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During the past five decades, dramatic progress has been made in the development of curative therapies for pediatric malignancies. More than 80% of children with cancer who have access to contemporary therapies are expected to survive into adulthood.[
Many approaches have been used to study the very long-term morbidity associated with childhood cancer and its contribution to early mortality. These initiatives have used a spectrum of resources, including data from the following:
High-quality data is needed to establish the occurrence of and risk profiles for late cancer treatment–related toxicity. The highest quality data typically comes from studies that report outcomes in survivors who have undergone medical assessments that provide well-characterized clinical statuses, treatment exposures, and specific late effects. Regardless of study methodology, it is important to consider selection and participation bias of the cohort studies in the context of the findings.
Prevalence of Late Effects in Childhood Cancer Survivors
Late effects are common in adults who have survived childhood cancer. Their prevalence increases as time from cancer diagnosis elapses. Multi-institutional and population-based studies have shown excess risk of hospital-related morbidity among childhood and young adult cancer survivors compared with age- and sex-matched controls, with some evidence that this risk is disproportionately high among survivors of racial and ethnic minority populations.[
Among adults who were treated for cancer during childhood, late effects contribute to a high burden of morbidity. Research has shown the following:[
The St. Jude Life (SJLIFE) cohort study aimed to describe the cumulative burden of cancer therapy 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 this 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 SJLIFE 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.
SJLIFE 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:
The presence of serious, disabling, and life-threatening chronic health conditions adversely affects the health status of aging survivors. The greatest impact is 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.[
CCSS investigators also evaluated the impact of race and ethnicity on late outcomes. The study compared 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 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.[
Figure 2. 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.[
The risk of late mortality and serious chronic health conditions have decreased over time among survivors of acute myeloid leukemia (AML). CCSS investigators evaluated the long-term morbidity, mortality, and health status of more than 800 5-year survivors of childhood AML based on treatment and treatment era. Survivors were compared by treatment group (hematopoietic stem cell transplant [HSCT]); chemotherapy with cranial radiation [CRT]; chemotherapy only) and decade of diagnosis.[
Population-based data from a state cancer registry was used to evaluate differences in survival and long-term outcomes by race and ethnicity among 4,222 children diagnosed with cancer between 1987 and 2012.[
An SJLIFE cohort study explored associations between modifiable chronic health conditions and late mortality within the context of social determinants of health.[
The CCSS and an SJLIFE cohort study investigated the contribution of cancer-predisposing variants to the risk of SMN-related late mortality (5 years or more after diagnosis).[
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 3).[
Cancer-related factors:
Treatment-related factors:
Host-related factors:
Figure 3. 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 based on the following:[
Part of long-term follow-up also focuses 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 individualized education 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 because 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—related to health issues, unemployment, and other societal factors—remains a significant concern for survivors of childhood cancer.[
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
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) are defined as histologically distinct neoplasms developing at least 2 months after completion of treatment for the primary malignancy. SNs may be benign or malignant. Childhood cancer survivors have increased risks of developing SNs that are multifactorial in etiology and vary 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.[
Several studies have described the excess risk of SNs.[
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:
Myelodysplastic Syndrome and Acute Myeloid Leukemia Postcytotoxic Therapy (MDS-pCT and AML-pCT)
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 MDS-pCT and AML-pCT include the following:[
Based on the updated definitions from the World Health Organization, MDS-pCT and AML-pCT are clonal disorders, which arise in patients previously exposed to cytotoxic therapy, either chemotherapy or large-field radiation therapy, for an unrelated neoplasm.[
The risk of alkylating agent–related MDS or 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 Neoplasms section in Childhood Acute Myeloid Leukemia Treatment.
Therapy-Related Solid SNs
Therapy-related solid SNs represent 80% of all SNs, 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 4).[
Figure 4. 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 longer 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.[
Subsequent neoplasms after hematopoietic stem cell transplant (HSCT)
Recipients of HSCT are treated with high-dose chemotherapy and, often, TBI, which makes their risk of SNs unique from that of 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, and the risk is based on multiple clinical factors. 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
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, the following was observed:[
Although current evidence does not show 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. Those with more limited treatment options because of previous exposure to radiation or anthracyclines may especially benefit.
In support of surveillance, SJLIFE investigators observed that breast cancers detected by imaging and/or prophylactic mastectomy were more likely to be in situ carcinomas, be smaller masses (3.3 cm mean tumor size detected by physical examination vs. 1.1 cm detected by imaging), 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 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.[
Another CCSS investigation quantified the association between temporal changes in cancer treatment over three decades and subsequent breast cancer risk.[
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%.[
In a Dutch case-control study, childhood cancer survivors with subsequent thyroid cancer were more likely to present with smaller tumors and bilateral tumors than the general population. Treatment outcomes were similar between subsequent and sporadic thyroid cancers.[
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 gliomas to benign meningiomas. 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.[
Proton radiation therapy for pediatric medulloblastoma is associated with low rates of brain stem injury and secondary malignancies. The long-term effects were reported in 178 pediatric patients with medulloblastoma who were treated with surgery, proton radiation therapy, and chemotherapy between 2002 and 2016 (median follow-up, 9.3 years).[
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) are one of the most common SNs among childhood cancer survivors and show a strong association with radiation therapy.[
The CCSS performed a randomized, controlled, comparative effectiveness trial to test methods to improve early detection of skin cancer among survivors of childhood cancer at high risk after radiation therapy exposure. Participants were randomly assigned to the experimental arm, which included print materials in combination with mHealth strategies (text messages and use of the Advancing Survivors' Knowledge website), or the control arm. Screening rates improved by 1.5-fold in the experimental arm. Rates of physician skin examination increased from baseline to 12 months, and rates of self-examination increased from baseline to 18 months in all three intervention groups. However, the increase in rates did not differ between the intervention groups.[
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 long-term, White survivors of retinoblastoma (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. There is a long latent period between the childhood cancer diagnosis and 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):
Oral cancers
The PanCareSurFup consortium reported on risks of oral second primary neoplasms (validated through pathology reports) in a cohort of 69,460 5-year childhood cancer survivors in Europe.[
Urogenital cancers
Development of subsequent primary urogenital cancers in childhood and adolescent cancer survivors is rare.
Using SEER data of 43,991 patients (aged <20 years) diagnosed with a first primary cancer from 1975 to 2016, the risk of urinary system cancer was higher for both females (SIR, 5.18; 95% CI, 3.65–7.14) and males (SIR, 2.80; 95% CI, 1.94–3.92), compared with the general population.[
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):
Human Papillomavirus (HPV)–Associated Malignancies
Evidence (HPV-associated SMNs):
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 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 variants 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 abnormalities, and range of developmental delays. | |||
a Adapted from Strahm et al.[ |
|||
b Dominant in a fraction of patients, spontaneous variants 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 | 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
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 variants 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 variants 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.[
Polygenic risk
With the decreased use of radiation therapy, it has become important to define the role of genetic susceptibility in chemotherapy-related SMNs. SJLIFE cohort study investigators evaluated treatment-related SMNs among long-term survivors of childhood cancer. An externally validated 179-variant polygenic risk score (PRS) associated with risks of common adult-onset cancers in the general population was calculated for each survivor.[
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,
All pediatric cancer survivor health screening guidelines employ a hybrid approach that is both evidence-based (using 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:
This section will also briefly discuss the influence of related conditions such as hypertension, dyslipidemia, and diabetes. However, this section will not provide a detailed review of 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 has been published.[
Cardiovascular Outcomes
Evidence (selected cohort studies describing cardiovascular outcomes):
Treatment Risk Factors
Chemotherapy (in particular, anthracyclines and anthraquinones) and 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:[
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 case per 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.
Based on available evidence about peripartum cardiomyopathy, the International Guideline Harmonization Group assessed that cardiomyopathy surveillance is reasonable before pregnancy or in the first trimester for female survivors of childhood, adolescent, and young adult cancer who are at moderate and high risk because they were treated with anthracyclines or chest radiation therapy.[
Mortality Risk After Major Cardiovascular Events
Survivors of childhood cancer represent a population at high risk of mortality after major cardiovascular events. Investigators estimated the cumulative incidence of all-cause and cardiovascular cause–specific mortality among survivors from the CCSS who had experienced a major cardiovascular event and compared them to siblings. They also compared the outcomes from the CCSS cancer survivors with a population-based cohort of racially diverse adults from the Coronary Artery Risk Development in Young Adults (CARDIA) study.[
Heart Transplant After Childhood Cancer
Data about the prevalence and outcomes of survivors with heart failure requiring heart transplant are 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
The International Guideline Harmonization Group has worked collaboratively to harmonize evidence-based cardiac surveillance recommendations and have identified knowledge deficits to help guide future studies.[
Consensus regarding evidence about screening, surveillance, and counseling
Risk Group | Anthracycline (mg/m2) | Chest-Directed Radiation Therapy (Gy) | Anthracycline (mg/m2) + Chest-Directed Radiation Therapy (Gy) | Is Screening Recommended? | At What Interval? |
---|---|---|---|---|---|
NA = not applicable. | |||||
a Adapted from Ehrhardt et al.[ |
|||||
High risk | ≥250 | ≥30 | ≥100 and ≥15 | Yes | 2 years |
Moderate risk | 100 to <250 | 15 to <30 | NA | Maybe | 5 years |
Low risk | >0 to <100 | >0 to <15 | NA | No | No screening |
Predicting Cardiovascular Disease Risk
Risk prediction and interventions 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 the |
||
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 examination |
Electrocardiography at entry into long-term follow-up | ||
Echocardiography 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 examination; consider Doppler ultrasonography 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 examination |
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; HSCT; 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 |
HSCT = hematopoietic stem cell transplant. |
References:
Neurocognitive
Neurocognitive late effects are commonly observed after treatment of malignancies that require central nervous system (CNS)–directed therapies, including the following:
Children with CNS 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.[
A Pediatric Normal Tissue Effects in the Clinic (PENTEC) comprehensive review was performed to develop models to facilitate the identification of dose constraints for radiation-associated CNS morbidities.[
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.[
A subsequent systematic review and meta-analysis compared the effects of physical activity or exercise interventions on cognitive function among individuals diagnosed with cancer (aged 0–19 years) with that of controls. Twenty-two unique studies (16 randomized controlled trials) were found with data on 12,767 individuals.[
Childhood cancer survivors may be at risk for cognitive decline throughout their lives (even if not present in the first 10 years after therapy). In a study of 2,375 adult survivors of childhood ALL, Hodgkin lymphoma, or CNS tumors (mean age at evaluation, 31.8 years) and their sibling controls, new onset memory impairment emerged more often in survivors, decades after cancer diagnosis and treatment.[
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 5. 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.
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.
An SJLIFE 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:
A study of very long-term adult survivors, who were on average 33 years postdiagnosis, demonstrated largely average cognitive functioning across domains of intelligence, memory, attention, and executive function.[
Hematopoietic stem cell transplant (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.
Peripheral neuropathy
Vinca alkaloid agents (vincristine and vinblastine) and heavy metals (cisplatin and carboplatin) may cause peripheral neuropathy.[
Stroke or other cerebrovascular effects
Hypersomnia (daytime sleepiness) or narcolepsy
Other neurological sequelae
Table 4 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 the |
||
Heavy metals (carboplatin, cisplatin) | Peripheral sensory neuropathy | Neurological examination |
Vinca alkaloid agents (vinblastine, vincristine) | Peripheral sensory or motor neuropathy (areflexia, weakness, foot drop, paresthesias) | Neurological examination |
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 examination | ||
Radiation exposing cerebrovascular structures | Cerebrovascular complications (stroke, Moyamoya disease, occlusive cerebral vasculopathy) | History: transient/permanent neurological events |
Blood pressure test | ||
Neurological examination | ||
Neurosurgery–brain | Motor and/or sensory deficits (paralysis, movement disorders, ataxia, eye problems [ocular nerve palsy, gaze paresis, nystagmus, papilledema, optic atrophy]); seizures | Neurological examination |
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 examination | ||
Predisposing Therapy | Neurocognitive 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, impaired health status, or other adverse psychosocial outcomes, compared with siblings or noncancer population groups.[
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.
Serious mental illnesses
A population-based study from Taiwan compared the prevalence of serious mental illnesses in 5,121 childhood and adolescent cancer survivors with that of population controls.[
A population-based study linked individuals with a history of six common cancers diagnosed at age 15 to 21 years to provincial health care data to compare rates of outpatient (family physician and psychiatrist) visits for psychiatric indications and time to severe psychiatric events (emergency room visit, hospitalization, and suicide). The study included 2,208 AYA cancer patients and 10,457 matched controls.[
PTSD 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 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 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):
References:
Dental
Overview
Chemotherapy, radiation therapy, and surgery can result in cosmetic and functional abnormalities of the oral cavity and dentition. The quality of current evidence regarding this outcome is limited by retrospective data collection, small sample size, cohort selection and participation bias, and heterogeneity in treatment approach, time since treatment, and method of ascertainment.
Oral and dental complications reported in childhood cancer survivors include the following:
Abnormalities of tooth development
Abnormalities of dental development reported in childhood cancer survivors include 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 Cancer Therapies.
Table 5 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; HSCT = hematopoietic stem cell transplant; MRI = magnetic resonance imaging. | ||
a Adapted from the |
||
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; HSCT 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 |
Examination: 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 6 summarizes digestive tract late effects and the related health screenings.
Predisposing Therapy | Gastrointestinal Effects | Health Screening/Interventions |
---|---|---|
GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplant; KUB = kidneys, ureter, bladder (plain abdominal radiograph). | ||
a Adapted from the |
||
Radiation exposing esophagus; HSCT with any history of chronic GVHD | Gastroesophageal reflux; esophageal dysmotility; esophageal stricture | History: dysphagia, heart burn |
Esophageal dilation, medical management, 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; gastroenterology consultation | ||
Surgical and/or gastroenterology consultation for symptomatic patients | ||
Radiation exposing bowel; laparotomy | Bowel obstruction | History: abdominal pain, distention, vomiting, constipation |
Examination: tenderness, abdominal guarding, distension (acute episode) | ||
Clinical evaluation in patients with symptoms of obstruction | ||
Surgical consultation in patients unresponsive to medical management | ||
Pelvic surgery; cystectomy | Fecal incontinence | History: chronic constipation, fecal soiling |
Rectal examination |
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
Acquired hemochromatosis
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 7 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 transplant. | ||
a Adapted from the |
||
Methotrexate; mercaptopurine/thioguanine; HSCT | Hepatic dysfunction | Laboratory tests: ALT, AST, bilirubin levels |
Ferritin in those treated with HSCT | ||
Mercaptopurine/thioguanine; HSCT | Veno-occlusive disease/sinusoidal obstructive syndrome | Examination: scleral icterus, jaundice, ascites, hepatomegaly, splenomegaly |
Laboratory tests: ALT, AST, bilirubin, platelet levels | ||
Ferritin in those treated with HSCT | ||
Radiation exposing liver/biliary tract; HSCT | Hepatic fibrosis/cirrhosis; focal nodular hyperplasia | Examination: jaundice, spider angiomas, palmar erythema, xanthomata, hepatomegaly, splenomegaly |
Laboratory tests: 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 |
Examination: right upper quadrant or epigastric tenderness (acute episode) | ||
Consider gallbladder ultrasonography 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
References:
Endocrine dysfunction is common among survivors of childhood cancer, especially in those who were treated with surgery or radiation therapy that involved hormone-producing organs and those who received alkylating agent chemotherapy.
Figure 6. 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
Thyroid radiation therapy. 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.[
Iodine I 131-metaiodobenzylguanidine (131I-MIBG).
Thyroidectomy. As observed in the general, noncancer population, partial or obviously subtotal surgical resection of the thyroid is a risk factor for subsequent hypothyroidism.[
Evidence (prevalence of and risk factors for hypothyroidism):
Mean Thyroid Dose | Risk of Hypothyroidismb | |||
---|---|---|---|---|
Age <14 yc | Age >15 yc | |||
Female | Male | Female | Male | |
a Adapted from Milano et al.[ |
||||
b Any hypothyroidism (i.e., compensated or uncompensated). | ||||
c Age 14 to 15 y was used as a cutoff because the two studies that analyzed age used different cut-points. Presumably, the risks of hypothyroidism in patients irradiated at ages 14 to 15 y would be intermediate to those shown for ages <14 y and >15 y. | ||||
10 Gy | 10% | 6% | 14% | 8% |
20 Gy | 22% | 13% | 29% | 17% |
30 Gy | 39% | 23% | 53% | 31% |
40 Gy | 59% | 35% | 79% | 47% |
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 transplant (HSCT) are at increased risk of thyroid dysfunction.[
TSH deficiency (central hypothyroidism) is discussed with late effects that affect the pituitary gland.
Table 9 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 the |
||
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 examination |
Thyroid ultrasonography |
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.
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. However, 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.
The risk of hypothalamus-pituitary dysfunction increases with higher doses of radiation therapy. When the radiation therapy dose exceeds 30 Gy, there is a higher risk of developing hypothalamus-pituitary disorders, including adrenocorticotropic hormone (ACTH) deficiency, luteinizing hormone (LH)/follicle-stimulating hormone (FSH) deficiency, and TSH deficiency.[
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 International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) consisting of 42 interdisciplinary international experts performed a systematic literature search on hypothalamic-pituitary axis surveillance in childhood cancer survivors.[
The six anterior pituitary hormones and their major hypothalamic regulatory factors are outlined in Table 10.
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 most common and often the first anterior pituitary deficit to occur after cranial radiation therapy. In childhood survivors of CNS tumors, the overall prevalence of growth hormone deficiency is 12.5%.[
Evidence (radiation-dose response relationship of growth hormone deficiency in childhood brain tumor survivors):
Figure 7. 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 transplant (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.[
As outlined in a consensus statement by the Growth Hormone Research Society, areas of uncertainty include the safety of growth hormone in children with cancer-predisposing conditions, its use in growth hormone–deficient children who are receiving maintenance therapy, and the overall benefit-risk ratio in adult survivors.[
Disorders of LH and 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. Among survivors of head and neck tumors treated with radiation therapy potentially exposing the hypothalamic-pituitary region and the thyroid gland, hypothyroidism may result from TRH and/or TSH deficiency (central hypothyroidism), thyroid gland dysfunction (primary hypothyroidism), or a combination of central and primary causes.
Prevalence and risk factors
Clinical presentation and diagnosis
Management of TSH deficiency
ACTH deficiency
Prevalence and risk factors
Diagnosis and management
Hyperprolactinemia
Table 11 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 the |
||
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 |
Examination: 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/examination: 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 survivors of childhood cancer. 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
For individuals treated at a young age (age <11 years), 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 12 summarizes metabolic syndrome late effects and the related health screenings.
Predisposing Therapy | Potential Late Effects | Health Screening |
---|---|---|
BMI = body mass index. | ||
a Adapted from the |
||
Abdominal irradiation; total-body irradiation. | Components of metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism) | Height, weight, BMI, blood pressure test |
Laboratory tests: 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 of developing obesity has been observed in females treated at a younger age.[
Survivors of craniopharyngioma have a substantially increased risk of developing extreme obesity because of the tumor location and the hypothalamic damage resulting from surgical resection.[
A cohort of 661 childhood survivors of brain tumors (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 survivors of childhood cancer 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 13 summarizes body composition late effects and the related health screenings.
Predisposing Therapy | Potential Late Effects | Health Screening |
---|---|---|
BMI = body mass index. | ||
a Adapted from the |
||
Cranial radiation therapy | Overweight/obesity | Height, weight, BMI, blood pressure test |
Laboratory tests: Fasting glucose and lipids |
For endocrine and metabolic syndrome late effects information, including risk factors, evaluation, and health counseling, see the
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 14 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 transplant; IgA = immunoglobulin A; T = temperature. | ||
a Adapted from the |
||
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 |
Examination: attention to eyes, nose/sinuses, and lungs |
For more information about posttransplant immunization, see the Centers for Disease Control and Prevention (CDC)
Humoral Immunity
Although the immune system appears to recover from the effects of active chemotherapy and radiation therapy, its effect on immune function into survivorship has not been well studied. Most studies have evaluated children treated for acute lymphoblastic leukemia (ALL), which in the disease itself, involves impaired lymphocyte maturation of either T or B cells in addition to lymphotoxic therapy.[
While there is a paucity of data regarding the benefits of administering active immunizations in this population, reimmunization is necessary to provide protective antibodies. The recommended reimmunization schedule will depend on previously received vaccinations and on the intensity of therapy.[
Immune status is also compromised after HSCT, particularly in association with GVHD.[
The major North American and European transplant groups, the CDC, and the Infectious Diseases Society of America have published follow-up recommendations for transplant recipients.[
Late effects after CD19-targeted CAR T-cell therapy for patients with relapsed or refractory ALL are largely unknown. Many patients will undergo an HSCT after CAR-T cell therapy, which complicates assessment of late effects. The most frequent late effect (as defined as >90 days post CAR T-cell therapy) is hypogammaglobulinemia.
Preexisting humoral immunity to vaccine-related antigens can persist in patients despite marked B-cell aplasia after CD19-targeted T-cell immunotherapy. Studies have shown that a population of plasma cells lacking CD19 expression survives long-term after CD19 CAR T-cell immunotherapy.[
Infection Risks
Infectious complications resulting in hospitalization occur in excess rates among long-term childhood cancer survivors.[
For immune system late effects information, including risk factors, evaluation, and health counseling, see the
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 anticancer treatment and delivery of anticancer modalities, particularly radiation therapy, have 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 survivors of CNS tumors and 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 Life (SJLIFE) cohort study (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
Adolescent and young adults (AYA)
Chronic comorbidities were assessed in a cohort of 6,778 2-year survivors of AYA cancer (defined as diagnosed with cancer between the ages of 15 and 39 years), with a median follow-up of 5.1 years after cancer diagnosis. The risk of developing chronic comorbidities was compared with matched individuals without a history of cancer. The incidence rate ratio (IRR) for all comorbidities was highest for osteonecrosis (IRR, 8.3), followed by osteoporosis (IRR, 5.75), and joint replacement (IRR, 3.89). The use of methotrexate (IRR, 21.6 for any dose) and corticosteroids (IRR, 5.4 for any dose) was significantly associated with osteonecrosis.[
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.
CCSS investigators evaluated risk factors for and outcomes of late amputation in survivors treated for lower extremity sarcomas.[
The incidence of late major surgical interventions among childhood cancer survivors was examined through data from the CCSS. In the report, survivors of Ewing sarcoma and osteosarcoma had the highest cumulative burden of late, major surgical interventions among all solid tumor survivors (mean cumulative counts of late surgical interventions was 322.9 per 100 survivors of Ewing sarcoma and 269.6 per 100 survivors of osteosarcoma). A large component of this burden is related to the increased rate of additional late musculoskeletal surgeries, such as arthroplasty, amputation, prosthetic revision caused by an infection, device failure, or associated fractures. Locoregional surgery or radiation therapy cancer treatments were associated with undergoing late surgical intervention in the same body region or organ system.[
Joint Contractures
HSCT with any history of chronic GVHD is associated with joint contractures.[
Table 15 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 transplant. | ||
a Adapted from the |
||
Radiation exposing musculoskeletal system | Hypoplasia; fibrosis; reduced/uneven growth (scoliosis, kyphosis); limb length discrepancy | Examination: 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 examination | ||
Radiation exposing musculoskeletal system | Radiation-induced fracture | Examination 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 examination | ||
Radiation with exposure to oral cavity | Osteoradionecrosis | History/oral examination: 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 |
Examination: 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, nonunion, fracture]) | History: pain, functional/activity limitations |
Examination: residual limb integrity | ||
Radiograph of affected limb | ||
Orthopedic evaluation | ||
HSCT with any history of chronic GVHD | Joint contracture | Musculoskeletal examination |
For musculoskeletal system late effects information, including risk factors, evaluation, and health counseling, see the
References:
Reproductive outcomes in childhood cancer survivors may be compromised by surgery, radiation therapy, or chemotherapy that negatively affects any component of the hypothalamic-pituitary axis or gonads. 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.[
The St. Jude Children's Research Hospital reported the cumulative risk of hypogonadism and infertility in a cohort of 156 pediatric patients with medulloblastomas who were treated with surgery, risk-adapted craniospinal irradiation, and dose-intensive chemotherapy in the SJMB03 study (2003–2013).[
In addition to anticancer therapy, age at treatment, and sex, it is likely that genetic factors influence the risk of permanent infertility. 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.
The 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
Radiation affecting testicular function
Among men who were treated for childhood cancer, gonadal injury may have occurred if radiation treatment fields included 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. However, 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 transplant (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. SJLIFE study 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
The main challenge for the pediatric surgeon in the management of ovarian tumors is finding the right balance between optimal tumor resection and maximal fertility preservation. Oophorectomy performed for the management of germ cell tumors may reduce ovarian reserve. Contemporary treatments use fertility-sparing surgical procedures combined with systemic chemotherapy to reduce this risk.[
Radiation affecting ovarian function
In women treated for childhood cancer, primary gonadal injury may have occurred if treatment fields involved 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 patient 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 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 patients in one series failed to enter puberty, and 26% of women experienced 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 insufficiency (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 survivors of childhood cancer. 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 |