, LH, estradiol or testosterone levels  
Tumor or surgery affecting hypothalamus/pituitary. Radiation impacting hypothalamic-pituitary axis.Central adrenal insufficiencyHistory: failure to thrive, anorexia, episodic dehydration, hypoglycemia, lethargy, unexplained hypotension
Endocrine consultation for those with radiation dose ≥30 Gy   
Radiation impacting hypothalamic-pituitary axis.Hyperprolactinemia History/exam: galactorrhea
Prolactin level   
Radiation impacting hypothalamic-pituitary axis.Overweight/obesityHeight, weight, BMI
Blood pressure  
Components of metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism)Fasting blood glucose level and lipid profile  
Tumor or surgery affecting hypothalamus/pituitary. Radiation impacting hypothalamic-pituitary axis.Central hypothyroidismTSHc free thyroxine (free T4) level
BMI = body mass index; FSH = follicle-stimulating hormone; LH = luteinizing hormone; T4 = thyroxine; TSH = thyroid-stimulating hormone.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
bTesticular volume measurements are not reliable in the assessment of pubertal development in boys exposed to chemotherapy or direct radiation to the testes.
cAppropriate only at diagnosis. TSH levels are not useful for follow-up during replacement therapy.

Testis and Ovary

Testicular and ovarian hormonal functions are discussed in the Late Effects of the Reproductive System section of this summary.

Metabolic Syndrome

An increased risk of metabolic syndrome or its components has been observed among cancer survivors. The evidence for this outcome ranges from clinically manifested conditions that are self-reported by survivors to retrospectively assessed data in medical records and hospital registries to systematic clinical evaluations of clinically well-characterized cohorts. Studies have been limited by cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment. Despite these limitations, compelling evidence indicates that metabolic syndrome is highly associated with cardiovascular events and mortality.

Definitions of metabolic syndrome are evolving but generally include a combination of central (abdominal) obesity with at least two of the following features:

Evidence (prevalence of and risk factors for metabolic syndrome in childhood cancer survivors):

  1. A study monitored 784 long-term childhood ALL survivors (median age, 31.7 years) for a median follow-up of 26.1 years. [70]
  2. A European cohort of 184 adult survivors of childhood leukemia (81.5% had ALL; median age, 21.2 years) were monitored for a median follow-up of 15.4 years. [71]
  3. Abdominal irradiation is an additional risk factor for metabolic syndrome. Survivors of developmental or embryonal tumors treated with abdominal irradiation are also at an increased risk of developing components of metabolic syndrome. In a prospective study of 164 long-term survivors (median follow-up, 26 years), nephroblastoma (OR, 5.2) and neuroblastoma (OR, 6.5) survivors had more components of metabolic syndrome than did controls. [72]

Long-term survivors of ALL, especially those treated with cranial radiation therapy, may have a higher prevalence of some potentially modifiable risk factors for cardiovascular disease such as impaired glucose tolerance or overt diabetes mellitus, dyslipidemia, hypertension, and obesity. [70] [71] [73] [74] [75] [76] [77] The contribution of modifiable risk factors associated with metabolic syndrome to the risk of major cardiac events suggests that survivors are good candidates for targeted screening and lifestyle counseling regarding risk-reduction measures. [78]

Several studies have provided support for the potential benefits of lifestyle modifications in reducing cardiovascular disease risk.

Evidence (lifestyle modifications to reduce cardiovascular risk in childhood cancer survivors):

  1. Survivors participating in the St. Jude Lifetime Cohort Study who were adherent to a heart-healthy lifestyle had a lower risk of metabolic syndrome. Females (RR, 2.4; 95% CI, 1.7–3.3) and males (RR, 2.2; 95% CI, 1.6–3.0) in the cohort who did not follow recommended dietary and physical activity guidelines had a more than twofold excess risk of having clinical features of the metabolic syndrome. [79]
  2. In a CCSS investigation evaluating the impact of exercise on cardiovascular disease risk among survivors of HL, vigorous exercise was associated with a lower risk of cardiovascular events in a dose-dependent manner, independent of cardiovascular risk profile and treatment. Survivors who were adherent to national vigorous-intensity exercise guidelines had a 51% reduction in the risk of any cardiovascular event compared with those not meeting the guidelines. [80]

Abnormal glucose metabolism

Abdominal radiation therapy and TBI are increasingly recognized as independent risk factors for diabetes mellitus in childhood cancer survivors. [2] [71] [72] [74] [81] [82] [83] [84] [85]

Evidence (risk factors for diabetes mellitus in childhood cancer survivors):

  1. A single-center cohort study of 532 long-term (median follow-up, 17.9 years) adult (median age, 25.6 years) survivors observed the following: [83]
  2. A cross-sectional study evaluated cardiovascular risk factors and insulin resistance in a clinically heterogeneous cohort of 319 childhood cancer survivors 5 or more years since diagnosis and 208 sibling controls. [86]
  3. In a European multicenter cohort of 2,520 childhood cancer survivors (median follow-up, 28 years), significant associations were found between diabetes mellitus and increasing doses of radiation therapy to the tail of the pancreas. These data support the contribution of radiation-induced islet cell injury to impairments of glucose homeostasis in this population. [84]
  4. A report from the CCSS compared 8,599 childhood cancer survivors with 2,936 randomly selected sibling controls, and adjusted for age, body mass index (BMI), and several demographic factors. [87]

Table 10 summarizes metabolic syndrome late effects and the related health screenings.

Table 10. Metabolic Syndrome Late Effectsa

Predisposing TherapyPotential Late EffectsHealth Screening
Abdominal irradiation. Total-body irradiation.Components of metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism) Height, weight, BMI, blood pressure
Labs: fasting glucose and lipids  
BMI = body mass index.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Body Composition: Underweight, Overweight, and Obesity

Childhood cancer survivors are at risk of experiencing abnormal body composition, which includes being underweight (BMI, <18.5), overweight (BMI, >25.0 to BMI, <30.0), or obese (BMI, ≥30.0). BMI at diagnosis has been identified as a significant predictor of being underweight or overweight at follow-up, suggesting that genetic or environmental factors contribute to the development or persistence of abnormal body composition. [88] [89]

CCSS investigators identified treatment-related risk factors for being underweight, including TBI (females) or abdominal irradiation (males), use of alkylating agents, and use of anthracyclines. [89] Among a cohort of 893 Dutch childhood cancer survivors monitored for a median of almost 15 years, being underweight was linked to a high prevalence of moderate to extreme adverse health statuses and reports of a major medical condition. [88]

To date, cancer patients with an increased incidence of being overweight and obese are primarily ALL [88] [90] [91] [92] [93] [94] [95] [96] and CNS tumor [4] [22] survivors who were treated with cranial radiation therapy. [89] [97] The development of obesity after cranial radiation therapy is multifactorial and includes the following: [93] [98] [99]

Also, craniopharyngioma survivors have a substantially increased risk of extreme obesity because of the tumor location and the hypothalamic damage resulting from surgical resection. [100] [101] [102] [103] [104] [105]

In addition to treatment factors, lifestyle factors and medication use can also contribute to the risk of obesity. CCSS investigators reported the following independent risk factors for obesity in childhood cancer survivors: [106]

Survivors who adhered to the U.S. Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82–0.97; P = .01) and who had a medium amount of anxiety (RR, 0.86; 95% CI, 0.75–0.99; P = .04) had a lower risk of obesity. [106]

Body composition alterations after childhood ALL

Moderate-dose cranial radiation therapy (18–24 Gy) among ALL survivors is associated with obesity, particularly in females treated at a young age. [75] [91] [93] [107] Female adult survivors of childhood ALL who were treated with cranial radiation therapy of 24 Gy before age 5 years are four times more likely to be obese than are women who have not been treated for a cancer. [91] In addition, women treated with 18 Gy to 24 Gy cranial radiation therapy before age 10 years have a substantially greater rate of increase in their BMI through their young adult years than do women who were treated for ALL with only chemotherapy or women in the general population. [93] It appears that these women also have a significantly increased visceral adiposity and associated insulin resistance. [108] [109]

These outcomes are attenuated in males. However, a study of long-term male survivors of ALL (mean age, 29 years) observed significantly higher body adiposity than in age-matched controls, despite normal weight and BMI. Potential indicators of increased adiposity included high leptin and low sex hormone–binding globulin levels. Serum testicular endocrine markers (testosterone, FSH, or inhibin B) did not correlate with body adiposity. [110]

ALL therapy regimens are associated with increases in BMI shortly after completion of therapy, and possibly with a higher risk of obesity in the long term. [94] [95] [96] [111] [112] Several studies have reported that survivors of childhood ALL treated with chemotherapy alone also exhibit long-term changes in body composition, with relative increases in body fat [109] [113] [114] [115] and visceral adiposity in comparison to lean mass. [108] These changes cannot be detected if BMI alone is used in the assessment of metabolic risk in this population.

Evidence (body composition changes in adult survivors of childhood ALL):

  1. A cohort study of 365 adult survivors of ALL (149 treated with cranial radiation therapy and 216 treated without cranial radiation therapy) compared body composition, energy balance, and fitness with age-, sex-, and race-matched peers. [116]
  2. In contrast, in a report from the CCSS, adult survivors of childhood ALL treated with chemotherapy alone did not have significantly higher rates of obesity than did sibling controls, [91] nor were there differences in BMI changes between these groups after a subsequent period of follow-up that averaged 7.8 years. [93]

Results from the CCSS, however, were based on self-reported height and weight measurements. Likewise, Children’s Oncology Group investigators also did not observe an increased risk of being overweight and obese based on BMI measurements in 269 patients with standard-risk ALL (age, 3.5 years at diagnosis and 13.3 years at follow-up) compared with peers without cancer. Again, these variable outcomes likely relate to the use of BMI as the metric for abnormal body composition, which does not adequately assess visceral adiposity that can contribute to metabolic risk in this population. [117]

Body composition alterations after treatment for CNS tumors

Among brain tumor survivors treated with higher doses of cranial radiation therapy, only females treated at a younger age appear to be at increased risk for obesity. [118]

Body composition alterations after hematopoietic cell transplantation

Survivors of childhood cancer treated with TBI in preparation for an allogeneic HSCT have increased measures of body fatness (percent fat) while often having a normal BMI. [81] [85] [119] Longitudinal decline in BMI related to substantial decrease in lean mass has been observed among survivors of hematological malignancies treated with allogeneic HSCT. This finding was largely attributable to TBI conditioning and severity of chronic GVHD. [120]

Body composition and frailty

Young adult childhood cancer survivors have a higher-than-expected prevalence of frailty, a phenotype characterized by low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Individuals are termed prefrail if they have two of these five characteristics and frail if they have three or more of these characteristics. The frailty phenotype increases in prevalence with aging, and has been associated with excess risk of mortality and onset of chronic conditions. [121] Ongoing research aims to elucidate the pathophysiology of frailty and develop/test interventions to prevent or reverse this condition.

Table 11 summarizes body composition late effects and the related health screenings.

Table 11. Body Composition Late Effectsa

Predisposing TherapyPotential Late EffectsHealth Screening
Cranial radiation therapyOverweight/obesityHeight, weight, BMI, blood pressure
Labs: fasting glucose and lipids   
BMI = body mass index.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for endocrine and metabolic syndrome late effects information, including risk factors, evaluation, and health counseling.

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  111. Kohler JA, Moon RJ, Wright S, et al.: Increased adiposity and altered adipocyte function in female survivors of childhood acute lymphoblastic leukaemia treated without cranial radiation. Horm Res Paediatr 75 (6): 433-40, 2011.
  112. Zhang FF, Rodday AM, Kelly MJ, et al.: Predictors of being overweight or obese in survivors of pediatric acute lymphoblastic leukemia (ALL). Pediatr Blood Cancer 61 (7): 1263-9, 2014.
  113. 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.
  114. Miller TL, Lipsitz SR, Lopez-Mitnik G, et al.: Characteristics and determinants of adiposity in pediatric cancer survivors. Cancer Epidemiol Biomarkers Prev 19 (8): 2013-22, 2010.
  115. Jarfelt M, Lannering B, Bosaeus I, et al.: Body composition in young adult survivors of childhood acute lymphoblastic leukaemia. Eur J Endocrinol 153 (1): 81-9, 2005.
  116. Ness KK, DeLany JP, Kaste SC, et al.: Energy balance and fitness in adult survivors of childhood acute lymphoblastic leukemia. Blood 125 (22): 3411-9, 2015.
  117. Lindemulder SJ, Stork LC, Bostrom B, et al.: Survivors of standard risk acute lymphoblastic leukemia do not have increased risk for overweight and obesity compared to non-cancer peers: a report from the Children's Oncology Group. Pediatr Blood Cancer 62 (6): 1035-41, 2015.
  118. Gurney JG, Ness KK, Stovall M, et al.: Final height and body mass index among adult survivors of childhood brain cancer: childhood cancer survivor study. J Clin Endocrinol Metab 88 (10): 4731-9, 2003.
  119. Nysom K, Holm K, Michaelsen KF, et al.: Degree of fatness after allogeneic BMT for childhood leukaemia or lymphoma. Bone Marrow Transplant 27 (8): 817-20, 2001.
  120. Inaba H, Yang J, Kaste SC, et al.: Longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation. J Clin Oncol 30 (32): 3991-7, 2012.
  121. Ness KK, Krull KR, Jones KE, et al.: Physiologic frailty as a sign of accelerated aging among adult survivors of childhood cancer: a report from the St Jude Lifetime cohort study. J Clin Oncol 31 (36): 4496-503, 2013.

Late Effects of the Immune System

Late effects of the immune system have not been well studied, especially in survivors treated with contemporary therapies. Reports published about long-term immune system outcomes are limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment.

Asplenia

Surgical or functional splenectomy increases the risk of life-threatening invasive bacterial infection: [1]

Individuals with asplenia, regardless of the reason for the asplenic state, have an increased risk of fulminant bacteremia, especially associated with encapsulated bacteria, which is associated with a high mortality rate. The risk of bacteremia is higher in younger children than in older children, and this risk may be greater during the years immediately after splenectomy. Fulminant septicemia, however, has been reported in adults up to 25 years after splenectomy.

Bacteremia may be caused by the following organisms:

Individuals with functional or surgical asplenia are also at increased risk of fatal malaria and severe babesiosis.

Posttherapy management

Clinicians should consider and encourage the administration of inactivated vaccines (e.g., influenza) and vaccines made of purified antigens (e.g., pneumococcus), bacterial components (e.g., diphtheria-tetanus-pertussis), or genetically engineered recombinant antigens (e.g., hepatitis B) in all cancer and transplant survivors according to recommended doses and schedules. [6] [7] [8]

Two primary doses of quadrivalent meningococcal conjugate vaccine should be administered 2 months apart to children with asplenia, from age 2 years through adolescence, and a booster dose should be administered every 5 years. [9] (Refer to the Scheduling Immunizations section of the Red Book for more information.) However, the efficacy of meningococcal vaccines in children with asplenia has not been established. (Refer to the Meningococcal Infections section of the Red Book for more information.) No known contraindication exists to giving these vaccines at the same time as other required vaccines, in separate syringes, at different sites.

Pneumococcal conjugate vaccine (PCV) and pneumococcal polysaccharide vaccine (PPSV) are indicated at the recommended age for all children with asplenia. Following the administration of the appropriate number of doses of PCV13, PPSV23 should be administered starting at age 24 months. A second dose should be administered 5 years later. For children aged 2 to 5 years with a complete PCV7 series who have not received PCV13, a supplemental dose of PCV13 should be administered. For asplenic individuals aged 6 to 18 years who have not received a dose of PCV13, a supplemental dose of PCV13 should be considered. [10] (Refer to the Pneumococcal Infections section of the Red Book for more information.) Hib immunization should be initiated at age 2 months, which is recommended for otherwise healthy young children and for all previously unimmunized children with asplenia. [10] (Refer to the Scheduling Immunizations section of the Red Book for more information.)

Daily antimicrobial prophylaxis against pneumococcal infections is recommended for many children with asplenia, regardless of their immunization status. Although the efficacy of antimicrobial prophylaxis has been proven only in patients with sickle cell anemia, other children with asplenia at particularly high risk, such as children with malignant neoplasms or thalassemia, should also receive daily chemoprophylaxis. In general, antimicrobial prophylaxis (in addition to immunization) should be considered for all children with asplenia younger than 5 years and for at least 1 year after splenectomy.

The age at which chemoprophylaxis is discontinued is often an empiric decision. On the basis of a multicenter study, prophylactic penicillin can be discontinued at age 5 years in children with sickle cell disease who are receiving regular medical attention and who have not had a severe pneumococcal infection or surgical splenectomy. The appropriate duration of prophylaxis is unknown for children with asplenia attributable to other causes. Some experts continue prophylaxis throughout childhood and into adulthood for particularly high-risk patients with asplenia.

Table 12 summarizes spleen late effects and the related health screenings.

Table 12. Spleen Late Effectsa

Predisposing TherapyImmunologic EffectsHealth Screening/Interventions
Radiation impacting spleen; splenectomy; HSCT with currently active GVHD Asplenia/hyposplenia; overwhelming post-splenectomy sepsisBlood cultures during febrile episodes (T >38.5°C); empiric antibiotics
   
HSCT with any history of chronic GVHD Immunologic complications (secretory IgA deficiency, hypogammaglobulinemia, decreased B cells, T cell dysfunction, chronic infections [e.g., conjunctivitis, sinusitis, and bronchitis associated with chronic GVHD])History: chronic conjunctivitis, chronic sinusitis, chronic bronchitis, recurrent or unusual infections, sepsis
Exam: attention to eyes, nose/sinuses, and lungs   
GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation; IgA = immunoglobulin A; T = temperature.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Refer to the Centers for Disease Control and Prevention (CDC) Guidelines for Preventing Opportunistic Infections Among Hematopoietic Stem Cell Transplant Recipients for more information on posttransplant immunization.

Humoral Immunity

Although the immune system appears to recover from the effects of active chemotherapy and radiation therapy, there is some evidence that lymphoid subsets may not always normalize. Innate immunity, thymopoiesis, and DNA damage responses to radiation were shown to be abnormal in survivors of childhood leukemia. [11] Defects in immune recovery characterized by B-cell depletion have been observed in 2-year survivors of standard-risk and intermediate-risk acute lymphoblastic leukemia (ALL). [12] Antibody levels to previous vaccinations are also reduced in patients off therapy for ALL for at least 1 year, [13] [14] suggesting persistence of abnormal humoral immunity [15] and a need for revaccination in such children. Many survivors of childhood cancer will remain susceptible to vaccine-preventable infections.

While there is a paucity of data regarding the benefits of administering active immunizations in this population, reimmunization is necessary to provide protective antibodies. The recommended reimmunization schedule will depend on previously received vaccinations and on the intensity of therapy. [16] [17] In some children who received intensive treatment, consideration may be given to evaluating the antibodies against common vaccination antigens to determine the need for revaccination. (Refer to the Scheduling Immunizations section of the Red Book for more information.)

Immune status is also compromised after HSCT, particularly in association with GVHD. [18] In a prospective, longitudinal study of 210 survivors treated with allogeneic HSCT, antibody responses lasting for more than 5 years after immunization were observed in most patients for tetanus (95.7%), rubella (92.3%), poliovirus (97.9%), and, in diphtheria-tetanus-acellular pertussis (DTaP) recipients, diphtheria (100%). However, responses to pertussis (25.0%), measles (66.7%), mumps (61.5%), hepatitis B (72.9%), and diphtheria in tetanus-diphtheria (Td) recipients (48.6%) were less favorable. Factors associated with vaccine failure include older age at immunization; lower CD3, CD4, or CD19 count; higher immunoglobulin M concentration; positive recipient cytomegalovirus serology; negative titer before immunization; history of acute or chronic GVHD; and radiation conditioning. [19]

Follow-up recommendations for transplant recipients have been published by the major North American and European transplant groups, the CDC, and the Infectious Diseases Society of America. [20] [21]

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for immune system late effects information including risk factors, evaluation, and health counseling.

References:

  1. Immunization in special circumstances. In: Kimberlin DW, Brady MT, Jackson MA, et al., eds.: Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, Ill: American Academy of Pediatrics, 2015, pp 68-107.
  2. Kaiser CW: Complications from staging laparotomy for Hodgkin disease. J Surg Oncol 16 (4): 319-25, 1981.
  3. 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.
  4. 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.
  5. 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.
  6. National Center for Immunization and Respiratory Diseases: General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 60 (RR02): 1-60, 2011. Available online Last accessed August 30, 2017.
  7. Bridges CB, Coyne-Beasley T; Advisory Committee on Immunization Practices: Advisory committee on immunization practices recommended immunization schedule for adults aged 19 years or older: United States, 2014. Ann Intern Med 160 (3): 190, 2014.
  8. Rubin LG, Levin MJ, Ljungman P, et al.: 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 58 (3): 309-18, 2014.
  9. Centers for Disease Control and Prevention (CDC): Recommendation of the Advisory Committee on Immunization Practices (ACIP) for use of quadrivalent meningococcal conjugate vaccine (MenACWY-D) among children aged 9 through 23 months at increased risk for invasive meningococcal disease. MMWR Morb Mortal Wkly Rep 60 (40): 1391-2, 2011.
  10. Kimberlin DW, Brady MT, Jackson MA, et al., eds.: Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, Ill: American Academy of Pediatrics, 2015. Also available online. Last accessed August 30, 2017.
  11. Schwartz C L, Hobbie WL, Constine LS, et al., eds.: Survivors of Childhood Cancer: Assessment and Management. St. Louis, Mo: Mosby, 1994.
  12. Koskenvuo M, Ekman I, Saha E, et al.: Immunological Reconstitution in Children After Completing Conventional Chemotherapy of Acute Lymphoblastic Leukemia is Marked by Impaired B-cell Compartment. Pediatr Blood Cancer 63 (9): 1653-6, 2016.
  13. Leung W, Neale G, Behm F, et al.: Deficient innate immunity, thymopoiesis, and gene expression response to radiation in survivors of childhood acute lymphoblastic leukemia. Cancer Epidemiol 34 (3): 303-8, 2010.
  14. Aytac S, Yalcin SS, Cetin M, et al.: Measles, mumps, and rubella antibody status and response to immunization in children after therapy for acute lymphoblastic leukemia. Pediatr Hematol Oncol 27 (5): 333-43, 2010.
  15. Brodtman DH, Rosenthal DW, Redner A, et al.: Immunodeficiency in children with acute lymphoblastic leukemia after completion of modern aggressive chemotherapeutic regimens. J Pediatr 146 (5): 654-61, 2005.
  16. Ruggiero A, Battista A, Coccia P, et al.: How to manage vaccinations in children with cancer. Pediatr Blood Cancer 57 (7): 1104-8, 2011.
  17. Patel SR, Chisholm JC, Heath PT: Vaccinations in children treated with standard-dose cancer therapy or hematopoietic stem cell transplantation. Pediatr Clin North Am 55 (1): 169-86, xi, 2008.
  18. Olkinuora HA, Taskinen MH, Saarinen-Pihkala UM, et al.: Multiple viral infections post-hematopoietic stem cell transplantation are linked to the appearance of chronic GVHD among pediatric recipients of allogeneic grafts. Pediatr Transplant 14 (2): 242-8, 2010.
  19. Inaba H, Hartford CM, Pei D, et al.: Longitudinal analysis of antibody response to immunization in paediatric survivors after allogeneic haematopoietic stem cell transplantation. Br J Haematol 156 (1): 109-17, 2012.
  20. Rizzo JD, Wingard JR, Tichelli A, et al.: Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, Center for International Blood and Marrow Transplant Research, and the American Society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT). Bone Marrow Transplant 37 (3): 249-61, 2006.
  21. Tomblyn M, Chiller T, Einsele H, et al.: Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 15 (10): 1143-238, 2009.

Late Effects of the Musculoskeletal System

The musculoskeletal system of growing children and adolescents is vulnerable to the cytotoxic effects of cancer therapies, including surgery, chemotherapy, and radiation therapy. Documented late effects include the following:

While these late effects are discussed individually, it is important to remember that the components of the musculoskeletal system are interrelated. For example, hypoplasia to a muscle group can negatively affect the function of the long bones and the resultant dysfunction can subsequently lead to disuse and osteoporosis.

The major strength of the published literature documenting musculoskeletal late effects among children and adolescents treated for cancer is that most studies have clearly defined outcomes and exposures. However, many studies are observational and cross-sectional or retrospective in design. Single-institution studies are common, and for some outcomes, only small convenience cohorts have been described. Thus, it is possible that studies either excluded patients with the most severe musculoskeletal effects because of death or inability to participate in follow-up testing, or oversampled those with the most severe musculoskeletal late effects because these patients were accessible because they returned for complication-related follow-up. Additionally, some of the results reported in adult survivors of childhood cancer may not be relevant to patients currently being treated because the delivery of anticancer modalities, particularly radiation therapy, has changed over the years in response to documented toxicities. [1] [2]

Bone and Joint

Abnormal bone growth

Radiation to the head and brain

In an age- and dose-dependent fashion, radiation can inhibit normal bone and muscle maturation and development. Radiation to the head (e.g., cranial, orbital, infratemporal, or nasopharyngeal radiation therapy) can cause craniofacial abnormalities, particularly in children treated before age 5 years or with radiation doses of 20 Gy or more. [3] [4] [5] [6] [7] Soft tissue sarcomas such as orbital rhabdomyosarcoma and retinoblastoma are two of the more common cancer groups treated with these radiation fields. Often, in addition to the cosmetic impact of the craniofacial abnormalities, there can be related dental and sinus problems.

Cranial radiation therapy damages the hypothalamic-pituitary axis in an age- and dose-response fashion, and can result in growth hormone deficiency (GHD). [8] [9] If untreated during the growing years, and sometimes, even with appropriate treatment, it leads to a substantially lower final height. Patients with a central nervous system tumor [8] [10] or acute lymphoblastic leukemia (ALL) [11] [12] [13] treated with 18 Gy or more of cranial radiation therapy are at highest risk. Also, patients treated with total-body irradiation (TBI), particularly single-fraction TBI, are at risk of GHD. [14] [15] [16] [17] In addition, if the spine is also irradiated (e.g., craniospinal radiation therapy for medulloblastoma or early ALL therapies in the 1960s), growth can be affected by two separate mechanisms—GHD and direct damage to the spine.

Radiation to the spine and long bones

Radiation therapy can also directly affect the growth of the spine and long bones (and associated muscle groups) and can cause premature closure of the epiphyses, leading to the following: [18] [19] [20] [21] [22] [23] [24]

Orthovoltage radiation therapy, commonly used before 1970, delivered high doses of radiation to bone and was commonly associated with subsequent abnormalities in bone growth. However, even with contemporary radiation therapy, if a solid tumor is located near an epiphysis or the spine, alterations in normal bone development can be difficult to avoid.

The effects of radiation therapy administered to the spine on stature in survivors of Wilms tumor have been assessed.

Osteoporosis/fractures

Maximal peak bone mass is an important factor influencing the risk of osteoporosis and fracture associated with aging. Treatment-related factors that affect bone mineral loss include the following:

Most of our knowledge about cancer and treatment effects on bone mineralization has been derived from studies of children with ALL. [26] [30] In this group, the leukemic process, and possibly vitamin D deficiency, may play a role in the alterations in bone metabolism and bone mass observed at diagnosis. [31] Antileukemic therapy causes further bone mineral density loss, [32] which has been reported to normalize over time [33] [34] or to persist for many years after completion of therapy. [35] [36] Clinical factors predicting higher risk of low bone mineral density include treatment with high cumulative doses of methotrexate (>40 g/m2), high cumulative doses of corticosteroids (>9 g/m2), cranial radiation therapy, or craniospinal radiation therapy, and use of more potent glucocorticoids like dexamethasone. [35] [37] [38] [39] [40]

Clinical assessment of bone mineral density in adults treated for childhood ALL indicates that most bone mineral deficits normalize over time after discontinuing osteotoxic therapy. Very low bone mineral density was relatively uncommon in a cohort of 845 adult survivors of childhood ALL evaluated at a median age of 31 years, with only 5.7% and 23.8% demonstrating bone mineral density z-scores consistent with osteoporosis and osteopenia, respectively. Cranial radiation dose of 24 Gy or greater, but not cumulative methotrexate or prednisone equivalent doses, was associated with a twofold elevated risk of bone mineral density z-scores of -1 or lower. In a subset of 400 survivors with longitudinal bone mineral density evaluations, bone mineral density z-scores tended to improve from adolescence to young adulthood. [39] Among 862 ALL survivors (median age, 31.3 years) evaluated by quantitative computed tomography of L1 through L2 vertebrae, 30% had low bone mineral density (z score below -1) and 18.6% met criteria for frailty or prefrailty. [41] The prefrail phenotype is characterized by having two of five characteristics (low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness) and the frail phenotype is characterized by having three or more of these characteristics. Modifiable factors such as growth hormone deficiency, smoking, and alcohol consumption were significant predictors for these outcomes, with varying impact on the basis of sex. These data underscore the importance of lifestyle counseling and screening for hormonal deficits during long-term survivors' follow-up evaluations.

Bone mineral density deficits that are likely multifactorial in etiology have been reported in allogeneic hematopoietic cell transplant recipients conditioned with TBI. [42] [43] French investigators observed a significant risk for lower femoral bone mineral density among adult survivors of childhood leukemia treated with hematopoietic stem cell transplantation (HSCT) who had gonadal deficiency. [44] Hormonal therapy has been shown to enhance bone mineral density of adolescent girls diagnosed with hypogonadism after HSCT. [45]

Despite disease- and treatment-related risks of bone mineral density deficits, the prevalence of self-reported fractures among Childhood Cancer Survivor Study (CCSS) participants was lower than that reported by sibling controls. Predictors of increased prevalence of fracture by multivariable analyses included the following: [46]

Radiation-induced fractures can occur with doses of radiation of 50 Gy or greater, as is often used in the treatment of Ewing sarcoma of the extremity. [47] [48]

Osteonecrosis

Osteonecrosis (also known as aseptic or avascular necrosis) is a rare, but well-recognized skeletal complication observed predominantly in survivors of pediatric hematological malignancies treated with corticosteroids. [49] [50] [51] The prevalence of osteonecrosis has varied from 1% to 22% based on the study population, treatment protocol, method of evaluation, and time from treatment. [51] [52] [53] [54] [55] [56] [57] The condition is characterized by death of one or more segments of bone that most often affects weight-bearing joints, especially the hips and knees. Longitudinal cohort studies have identified a spectrum of clinical manifestations of osteonecrosis, ranging from asymptomatic, spontaneously-resolving imaging changes to painful progressive articular collapse requiring joint replacement. [58] [59] Symptomatic osteonecrosis characterized by pain, joint swelling, and reduced mobility typically presents during the first 2 years of therapy, particularly in patients with ALL. These symptoms may improve over time, persist, or progress in the years after completion of therapy. In one series, 60% of patients continued to have symptoms at a median follow-up of 4.9 years after diagnosis of osteonecrosis. [60] Surgical procedures, including core decompression, osteotomy and joint replacements, are sometimes performed in those with persistently severe symptoms. [60]

Factors that increase the risk of osteonecrosis include the following:

Studies evaluating the influence of sex on the risk of osteonecrosis have yielded conflicting results, with some suggesting a higher incidence in females [58] [60] [66] that has not been confirmed by others. [50] [58]

Osteochondroma

Osteochondromas are benign boney protrusions that can be spontaneous or associated with radiation therapy. They generally occur as a single lesion, however multiple lesions may develop in the context of hereditary multiple osteochondromatosis. [67] Approximately 5% of children undergoing myeloablative stem cell transplantation will develop osteochondroma, which most commonly presents in the metaphyseal regions of long bones. [67] A large Italian study reported a 6.1% cumulative risk of developing osteochondroma at 15 years posttransplant, with increased risk associated with younger age at transplant (≤3 years) and use of TBI. [68] Osteochondromas have been reported in patients with neuroblastoma who received local radiation therapy, anti-GD2 monoclonal antibody therapy, and isotretinoin. They occurred at a median of 8.2 years from diagnosis and the cumulative incidence rate was 4.9% at 10 years from diagnosis among 362 patients younger than 10 years. In this series, most of the osteochondromas were unrelated to radiation and had features characteristic of benign developmental osteochondroma. The pathogenic role for chemotherapy, anti-GD2 monoclonal antibody therapy, or isotretinoin in the development of osteochondroma remains speculative. [69] Growth hormone therapy may influence the onset and pace of growth of osteochondromas. [17] [70]

Because malignant degeneration of these lesions is exceptionally rare, clinical rather than radiological follow-up is most appropriate. [71] Surgical resection is only necessary when the lesion interferes with joint alignment and movement. [72]

Amputation and limb-sparing surgery

Amputation and limb-sparing surgery prevent local recurrence of bone tumors by removal of all gross and microscopic disease. If optimally executed, both procedures accomplish an en bloc excision of tumor with a margin of normal uninvolved tissue. The type of surgical procedure, the primary tumor site, and the age of the patient affect the risk of postsurgical complications. [30] Complications in survivors treated with amputation include prosthetic fit problems, chronic pain in the residual limb, phantom limb pain, and bone overgrowth. [73] [74] While limb-sparing surgeries may offer a more aesthetically pleasing outcome, complications have been reported more frequently in survivors who underwent these procedures than in those treated with amputation. Complications after limb-sparing surgery include non-union, pathologic fracture, aseptic loosening, limb-length discrepancy, endoprosthetic fracture, and limited joint range of motion. [73] [75] Occasionally, refractory complications develop after limb-sparing surgery and require amputation. [76] [77]

A number of studies have compared functional outcomes after amputation and limb-sparing surgery, but results have been limited by inconsistent methods of functional assessment and small cohort sizes. Overall, data suggest that limb-sparing surgery results in better function than amputation, but differences are relatively modest. [73] [77] Similarly, long-term quality of life outcomes among survivors undergoing amputation and limb sparing procedures have not differed substantially. [76] A longitudinal analysis of health status among extremity sarcoma survivors in the CCSS indicates an association between lower extremity amputation and increasing activity limitations with age, and an association between upper extremity amputation and lower educational attainment. [78]

Joint contractures

HCT with any history of chronic GVHD is associated with joint contractures. [79] [80] [81]

Table 13 summarizes bone and joint late effects and the related health screenings.

Table 13. Bone and Joint Late Effectsa

Predisposing TherapyMusculoskeletal EffectsHealth Screening
Radiation impacting musculoskeletal system Hypoplasia; fibrosis; reduced/uneven growth (scoliosis, kyphosis); limb length discrepancyExam: bones and soft tissues in radiation fields
Radiation impacting head and neck Craniofacial abnormalitiesHistory: psychosocial assessment, with attention to: educational and/or vocational progress, depression, anxiety, posttraumatic stress, social withdrawal
Head and neck exam  
Radiation impacting musculoskeletal system Radiation-induced fractureExam of affected bone
Methotrexate; corticosteroids (dexamethasone, prednisone); radiation impacting skeletal structures; HSCTReduced bone mineral densityBone mineral density test (DXA or quantitative CT)
Corticosteroids (dexamethasone, prednisone) OsteonecrosisHistory: joint pain, swelling, immobility, limited range of motion
Musculoskeletal exam  
Radiation with impact to oral cavity OsteoradionecrosisHistory/oral exam: impaired or delayed healing after dental work, persistent jaw pain or swelling, trismus
Amputation Amputation-related complications (impaired cosmesis, functional/activity limitations, residual limb integrity, chronic pain, increased energy expenditure)History: pain, functional/activity limitations
Exam: residual limb integrity   
Prosthetic evaluation  
Limb-sparing surgery Limb-sparing surgical complications (functional/activity limitations, fibrosis, contractures, chronic infection, chronic pain, limb length discrepancy, increased energy expenditure, prosthetic malfunction [loosening, non-union, fracture]) History: pain, functional/activity limitations
Exam: residual limb integrity  
Radiograph of affected limb  
Orthopedic evaluation   
HSCT with any history of chronic GVHD Joint contractureMusculoskeletal exam
CT = computed tomography; DXA = dual-energy x-ray absorptiometry; GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for musculoskeletal system late effects information, including risk factors, evaluation, and health counseling.

References:

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  42. Benmiloud S, Steffens M, Beauloye V, et al.: Long-term effects on bone mineral density of different therapeutic schemes for acute lymphoblastic leukemia or non-Hodgkin lymphoma during childhood. Horm Res Paediatr 74 (4): 241-50, 2010.
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  46. Wilson CL, Dilley K, Ness KK, et al.: Fractures among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 118 (23): 5920-8, 2012.
  47. Paulino AC: Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat Oncol Biol Phys 60 (1): 265-74, 2004.
  48. Wagner LM, Neel MD, Pappo AS, et al.: Fractures in pediatric Ewing sarcoma. J Pediatr Hematol Oncol 23 (9): 568-71, 2001.
  49. Sala A, Mattano LA Jr, Barr RD: Osteonecrosis in children and adolescents with cancer - an adverse effect of systemic therapy. Eur J Cancer 43 (4): 683-9, 2007.
  50. Elmantaser M, Stewart G, Young D, et al.: Skeletal morbidity in children receiving chemotherapy for acute lymphoblastic leukaemia. Arch Dis Child 95 (10): 805-9, 2010.
  51. Mattano LA Jr, Devidas M, Nachman JB, et al.: Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol 13 (9): 906-15, 2012.
  52. Bürger B, Beier R, Zimmermann M, et al.: Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)--experiences from trial ALL-BFM 95. Pediatr Blood Cancer 44 (3): 220-5, 2005.
  53. Karimova EJ, Rai SN, Howard SC, et al.: Femoral head osteonecrosis in pediatric and young adult patients with leukemia or lymphoma. J Clin Oncol 25 (12): 1525-31, 2007.
  54. Karimova EJ, Wozniak A, Wu J, et al.: How does osteonecrosis about the knee progress in young patients with leukemia?: a 2- to 7-year study. Clin Orthop Relat Res 468 (9): 2454-9, 2010.
  55. Campbell S, Sun CL, Kurian S, et al.: Predictors of avascular necrosis of bone in long-term survivors of hematopoietic cell transplantation. Cancer 115 (18): 4127-35, 2009.
  56. Kawedia JD, Kaste SC, Pei D, et al.: Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood 117 (8): 2340-7; quiz 2556, 2011.
  57. Girard P, Auquier P, Barlogis V, et al.: Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood. Haematologica 98 (7): 1089-97, 2013.
  58. Aricò M, Boccalatte MF, Silvestri D, et al.: Osteonecrosis: An emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia. Haematologica 88 (7): 747-53, 2003.
  59. Ribeiro RC, Fletcher BD, Kennedy W, et al.: Magnetic resonance imaging detection of avascular necrosis of the bone in children receiving intensive prednisone therapy for acute lymphoblastic leukemia or non-Hodgkin lymphoma. Leukemia 15 (6): 891-7, 2001.
  60. te Winkel ML, Pieters R, Hop WC, et al.: Prospective study on incidence, risk factors, and long-term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia. J Clin Oncol 29 (31): 4143-50, 2011.
  61. Faraci M, Calevo MG, Lanino E, et al.: Osteonecrosis after allogeneic stem cell transplantation in childhood. A case-control study in Italy. Haematologica 91 (8): 1096-9, 2006.
  62. Relling MV, Yang W, Das S, et al.: Pharmacogenetic risk factors for osteonecrosis of the hip among children with leukemia. J Clin Oncol 22 (19): 3930-6, 2004.
  63. Vrooman LM, Stevenson KE, Supko JG, et al.: Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31 (9): 1202-10, 2013.
  64. Yang L, Panetta JC, Cai X, et al.: Asparaginase may influence dexamethasone pharmacokinetics in acute lymphoblastic leukemia. J Clin Oncol 26 (12): 1932-9, 2008.
  65. Li X, Brazauskas R, Wang Z, et al.: Avascular necrosis of bone after allogeneic hematopoietic cell transplantation in children and adolescents. Biol Blood Marrow Transplant 20 (4): 587-92, 2014.
  66. Mattano LA Jr, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18 (18): 3262-72, 2000.
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Late Effects of the Reproductive System

Surgery, radiation therapy, or chemotherapy that negatively affects any component of the hypothalamic-pituitary axis or gonads may compromise reproductive outcomes in childhood cancer survivors. Evidence for this outcome in childhood cancer survivors is limited by studies characterized by small sample size, cohort selection and participation bias, cross-sectional assessment, heterogeneity in treatment approach, time since treatment, and method of ascertainment. In particular, the literature is deficient regarding hard outcomes of reproductive potential (e.g., semen analysis in men, primordial follicle count in women) and outcomes after contemporary risk-adapted treatment approaches. [1] [2]

The risk of infertility is generally related to the tissues or organs involved by the cancer and the specific type, dose, and combination of cytotoxic therapy.

In addition to anticancer therapy, age at treatment, and sex, it is likely that genetic factors influence the risk of permanent infertility. It should be noted that pediatric cancer treatment protocols often prescribe combined-modality therapy; thus, the additive effects of gonadotoxic exposures may need to be considered in assessing reproductive potential. Detailed information about the specific cancer treatment modalities including specific surgical procedures, the type and cumulative doses of chemotherapeutic agents, and radiation treatment volumes and doses are needed to estimate risks for gonadal dysfunction and infertility.

Testis

Cancer treatments that may impair testicular and reproductive function include the following:

Surgery affecting testicular function

Patients who undergo unilateral orchiectomy for testicular torsion may have subnormal sperm counts at long-term follow-up. [3] [4] Retrograde ejaculation is a frequent complication of bilateral retroperitoneal lymph node dissection performed on males with testicular neoplasms, [5] [6] and impotence may occur after extensive pelvic dissections to remove a rhabdomyosarcoma of the prostate. [7]

Radiation affecting testicular function

Among men treated for childhood cancer, the potential for gonadal injury exists if radiation treatment fields include the pelvis, gonads, or total body. The germinal epithelium is more sensitive to radiation injury than are the androgen-producing Leydig cells. A decrease in sperm counts can be seen 3 to 6 weeks after such irradiation, and depending on the dosage, recovery may take 1 to 3 years. The germinal epithelium is damaged by much lower dosages (<1 Gy) of radiation than are Leydig cells (20–30 Gy). Irreversible germ cell failure may occur with fractionated radiation doses of greater than 2 Gy to 4 Gy. [8] Administration of higher radiation doses, such as 24 Gy, which was used for the treatment of testicular relapse of acute lymphoblastic leukemia (ALL), results in both germ cell failure and Leydig cell dysfunction. [9]

Radiation injury to Leydig cells is related to the dose delivered and age at treatment. Testosterone production may be normal in prepubertal boys treated with less than 12 Gy fractionated testicular irradiation, but elevated plasma concentrations of luteinizing hormone observed in this group suggest subclinical injury. Gonadal failure typically results when prepubertal boys are treated with more than 20 Gy of radiation to the testes; androgen therapy is required for masculinization. Leydig cell function is usually preserved in sexually mature male patients if radiation doses do not exceed 30 Gy. Although available data suggest that Leydig cells are more vulnerable when exposed to radiation before puberty, confounding factors, such as the age at testing and the effects of both orchiectomy and chemotherapy, limit the reliability of this observation. [10]

Chemotherapy affecting testicular function

Cumulative alkylating agent (e.g., cyclophosphamide, mechlorethamine, dacarbazine) dose is an important factor in estimating the risk of testicular germ cell injury, but limited data are available that correlate results of semen analyses in clinically well-characterized cohorts. [11] In general, Leydig cell function is preserved, but germ cell failure is common in men treated with high cumulative doses of cyclophosphamide (7,500 mg/m2 or more) and more than 3 months of combination alkylating agent therapy. Most studies suggest that prepubertal males are not at lower risk for chemotherapy-induced testicular damage than are postpubertal patients. [12] [13] [14] [15]

Studies of testicular germ cell injury, as evidenced by oligospermia or azoospermia, after alkylating agent administration with or without radiation therapy, have reported the following:

Testicular function after hematopoietic stem cell transplantation (HSCT)

The risk of gonadal dysfunction and infertility related to conditioning with total-body irradiation (TBI), high-dose alkylating agent chemotherapy, or both is substantial. Because transplantation is often undertaken for relapsed or refractory cancer, previous treatment with alkylating agent chemotherapy or hypothalamic-pituitary axis or gonadal radiation therapy may confer additional risks. Age at treatment also influences the risk of gonadal injury. Young boys and adolescents treated with high-dose cyclophosphamide (200 mg/kg) will generally maintain Leydig cell function and testosterone production, but germ cell failure is common. After TBI conditioning, most male patients retain their ability to produce testosterone but will experience germ cell failure. [31]

Limited data suggest that a greater proportion of boys will retain germinal function or recovery of spermatogenesis (based on pubertal progress and gonadotropin levels) after reduced-intensity conditioning with fludarabine/melphalan than will those treated with myeloablative conditioning with busulfan/cyclophosphamide. [32]

Recovery of gonadal function

Recovery of gonadal function after cytotoxic chemotherapy and radiation therapy is possible. Dutch investigators used inhibin B as a surrogate marker of gonadal function in a cross-sectional, retrospective study of 201 male survivors of childhood cancer, with a median follow-up of 15.7 years (range, 3–37 years) from diagnosis. The median inhibin B level among the cohort increased based on serial measurements performed over a median of 3.3 years (range, 0.7–11.3 years). The probability of recovery of the serum inhibin B level was significantly influenced by baseline inhibin B level, but not age at diagnosis, age at study evaluation, interval between discontinuation of treatment and study evaluation, gonadal irradiation, and alkylating agent dose score. These results suggest that recovery can occur but not if inhibin B is already at a critically low level. [33]

Inhibin B and FSH levels are correlated with sperm concentration and often used to estimate the presence of spermatogenesis; however, limitations in the specificity and positive predictive value of these tests have been reported. [34] Hence, male survivors should be advised that semen analysis is the most accurate assessment of adequacy of spermatogenesis.

Ovary

Cancer treatments that may impair ovarian function/reserve include the following:

Surgery affecting ovarian function

Oophorectomy performed for the management of germ cell tumors may reduce ovarian reserve. Contemporary treatments utilize fertility-sparing surgical procedures combined with systemic chemotherapy to reduce this risk. [35]

Radiation affecting ovarian function

In women treated for childhood cancer, the potential for primary gonadal injury exists if treatment fields involve the lumbosacral spine, abdomen, pelvis, or total body. The frequency of ovarian failure after abdominal radiation therapy is related to both the age of the woman at the time of irradiation and the radiation therapy dose received by the ovaries. The ovaries of younger individuals are more resistant to radiation damage than are those of older women because of their greater complement of primordial follicles.

Whole-abdomen irradiation at doses of 20 Gy or greater is associated with the highest risk of ovarian dysfunction. Seventy-one percent of women in one series failed to enter puberty, and 26% had premature menopause after receiving whole-abdominal radiation therapy doses of 20 Gy to 30 Gy. [36] Other studies reported similar results in women treated with whole-abdomen irradiation [37] or craniospinal irradiation [38] [39] during childhood.

Chemotherapy affecting ovarian function

Ovarian function may be impaired after treatment with combination chemotherapy that includes an alkylating agent and procarbazine. In general, girls maintain gonadal function at higher cumulative alkylating agent doses than do boys. Most female childhood cancer survivors who are treated with risk-adapted combination chemotherapy retain or recover ovarian function. However, the risk of acute ovarian failure and premature menopause is substantial if treatment includes combined-modality therapy with alkylating agent chemotherapy and abdominal or pelvic radiation therapy or dose-intensive alkylating agents for myeloablative conditioning before HSCT. [40] [41] [42] [43]

Premature ovarian failure

Premature ovarian failure is well documented in childhood cancer survivors, especially in women treated with both an alkylating agent and abdominal radiation therapy. [40] [44] [45] Studies have associated the following factors with an increased rate of premature ovarian failure (acute ovarian failure and premature menopause):

The presence of apparently normal ovarian function at the completion of chemotherapy should not be interpreted as evidence that no ovarian injury has occurred.

Evidence (acute ovarian failure and premature menopause in childhood cancer survivors):

  1. Of 3,390 eligible participants in the Childhood Cancer Survivor Study (CCSS), 215 (6.3%) developed acute ovarian failure (defined as never having menses or ceased having menses within 5 years of diagnosis). [41]
  2. A total of 126 childhood cancer survivors and 33 control siblings who participated in the CCSS developed premature menopause, defined as cessation of menses before 40 years. [40]
  3. A French cohort study of 1,109 female survivors of childhood solid cancer identified the following risk factors for nonsurgical menopause: [45]
    1. Exposure to and dose of alkylating agents, especially during adolescence.
    2. Radiation dose to the ovaries.
    3. Oophorectomy.
  4. In Europe, survivors of Hodgkin lymphoma treated between the ages 15 years and 40 years and who were not receiving hormonal contraceptives were surveyed for the occurrence of premature ovarian failure. [44]

Ovarian function after HSCT

The preservation of ovarian function among women treated with HSCT is related to age at treatment, receipt of pretransplant alkylating agent chemotherapy and abdominal-pelvic radiation therapy, and transplant conditioning regimen. [42] [46]

Evidence (ovarian function among women treated with HSCT):

  1. Girls and young women conditioned with TBI or busulfan-based regimens appear to be at equally high risk of declining ovarian function and premature menopause compared with patients conditioned with cyclophosphamide only. [42] All women who received high-dose (50 mg/kg/day x 4 days) cyclophosphamide before HSCT for aplastic anemia developed amenorrhea after transplantation.
  2. TBI is especially damaging when given in a single fraction. [42] Most postpubertal women who receive TBI before HSCT develop amenorrhea.
  3. Among women with leukemia, cranial irradiation before transplantation further decreased the possibility of retaining ovarian function. [42]
  4. Ovarian function may be better preserved (based on pubertal progress and gonadotropin levels) in females undergoing HSCT with reduced-intensity conditioning using fludarabine/melphalan than in those undergoing conditioning with myeloablative busulfan/cyclophosphamide. [32]

Fertility

Infertility remains one of the most common life-altering treatment effects experienced by long-term childhood survivors. Pediatric cancer cohort studies have demonstrated the impact of cytotoxic therapy on reproductive outcomes. CCSS investigations have elucidated factors contributing to subfertility among childhood cancer survivors. [47] [48]

Fertility was evaluated in 10,938 CCSS participants (5,640 males, 5,298 females) and 3,949 siblings. [47]

Fertility may be impaired by factors other than the absence of sperm and ova. Conception requires delivery of sperm to the uterine cervix, patency of the fallopian tubes for fertilization to occur, and appropriate conditions in the uterus for implantation. [5] [6] [49]

Reproduction

For survivors who maintain fertility, numerous investigations have evaluated the prevalence of and risk factors for pregnancy complications in adults treated for cancer during childhood. Pregnancy complications including hypertension, fetal malposition, fetal loss/spontaneous abortion, preterm labor, and low birth weight have been observed in association with specific diagnostic and treatment groups. [50] [51] [52] [53] [54]

Evidence (pregnancy complications in adults treated for childhood cancer):

  1. 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. [50]
  2. In the National Wilms Tumor Study, records were obtained for 1,021 pregnancies of more than 20 weeks duration. In this group, there were 955 single live births. [56]
  3. Another CCSS study evaluated pregnancy outcomes of partners of male survivors. [51]
  4. Results from a Danish study confirm the association of uterine irradiation with spontaneous abortion, but not other types of abortion. Thirty-four thousand pregnancies were evaluated in a population of 1,688 female survivors of childhood cancer in the Danish Cancer Registry. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in the population were identified. [52]
  5. In a retrospective cohort analysis from the CCSS of 1,148 men and 1,657 women who had survived cancer, there were 4,946 pregnancies. [53]
  6. Most pregnancies reported by HSCT survivors and their partners result in live births. [54]
  7. Preservation of fertility and successful pregnancies may occur after HSCT, although the conditioning regimens that include TBI, cyclophosphamide, and busulfan are highly gonadotoxic. One study evaluated pregnancy outcomes in a group of females treated with HSCT. [57]
  8. A German study demonstrated that the rate of childbearing for female survivors of Hodgkin lymphoma was similar to that of the general population, although the rate of childbearing was lower for survivors who received pelvic radiation therapy. [58]
  9. British CCSS investigators evaluated pregnancy and labor complications among female survivors of childhood cancer treated with abdominal radiation by linking British CCSS cohort data to a national hospital registry. [59]

Fertility preservation

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. [60] 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. [61] [62] For those unable to bank sperm, newer technologies such as testicular sperm extraction may be an option. 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. [63]

For females, the most successful assisted-reproductive techniques depend on harvesting and banking the postpubertal patient’s oocytes and cryopreserving unfertilized oocytes or embryos before gonadotoxic therapy. [64] Options for prepubertal patients are limited to investigational ovarian tissue cryopreservation for later autotransplantation, which may be offered to girls with nonovarian, nonhematologic cancers. [65]

Offspring of childhood cancer survivors

For childhood cancer survivors who have offspring, there is concern about congenital anomalies, genetic disease, or risk of cancer in the offspring. Children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parents' exposure to mutagenic cancer treatments.

Evidence (children of cancer survivors not at significantly increased risk of congenital anomalies):

  1. A retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female participants of the CCSS observed the following: [66]
  2. A study compared 2,198 offspring of adult survivors treated for childhood cancer between 1945 and 1975 with 4,544 offspring of sibling controls. [67]
  3. A population-based study of 2,630 live-born offspring of childhood cancer survivors versus 5,504 live-born offspring of the survivors' siblings found no differences in proportion of abnormal karyotypes or incidence of Down syndrome or Turner syndrome between survivor and sibling offspring. [68]

    In the same population-based cohort, survivors treated with abdominal radiation therapy and/or alkylating agents did not have an increased risk of offspring with genetic disease, compared with survivors not exposed to these agents.

  4. In a study of 5,847 offspring of survivors of childhood cancers treated in five Scandinavian countries, in the absence of a hereditary cancer syndrome (such as hereditary retinoblastoma), there was no increased risk of cancer. [69] Data from the five-center study also indicated no excess risk of single-gene disorders, congenital malformations, or chromosomal syndromes among the offspring of former patients compared with the offspring of siblings. [70]
  5. In a study that evaluated pregnancy outcomes in 19,412 allogeneic and 17,950 autologous transplant patients, European Group for Blood and Marrow Transplantation investigators did not observe an increased risk of birth defects, developmental delay, or cancer among offspring of male and female HSCT recipients. [54]

Table 15 summarizes reproductive late effects and the related health screenings.

Table 15. Reproductive Late Effectsa

Predisposing Therapy Reproductive Late EffectsHealth Screening
Alkylating agents; gonadal irradiation Testicular hormonal dysfunction: Testosterone deficiency/insufficiency; delayed/arrested puberty Tanner stage
Morning testosterone  
LH  
Impaired spermatogenesis: Reduced fertility; oligospermia; azoospermia; infertility Semen analysis  
FSH  
Inhibin B   
Ovarian hormone deficiencies: Delayed/arrested puberty; premature ovarian insufficiency/premature menopause. Reduced ovarian follicular pool: Diminished ovarian reserve; infertility. Tanner stage 
Menstrual cycle history  
Estradiol  
FSH  
LH  
AMH  
Antral follicle count  
AMH = anti-mullerian hormone; FSH = follicle-stimulating hormone; LH = luteinizing hormone.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for reproductive late effects information including risk factors, evaluation, and health counseling.

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Late Effects of the Respiratory System

Specific chemotherapeutic agents, thoracic radiation therapy, pulmonary/chest wall surgery, and hematopoietic stem cell transplantation (HSCT) can compromise respiratory function in long-term survivors of childhood cancer. The effects of early lung injury from cancer treatment may be exacerbated by the decline in lung function associated with normal aging, other comorbid chronic health conditions, or smoking. The quality of current evidence regarding this outcome is limited by retrospective data collection, small sample size, cohort selection and participation bias, description of outcomes following antiquated treatment approaches, and variability in time since treatment and method of ascertainment.

The true prevalence or incidence of pulmonary dysfunction in childhood cancer survivors is not clear. For children treated with HSCT, significant clinical disease has been observed. Evidence for this outcome in childhood cancer survivors is limited by studies characterized by small sample size, cohort selection and participation bias, cross-sectional assessment, heterogeneity in treatment approach, time since treatment, and method of ascertainment. Notably, no large cohort studies have been performed with clinical evaluations coupled with functional and quality-of-life assessments.

Results from selected cohort studies featuring long-term pulmonary function outcomes include the following:

Respiratory complications following radiation therapy

Radiation therapy that exposes the lung parenchyma can result in pulmonary dysfunction related to reduced lung volume, impaired dynamic compliance, and deformity of both the lung and chest wall. The potential for chronic pulmonary sequelae is related to the radiation dose administered, the volume of lung irradiated, and the fractional radiation therapy doses. [5] Combined-modality therapy including radiation therapy and pulmonary toxic chemotherapy or thoracic/chest wall surgery increases the risk of pulmonary function impairment. [2]

Chronic pulmonary complications reported after treatment for pediatric malignancies include restrictive or obstructive chronic pulmonary disease, pulmonary fibrosis, and spontaneous pneumothorax. [6] These sequelae are uncommon after contemporary therapy, which most often results in subclinical injury that is detected only by imaging or formal pulmonary function testing.

Pulmonary outcomes reported from selected cohort studies treated with thoracic radiation therapy include the following:

Respiratory complications following chemotherapy

Chemotherapy agents with potential pulmonary toxic effects commonly used in the treatment of pediatric malignancies include bleomycin, busulfan, and the nitrosoureas (carmustine and lomustine). These agents induce lung damage on their own or potentiate the damaging effects of radiation to the lung. Combined-modality therapy including pulmonary toxic chemotherapy and thoracic radiation therapy or thoracic/chest wall surgery increases the risk of pulmonary function impairment. [2] Outcomes observed among cohorts treated with pulmonary toxic chemotherapy include the following:

Respiratory complications associated with HSCT

Patients undergoing HSCT are at increased risk of pulmonary toxic effects related to the following: [18] [19] [20]

Although most survivors of transplant are not clinically compromised, restrictive lung disease may occur and has been reported to increase in prevalence with increasing time from HSCT, based on limited data from longitudinally followed cohorts. [21] [22] 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. [19] [23] [24]

Other factors associated with respiratory late effects

Additional factors contributing to chronic pulmonary toxic effects include superimposed infection, underlying pneumonopathy (e.g., asthma), respiratory toxic effects, chronic GVHD, and the effects of chronic pulmonary involvement by tumor or reaction to tumor. Lung lobectomy during childhood appears to have no significant impact on long-term pulmonary function, [25] but the long-term effect of lung surgery for children with cancer is not well defined.

Pulmonary complications may also be exacerbated by smoking cigarettes or other substances. While smoking rates in survivors of childhood cancer tend to be lower than the general population, it is still important to prevent initiation of smoking and promote cessation in this distinct population. [26]

Pulmonary function evaluations of 433 adult childhood cancer survivors treated with pulmonary toxic modalities demonstrated significantly higher risk for pulmonary dysfunction among smokers compared to nonsmokers. FEV1/FVC median values among current and former smokers were lower than those who had never smoked. Median FEV1/FVC values were lower among those who smoked less than 6 pack-years and those who smoked 6 pack-years or more compared with those who had never smoked suggesting that survivors who are former or current smokers have an increased risk for future obstructive and restrictive lung disease. [27]

Table 16 summarizes respiratory late effects and the related health screenings.

Table 16. Respiratory Late Effectsa

Predisposing TherapyRespiratory EffectsHealth Screening/Interventions
Busulfan; carmustine (BCNU)/lomustine (CCNU); bleomycin; radiation impacting lungs; surgery impacting pulmonary function (lobectomy, metastasectomy, wedge resection) Subclinical pulmonary dysfunction; interstitial pneumonitis; pulmonary fibrosis; restrictive lung disease; obstructive lung disease History: cough, shortness of breath, dyspnea on exertion, wheezing
Pulmonary exam  
Pulmonary function tests (including DLCO and spirometry)  
Chest x-ray  
Counsel regarding tobacco avoidance/smoking cessation  
In patients with abnormal pulmonary function tests and/or chest x-ray, consider repeat evaluation before general anesthesia  
Pulmonary consultation for patients with symptomatic pulmonary dysfunction  
Influenza and pneumococcal vaccinations  
Hematopoietic cell transplantation with any history of chronic GVHD Pulmonary toxicity (bronchiolitis obliterans, chronic bronchitis, bronchiectasis)History: cough, shortness of breath, dyspnea on exertion, wheezing
Pulmonary exam  
Pulmonary function tests (including DLCO and spirometry)  
Chest x-ray  
Counsel regarding tobacco avoidance/smoking cessation  
In patients with abnormal pulmonary function tests and/or chest x-ray, consider repeat evaluation before general anesthesia  
Pulmonary consultation for patients with symptomatic pulmonary dysfunction  
Influenza and pneumococcal vaccinations  
DLCO = diffusing capacity of the lung for carbon monoxide; GVHD = graft-versus-host disease.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for respiratory late effects information including risk factors, evaluation, and health counseling. [28]

References:

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Late Effects of the Special Senses

Hearing

Hearing loss as a late effect of therapy can occur after exposure to platinum compounds (cisplatin and carboplatin), cranial radiation therapy, or both. These therapeutic exposures are most common in the treatment of central nervous system (CNS) and non-CNS solid tumors. Children are more susceptible to otologic toxic effects from platinum agents than are adults. [1] [2] A report from the Swiss Childhood Cancer Survivor Study (CCSS) (N = 2,061) estimated the prevalence of hearing loss in survivors at 10%, compared with 3% in siblings. Hearing loss was most common in survivors of CNS tumors (25%), neuroblastoma (23%), hepatic tumor (21%), germ cell tumor (20%), bone tumor (16%), and soft tissue sarcoma (16%). [3] Data from the Swiss CCSS indicate that the relative rate of first occurrence of auditory complications (problems hearing sounds, tinnitus, hearing loss, deafness) is greatest in the time period from diagnosis to 5 years postdiagnosis; however, during the period of 5 or more years postdiagnosis, the risk of developing such conditions for survivors remained significantly higher than for siblings. [4]

Risk factors associated with hearing loss include the following:

Hearing loss and platinum-based therapy

Platinum-related sensorineural hearing loss develops as an acute toxicity that is generally irreversible and bilateral. Hearing loss manifests initially in the high frequencies and progresses to the speech frequencies with increasing cumulative exposure. The prevalence of hearing loss has varied widely per series and is based on platinum treatment (e.g., platinum type, dose, infusion duration); host factors (e.g., age, genetic susceptibility, renal function); receipt of additional ototoxic therapy (cranial radiation therapy, aminoglycosides, loop diuretics), and the grading criteria used to report prevalence and severity of hearing loss. [6]

Hearing loss and cranial radiation therapy

Cranial radiation therapy, when used as a single modality, may result in otologic toxic effects that may be gradual in onset, manifesting months to years after exposure. The threshold dose for auditory toxicity after radiation therapy alone is in the range of 35 to 45 Gy for children. [14] High-frequency sensorineural hearing loss is uncommon at cumulative radiation doses below 35 Gy, and is rarely severe below doses of 45 Gy. [15] The exception is for patients with supratentorial tumors and ventriculoperitoneal shunts, in whom doses below 30 Gy may be associated with intermediate frequency (1,000–2,000 Hz) hearing loss. [14] [16] To reduce the risk of hearing loss, the average cochlear dose should not exceed 30 to 35 Gy, delivered over 6 weeks. Young patient age and presence of a brain tumor and/or hydrocephalus can increase susceptibility to hearing loss.

Sensorineural hearing loss after cranial radiation therapy can progress over time. In a study of 235 pediatric brain tumor patients treated with conformal or intensity-modulated radiation therapy (without cisplatin or pre-existing hearing loss) and monitored for a median of 9 years, sensorineural hearing loss was prevalent in 14% of patients, with a median time to onset of 3.6 years from radiation therapy. Follow-up evaluations among 29 patients identified continued decline in hearing sensitivity. Risk factors for cranial radiation–associated sensorineural hearing loss included younger age at initiation of radiation, higher cochlear radiation dose, and cerebrospinal fluid shunting. [17]

When used concomitantly with cisplatin, radiation therapy can substantially exacerbate the hearing loss associated with platinum chemotherapy. [14] [18] [19] [20] In a report from the CCSS, 5-year survivors were at increased risk of problems with hearing sounds (relative risk [RR], 2.3), tinnitus (RR, 1.7), hearing loss requiring an aid (RR, 4.4), and hearing loss in one or both ears not corrected by a hearing aid (RR, 5.2), compared with siblings. Temporal lobe irradiation (>30 Gy) and posterior fossa irradiation (>50 Gy but also 30–49.9 Gy) were associated with these adverse outcomes. Exposure to platinum was associated with an increased risk of problems with hearing sounds (RR, 2.1), tinnitus (RR, 2.8), and hearing loss requiring an aid (RR, 4.1). [4]

Hearing loss and quality of life

Importantly, children treated for malignancies may be at risk of early- or delayed-onset hearing loss that can affect learning, communication, school performance, social interaction, and overall quality of life.

The Children’s Oncology Group has published recommendations for the evaluation and management of hearing loss in survivors of childhood and adolescent cancers to promote early identification of at-risk survivors and timely referral for remedial services. [23]

Table 17 summarizes auditory late effects and the related health screenings.

Table 17. Auditory Late Effectsa

Predisposing TherapyPotential Auditory EffectsHealth Screening/Interventions
Platinum agents (cisplatin, carboplatin); radiation impacting the earOtologic toxic effects; sensorineural hearing loss; tinnitus; vertigo; dehydrated ceruminosis; conductive hearing loss History: hearing difficulties, tinnitus, vertigo
Otoscopic exam   
Audiology evaluation   
Amplification in patients with progressive hearing loss  
Speech and language therapy for children with hearing loss  
Otolaryngology consultation in patients with chronic infection, cerumen impaction, or other anatomical problems exacerbating or contributing to hearing loss  
Educational accommodations (e.g., preferential classroom seating, FM amplification system, etc.)  
FM = frequency modulated.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Orbital and Optic

Orbital complications are common after radiation therapy for retinoblastoma and after total-body irradiation (TBI) and in children with head and neck sarcomas and CNS tumors.

Retinoblastoma

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 finding is not consistent across studies. [24] [25] Progress has been made in the management of retinoblastoma, with better enucleation implants, intravenous chemoreduction, and intra-arterial chemotherapy in addition to thermotherapy, cryotherapy, and plaque radiation therapy. Longer follow-up is needed to assess the impact on vision in patients undergoing these more contemporary treatment modalities. [24] [26] [27] Previously, tumors located near the macula and fovea were associated with an increased risk of complications leading to vision loss, although treatment of these tumors with foveal laser ablation has shown promise in preserving vision. [28] [29] [30] [31]

(Refer to the PDQ summary on Retinoblastoma Treatment for more information on the treatment of retinoblastoma.)

Rhabdomyosarcoma

Survivors of orbital rhabdomyosarcoma are at risk of dry eye, cataract, orbital hypoplasia, ptosis, retinopathy, keratoconjunctivitis, optic neuropathy, lid epithelioma, and impairment of vision after 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 higher than 2 Gy. [32] Cataracts are reported after lower doses of 10 Gy to 18 Gy. [33] [34] [35]

(Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information on the treatment of rhabdomyosarcoma in children.)

Low-grade optic pathway glioma and craniopharyngioma

Survivors of optic pathway glioma and craniopharyngioma are also at risk of visual complications, resulting in part from tumor proximity to the optic nerve.

Longitudinal follow-up (mean, 9 years) of 21 patients with optic pathway gliomas indicated that before treatment, 81% of patients had reduced visual acuity, 81% had optic nerve pallor, and all had reduced visual evoked potentials in one or both eyes. Treatment arrested acuity loss for 4 to 5 years. Visual acuity was stable or improved in 33% of patients at last follow-up; however, it declined on average. Visual acuity at follow-up was related to tumor volume at initial presentation. [36]

In a study of 25 patients diagnosed with craniopharyngioma, 67% had visual complications at a mean follow-up of 11 years. [37] A retrospective review of 30 children with craniopharyngioma revealed that 19 patients had vision loss before surgery; 21 patients had postsurgical vision loss. Preoperative vision loss was predicative of postoperative vision loss. [38]

CCSS investigators evaluated the impact of impaired vision on cognitive and psychosocial outcomes among 1,233 adult survivors of childhood low-grade gliomas. Some degree of visual impairment was prevalent in 22.5% of patients, and 3.8% of patients were blind in both eyes. Survivors who were blind in both eyes were more likely to be unmarried, live dependently, and be unemployed than were survivors with unimpaired vision. However, bilateral blindness did not impact self-reported cognitive or emotional outcomes. Impaired (with some remaining) vision was not associated with psychological or economic outcomes. [39]

Treatment-specific effects

Survivors of childhood cancer are at increased risk for ocular late effects related to both glucocorticoid and radiation exposure to the eye.

Evidence (ocular effects of radiation exposure):

  1. The CCSS reported that survivors who were 5 or more years from diagnosis were at increased risk of developing cataracts (RR, 10.8), glaucoma (RR, 2.5), legal blindness (RR, 2.6), double vision (RR, 4.1), and dry eye (RR, 1.9), compared with siblings. [40]
  2. The 15-year cumulative incidence of cataract was 4.5% among 517 survivors of childhood acute lymphoblastic leukemia (median, 10.9 years from diagnosis), systematically evaluated by slit lamp examination. CNS radiation therapy was the only treatment-related risk factor identified for cataract development, which occurred in 11.1% of irradiated survivors, compared with 2.8% of those who were not irradiated. [41]
  3. A report from the CCSS provides additional data on the interval from radiation therapy and the radiation dose associated with the development of cataracts. [42]

Ocular complications, such as cataracts and dry eye syndrome, are common after stem cell transplantation in childhood.

Evidence (ocular effects of stem cell transplantation):

  1. Compared with patients treated with busulfan or other chemotherapy, patients treated with single-dose or fractionated TBI are 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. [43] [44] [45] [46]
  2. Patients receiving TBI doses of less than 40 Gy have a less than 10% chance of developing severe cataracts. [46]
  3. Corticosteroids and graft-versus-host disease may further increase risk. [43] [47]
  4. The prevalence of cataracts, evaluated by serial slit lamp testing, among 271 participants (mean follow-up, 10.3 years) in the Leucémie Enfants Adolescents (LEA) program was 41.7%, with 8.1% requiring surgical intervention. [48] In this cohort, the cumulative incidence of cataracts among those treated with TBI increased over time from 30% at 5 years to 70.8% at 15 years and 78% at 20 years. The lack of a plateau in cataract incidence suggests that nearly all patients treated with TBI will develop cataracts as follow-up increases. In contrast, the 15-year cumulative incidence of cataracts was 12.5% among those conditioned with busulfan. Multivariable analysis identified high cumulative steroid dose as a potential cofactor with TBI for cataract risk.
  5. Dry eye syndrome has been shown to be more common if the patient was exposed to repeated high trough levels of cyclosporine. [49]

Table 18 summarizes ocular late effects and the related health screenings.

Table 18. Ocular Late Effectsa

Predisposing TherapyOcular/Vision EffectsHealth Screening/Interventions
Busulfan; corticosteroids; radiation impacting the eye CataractsHistory: decreased acuity, halos, diplopia
Eye exam: visual acuity, funduscopy  
Ophthalmology consultation  
Radiation impacting the eye, including radioiodine (131I) Ocular toxicity (orbital hypoplasia, lacrimal duct atrophy, xerophthalmia [keratoconjunctivitis sicca], keratitis, telangiectasias, retinopathy, optic chiasm neuropathy, enophthalmos, chronic painful eye, maculopathy, papillopathy, glaucoma)History: visual changes (decreased acuity, halos, diplopia), dry eye, persistent eye irritation, excessive tearing, light sensitivity, poor night vision, painful eye
Eye exam: visual acuity, funduscopy  
Ophthalmology consultation  
Hematopoietic cell transplantation with any history of chronic GVHDXerophthalmia (keratoconjunctivitis sicca) History: dry eye (burning, itching, foreign body sensation, inflammation)
Eye exam: visual acuity, funduscopy  
EnucleationImpaired cosmesis; poor prosthetic fit; orbital hypoplasia Ocular prosthetic evaluation
Ophthalmology  
GVHD = graft-versus-host disease; 131I = iodine I 131.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for information on the late effects of special senses, including risk factors, evaluation, and health counseling.

References:

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  2. Li Y, Womer RB, Silber JH: Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose. Eur J Cancer 40 (16): 2445-51, 2004.
  3. Weiss A, Sommer G, Kasteler R, et al.: Long-term auditory complications after childhood cancer: A report from the Swiss Childhood Cancer Survivor Study. Pediatr Blood Cancer 64 (2): 364-373, 2017.
  4. Whelan K, Stratton K, Kawashima T, et al.: Auditory complications in childhood cancer survivors: a report from the childhood cancer survivor study. Pediatr Blood Cancer 57 (1): 126-34, 2011.
  5. Landier W, Knight K, Wong FL, et al.: Ototoxicity in children with high-risk neuroblastoma: prevalence, risk factors, and concordance of grading scales--a report from the Children's Oncology Group. J Clin Oncol 32 (6): 527-34, 2014.
  6. Brock PR, Knight KR, Freyer DR, et al.: Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J Clin Oncol 30 (19): 2408-17, 2012.
  7. Kushner BH, Budnick A, Kramer K, et al.: Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer 107 (2): 417-22, 2006.
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  9. Bertolini P, Lassalle M, Mercier G, et al.: Platinum compound-related ototoxicity in children: long-term follow-up reveals continuous worsening of hearing loss. J Pediatr Hematol Oncol 26 (10): 649-55, 2004.
  10. Kolinsky DC, Hayashi SS, Karzon R, et al.: Late onset hearing loss: a significant complication of cancer survivors treated with Cisplatin containing chemotherapy regimens. J Pediatr Hematol Oncol 32 (2): 119-23, 2010.
  11. Fouladi M, Gururangan S, Moghrabi A, et al.: Carboplatin-based primary chemotherapy for infants and young children with CNS tumors. Cancer 115 (14): 3243-53, 2009.
  12. Jehanne M, Lumbroso-Le Rouic L, Savignoni A, et al.: Analysis of ototoxicity in young children receiving carboplatin in the context of conservative management of unilateral or bilateral retinoblastoma. Pediatr Blood Cancer 52 (5): 637-43, 2009.
  13. Qaddoumi I, Bass JK, Wu J, et al.: Carboplatin-associated ototoxicity in children with retinoblastoma. J Clin Oncol 30 (10): 1034-41, 2012.
  14. Hua C, Bass JK, Khan R, et al.: Hearing loss after radiotherapy for pediatric brain tumors: effect of cochlear dose. Int J Radiat Oncol Biol Phys 72 (3): 892-9, 2008.
  15. Bhandare N, Jackson A, Eisbruch A, et al.: Radiation therapy and hearing loss. Int J Radiat Oncol Biol Phys 76 (3 Suppl): S50-7, 2010.
  16. 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.
  17. Bass JK, Hua CH, Huang J, et al.: Hearing Loss in Patients Who Received Cranial Radiation Therapy for Childhood Cancer. J Clin Oncol 34 (11): 1248-55, 2016.
  18. Cheuk DK, Billups CA, Martin MG, et al.: Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma. Cancer 117 (1): 197-206, 2011.
  19. Merchant TE, Hua CH, Shukla H, et al.: Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer 51 (1): 110-7, 2008.
  20. Paulino AC, Lobo M, Teh BS, et al.: Ototoxicity after intensity-modulated radiation therapy and cisplatin-based chemotherapy in children with medulloblastoma. Int J Radiat Oncol Biol Phys 78 (5): 1445-50, 2010.
  21. Gurney JG, Tersak JM, Ness KK, et al.: Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: a report from the Children's Oncology Group. Pediatrics 120 (5): e1229-36, 2007.
  22. Brinkman TM, Bass JK, Li Z, et al.: Treatment-induced hearing loss and adult social outcomes in survivors of childhood CNS and non-CNS solid tumors: Results from the St. Jude Lifetime Cohort Study. Cancer 121 (22): 4053-61, 2015.
  23. Bass JK, Knight KR, Yock TI, et al.: Evaluation and Management of Hearing Loss in Survivors of Childhood and Adolescent Cancers: A Report From the Children's Oncology Group. Pediatr Blood Cancer 63 (7): 1152-62, 2016.
  24. Kaste SC, Chen G, Fontanesi J, et al.: Orbital development in long-term survivors of retinoblastoma. J Clin Oncol 15 (3): 1183-9, 1997.
  25. 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.
  26. Shields CL, Shields JA: Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin Ophthalmol 21 (3): 203-12, 2010.
  27. Abramson DH, Dunkel IJ, Brodie SE, et al.: Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology 117 (8): 1623-9, 2010.
  28. 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.
  29. 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.
  30. Shields JA, Shields CL: Pediatric ocular and periocular tumors. Pediatr Ann 30 (8): 491-501, 2001.
  31. Schefler AC, Cicciarelli N, Feuer W, et al.: Macular retinoblastoma: evaluation of tumor control, local complications, and visual outcomes for eyes treated with chemotherapy and repetitive foveal laser ablation. Ophthalmology 114 (1): 162-9, 2007.
  32. Kline LB, Kim JY, Ceballos R: Radiation optic neuropathy. Ophthalmology 92 (8): 1118-26, 1985.
  33. 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.
  34. 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.
  35. 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.
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  39. de Blank PM, Fisher MJ, Lu L, et al.: Impact of vision loss among survivors of childhood central nervous system astroglial tumors. Cancer 122 (5): 730-9, 2016.
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  48. Horwitz M, Auquier P, Barlogis V, et al.: Incidence and risk factors for cataract after haematopoietic stem cell transplantation for childhood leukaemia: an LEA study. Br J Haematol 168 (4): 518-25, 2015.
  49. Fahnehjelm KT, Törnquist AL, Winiarski J: Dry-eye syndrome after allogeneic stem-cell transplantation in children. Acta Ophthalmol 86 (3): 253-8, 2008.

Late Effects of the Urinary System

Acute toxicity of the urinary system from cancer therapy is well known. Less is known about the genitourinary outcomes in long-term survivors. [1] The evidence for long-term renal injury in childhood cancer survivors is limited by studies characterized by small sample size, cohort selection and participation bias, cross-sectional assessment, heterogeneity in time since treatment, and method of ascertainment. In particular, the inaccuracies of diagnosing chronic kidney dysfunction by estimating equations of glomerular dysfunction should be considered. [2] Cancer treatments predisposing to renal injury and/or high blood pressure later in life include chemotherapeutic drugs (cisplatin, carboplatin, ifosfamide, methotrexate), renal radiation therapy, and nephrectomy. The risk and the degree of renal dysfunction depend on type and intensity of therapy and interpretation of the studies is compromised by variability in testing.

Few large-scale studies have evaluated late renal-health outcomes and risk factors for renal dysfunction among survivors treated with potentially nephrotoxic modalities. In a large cross-sectional study of 1,442 childhood cancer survivors (median attained age, 19.3 years; median time from diagnosis, 12.1 years), Dutch investigators assessed the presence of albuminuria, hypomagnesemia, hypophosphatemia, and hypertension and estimated glomerular filtration rate (GFR) among survivors treated with ifosfamide, cisplatin, carboplatin, high-dose cyclophosphamide (>1 g/m2 or more per course), or high-dose methotrexate (>1 g/m2 or more per course), radiation therapy to the kidney region, total-body irradiation (TBI), or nephrectomy. At least one abnormality of renal function or hypertension was detected in 28.1% of survivors. History of nephrectomy (odds ratio [OR], 8.6; 95% confidence interval [CI], 3.4–21.4) had the strongest association with a GFR of less than 90 mL/min per 1.73 m2. The prevalence of decreased GFR was highest among those treated with multimodality therapy including nephrectomy, nephrotoxic chemotherapy, and abdominal radiation therapy. Nearly 5% of these survivors had a GFR of less than 90 mL/min per 1.73 m2. Abdominal irradiation was the only significant treatment-related risk factor for hypertension (OR, 2.5; 95% CI, 1.4–4.5). [3]

Therapy-related factors affecting the kidney

Cancer treatments predisposing to late renal injury and hypertension include the following: [4] [5] [6]

Genetic factors predisposing to renal dysfunction

Many childhood survivors of Wilms tumor who develop chronic renal failure have syndromes accompanying WT1 mutations or deletions that predispose to renal disease. Data from the National Wilms Tumor Study Group and the U.S. Renal Data System indicate that the 20-year cumulative incidence of end-stage renal disease in children with unilateral Wilms tumor and Denys-Drash syndrome is 74%, 36% for those with WAGR (Wilms tumor, aniridia, genitourinary abnormalities, mental retardation) syndrome, 7% for male patients with genitourinary anomalies, and 0.6% for 5,347 patients with none of these conditions. [28] For patients with bilateral Wilms tumors, the incidence of end-stage renal disease is 50% for Denys-Drash syndrome, 90% for WAGR, 25% for genitourinary anomaly, and 12% for patients for all others. [28] [29] End-stage renal disease in patients with WAGR and genitourinary anomalies tended to occur relatively late, and often during or after adolescence. [28]

Therapy-related bladder complications

Pelvic or central nervous system surgery, alkylator-containing chemotherapy including cyclophosphamide or ifosfamide, pelvic radiation therapy, and certain spinal and genitourinary surgical procedures have been associated with the following urinary bladder late effects: [30]

Table 19 summarizes kidney and bladder late effects and the related health screenings.

Table 19. Kidney and Bladder Late Effectsa

Predisposing TherapyRenal/Genitourinary EffectsHealth Screening
Cisplatin/carboplatin; ifosfamide Renal toxicity (glomerular injury, tubular injury [renal tubular acidosis], Fanconi syndrome, hypophosphatemic rickets) Blood pressure
BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levels  
Urinalysis  
Electrolyte supplements for patients with persistent electrolyte wasting  
Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiency  
Methotrexate; radiation impacting kidneys/urinary tract Renal toxicity (renal insufficiency, hypertension)Blood pressure
BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levels  
Urinalysis   
Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiency  
Nephrectomy Renal toxicity (proteinuria, hyperfiltration, renal insufficiency)Blood pressure
BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levels  
Urinalysis  
Discuss contact sports, bicycle safety (e.g., avoiding handlebar injuries), and proper use of seatbelts (i.e., wearing lap belts around hips, not waist)  
Counsel to use NSAIDs with caution  
Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiency  
Nephrectomy; pelvic surgery; cystectomy Hydrocele Testicular exam
Cystectomy Cystectomy-related complications (chronic urinary tract infections, renal dysfunction, vesicoureteral reflux, hydronephrosis, reservoir calculi, spontaneous neobladder perforation, vitamin B12/folate/carotene deficiency [patients with ileal enterocystoplasty only])Urology evaluation
Vitamin B12 level   
Pelvic surgery; cystectomy Urinary incontinence; urinary tract obstruction History: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary stream
Counsel regarding adequate fluid intake, regular voiding, seeking medical attention for symptoms of voiding dysfunction or urinary tract infection, compliance with recommended bladder catheterization regimen  
Urologic consultation for patients with dysfunctional voiding or recurrent urinary tract infections  
Cyclophosphamide/Ifosfamide; radiation impacting bladder/urinary tract Bladder toxicity (hemorrhagic cystitis, bladder fibrosis, dysfunctional voiding, vesicoureteral reflux, hydronephrosis)History: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary stream
Urinalysis   
Urine culture, spot urine calcium/creatinine ratio, and ultrasound of kidneys and bladder for patients with microscopic hematuria (defined as ≥5 RBC/HFP on at least 2 occasions)  
Nephrology or urology referral for patients with culture-negative microscopic hematuria AND abnormal ultrasound and/or abnormal calcium/creatinine ratio  
Urology referral for patients with culture negative macroscopic hematuria  
BUN = blood urea nitrogen; NSAIDs = nonsteroidal anti-inflammatory drugs; RBC/HFP = red blood cells per high-field power (microscopic exam).
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for urinary late effects information including risk factors, evaluation, and health counseling.

References:

  1. Shnorhavorian M, Friedman DL, Koyle MA: Genitourinary long-term outcomes for childhood cancer survivors. Curr Urol Rep 10 (2): 134-7, 2009.
  2. Green DM: Evaluation of renal function after successful treatment for unilateral, non-syndromic Wilms tumor. Pediatr Blood Cancer 60 (12): 1929-35, 2013.
  3. Knijnenburg SL, Jaspers MW, van der Pal HJ, et al.: Renal dysfunction and elevated blood pressure in long-term childhood cancer survivors. Clin J Am Soc Nephrol 7 (9): 1416-27, 2012.
  4. Jones DP, Spunt SL, Green D, et al.: Renal late effects in patients treated for cancer in childhood: a report from the Children's Oncology Group. Pediatr Blood Cancer 51 (6): 724-31, 2008.
  5. Dekkers IA, Blijdorp K, Cransberg K, et al.: Long-term nephrotoxicity in adult survivors of childhood cancer. Clin J Am Soc Nephrol 8 (6): 922-9, 2013.
  6. Mulder RL, Knijnenburg SL, Geskus RB, et al.: Glomerular function time trends in long-term survivors of childhood cancer: a longitudinal study. Cancer Epidemiol Biomarkers Prev 22 (10): 1736-46, 2013.
  7. Interiano RB, Delos Santos N, Huang S, et al.: Renal function in survivors of nonsyndromic Wilms tumor treated with unilateral radical nephrectomy. Cancer 121 (14): 2449-56, 2015.
  8. Marina NM, Poquette CA, Cain AM, et al.: Comparative renal tubular toxicity of chemotherapy regimens including ifosfamide in patients with newly diagnosed sarcomas. J Pediatr Hematol Oncol 22 (2): 112-8, 2000 Mar-Apr.
  9. Hartmann JT, Fels LM, Franzke A, et al.: Comparative study of the acute nephrotoxicity from standard dose cisplatin +/- ifosfamide and high-dose chemotherapy with carboplatin and ifosfamide. Anticancer Res 20 (5C): 3767-73, 2000 Sep-Oct.
  10. Skinner R, Parry A, Price L, et al.: Persistent nephrotoxicity during 10-year follow-up after cisplatin or carboplatin treatment in childhood: relevance of age and dose as risk factors. Eur J Cancer 45 (18): 3213-9, 2009.
  11. Skinner R, Kaplan R, Nathan PC: Renal and pulmonary late effects of cancer therapy. Semin Oncol 40 (6): 757-73, 2013.
  12. Stöhr W, Paulides M, Bielack S, et al.: Nephrotoxicity of cisplatin and carboplatin in sarcoma patients: a report from the late effects surveillance system. Pediatr Blood Cancer 48 (2): 140-7, 2007.
  13. Skinner R, Cotterill SJ, Stevens MC: Risk factors for nephrotoxicity after ifosfamide treatment in children: a UKCCSG Late Effects Group study. United Kingdom Children's Cancer Study Group. Br J Cancer 82 (10): 1636-45, 2000.
  14. Stöhr W, Paulides M, Bielack S, et al.: Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System. Pediatr Blood Cancer 48 (4): 447-52, 2007.
  15. Oberlin O, Fawaz O, Rey A, et al.: Long-term evaluation of Ifosfamide-related nephrotoxicity in children. J Clin Oncol 27 (32): 5350-5, 2009.
  16. Widemann BC, Balis FM, Kim A, et al.: Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol 28 (25): 3979-86, 2010.
  17. Cohen EP, Robbins ME: Radiation nephropathy. Semin Nephrol 23 (5): 486-99, 2003.
  18. Dawson LA, Kavanagh BD, Paulino AC, et al.: Radiation-associated kidney injury. Int J Radiat Oncol Biol Phys 76 (3 Suppl): S108-15, 2010.
  19. Mitus A, Tefft M, Fellers FX: Long-term follow-up of renal functions of 108 children who underwent nephrectomy for malignant disease. Pediatrics 44 (6): 912-21, 1969.
  20. Bölling T, Ernst I, Pape H, et al.: Dose-volume analysis of radiation nephropathy in children: preliminary report of the risk consortium. Int J Radiat Oncol Biol Phys 80 (3): 840-4, 2011.
  21. Peschel RE, Chen M, Seashore J: The treatment of massive hepatomegaly in stage IV-S neuroblastoma. Int J Radiat Oncol Biol Phys 7 (4): 549-53, 1981.
  22. 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.
  23. Paulino AC, Wilimas J, Marina N, et al.: Local control in synchronous bilateral Wilms tumor. Int J Radiat Oncol Biol Phys 36 (3): 541-8, 1996.
  24. Cheng JC, Schultheiss TE, Wong JY: Impact of drug therapy, radiation dose, and dose rate on renal toxicity following bone marrow transplantation. Int J Radiat Oncol Biol Phys 71 (5): 1436-43, 2008.
  25. Hoffmeister PA, Hingorani SR, Storer BE, et al.: Hypertension in long-term survivors of pediatric hematopoietic cell transplantation. Biol Blood Marrow Transplant 16 (4): 515-24, 2010.
  26. Abboud I, Porcher R, Robin M, et al.: Chronic kidney dysfunction in patients alive without relapse 2 years after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 15 (10): 1251-7, 2009.
  27. Ellis MJ, Parikh CR, Inrig JK, et al.: Chronic kidney disease after hematopoietic cell transplantation: a systematic review. Am J Transplant 8 (11): 2378-90, 2008.
  28. Breslow NE, Collins AJ, Ritchey ML, et al.: End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol 174 (5): 1972-5, 2005.
  29. Hamilton TE, Ritchey ML, Haase GM, et al.: The management of synchronous bilateral Wilms tumor: a report from the National Wilms Tumor Study Group. Ann Surg 253 (5): 1004-10, 2011.
  30. Ritchey M, Ferrer F, Shearer P, et al.: Late effects on the urinary bladder in patients treated for cancer in childhood: a report from the Children's Oncology Group. Pediatr Blood Cancer 52 (4): 439-46, 2009.
  31. Hudson MM, Ness KK, Gurney JG, et al.: Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309 (22): 2371-81, 2013.
  32. Landier W, Armenian SH, Lee J, et al.: Yield of screening for long-term complications using the children's oncology group long-term follow-up guidelines. J Clin Oncol 30 (35): 4401-8, 2012.
  33. Riachy E, Krauel L, Rich BS, et al.: Risk factors and predictors of severity score and complications of pediatric hemorrhagic cystitis. J Urol 191 (1): 186-92, 2014.
  34. Kersun LS, Wimmer RS, Hoot AC, et al.: Secondary malignant neoplasms of the bladder after cyclophosphamide treatment for childhood acute lymphocytic leukemia. Pediatr Blood Cancer 42 (3): 289-91, 2004.
  35. Frobisher C, Gurung PM, Leiper A, et al.: Risk of bladder tumours after childhood cancer: the British Childhood Cancer Survivor Study. BJU Int 106 (7): 1060-9, 2010.

Changes to This Summary (09/28/2017)

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.

General Information About Late Effects of Treatment for Childhood Cancer

This section was comprehensively reviewed and extensively revised.

Subsequent Neoplasms

This section was comprehensively reviewed and extensively revised.

Late Effects of the Cardiovascular System

Revised text about a study of 670 survivors of Hodgkin lymphoma who have lived 10 or more years that found myocardial infarction and structural heart defects were the major contributors to the excess grade 3 to grade 5 cumulative burden in survivors.

Added text about dexrazoxane’s association with secondary cancers (cited Chow et al., Tebbi et al., and Walker et al. as references 41, 42, and 43, respectively).

Added text about the results of a study of 3,172 5-year survivors of childhood cancer who received 10 Gy or higher to the Circle of Willis and at age 45 years the cumulative incidence of stroke was 11.3% (cited El-Fayech et al. as reference 51).

Late Effects of the Central Nervous System

This section was comprehensively reviewed and extensively revised.

Late Effects of the Musculoskeletal System

Added text to state that the prefrail phenotype is characterized by having two of five characteristics (low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness) and the frail phenotype is characterized by having three or more of these characteristics.

Late Effects of the Reproductive System

This section was comprehensively reviewed and extensively revised.

Late Effects of the Respiratory System

Added text about a Childhood Cancer Survivor Study that compared self-reported pulmonary outcomes and their impact on daily activities among 5-year cancer survivors and a sibling cohort noting that by age 45 years, the cumulative incidence of any pulmonary condition was 29.6% for survivors (cited Dietz et al. as reference 4).

Late Effects of the Special Senses

This section was comprehensively reviewed and extensively revised.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the late effects of treatment for childhood cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Late Effects of Treatment for Childhood Cancer are:

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Late Effects of Treatment for Childhood Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/childhood-cancers/late-effects-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389273]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Date first published: 2004-04-23 Date last modified: 2017-09-28

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Dr. G. Quade
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