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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.[
Many 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 used a spectrum of resources, including investigation of data from the following:
Studies reporting outcomes in survivors who have been well characterized regarding clinical status and treatment exposures, and comprehensively ascertained for specific effects through medical assessments, typically provide the highest quality 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. Multi-institutional and population-based studies support excess hospital-related morbidity among childhood and young adult cancer survivors compared with age- and sex-matched controls.[
Research has demonstrated that among adults treated for cancer during childhood, late effects contribute to a high burden of morbidity, including the following:[
Using the cumulative burden metric—which incorporates multiple health conditions and recurrent events into a single metric that takes into account competing risks—by age 50 years, survivors in the St. Jude Lifetime Cohort experienced an average of 17.1 chronic health conditions, 4.7 of which were severe/disabling, life threatening, or fatal.[
Figure 1. Figure shows distribution of cumulative burden by age among childhood cancer survivors of specific pediatric cancer subtypes and community controls participating in the St. Jude Lifetime Cohort Study. The cumulative burden at age 30 years and rate of cumulative burden growth is variable across cancer subtypes and organ systems. Reprinted from The Lancet, Volume 390, Issue 10112, Bhakta N, Liu Q, Ness KK, Baassiri M, Eissa H, Yeo F, Chemaitilly W, Ehrhardt MJ, Bass J, Bishop MW, Shelton K, Lu L, Huang S, Li Z, Caron E, Lanctot J, Howell C, Folse T, Joshi V, Green DM, Mulrooney DA, Armstrong GT, Krull KR, Brinkman TM, Khan RB, Srivastava DK, Hudson MM, Yasui Y, Robison LL, The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE), Pages 2569–2582, Copyright (2017), with permission from Elsevier.
St. Jude Lifetime Cohort Study investigators compared the cumulative burden of chronic health conditions among 4,612 adolescent and young adult survivors at the ages of 18 years (the time of transition from pediatric to adult health care systems) and 26 years (the time of transition from family to individual health insurance plans) with that of 625 controls.[
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 (see Figure 2).[
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.[
Figure 2. 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. Armstrong GT, Kawashima T, Leisenring W, et al: Aging and Risk of Severe, Disabling, Life-Threatening, and Fatal Events in the Childhood Cancer Survivor Study. Journal of Clinical Oncology (https://ascopubs.org/journal/jco), Volume 32 (Issue 12), 2014: Pages 1218-1227. Reprinted with permission. Copyright © 2014 Wolters Kluwer Health, Inc. and 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 those in non-Hispanic White participants (n = 12,397).[
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 on the basis of 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.[
A CCSS investigation examined temporal patterns in the cumulative incidence of severe to fatal chronic health conditions among survivors treated from 1970 to 1999. The 20-year cumulative incidence of at least one grade 3 to 5 chronic condition decreased significantly, from 33.2% for survivors diagnosed between 1970 and 1979, to 29.3% for those diagnosed between 1980 and 1989, to 27.5% for those diagnosed between 1990 and 1999, compared with a 4.6% incidence in a sibling cohort. The overall decrease in incidence of chronic conditions across the three treatment decades was, in part, because of a substantial reduction of endocrinopathies, subsequent malignant neoplasms (SMNs), musculoskeletal conditions, and gastrointestinal conditions, whereas the cumulative incidence of hearing loss increased during this time. Declines in morbidity were not uniform across the diagnosis groups or condition types because of differences in treatment and survival patterns over time. For more information, see Figure 3.[
Figure 3. Cumulative incidence of grade 3–5 chronic health conditions in 5-year survivors of childhood cancer by diagnosis decade and siblings. (A) Cumulative incidence of a first grade 3–5 condition. (B) Cumulative incidence of two or more grade 3–5 conditions. The shaded area represents the 95% confidence interval (CI). The number of participants at risk (number censored) at each 5-year interval post-diagnosis is listed below the x-axis. The number censored does not include those who experienced a competing risk event (death from a cause other than a grade 5 chronic condition). Reprinted from The Lancet Oncology, Volume 19, Issue 12, Todd M Gibson, Sogol Mostoufi-Moab, Kayla L Stratton, Wendy M Leisenring, Dana Barnea, Eric J Chow, Sarah S Donaldson, Rebecca M Howell, Melissa M Hudson, Anita Mahajan, Paul C Nathan, Kirsten K Ness, Charles A Sklar, Emily S Tonorezos, Christopher B Weldon, Elizabeth M Wells, Yutaka Yasui, Gregory T Armstrong, Leslie L Robinson, Kevin C Oeffinger, Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970–99: a report from the Childhood Cancer Survivor Study cohort. Pages 1590-1601, Copyright (2018), with permission from Elsevier.
Mortality
Late effects also contribute to an excess risk of premature death among long-term survivors of childhood cancer, as observed in the following studies:
Despite high premature morbidity rates, overall mortality has decreased over time.[
CCSS investigators evaluated all-cause and health-related late mortality (including late effects of cancer therapy), SMNs, chronic health conditions, and neurocognitive outcomes among 6,148 survivors of childhood acute lymphoblastic leukemia (median age, 27.9 years; range, 5.9–61.9 years) diagnosed between 1970 and 1999.[
Survivors of adolescent and young adult (AYA) cancers
Little information is available on late mortality among survivors of AYA cancer.[
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. Consequently, the results of late effects research have played an important role in the following areas:[
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. Multiple factors should be considered in the risk assessment for a given late effect (see Figure 4).[
Tumor-related factors
Treatment-related factors
Host-related factors
Figure 4. Factors influencing morbidity and mortality of the childhood cancer survivor. Each arrow indicates a different factor affecting morbidity and mortality that exerts its effect along a continuum of care. Note that all effectors can begin exerting influence on morbidity during the period of cancer-directed therapy. Factors are separated into those that cannot be modified (red), those for which future interventions are plausible (yellow), and those for which there are known targets for interventions or areas in which therapy and surveillance have already been modified (blue). Reprinted from CA: A Cancer Journal for Clinicians, Volume 68, Issue 2, Dixon SB, Bjornard KL, Alberts NM, et al., Factors influencing risk-based care of the childhood cancer survivor in the 21st century, Pages 133–152, Copyright © 2018 American Cancer Society, with permission from John Wiley and Sons.
Resources to Support Survivor Care
Risk-based screening
The need for long-term follow-up of 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 on the basis of the following:[
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 effects on functional status, educational attainment, and future vocational opportunities. In support of this, a CCSS investigation observed the following:[
These data emphasize the importance of facilitating survivor access to remedial services, which has been demonstrated to have a positive impact on education achievement,[
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. Educational efforts focused on healthy lifestyle behaviors include the following:
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 despite their increased risk of cardiac, pulmonary, and metabolic late effects.[
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.[
Overall, lack of health insurance remains a significant concern for survivors of childhood cancer because of health issues, unemployment, and other societal factors.[
Transition to 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.[
An essential service of long-term follow-up programs is the organization of an individualized survivorship care plan that includes the following:
A CCSS investigation that evaluated perceptions of future health and cancer risk highlighted the importance of continuing education of survivors during long-term follow-up evaluations. A substantial subgroup of adult survivors reported a lack of concern about future health (24%) and subsequent cancer risks (35%), even after exposure to treatments associated with increased risks. These findings present concerns that survivors may be less likely to engage in beneficial screenings and risk-reduction activities.[
The CCSS evaluated the surveillance and screening practices of 11,337 childhood cancer survivors. They found that fewer than half of high-risk survivors at increased risk of developing SMNs or cardiac dysfunction received the recommended surveillance, which likely exposes them to preventable morbidity and mortality.[
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. For more information, see the COG Survivorship Guidelines, Appendix 1.
COG long-term follow-up guidelines for childhood and AYA cancer survivors
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.[
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.[
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 the cost effectiveness of screening in the context of consideration of benefits, risks, and harms.
References:
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 is multifactorial in etiology and 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).[
This represents a sixfold increased risk of SNs among cancer survivors, compared with the general population.[
The excess risk of SNs has been described in several studies.[
Evidence (excess risk of SNs):
Prolonged follow-up has established that multiple SNs are common among aging childhood cancer survivors.[
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 (t-MDS) and Therapy-Related Acute Myeloid Leukemia (t-AML)
Subsequent primary leukemias have been reported in survivors of Hodgkin lymphoma, leukemia, sarcoma, CNS tumors, non-Hodgkin lymphoma, neuroblastoma, and Wilms tumor. In a cohort of nearly 70,000 5-year childhood cancer survivors, survivors had a fourfold increased risk (SIR, 3.7) of developing a leukemia, with an absolute excess risk of 7.5. Specifically, a sixfold relative risk of developing a myeloid leukemia (SIR, 5.8) was reported.[
A pooled analysis examined all published studies with detailed treatment data for children with cancer diagnosed between 1930 and 2000. Treatment data included estimated radiation doses to the active bone marrow and doses of specific chemotherapy agents. In this report, 147 cases of second primary leukemia (69% of cases were AML) were matched to 522 controls.[
Characteristics of t-MDS and t-AML include the following:[
t-MDS and t-AML are clonal disorders characterized by distinct chromosomal changes. The following two types of t-MDS and t-AML are recognized by the World Health Organization classification:[
The risk of alkylating agent–related t-MDS or t-AML is dose dependent, with a latency of 3 to 5 years after exposure; it is associated with abnormalities involving chromosomes 5 (-5/del(5q)) and 7 (-7/del(7q)).[
Most of the translocations observed in patients exposed to topoisomerase II inhibitors disrupt a breakpoint cluster region between exons 5 and 11 of the band 11q23 and fuse KMT2A with a partner gene.[
For more information, see the Therapy-Related AML and Therapy-Related Myelodysplastic Syndromes section in Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment.
Therapy-Related Solid SNs
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:[
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) (see Figure 5).[
Figure 5. Fitted radiation dose-response by type of second cancer, based on previously published studies of second sarcoma, skin, meningioma, salivary gland, glioma, breast, and thyroid gland. The order of second cancers from top to bottom in the graph is the same as in the key to the right of the panel. Reprinted from International Journal of Radiation Oncology*Biology*Physics, Volume 94, Issue 4, Inskip PD, Sigurdson AJ, Veiga L, et al., Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects, Pages 800–807, Copyright © 2016, with permission from Elsevier.
Solid SNs in childhood cancer survivors most commonly involve the following:[
With more prolonged follow-up of adult survivors of childhood cancer cohorts, epithelial neoplasms have been observed in the following:[
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.[
Recipients of HCT are treated with high-dose chemotherapy and, often, TBI, which makes their risk of SNs unique from the general oncology population.
Some well-established solid SNs are described in the following sections.
Breast cancer
Female survivors of childhood, adolescent, and young adult cancer treated with radiation therapy to fields including the chest are at increased risk of developing breast cancer.
Evidence (excess risk of breast cancer):
Breast cancer risk varies among childhood cancer survivors who are treated with chest radiation therapy. The first personalized breast cancer risk prediction model was developed and validated using multinational cohorts of female 5-year cancer survivors who were diagnosed at younger than 21 years and treated with chest irradiation (n = 2,147). The model includes current age, chest radiation field, whether chest radiation was delivered within 1 year of menarche, anthracycline exposure, age of menopause, and history of a first-degree relative with breast cancer. The model is available as an online risk calculator.[
Subsequent versus de novo breast cancer
Several studies have investigated the clinical characteristics of subsequent breast cancers arising in women treated with radiation therapy for childhood cancer.[
Mortality after subsequent breast cancer
In a study of female participants in the CCSS who were subsequently diagnosed with breast cancer (n = 274) and matched to a control group of women (n = 1,095) with de novo breast cancer, survivors of childhood cancer were found to have elevated mortality rates (HR, 2.2; 95% CI, 1.7–3.0) even after adjusting for breast cancer treatment.[
Although currently available evidence is insufficient to demonstrate a survival benefit from the initiation of breast cancer surveillance in women treated with radiation therapy to the chest for childhood cancer, interventions to promote detection of small and early-stage tumors may improve prognosis, particularly for those who may have more limited treatment options because of previous exposure to radiation or anthracyclines.
In support of this, SJLIFE investigators observed that breast cancers detected by imaging and/or prophylactic mastectomy were more likely to be in situ carcinomas, be smaller masses, have no lymph node involvement, and be treated without chemotherapy, compared with breast cancers detected by physical findings.[
Investigators used data from the CCSS and two Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer simulation models to estimate the clinical benefits, harms, and cost-effectiveness of breast cancer screening among childhood cancer survivors who were previously treated with chest radiation.[
Thyroid cancer
Thyroid cancer is observed after the following:[
The 25-year cumulative incidence of thyroid cancer among survivors of childhood cancer is 0.5.[
For information about detecting thyroid nodules and thyroid cancer, see the Thyroid nodules section.
CNS tumors
Subsequent CNS tumors represent a spectrum of histological subtypes from high-grade glioma to benign meningioma. The CCSS has reported briefer latency for gliomas than for meningiomas.[
Brain tumors develop after cranial irradiation for histologically distinct brain tumors or for management of disease among ALL or non-Hodgkin lymphoma patients.[
The risk of subsequent brain tumors demonstrates a linear relationship with radiation dose.[
The Dutch Long-Term Effects after Childhood Cancer (LATER) investigators have described the clinical characteristics of childhood cancer survivors who developed histologically confirmed meningiomas.[
Neurological sequelae associated with meningiomas can include seizures, auditory-vestibular-visual deficits, focal neurological dysfunction, and severe headaches.[
Bone and soft tissue tumors
Survivors of hereditary retinoblastoma, Ewing sarcoma, and other malignant bone tumors are at a particularly increased risk of developing subsequent bone and soft tissue tumors.[
Evidence (excess risk of bone and soft tissue tumors):
Skin cancer
Nonmelanoma skin cancers (NMSCs) represent one of the most common SNs among childhood cancer survivors and exhibit a strong association with radiation therapy.[
Evidence (excess risk of NMSCs):
Malignant melanoma has also been reported as an SN in childhood cancer survivor cohorts, although at a much lower incidence than NMSCs.
Risk factors for malignant melanoma identified among these studies include the following:[
Evidence (excess risk of melanoma):
Skin cancer risk after retinoblastoma
The incidence of melanoma and NMSC was evaluated in a cohort of 1,851 White, long-term retinoblastoma survivors (1,020 hereditary and 831 nonhereditary) who were diagnosed from 1914 to 2006 and monitored through 2016.[
Lung cancer
Among childhood cancer survivor cohorts, lung cancer represents a relatively uncommon SN, with a long latency from the childhood cancer diagnosis to the development of a lung SN.[
Evidence (excess risk of lung cancer):
Gastrointestinal (GI) cancer
There is substantial evidence that childhood cancer survivors develop GI malignancies more frequently and at a younger age than the general population; this evidence supports the need for early initiation of colorectal carcinoma surveillance.[
Evidence (excess risk of GI cancer):
Renal carcinoma
Consistent with reports among survivors of adult-onset cancer, an increased risk of renal carcinoma has been observed in survivors of childhood cancer.[
Evidence (excess risk of renal carcinoma):
Survival Outcomes After SNs
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.[
Using data from the Surveillance, Epidemiology, and End Results (SEER) Program, individuals younger than 60 years with first primary malignancies (n = 1,332,203) were compared with childhood cancer survivors (n = 1,409) who had a second primary malignancy.[
In a study of female participants in the CCSS who were subsequently diagnosed with breast cancer (n = 274) and matched to a control group of women (n = 1,095) with de novo breast cancer, survivors of childhood cancer were found to have elevated mortality rates (HR, 2.2; 95% CI, 1.7–3.0) even after adjusting for breast cancer treatment.[
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 syndromes confer an increased risk of cancer, such as Li-Fraumeni syndrome.[
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.[
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).[
Likewise, children with neurofibromatosis type 1 (NF1) who develop a primary tumor are at an increased risk of SNs compared with childhood cancer survivors without NF1. Treatment with radiation, but not alkylating agents, increases the risk of SNs in survivors with NF1.[
Table 1 summarizes the spectrum of neoplasms, affected genes, and Mendelian mode of inheritance of selected syndromes of inherited cancer predisposition.
Syndrome | Major Tumor Types | Affected Gene | Mode of Inheritance |
---|---|---|---|
AML = acute myeloid leukemia; MDS = myelodysplastic syndromes; WAGR = Wilms tumor, aniridia, genitourinary anomalies, mental retardation. | |||
a Adapted from Strahm et al.[ |
|||
b Dominant in a fraction of patients, spontaneous mutations can occur. | |||
Adenomatous polyposis of the colon | Colon, hepatoblastoma, intestinal cancers, stomach, thyroid cancer | APC | Dominant |
Ataxia-telangiectasia | Leukemia, lymphoma | ATM | Recessive |
Beckwith-Wiedemann syndrome | Adrenal carcinoma, hepatoblastoma, rhabdomyosarcoma, Wilms tumor | CDKN1C/NSD1 | Dominant |
Bloom syndrome | Leukemia, lymphoma, skin cancer | BLM | Recessive |
Diamond-Blackfan anemia | Colon cancer, osteogenic sarcoma, AML/MDS | RPS19and otherRPgenes | Dominant, spontaneousb |
Fanconi anemia | Gynecological tumors, leukemia, squamous cell carcinoma | FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG | Recessive |
Juvenile polyposis syndrome | Gastrointestinal tumors | SMAD4/DPC4 | Dominant |
Li-Fraumeni syndrome | Adrenocortical carcinoma, brain tumor, breast carcinoma, leukemia, osteosarcoma, soft tissue sarcoma | TP53 | Dominant |
Multiple endocrine neoplasia 1 | Pancreatic islet cell tumor, parathyroid adenoma, pituitary adenoma | MEN1 | Dominant |
Multiple endocrine neoplasia 2 | Medullary thyroid carcinoma, pheochromocytoma | RET | Dominant |
Neurofibromatosis type 1 | Neurofibroma, optic pathway glioma, peripheral nerve sheath tumor | NF1 | Dominant |
Neurofibromatosis type 2 | Vestibular schwannoma | NF2 | Dominant |
Nevoid basal cell carcinoma syndrome | Basal cell carcinoma, medulloblastoma | PTCH | Dominant |
Peutz-Jeghers syndrome | Intestinal cancers, ovarian carcinoma, pancreatic carcinoma | STK11 | Dominant |
Retinoblastoma | Osteosarcoma, retinoblastoma | RB1 | Dominant |
Tuberous sclerosis | Hamartoma, renal angiomyolipoma, renal cell carcinoma | TSC1/TSC2 | Dominant |
von Hippel-Lindau syndrome | Hemangioblastoma, pheochromocytoma, renal cell carcinoma, retinal and central nervous system tumors | VHL | Dominant |
WAGR syndrome | Gonadoblastoma, Wilms tumor | WT1 | Dominant |
Wilms tumor syndrome | Wilms tumor | WT1 | Dominant |
Xeroderma pigmentosum | Leukemia, melanoma | XPA, XPB, XPC, XPD, XPE, XPF, XPG, POLH | Recessive |
The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) tool identifies children with cancer who have an increased likelihood of having a cancer predisposition syndrome. This tool guides clinicians through a series of yes or no questions, and it generates a recommendation for or against genetic evaluation.[
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.
In related research, SJLIFE investigators evaluated cancer treatments and pathogenic germline mutations in 127 genes from six major DNA repair pathways to identify childhood cancer survivors at an increased risk of SNs.[
The following three groups were identified to have an elevated risk of SNs:
Drug-metabolizing enzymes
Metabolism of genotoxic agents occurs in two phases.
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.[
Screening and Follow-up for Subsequent Neoplasms
Vigilant screening is important for childhood cancer survivors at risk.[
Well-conducted studies of 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], DCOG) to develop consensus-based clinical practice guidelines to increase awareness and standardize the immediate care needs of medically vulnerable childhood cancer survivors.[
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.[
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.[
Specific comments about screening for more common radiation-associated SNs are as follows:
Mammography, the most widely accepted screening tool for breast cancer in the general population, may not be the ideal screening tool by itself for radiation-related breast cancers occurring in relatively young women with dense breasts. On the basis of research among young women with inherited susceptibility to breast cancer, dual-imaging modalities may enhance early detection related to the higher sensitivity of MRI in detecting lesions in premenopausal dense breasts and the superiority of mammography in identifying ductal carcinoma in situ;[
Many clinicians are concerned about potential harms related to radiation exposure associated with annual mammography in these young women. In this regard, it is important to consider that the estimated mean breast dose with contemporary standard two-view screening mammograms is about 3.85 mGy to 4.5 mGy.[
To keep young women engaged in breast health surveillance, the COG Guideline recommends the following for females who received a radiation dose of 10 Gy or higher to the mantle, mediastinal, whole lung, and axillary fields:
The risk of breast cancer in patients who received less than 10 Gy of radiation with potential impact to the breast is of a lower magnitude compared with those who received 10 Gy or higher. Monitoring of patients treated with less than 10 Gy of radiation with potential impact to the breast is determined on an individual basis after a discussion with the provider regarding the benefits and risk/harms of screening. If a decision is made to screen, the recommendations for women exposed to 10 Gy or higher are used.
References:
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.[
Evidence (excess risk of premature cardiovascular mortality):
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 of long-term cardiovascular toxicity in childhood and young adult survivors of cancer, issued by the American Heart Association, has been published.[
Cardiovascular Outcomes
Evidence (selected cohort studies describing cardiovascular outcomes):
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.[
Anthracyclines and related agents
Anthracyclines (e.g., doxorubicin, daunorubicin, idarubicin, and epirubicin) and anthraquinones (e.g., mitoxantrone) are known to directly injure cardiomyocytes through inhibition of topoisomerase 2-beta in cardiomyocytes and formation of reactive oxygen species, resulting in activation of cell-death pathways and inhibition of mitochondrial apoptosis.[
Risk factors for anthracycline-related cardiomyopathy include the following:[
Figure 7. 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
Traditionally, anthracycline dose equivalence has largely been based on acute hematologic toxicity equivalence rather than late cardiac toxicity.[
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.[
Cardiovascular disease
Late effects of radiation therapy to the heart specifically include the following:
These cardiac late effects are related to the following:
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.[
Cerebrovascular disease
Cerebrovascular disease after radiation therapy exposure is another potential late effect observed in survivors.
Evidence (selected studies describing prevalence of and risk factors for cerebrovascular accident [CVA]/vascular disease):
Venous thromboembolism
Children with cancer have an excess risk of venous thromboembolism within the first 5 years after diagnosis; however, the long-term risk of venous thromboembolism among childhood cancer survivors has not been well studied.[
CCSS investigators evaluated self-reported late-onset (5 or more years after cancer diagnosis) venous thromboembolism among cohort members (median follow-up, 21.3 years).[
Conventional cardiovascular conditions
Other Risk Factors
Peripartum Cardiac Dysfunction
Long-term survivors of childhood, adolescent, and young adult malignancies with past exposure to potentially cardiotoxic treatments are at risk of peripartum cardiac dysfunction.
In the general population, peripartum cardiomyopathy (PPCM) is a rare condition characterized by heart failure during pregnancy (usually the last trimester or <5 months postpartum). The estimated incidence in the general population is 1:3,000 live births.[
There are limited data available about the prevalence in survivors of pediatric, adolescent, and young adult malignancies who have received cardiotoxic therapies.
The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers recommend cardiology evaluations with baseline echocardiograms for patients who are pregnant or planning to become pregnant if their cancer treatment included anthracycline doses higher than 250 mg/m2, chest radiation therapy doses higher than 35 Gy, or anthracyclines (any dose) combined with chest radiation therapy (>15 Gy).
For survivors without previous abnormalities or those with normal prepregnancy or early pregnancy baselines, follow-up echocardiograms may be performed at the providers' discretion.
Survivors with a history of systolic dysfunction or prepregnancy or early pregnancy systolic dysfunction are at highest risk of peripartum cardiomyopathy and should be monitored for cardiac failure periodically during pregnancy, labor, and delivery.
Heart Transplant After Childhood Cancer
Data about the prevalence and outcomes of survivors with heart failure requiring heart transplantation is limited.
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 Children's Oncology Group (COG) (see Table 2), have published recommendations regarding screening and surveillance for cardiovascular and other late effects among childhood cancer survivors.[
Professional groups (both pediatric and adult) have developed evidence-based health surveillance recommendations and have identified knowledge deficits to help guide future studies.[
Adult oncology professional and national groups have also issued recommendations related to cardiac toxicity monitoring.[
Consensus regarding evidence about screening, surveillance, and counseling
Predicting Cardiovascular Disease Risk
Risk prediction for cardiovascular diseases
Predisposing Therapy | Potential Cardiovascular Effects | Health Screening |
---|---|---|
a The Children's Oncology Group (COG) guidelines also cover other conditions that may influence cardiovascular risk, such as obesity and diabetes mellitus/impaired glucose metabolism. | ||
b Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
Any anthracycline and/or any radiation exposing the heart | Cardiac 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 exposing the neck and base of skull (especially ≥40 Gy) | Carotid and/or subclavian artery disease | Yearly medical history and physical exam; consider Doppler ultrasound 10 years after exposure |
Radiation exposing the brain/cranium (especially ≥18 Gy) | Cerebrovascular disease (cavernomas, moyamoya, occlusive cerebral vasculopathy, stroke) | Yearly medical history and physical exam |
Radiation exposing the abdomen | Diabetes | Diabetes screening every 2 years |
Total-body irradiation (usually <14 Gy) | Dyslipidemia; diabetes | Fasting lipid profile and diabetes screening every 2 years |
Heavy metals (carboplatin, cisplatin), and ifosfamide exposure; radiation exposing the kidneys; hematopoietic cell transplantation; nephrectomy | Hypertension (from renal toxicity) | Yearly blood pressure test; renal function laboratory studies at entry into long-term follow-up and repeat as clinically indicated |
References:
Neurocognitive
Neurocognitive late effects are commonly observed after treatment of malignancies that require central nervous system (CNS)–directed therapies. While considerable evidence has been 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:[
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 (ADHD) in that few survivors demonstrate significant hyperactivity/impulsivity, but instead have associated difficulties with processing speed and executive function.[
In addition to the direct effects of neurotoxic therapies like cranial radiation, Childhood Cancer Survivor Study (CCSS) investigators observed that chronic health conditions resulting from non-neurotoxic treatment exposures (e.g., thoracic radiation) can adversely impact neurocognitive function presumably mediated by chronic cardiopulmonary and endocrine dysfunction.[
A related investigation from the CCSS evaluated longitudinal associations between physical activity and neurocognitive problems in adult survivors of childhood cancer.[
Neurocognitive outcomes in brain tumor survivors
Long-term cognitive effects caused by illness and associated treatments are well-established morbidities in survivors of childhood and adolescent brain tumors. Risk factors for adverse neurocognitive effects in this group 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.[
Evidence (predictors of cognitive decline among survivors of CNS tumors):
Longitudinal cohort studies have provided insight into the trajectory and predictors of cognitive decline among survivors of CNS tumors.
Figure 8. Modeled intelligence quotient (IQ) scores after conformal radiation therapy (CRT) by age for pediatric low-grade glioma. Age is measured in years, and time is measured in months after the start of CRT. Thomas E. Merchant, Heather M. Conklin, Shengjie Wu, Robert H. Lustig, and Xiaoping Xiong, Late Effects of Conformal Radiation Therapy for Pediatric Patients With Low-Grade Glioma: Prospective Evaluation of Cognitive, Endocrine, and Hearing Deficits, Journal of Clinical Oncology, volume 27, issue 22, pages 3691-3697. Reprinted with permission. © (2009) American Society of Clinical Oncology. All rights reserved.
Evidence (predictors of cognitive decline among long-term survivors of CNS tumors):
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.
Cognitive outcomes after proton radiation therapy
Data are emerging regarding cognitive outcomes after proton radiation to the CNS;[
Considering the relatively brief follow-up time from radiation, longitudinal follow-up is important to determine whether proton radiation provides a clinically meaningful benefit in sparing cognitive function compared with photon radiation. In addition, more targeted radiation treatment volumes with photons may diminish potential differences.
Neurocognitive outcomes in acute lymphoblastic leukemia (ALL) survivors
To minimize the risk of late cognitive sequelae, contemporary therapy for ALL uses a risk-stratified approach that reserves cranial irradiation for children who are considered at high risk of CNS relapse.
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 neurological 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.
Evidence (neurocognitive functioning in large pediatric cancer survivor cohorts):
ALL and steroid therapy
The type of steroid used for ALL systemic treatment may affect cognitive functioning.
Other cancers
Neurocognitive abnormalities have been reported in other groups of cancer survivors. A study of adult survivors of childhood non-CNS cancers (including ALL, n = 5,937) reported the following:[
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.
A St. Jude Lifetime Cohort study evaluated whether children who experienced CNS injury were at higher risk of neurocognitive impairment associated with subsequent late-onset chronic health conditions. A total of 2,859 survivors who were aged 18 years or older and at least 10 years from diagnosis completed a neurocognitive battery and clinical examination. Of these patients, 1,598 had received CNS-directed therapy, including cranial radiation, intrathecal methotrexate, or neurosurgery.[
Neurocognitive abnormalities have been reported for the following cancers:
Later studies have yielded mixed results, with conflicting findings, in part, resulting from the low test-retest reliability of measures used to assess cognitive outcomes at a very young age, as well as temporal differences in treatment exposures.
Hematopoietic stem cell transplantation (HSCT)
Cognitive and academic consequences of HSCT in children have also been evaluated and include, but are not limited to, the following:
Neurological Sequelae
Risk of neurological 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.
CNS tumor survivors remain at higher risk of new-onset adverse neurological events across their lifetimes than siblings. No plateau has been reached for new adverse sequelae, even 30 years from diagnosis, according to a longitudinal study of 1,876 5-year survivors of CNS tumors from the CCSS. The median time from diagnosis was 23 years, and the median age of the patients studied was 30.3 years.[
Neurological complications that may occur in survivors of childhood cancer include the following:
Seizures
The development of seizures may occur secondary to tumor mass effect within the CNS and/or from neurotoxic CNS-directed therapies.
Leukoencephalopathy
Peripheral neuropathy
Vinca alkaloid agents (vincristine and vinblastine) and cisplatin may cause peripheral neuropathy.[
These studies underscore the importance of assessment and referral to rehabilitative services to optimize functional outcomes among long-term survivors.
Stroke
Hypersomnia (daytime sleepiness) or narcolepsy
Other neurological sequelae
Table 3 summarizes CNS late effects and the related health screenings.
Predisposing Therapy | Neurological Effects | Health Screening |
---|---|---|
IQ = intelligence quotient; IT = intrathecal; IV = intravenous. | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
Platinum agents (carboplatin, cisplatin) | Peripheral sensory neuropathy | Neurological exam |
Plant alkaloid agents (vinblastine, vincristine) | Peripheral sensory or motor neuropathy (areflexia, weakness, foot drop, paresthesias) | Neurological exam |
Methotrexate (high dose IV or IT); cytarabine (high dose IV or IT); radiation exposing the brain | Clinical leukoencephalopathy (spasticity, ataxia, dysarthria, dysphagia, hemiparesis, seizures); headaches; seizures; sensory deficits | History: cognitive, motor, and/or sensory deficits, seizures |
Neurological exam | ||
Radiation exposing cerebrovascular structures | Cerebrovascular complications (stroke, Moyamoya disease, occlusive cerebral vasculopathy) | History: transient/permanent neurological events |
Blood pressure test | ||
Neurological exam | ||
Neurosurgery–brain | Motor and/or sensory deficits (paralysis, movement disorders, ataxia, eye problems [ocular nerve palsy, gaze paresis, nystagmus, papilledema, optic atrophy]); seizures | Neurological 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 incontinence | History: chronic constipation, fecal soiling |
Rectal exam | ||
Predisposing Therapy | Neuropsychological Effects | Health Screening |
Methotrexate (high-dose IV or IT); cytarabine (high-dose IV or IT); radiation exposing 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 |
Psychosocial
Many childhood cancer survivors report reduced quality of life or other adverse psychosocial outcomes. The diagnosis of childhood cancer may also affect psychosocial outcomes and the expected attainment of functional and social independence in adulthood. Several investigations have demonstrated that survivors of pediatric CNS tumors are particularly vulnerable.[
Evidence for adverse psychosocial adjustment after childhood cancer has been derived from 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.
Achievement of social milestones
Survivors with neurocognitive deficits are particularly vulnerable to deficits in achievement of expected social outcomes during adulthood.
Psychological distress and suicidality
Childhood cancer survivors are also at risk of developing symptoms of psychological distress and suicidality.[
The presence of chronic health conditions can also impact aspects of psychological health.
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.
For more information about psychological distress, depression, and cancer patients, see Adjustment to Cancer: Anxiety and Distress and Depression.
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.[
Psychosocial outcomes among childhood, adolescent, and young adult cancer survivors
Most research on late effects after cancer has focused on individuals with a cancer diagnosis 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):
Overall results support that behavioral, emotional, and social symptoms frequently co-occur and are associated with treatment exposures (cranial radiation, corticosteroids, and methotrexate) and late effects (obesity, cancer-related pain, and sensory impairments) in adolescent survivors diagnosed between 1970 and 1986.
Evidence (functional and social independence):
Social withdrawal in adolescence has been associated with adult obesity and physical inactivity.[
Because of the challenges experienced by AYA patients 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.[
For CNS and psychosocial late effects information, including risk factors, evaluation, and health counseling, see the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
References:
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:
Osteoradionecrosis and second cancers in the oral cavity also occur.
Abnormalities of tooth development
Abnormalities of dental development reported in childhood cancer survivors include the following:[
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 the following:[
Children younger than 5 years are at greatest risk of dental anomalies, including 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.[
Key findings related to cancer treatment effect on tooth development include the following:
Radiation therapy
Chemotherapy
HSCT
Salivary gland dysfunction
Xerostomia, the sensation of dry mouth, is a potential side effect after head and neck irradiation or HSCT that can severely impact quality of life.[
Key findings related to cancer treatment effect on salivary gland function include the following:
Radiation therapy
HSCT
Chemotherapy
Abnormalities of craniofacial development
Other oral health complications
Posttherapy management
For more information about oral complications in cancer patients, see Oral Complications of Chemotherapy and Head/Neck Radiation.
Table 4 summarizes oral and dental late effects and the related health screenings.
Predisposing Therapy | Oral/Dental Effects | Health Screening/Interventions |
---|---|---|
CT = computed tomography; GVHD = graft-versus-host disease; MRI = magnetic resonance imaging. | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
Any chemotherapy; radiation exposing 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 exposing 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 | ||
Referral to otolaryngologist for assistive devices for jaw opening | ||
Radiation exposing 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 | ||
Referral for biopsy of suspicious lesions | ||
Radiation exposing oral cavity (≥40 Gy) | Osteoradionecrosis | History: 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 |
Digestive Tract
Overview
The gastrointestinal (GI) tract is sensitive to the acute toxicities of chemotherapy, radiation therapy, and surgery. 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.
Treatment-related late effects include the following:
Digestive tract–related late effects include the following:
Impact of cancer histology on GI outcomes
The abdomen is 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, bowel-injuring chemotherapy, and/or radiation therapy. Thus, these tumors would be expected to be particularly prone to long-term digestive tract issues.
GI outcomes from selected cohort studies
Evidence (GI outcomes from selected cohort studies):
Factors predicting higher risk of specific GI complications include the following:
Radiation-related GI injury
A limited number of reports describe GI complications in pediatric patients with genitourinary solid tumors treated with radiation therapy:[
Table 5 summarizes digestive tract late effects and the related health screenings.
Predisposing Therapy | Gastrointestinal Effects | Health Screening/Interventions |
---|---|---|
GVHD = graft-versus-host disease; KUB = kidneys, ureter, bladder (plain abdominal radiograph). | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
Radiation exposing esophagus; hematopoietic cell transplantation with any history of chronic GVHD | Gastroesophageal reflux; esophageal dysmotility; esophageal stricture | History: dysphagia, heart burn |
Esophageal dilation, antireflux surgery | ||
Radiation exposing 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 exposing 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 |
Hepatobiliary
Overview
Hepatic complications resulting from childhood cancer therapy are observed primarily as acute treatment toxicities.[
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 late effects
Asymptomatic elevation of liver enzymes is the most common hepatobiliary complication.
Less commonly reported hepatobiliary complications include the following:[
Cholelithiasis
Focal nodular hyperplasia
Nodular regenerative hyperplasia
Microvesicular fatty change
Transfusion-related iron overload
Treatment-related risk factors for hepatobiliary late effects
The type and intensity of previous therapy influences risk for late-occurring hepatobiliary effects. 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.
Key findings related to cancer treatment effect on hepatobiliary complications include the following:
Chemotherapy
Radiation therapy
HSCT
Infectious risk factors for hepatobiliary late effects
Viral hepatitis B and C may complicate the treatment course of childhood cancer and result in chronic hepatic dysfunction.
Posttherapy management
Survivors with liver dysfunction should be counseled regarding risk-reduction methods to prevent hepatic injury.
Table 6 summarizes hepatobiliary late effects and the related health screenings.
Predisposing Therapy | Hepatic Effects | Health Screening/Interventions |
---|---|---|
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HSCT = hematopoietic stem cell transplantation. | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
Methotrexate; mercaptopurine/thioguanine; HSCT | Hepatic dysfunction | Lab: ALT, AST, bilirubin levels |
Ferritin in those treated with HSCT | ||
Mercaptopurine/thioguanine; HSCT | Veno-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 exposing liver/biliary tract; HSCT | Hepatic fibrosis/cirrhosis; focal nodular hyperplasia | 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 exposing liver/biliary tract | Cholelithiasis | History: 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 |
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.[
While corticosteroids and asparaginase are associated with acute toxicity to the pancreas, late sequelae in the form of exocrine or endocrine pancreatic function for those who sustain acute injury have not been reported.
Evidence (risk of diabetes mellitus):
For digestive system late effects information, including risk factors, evaluation, and health counseling, see the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
References:
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.
Figure 9. Prevalence of endocrine disorders at the last follow-up visit, by sex. Brignardello E, Felicetti F, Castiglione A, et al.: Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up clinics. European Journal of Endocrinology 168 (3): 465-472, 2013. Copyright © 2013, European Society of Endocrinology.
The prevalence of specific endocrine disorders is affected by the following:[
Endocrinologic late effects can be broadly categorized as those resulting from hypothalamic/pituitary injury or from peripheral glandular compromise.[
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
Hypothyroidism
Risk factors
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 Hodgkin lymphoma.[
Treatment with iodine I 131-metaiodobenzylguanidine (131I-MIBG) can cause primary hypothyroidism despite thyroid protection through potassium iodide, perchlorate, or the combination of potassium iodide, thyroxine (T4) and a thiamazole, which decreases but does not entirely eliminate the risk of 131I-MIBG-induced hypothyroidism.[
Evidence (prevalence of and risk factors for hypothyroidism):
For more information about the probability of developing hypothyroidism, see Figure 10.
Clinical presentation
Hyperthyroidism
While less common than hypothyroidism, childhood cancer survivors also experience an increased risk of hyperthyroidism.[
Evidence (prevalence of and risk factors for hyperthyroidism):
Thyroid nodules
The clinical manifestation of thyroid neoplasia among childhood cancer survivors ranges from asymptomatic, small, solitary nodules to large, intrathoracic goiters that compress adjacent structures.
The following factors are linked to an increased risk of thyroid nodule development:
Screening for thyroid cancer
For information about subsequent thyroid cancers, see the Subsequent Neoplasms section.
Posttransplant thyroid dysfunction
Survivors of pediatric hematopoietic stem cell transplantation (HSCT) are at increased risk of thyroid dysfunction.[
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.
Predisposing Therapy | Endocrine/Metabolic Effects | Health Screening |
---|---|---|
131I-MIBG = Iodine I 131-metaiodobenzylguanidine; T4 = thyroxine; TSH = thyroid-stimulating hormone. | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
Radiation exposing thyroid gland; thyroidectomy | Primary hypothyroidism | TSH level |
Radiation exposing thyroid gland | Hyperthyroidism | Free T4 level |
TSH level | ||
Radiation exposing thyroid gland, including 131I-MIBG | Thyroid nodules | Thyroid exam |
Thyroid ultrasound |
Hypothalamus-Pituitary Axis
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.
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 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.[
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):
The six anterior pituitary hormones and their major hypothalamic regulatory factors are outlined in Table 8.
Pituitary Hormone | Hypothalamic Factor | Hypothalamic Regulation of the Pituitary Hormone |
---|---|---|
(–) = inhibitory; (+) = stimulatory. | ||
Growth hormone (GH) | GH-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 | – | |
Adrenocorticotropic hormone (ACTH) | Corticotropin-releasing hormone | + |
Vasopressin | + |
Growth hormone deficiency
Growth hormone deficiency is the earliest hormonal deficiency associated with cranial radiation therapy in childhood cancer survivors.
Evidence (radiation-dose response relationship of growth hormone deficiency in childhood brain tumor survivors):
Figure 11. 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.
Evidence (risk of growth deficits in childhood cancer survivors):
Growth after hematopoietic stem cell transplantation (HSCT)
Evidence (growth hormone deficiency in childhood HSCT survivors):
Growth hormone replacement therapy
Evidence (subsequent neoplasm risk after growth hormone deficiency replacement therapy):
In general, the data addressing subsequent malignancies among childhood cancer survivors treated with growth hormone therapy should be interpreted with caution given the small number of events.[
Disorders of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
Central precocious puberty
Prevalence and risk factors
Diagnosis
Treatment and outcomes associated with central precocious puberty
LH/FSH deficiency
TSH deficiency
TSH deficiency (also referred to as central hypothyroidism) in survivors of childhood cancer can have profound clinical consequences and be underappreciated.
Prevalence and risk factors
Clinical presentation and diagnosis
Management of TSH deficiency
Adrenocorticotropic hormone (ACTH) deficiency
Prevalence and risk factors
Diagnosis and management
Hyperprolactinemia
Table 9 summarizes pituitary gland late effects and the related health screenings.
Predisposing Therapy | Endocrine/Metabolic Effects | Health Screening |
---|---|---|
BMI = body mass index; FSH = follicle-stimulating hormone; LH = luteinizing hormone; T4 = thyroxine; TSH = thyroid-stimulating hormone. | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
b Testicular volume measurements are not reliable in the assessment of pubertal development in boys exposed to chemotherapy or direct radiation to the testes. | ||
c Appropriate only at diagnosis. TSH levels are not useful for follow-up during replacement therapy. | ||
Tumor or surgery affecting hypothalamus/pituitary. Radiation exposing hypothalamic-pituitary axis. | Growth hormone deficiency | Assessment of nutritional status |
Height, weight, BMI, Tanner stageb | ||
Tumor or surgery affecting hypothalamus/pituitary or optic pathways; hydrocephalus. Radiation exposing hypothalamic-pituitary axis. | Precocious puberty | Height, weight, BMI, Tanner stageb |
FSH, LH, estradiol, or testosterone levels | ||
Tumor or surgery affecting hypothalamus/pituitary. Radiation exposing hypothalamic-pituitary axis. | Gonadotropin deficiency | History: puberty, sexual function |
Exam: Tanner stageb | ||
FSH, LH, estradiol or testosterone levels | ||
Tumor or surgery affecting hypothalamus/pituitary. Radiation exposing hypothalamic-pituitary axis. | Central adrenal insufficiency | History: failure to thrive, anorexia, episodic dehydration, hypoglycemia, lethargy, unexplained hypotension |
Endocrine consultation for those with radiation dose ≥30 Gy | ||
Radiation exposing hypothalamic-pituitary axis. | Hyperprolactinemia | History/exam: galactorrhea |
Prolactin level | ||
Radiation exposing hypothalamic-pituitary axis. | Overweight/obesity | Height, weight, BMI |
Blood pressure test | ||
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 exposing hypothalamic-pituitary axis. | Central hypothyroidism | TSHc free thyroxine (free T4) level |
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 childhood 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):
Lifestyle impact on modifiable risk factors
Evidence (lifestyle modifications to reduce cardiovascular risk in childhood cancer survivors):
Abnormal glucose metabolism
Abdominal radiation therapy and TBI are increasingly recognized as independent risk factors for diabetes mellitus in childhood cancer survivors.[
Evidence (risk factors for diabetes mellitus in childhood cancer survivors):
Table 10 summarizes metabolic syndrome late effects and the related health screenings.
Predisposing Therapy | Potential Late Effects | Health Screening |
---|---|---|
BMI = body mass index. | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
Abdominal irradiation; total-body irradiation. | Components of metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism) | Height, weight, BMI, blood pressure test |
Labs: fasting glucose and lipids |
Body Composition: Underweight, Overweight, and Obesity
Underweight
Overweight/Obesity
Evidence (risk factors for overweight/obesity):
Body composition alterations after childhood ALL
Evidence (risk factors for body composition alterations):
Evidence (body composition changes in adult survivors of childhood ALL):
Variable outcomes across studies 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.[
Body composition alterations after treatment for CNS tumors
Among brain tumor survivors treated with higher doses of cranial radiation therapy, the highest risk for obesity has been observed in females treated at a younger age.[
Craniopharyngioma survivors have a substantially increased risk of extreme obesity because of the tumor location and the hypothalamic damage resulting from surgical resection.[
A cohort of 661 childhood brain tumor survivors (mean follow-up time, 7.3 years) was evaluated for weight gain associated with hypothalamic-pituitary dysfunction. This cohort excluded survivors who had craniopharyngiomas or pituitary tumors.[
Body composition alterations after HSCT
Body composition alterations after solid malignancies
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.[
Table 11 summarizes body composition late effects and the related health screenings.
Predisposing Therapy | Potential Late Effects | Health Screening |
---|---|---|
BMI = body mass index. | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
Cranial radiation therapy | Overweight/obesity | Height, weight, BMI, blood pressure test |
Labs: fasting glucose and lipids |
For endocrine and metabolic syndrome late effects information, including risk factors, evaluation, and health counseling, see the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
References:
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:[
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 higher 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 in asplenic survivors:
Individuals with functional or surgical asplenia are also at increased risk of fatal malaria and severe babesiosis.
Posttherapy management
Daily antimicrobial prophylaxis against pneumococcal infections is recommended for young children with asplenia, regardless of their immunization status.
Table 12 summarizes spleen late effects and the related health screenings.
Predisposing Therapy | Immunologic Effects | Health Screening/Interventions |
---|---|---|
GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation; IgA = immunoglobulin A; T = temperature. | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
Radiation exposing spleen; splenectomy; HSCT with currently active GVHD | Asplenia/hyposplenia; overwhelming post-splenectomy sepsis | Blood cultures during febrile episodes (T >38.5°C); empiric antibiotics |
Immunization for encapsulated organisms (pneumococcal,Haemophilus influenzaetype b, and meningococcal vaccines) | ||
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 |
For more information about posttransplant immunization, see the Centers for Disease Control and Prevention (CDC) Guidelines for Preventing Opportunistic Infections Among Hematopoietic Stem Cell Transplant Recipients.
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 do not normalize in all survivors. Innate immunity, thymopoiesis, and DNA damage responses to radiation were shown to be abnormal in survivors of childhood leukemia.[
While there is a paucity of data regarding the benefits of administering active immunizations in this population, reimmunization is necessary to provide protective antibodies.
Immune status is also compromised after HSCT, particularly in association with GVHD.[
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.[
For immune system late effects information, including risk factors, evaluation, and health counseling, see the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
References:
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 of 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 they oversampled those with the most severe musculoskeletal late effects because these patients were accessible as 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.
Abnormal Bone Growth
The effect of radiation on bone growth depends on the sites irradiated, as follows:
Radiation to the head and brain
In an age- and dose-dependent fashion, radiation can inhibit normal bone and muscle maturation and development.
Cranial radiation therapy damages the hypothalamic-pituitary axis in an age- and dose-response fashion and can result in growth hormone deficiency.[
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:[
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.
Evidence (effect of radiation therapy on the spine and long bones):
Osteoporosis and Fractures
Although increased rates of fracture are not reported among long-term survivors of childhood cancer,[
Most of our knowledge about cancer and treatment effects on bone mineralization has been derived from studies of children with ALL.[
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.[
Evidence (low bone mineral density):
Fracture risk in childhood cancer survivors
Risk prediction model for bone mineral density deficits
Data from the St. Jude Lifetime Cohort (development) and Erasmus Medical Center (validation) in the Netherlands were used to develop and validate prediction models for low and very low bone mineral density on the basis of clinical and treatment characteristics that identify adult survivors of childhood cancer who require screening by dual-energy x-ray absorptiometry.[
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.[
Factors that increase the risk of osteonecrosis include the following:
Exposure to corticosteroids and, possibly, methotrexate and concurrent asparaginase
Development of thromboembolism during antileukemic therapy
HSCT conditioning and course
Age at time of diagnosis or transplant
Race
Genetic factors
Sex
Osteochondroma
Evidence (risk of osteochondroma):
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.
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.
Joint Contractures
HSCT with any history of chronic GVHD is associated with joint contractures.[
Table 13 summarizes bone and joint late effects and the related health screenings.
Predisposing Therapy | Musculoskeletal Effects | Health Screening |
---|---|---|
CT = computed tomography; DXA = dual-energy x-ray absorptiometry; GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation. | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
Radiation exposing musculoskeletal system | Hypoplasia; fibrosis; reduced/uneven growth (scoliosis, kyphosis); limb length discrepancy | Exam: bones and soft tissues in radiation fields |
Radiation exposing head and neck | Craniofacial abnormalities | History: psychosocial assessment, with attention to educational and/or vocational progress, depression, anxiety, posttraumatic stress, social withdrawal |
Head and neck exam | ||
Radiation exposing musculoskeletal system | Radiation-induced fracture | Exam of affected bone |
Methotrexate; corticosteroids (dexamethasone, prednisone); radiation exposing skeletal structures; HSCT | Reduced bone mineral density | Bone mineral density test (DXA or quantitative CT) |
Corticosteroids (dexamethasone, prednisone) | Osteonecrosis | History: joint pain, swelling, immobility, limited range of motion |
Musculoskeletal exam | ||
Radiation with exposure to oral cavity | Osteoradionecrosis | History/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 contracture | Musculoskeletal exam |
For musculoskeletal system late effects information, including risk factors, evaluation, and health counseling, see the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
References:
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.[
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.
Earlier studies used the alkylating agent dose to define dose levels associated with the risk of gonadal toxicity within a specific study cohort. Childhood Cancer Survivor Study (CCSS) investigators developed the cyclophosphamide equivalent dose, which is a metric for normalization of the cumulative doses of various alkylating agents that is independent of the study population. The alkylating agent dose and cyclophosphamide equivalent dose perform similarly when used in several models for different survivor outcomes that include treatment exposures, but only the cyclophosphamide equivalent dose permits comparison across variably treated cohorts. Investigations that evaluate risk factors for gonadal toxicity vary in the use of cumulative doses based on individual alkylating agents, the alkylating agent dose, and the cyclophosphamide equivalent dose.[
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.
It should be noted that treatment-indicated risk of infertility does not simply translate into adult fertility status. This is particularly important for patients who were unable to participate in sperm/oocyte preservation because of their young age when diagnosed and treated for cancer.
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.[
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.
Radiation injury to Leydig cells is related to the dose delivered and age at treatment.
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.[
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.[
Recovery of germ cell function
Recovery of germ cell function after cytotoxic chemotherapy and radiation therapy is possible; however, evidence based on hard outcomes like sperm count is limited. Most studies use hormonal biomarkers like inhibin B and FSH levels to estimate the presence of spermatogenesis; however, limitations in the specificity and positive predictive value of these tests have been reported.[
Leydig cell function in long-term survivors of childhood cancer
Leydig cell function in childhood cancer survivors has not been well studied. St. Jude Lifetime Cohort investigators evaluated the prevalence of and risk factors for Leydig cell failure and Leydig cell dysfunction in 1,516 men (median age, 30.8 years; median time from diagnosis, 22 years).[
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.[
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 higher is associated with the greatest 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.[
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.[
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.[
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 (excess risk of premature ovarian insufficiency after chemotherapy and radiation):
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.[
Evidence (excess risk of premature ovarian insufficiency after HSCT):
Predicting premature ovarian failure
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.[
No abnormalities in fertility (reproductive characteristics and AMH levels as compared with controls) were identified in a series of 56 long-term female survivors of childhood differentiated thyroid cancer who received iodine I 131 (131I) for treatment. The median follow-up was 15.4 years (range, 8.3–24.7 years), and the median cumulative dose of 131I was 7.4 GBq/200.0 mCi. None of the survivors reported premature menopause.[
Evidence (excess risk of impaired fertility):
Cyclophosphamide Equivalent Dose by Tertile | Male | Female | ||
---|---|---|---|---|
| HR (95% CI) | P Value | HR (95% CI) | P Value |
CI = confidence interval; HR = hazard ratio. | ||||
Lower (<4,897 mg/m2) | 1.14 (1.00–1.30) | .045 | 0.97 (0.86–1.08) | .55 |
Middle (4,897–9,638 mg/m2) | 0.79 (0.68–0.91) | .0010 | 0.98 (0.87–1.11) | .76 |
Upper (≥9,639 mg/m2) | 0.55 (0.47–0.64) | <.0001 | 0.90 (0.79–1.01) | .07 |
Sexual Function
The psychosexual health of adults who were treated for cancer during childhood, adolescence, and young adulthood has not been well studied.
A St. Jude Lifetime Cohort Study estimated the prevalence of and risk factors for sexual dysfunction among 936 adult female survivors of childhood cancer. The study also evaluated associations between sexual dysfunction and psychological symptoms/quality of life.[
Reproduction
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.[
Risk of pregnancy complications
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.[
Evidence (excess risk of pregnancy complications):
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 of congenital anomalies stemming from their parents' exposure to mutagenic cancer treatments.
Evidence (children of cancer survivors not at significantly increased risk of congenital anomalies):
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.
Table 15 summarizes reproductive late effects and the related health screenings.
Predisposing Therapy | Reproductive Late Effects | Health Screening |
---|---|---|
AMH = antimüllerian hormone; FSH = follicle-stimulating hormone; LH = luteinizing hormone. | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
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 |
For reproductive late effects information, including risk factors, evaluation, and health counseling, see the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.
References:
Respiratory function may be compromised in long-term survivors of childhood cancer who were treated with the following therapies:
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. No large cohort studies have been performed that include clinical evaluations coupled with functional and quality-of-life assessments.
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. Population-based studies have demonstrated that survivors experience excess morbidity and mortality related to respiratory conditions.[
Evidence (selected cohort studies describing long-term pulmonary function outcomes):
Respiratory complications after 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.
Evidence (selected cohort studies describing pulmonary outcomes):
Respiratory complications after 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.[
Evidence (outcomes among cohorts treated with pulmonary toxic chemotherapy):
Respiratory complications associated with HSCT
Other factors associated with respiratory late effects
Evidence (pulmonary dysfunction in former or current smokers):
Table 16 summarizes respiratory late effects and the related health screenings.
Predisposing Therapy | Respiratory Effects | Health Screening/Interventions |
---|---|---|
DLCO = diffusing capacity of the lung for carbon monoxide; GVHD = graft-versus-host disease. | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
Busulfan; carmustine (BCNU)/lomustine (CCNU); bleomycin; radiation exposing 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 |
For respiratory late effects information, including risk factors, evaluation, and health counseling, see the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.[
References:
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.[
Evidence (hearing loss):
Risk factors associated with hearing loss include the following:
Hearing loss and platinum-based therapy
Hearing loss and cranial radiation therapy
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.[
Table 17 summarizes auditory late effects and the related health screenings.
Predisposing Therapy | Potential Auditory Effects | Health Screening/Interventions |
---|---|---|
FM = frequency modulated. | ||
a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
Platinum agents (cisplatin, carboplatin); radiation exposing the ear | Otologic 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.) |
Orbital and Optic
Orbital complications are common after radiation therapy for retinoblastoma, head and neck sarcomas, CNS tumors, and after total-body irradiation (TBI).
Retinoblastoma
For more information about the treatment of retinoblastoma, see Retinoblastoma Treatment.
Rhabdomyosarcoma
For more information about the treatment of rhabdomyosarcoma in children, see Childhood Rhabdomyosarcoma Treatment.
Low-grade optic pathway glioma
Survivors of optic pathway gliomas are also at risk of visual complications, resulting in part from tumor proximity to the optic nerve.
Treatment-specific effects
Survivors of childhood cancer are at increased risk of ocular late effects related to both glucocorticoid and radiation exposure to the eye.