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During the past five decades, dramatic progress has been made in the development of curative therapy for pediatric malignancies. Long-term survival into adulthood is the expectation for 80% of children with access to contemporary therapies for pediatric malignancies. The therapy responsible for this survival can also produce adverse long-term health-related outcomes, referred to as "late effects," that manifest months to years after completion of cancer treatment. A variety of approaches have been used to advance knowledge about the very long-term morbidity associated with childhood cancer and its contribution to early mortality. These initiatives have utilized a spectrum of resources including investigation of data from population-based registries, self-reported outcomes provided through large-scale cohort studies, and information collected from medical assessments. Studies reporting outcomes in survivors who have been well characterized in regards to clinical status and treatment exposures, and comprehensively ascertained for specific effects through medical assessments, typically provide the highest quality of data to establish the occurrence and risk profiles for late cancer treatment-related toxicity. Regardless of study methodology, it is important to consider selection and participation bias of the cohort studies in the context of the findings reported.
Figure 1. Investigators from the Childhood Cancer Survivor Study (CCSS), a retrospective multi-institutional cohort investigation that has been monitoring health outcomes of more than 20,000 long-term childhood cancer survivors for more than 15 years, estimated a cumulative incidence of 73.4% for at least one chronic health problem (grades 1–5) by age 40 years among the 10,397 adult participants (mean age, 26.6 years); more than 40% will experience a chronic condition that is severe, life-threatening, or fatal (grades 3–5). The risk of specific late effects in an individual is dependent upon the type and location of the cancer and therapeutic interventions undertaken to control the cancer. Oeffinger KC, Mertens AC, Sklar CA, et al.: Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 355 (15): 1572-82, 2006. Copyright © 2006 Massachusetts Medical Society.
Late effects are commonly experienced by adults who have survived childhood cancer and demonstrate an increasing prevalence associated with longer time elapsed from cancer diagnosis. Population-based studies support excess hospital-related morbidity among childhood cancer survivors compared with age- and gender-matched controls.[3,4,5,6,7] Research has clearly demonstrated that late effects contribute to a high burden of morbidity among adults treated for cancer during childhood, with 60% to almost 90% developing one or more chronic health conditions and 20% to 40% experiencing severe or life-threatening complications during adulthood.[2,8,9,10,11] 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 the majority of pediatric malignancies has evolved to a risk-adapted approach that is assigned based on a variety of clinical, biological, and sometimes genetic factors. With the exception of survivors requiring intensive multimodality therapy for aggressive or refractory/relapsed malignancies, life-threatening treatment effects are relatively uncommon after contemporary therapy in early follow-up (up to 10 years after diagnosis). However, survivors still frequently experience life-altering morbidity related to effects of cancer treatment on endocrine, reproductive, musculoskeletal, and neurologic function.
Late effects also contribute to an excess risk of premature death among long-term survivors of childhood cancer. Several studies of very large cohorts of survivors have reported early mortality among individuals treated for childhood cancer compared with age- and gender-matched general population controls. Relapsed/refractory primary cancer remains the most frequent cause of death, followed by excess cause-specific mortality from subsequent primary cancers and cardiac and pulmonary toxicity.[12,13,14,15,16,17,18]; [Level of evidence: 3iA] Despite high premature morbidity rates, overall mortality has decreased over time.[20,21] This reduction is related to a decrease in deaths from the primary cancer without an associated increase in mortality from subsequent cancers or treatment-related toxicities. The former reflects improvements in therapeutic efficacy, and the latter reflects changes in therapy made subsequent to studying the causes of late effects. The expectation that mortality rates in survivors will continue to exceed those in the general population is based on the long-term sequelae that are likely to increase with attained age. If patients treated on therapeutic protocols are followed for long periods into adulthood, it will be possible to evaluate the excess lifetime mortality in relation to specific therapeutic interventions.
Previous studies have shown excess late mortality in childhood cancer survivors. In a population-based study in Finland, the long-term mortality risks from major nonmalignant diseases in 5-year survivors of childhood and adolescent and young adult (AYA) cancer diagnosed before age 35 years were evaluated and included more than 6,000 AYA cancer survivors. In this study, standardized mortality rates (SMRs) were 90% higher for nonmalignant diseases (SMR, 1.9; 95% CI, 1.7–2.2) than expected for the entire cohort, with SMRs similarly elevated for patient subgroups with circulatory disease and respiratory disease. These risks remained elevated for Hodgkin and non-Hodgkin lymphoma survivors diagnosed between the ages of 15 and 34 years. The risk of death from respiratory disease was significantly elevated by 140% (SMR, 2.4; 95% CI, 1.3–4.1) in young adult patients diagnosed with cancer between the ages of 20 and 34 years.
Monitoring for Late Effects
Recognition of both acute and late modality–specific toxicity has motivated investigations evaluating the pathophysiology and prognostic factors for cancer treatment–related effects. The results of these studies have played an important role in changing pediatric cancer therapeutic approaches and reducing treatment-related mortality among survivors treated in more recent eras.[20,21] These investigations have also informed the development of risk counseling and health screening recommendations of long-term survivors by identifying the clinical and treatment characteristics of those at highest risk for treatment complications. The common late effects of pediatric cancer encompass several broad domains including growth and development, organ function, reproductive capacity and health of offspring, and secondary carcinogenesis. In addition, survivors of childhood cancer may experience a variety of adverse psychosocial sequelae related to the primary cancer, its treatment, or maladjustment associated with the cancer experience.
Late sequelae of therapy for childhood cancer can be anticipated based on therapeutic exposures, but the magnitude of risk and the manifestations in an individual patient are influenced by numerous factors. Factors that should be considered in the risk assessment for a given late effect include the following:
Resources to Support Survivor Care
The need for long-term follow-up for childhood cancer survivors is supported by the American Society of Pediatric Hematology/Oncology, the International Society of Pediatric Oncology, the American Academy of Pediatrics, the Children's Oncology Group (COG), and the Institute of Medicine. Specifically, 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 previous cancer, cancer therapy, genetic predisposition, lifestyle behaviors, and comorbid conditions.[23,24] Part of long-term follow-up should also be focused on appropriate screening of educational and vocational progress. Specific treatments for childhood cancer, especially those that directly impact nervous system structures, may result in sensory, motor, and neurocognitive deficits that may have adverse consequences on functional status, educational attainment, and future vocational opportunities. A Childhood Cancer Survivor Study (CCSS) investigation observed that treatment with cranial radiation doses of 25 Gy or higher was associated with higher odds of unemployment (health related: odds ratio [OR] = 3.47; 95% confidence interval [CI], 2.54–4.74; seeking work: OR = 1.77; 95% CI, 1.15–2.71). Unemployed survivors reported higher levels of poor physical functioning than employed survivors, had lower education and income, and were more likely to be publicly insured than unemployed siblings. These data emphasize the importance of facilitating survivor access to remedial services, which has been demonstrated to have a positive impact on education achievement, which may in turn enhance vocational opportunities.
In addition to risk-based screening for medical late effects, the impact of health behaviors on cancer-related health risks should also be emphasized. Health-promoting behaviors should be stressed for survivors of childhood cancer, as targeted educational efforts appear to be worthwhile.[28,29,30,31] Smoking, excess alcohol use, and illicit drug use increase risk of organ toxicity and, potentially, subsequent neoplasms. Unhealthy dietary practices and sedentary lifestyle may exacerbate treatment-related metabolic and cardiovascular complications. Proactively addressing unhealthy and risky behaviors is pertinent, as several research investigations confirm that long-term survivors use tobacco and alcohol and have inactive lifestyles at higher rates than is ideal given their increased risk of cardiac, pulmonary, and metabolic late effects.[32,33,34]
Unfortunately, the majority of childhood cancer survivors do not receive recommended risk-based care. The CCSS reported that 88.8% of survivors were receiving some form of medical care; however, only 31.5% reported receiving care that focused on their prior cancer (survivor-focused care), and 17.8% reported receiving survivor-focused care that included advice about risk reduction and discussion or ordering of screening tests. Among the same cohort, surveillance for new cases of cancer was very low in survivors at the highest risk for colon, breast, or skin cancer, suggesting that survivors and their physicians need education about their risks and recommended surveillance. Health insurance access appears to play an important role in access to risk-based survivor care. In a related CCSS study, uninsured survivors were less likely than those privately insured to report a cancer-related visit (adjusted relative risk [RR] = 0.83; 95% CI, 0.75–0.91) or a cancer center visit (adjusted RR = 0.83; 95% CI, 0.71–0.98). Uninsured survivors had lower levels of utilization in all measures of care compared with privately insured survivors. In contrast, publicly insured survivors were more likely to report a cancer-related visit (adjusted RR = 1.22; 95% CI, 1.11–1.35) or a cancer center visit (adjusted RR = 1.41; 95% CI, 1.18–1.70) than were privately insured survivors. In a study comparing health care outcomes for long-term survivors of AYA cancer with young adults who have a cancer history, the proportion of uninsured survivors did not differ between the two groups. Subgroups of AYA survivors may be at additional risk for facing health care barriers. Younger survivors (aged 20–29 years), females, nonwhites, and survivors reporting poorer health faced more cost barriers, which may inhibit the early detection of late effects. Overall, lack of health insurance remains a significant concern for survivors of childhood cancer because of health issues, unemployment, and other societal factors. Legislation, like the Health Insurance Portability and Accountability Act legislation, has improved access and retention of health insurance among survivors, although the quality and limitations associated with these policies have not been well studied.[38,39]
Transition of Survivor Care
Transition of care from the pediatric to the adult health care setting is necessary for most childhood cancer survivors in the United States. When available, multidisciplinary long-term follow-up (LTFU) 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 LTFU programs is the organization of an individualized survivorship care plan that includes details about therapeutic interventions undertaken for childhood cancer and their potential health risks, personalized health screening recommendations, and information about lifestyle factors that modify risks. 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 (see the COG Survivorship Guidelines Appendix 1).
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 COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers are appropriate for asymptomatic survivors presenting for routine exposure-based medical follow-up 2 or more years after completion of therapy. Patient education materials called ‘‘Health Links'' provide detailed information on guideline-specific topics to enhance health maintenance and promotion among this population of cancer survivors. Multidisciplinary system-based (e.g., cardiovascular, neurocognitive, and reproductive) task forces who are responsible for monitoring the literature, evaluating guideline content, and providing recommendations for guideline revisions as new information becomes available have also published several comprehensive reviews that address specific late effects of childhood cancer.[42,43,44,45,46,47,48,49,50] Information concerning late effects is summarized in tables throughout this summary.
Subsequent neoplasms (SNs), which may be benign or malignant, are defined as histologically distinct neoplasms developing at least 2 months after completion of treatment for the primary malignancy. Childhood cancer survivors have an increased risk of developing SNs that varies by host factors (e.g., genetics, immune function, hormone status), primary cancer therapy, environmental exposures, and lifestyle factors. The Childhood Cancer Survivor Study (CCSS) reported a 30-year cumulative incidence of 20.5% (95% confidence interval [CI], 19.1%–21.8%) for all SNs, 7.9% (95% CI, 7.2%–8.5%) for SNs with malignant histologies (excluding nonmelanoma skin cancer [NMSC]), 9.1% (95% CI, 8.1%–10.1%) for NMSC, and 3.1% (95% CI, 2.5%–3.8%) for meningioma. This represents a sixfold increased risk of SNs among cancer survivors, compared with the general population. SNs are the leading cause of nonrelapse late mortality (standardized mortality ratio = 15.2; 95% CI, 13.9–16.6). The risk of SNs remains elevated for more than 30 years from diagnosis of the primary cancer. Moreover, prolonged follow-up has established that multiple SNs are common among aging childhood cancer survivors.
The development of an SN is likely multi-factorial in etiology and results from combinations of influences including gene-environment and gene-gene interactions. Outcome following 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. The incidence and type of SNs differ with the primary cancer diagnosis, type of therapy received, and presence of genetic conditions. Unique associations with specific therapeutic exposures have resulted in the classification of SNs into the following two distinct groups:
Characteristics of t-MDS/AML include a short latency (<10 years from primary cancer diagnosis) and association with alkylating agents and/or topoisomerase II inhibitors.[5,6] Although the long-term risk of subsequent leukemia more than 15 years from primary diagnosis remains significantly elevated (standardized incidence ratio [SIR] = 3.5; 95% CI, 1.9–6.0), these events are relatively rare with an absolute excess risk of 0.02 cases per 1000 person-years. Solid SNs have a strong and well-defined association with radiation and are characterized by a latency that exceeds 10 years. Furthermore, the risk of solid SNs continues to climb with increasing follow-up, whereas the risk of t-MDS/AML plateaus after 10 to 15 years.
Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) has been reported after treatment of Hodgkin lymphoma (HL), acute lymphoblastic leukemia (ALL), and sarcomas, with the cumulative incidence approaching 2% at 15 years after therapy.[8,9,10,11] Some cases of late recurrence among childhood acute lymphoblastic leukemia have been shown to represent cases of new primary leukemia based on TCR gene rearrangement.[12,13] t-MDS/AML is a clonal disorder characterized by distinct chromosomal changes. The following two types are recognized by the World Health Organization classification:
Therapy-Related Solid Neoplasms
Therapy-related solid SNs represent 80% of all SNs and demonstrate a strong relationship with ionizing radiation. 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).[1,11,16,17,18] SN solid tumors in childhood cancer survivors most commonly involve the breast, thyroid, central nervous system (CNS), bones, and soft tissues.[1,8,11,17,19] With more prolonged follow-up of cohorts of adults surviving childhood cancer, epithelial neoplasms involving the gastrointestinal tract and lung have emerged.[1,8,16] Benign and low-grade SNs, including NMSCs and meningiomas, have also been observed with increasing prevalence in survivors treated with radiation for childhood cancer.[1,17,18]
The risk of solid SNs is highest when the exposure occurs at a younger age, increases with the total dose of radiation, and with increasing follow-up after radiation. In recipients of a hematopoietic cell transplant conditioned with high-dose busulfan and cyclophosphamide (Bu-Cy), the cumulative incidence of new solid cancers appears to be similar regardless of exposure to radiation. In a registry-based, retrospective, cohort study, Bu-Cy conditioning without total-body irradiation (TBI) was associated with higher risks of solid SNs compared with the general population. Chronic graft-versus-host disease increased the risk of SN, especially those involving the oral cavity. Some of the well-established radiation-related solid SNs include the following:
Malignant melanoma has also been reported as a SN in childhood cancer survivor cohorts, although at a much lower incidence than NMSCs. A systematic review including data from 19 original studies (total N = 151,575 survivors; median follow-up of 13 years) observed an incidence of 10.8 cases of malignant melanoma per 100,000 childhood cancer survivors per year. Risk factors for malignant melanoma identified among these studies included radiation therapy or the combination of alkylating agents and antimitotic drugs. Melanomas most frequently developed in survivors of Hodgkin lymphoma, hereditary retinoblastoma, soft tissue sarcoma, and gonadal tumors, but the relatively small number of survivors represented in the relevant studies preclude assessment of melanoma risk among other types of childhood cancer.
In a French and British cohort-nested, case-control study of childhood solid cancer survivors diagnosed before age 17 years, the risk of developing a SN in the digestive organs varied with therapy. The SNs most often involved the colon/rectum (42%), liver (24%), and stomach (19%). The risk was 9.7-fold higher compared with population controls and exhibited a strong radiation dose-response relationship with an OR of 5.2 (95% CI, 1.7–16.0) for local radiation doses between 10 Gy and 29 Gy and 9.6 (95% CI, 2.6–35.2) for doses of 30 Gy and above, compared with survivors who had not received radiation. Chemotherapy alone and combined-modality therapy were associated with a significantly increased risk of developing a GI SN (SIR = 9.1; 95% CI, 2.3–23.6; SIR = 29.0; 95% CI, 20.5–39.8).
CCSS investigators reported a 4.6-fold higher risk for GI SNs among their study participants compared with the general population (95% CI, 3.4–6.1). The most prevalent GI SN histology was adenocarcinoma (56%). The SNs most often involved the colon (39%), rectum/anus (16%), liver (18%), and stomach (13%). The highest risk for GI SNs was associated with abdominal radiation (SIR = 11.2; CI, 7.6–16.4), but survivors not exposed to radiation also had a significantly increased risk (SIR = 2.4; CI, 1.4–3.9). High-dose procarbazine (RR = 3.2; CI 1.1–9.4) and platinum drugs (RR = 7.6; CI, 2.3–25.5) independently increased the risk for GI SNs. The SIR for colorectal cancer was 4.2 (CI, 2.8–6.3).
St. Jude Children's Research Hospital investigators observed that the incidence of a subsequent colorectal carcinoma increased steeply with advancing age, with a 40-year cumulative incidence of 1.4% ± 0.53% among the entire cohort (N = 13,048) and 2.3% ± 0.83% for 5-year survivors. The SIR for subsequent colorectal carcinoma was 10.9 (95% CI, 6.6–17.0) compared with U.S. population controls. Colorectal carcinoma risk increased by 70% with each 10 Gy increase in radiation dose and increasing radiation volume also increased risk. Treatment with alkylating agent chemotherapy was also associated with an 8.8-fold excess risk of subsequent colorectal carcinoma. Collectively, these studies support the need for initiation of colorectal carcinoma surveillance at a young age among survivors receiving high-risk exposures.
Subsequent Neoplasms and Genetic Susceptibility
Literature clearly supports the role of chemotherapy and radiation in the development of SNs. However, interindividual variability exists, suggesting that genetic variation has a role in susceptibility to genotoxic exposures, or that genetic susceptibility syndrome confers an increased risk of cancer, such as Li-Fraumeni syndrome. Previous studies have demonstrated that childhood cancer survivors with either a family history of cancer, but more so, presence of Li-Fraumeni syndrome, carry an increased risk of developing an SN.[47,48] The risk of SNs could potentially be modified by mutations in high-penetrance genes that lead to these serious genetic diseases (e.g., Li-Fraumeni syndrome). However, the attributable risk is expected to be very small because of the extremely low prevalence of mutations in high-penetrance genes. Table 1 below summarizes the spectrum of neoplasms, affected genes, and Mendelian mode of inheritance of selected syndromes of inherited cancer predisposition.
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.
Metabolism of genotoxic agents occurs in two phases. Phase I involves activation of substrates into highly reactive electrophilic intermediates that can damage DNA, a reaction principally performed by the cytochrome p450 (CYP) family of enzymes. Phase II enzymes (conjugation) function to inactivate genotoxic substrates. The phase II proteins comprise the glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase-1 (NQO1), and others. The balance between the two sets of enzymes is critical to the cellular response to xenobiotics; for example, high activity of a phase I enzyme and low activity of a phase II enzyme can result in DNA damage.
DNA repair polymorphisms
DNA repair mechanisms protect somatic cells from mutations in tumor suppressor genes and oncogenes that can lead to cancer initiation and progression. An individual's DNA repair capacity appears to be genetically determined. A number of DNA repair genes contain polymorphic variants, resulting in large interindividual variations in DNA repair capacity. Evaluation of the contribution of polymorphisms influencing DNA repair to the risk of SN represents an active area of research.
Screening and Follow-up for Subsequent Neoplasms
Vigilant screening is important for those at risk. Because of the relatively small size of the pediatric cancer survivor population and the prevalence and time to onset of therapy-related complications, undertaking clinical studies to assess the impact of screening recommendations on the morbidity and mortality associated with the late effect is not feasible. However, well-conducted studies on large populations of childhood cancer survivors have provided compelling evidence linking specific therapeutic exposures and late effects. This evidence has been used by several national and international cooperative groups (Scottish Collegiate Guidelines Network, Children's Cancer and Leukaemia Group, Children's Oncology Group [COG]) to develop consensus-based clinical practice guidelines to increase awareness and standardize the immediate care needs of medically vulnerable childhood cancer survivors. The COG Guidelines employ a hybrid approach that is both evidence-based (utilizing established associations between therapeutic exposures and late effects to identify high-risk categories) and grounded in the collective clinical experience of experts (matching the magnitude of the risk with the intensity of the screening recommendations). The screening recommendations in these guidelines represent a statement of consensus from a panel of experts in the late effects of pediatric cancer treatment.
In regard to screening for malignant SNs recommended by the COG Guidelines, certain high-risk populations of childhood cancer survivors merit heightened surveillance due to predisposing host, behavioral, or therapeutic factors.
Radiation, chemotherapy, and biologic agents, both independently and in combination, increase the risk of cardiovascular disease in survivors of childhood cancer; in fact, cardiovascular death has been reported to account for 26% of the excess absolute risk of death by 45 or more years from diagnosis in adults who survived childhood cancers, and is the leading cause of noncancer mortality in select cancers such as Hodgkin lymphoma (HL).[1,2] During the 30 years after cancer treatment, survivors are eight times more likely to die from cardiac causes and 15 times more likely to be diagnosed with congestive heart failure (CHF) than the general population.[3,4] Therapeutic exposures conferring the highest risk are the anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, and mitoxantrone) and thoracic radiation. The risks to the heart are related to cumulative anthracycline dose, method of administration, amount of radiation delivered to different depths of the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, latency period, and gender.
The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. However, several reports do allow some segregation of the effects of radiation from those of chemotherapy. Of note, the pathogenesis of injury differs, with radiation primarily affecting the fine vasculature of the heart and anthracyclines directly damaging myocytes.[5,6] Late effects of radiation to the heart include the following:[7,8,9]
These cardiac toxic effects are related to total radiation dose, individual radiation fraction size, and the volume of the heart that is exposed. Modern radiation techniques allow a reduction in the volume of cardiac tissue incidentally exposed to the higher radiation doses. This may translate into a reduced risk for adverse cardiac events.
Increased risk of anthracycline-related cardiomyopathy is associated with the following:[10,11,12,13,14,15,16,17,18,19,20,21]
Among these factors, cumulative dose appears to be the most significant in regard to risk of CHF, which develops in less than 5% of survivors after anthracycline exposure of less than 300 mg/m2, approaches 15% at doses between 300 and 500 mg/m2, and exceeds 30% for doses greater than 600 mg/m2.[5,12,22,23]
Schedule of administration of doxorubicin may influence risk of cardiomyopathy. One study looked at the effect of continuous (48 hour) versus bolus (1 hour) infusions of doxorubicin in 121 children who received a cumulative dose of 360 mg/m2 for treatment of acute lymphoblastic leukemia (ALL) and found no difference in the degree or spectrum of cardiotoxicity in the two groups. Because the follow-up time in this study was relatively short, it is not yet clear whether the frequency of progressive cardiomyopathy will differ between the two groups over time. Another study compared cardiac dysfunction in 113 children who received doxorubicin either by single-dose infusion or by a consecutive divided daily-dose schedule. The divided-dose patients received one-third of the total cycle dose over 20 minutes for 3 consecutive days. Patients treated according to a single-dose schedule received the cycle dose as a 20-minute infusion. There was no significant difference in the incidence of cardiac dysfunction between the divided-dose and single-dose infusion groups. Earlier studies in adults have shown decreased cardiotoxicity with prolonged infusion; thus, further evaluation of this question is warranted.
Prevention or amelioration of doxorubicin-induced cardiomyopathy is clearly important because the continued use of doxorubicin is required in cancer therapy. Dexrazoxane is a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent. Evidence supports its capacity to mitigate cardiac toxicity in patients treated with doxorubicin.[25,26,27,28,29] Studies suggest that dexrazoxane is safe and does not interfere with chemotherapeutic efficacy. There is a single-study experience suggesting that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity; other studies, however, do not show increased risk of malignancies.[29,30,31,32] However, at this time, this should not preclude treatment with dexrazoxane.[33,34]
Two closed Pediatric Oncology Group therapeutic phase III studies for Hodgkin lymphoma (HL) [34,35] measured myocardial toxicity clinically and sequentially over time by echocardiography and electrocardiography, and by determination of levels of cardiac troponin T (cTnT), a protein that is elevated after myocardial damage.[28,36,37,38,39,40] Long-term outcomes for these patients are not yet available.
The angiotensin-converting enzyme inhibitor enalapril has been used in the attempt to ameliorate doxorubicin-induced left ventricular dysfunction. Although a transient improvement in left ventricular function and structure was noted in 18 children, left ventricular wall thinning continued to deteriorate; thus, the intervention with enalapril was not considered successful. For this reason, studies to date in doxorubicin-treated cancer survivors have not demonstrated a benefit of enalapril in preventing progressive cardiac toxicity.[26,27]
A number of studies have examined cardiac function after radiation therapy and doxorubicin exposure using cardiopulmonary exercise stress tests and have found abnormalities in exercise endurance, cardiac output, aerobic capacity, echocardiography during exercise testing, and ectopic rhythms.[41,42,43,44,45] In addition to subclinical abnormalities of systolic function observed by conventional echocardiography, diastolic dysfunction (impaired ventricular relaxation) has also been observed, which may precede impairment of systolic function. Specific abnormalities of cardiac function may progress over time after therapy, as suggested by a report targeting parameters of left ventricular contractility. An increased prevalence of diastolic dysfunction has also been reported in childhood cancer survivors, consistent with the hypothesis of increased vascular and ventricular stiffness associated with precocious cardiovascular aging. It remains unclear whether these abnormalities will have clinical impact. Asymptomatic cardiac toxic effects can be demonstrated in patients who have normal clinical assessments, and abnormalities can be linked to lower self-reported health and New York Heart Association cardiac function scores.[49,50] Clearly, additional studies with long-term follow-up will be necessary to determine optimal screening modalities and frequencies.
Prevalence, Clinical Manifestations, and Risk Factors for Cardiac Toxicity
Children's Cancer Survivors Study (CCSS) investigators detailed dose-response evaluations for both radiation therapy and anthracycline administration to analyze risks (self-reported) of CHF, myocardial infarction (MI), pericardial disease, and valvular abnormalities (see Figure 2).
Figure 2. Cumulative incidence of cardiac disorders among childhood cancer survivors by average cardiac radiation dose. BMJ 2009; 339:b4606. © 2009 by British Medical Journal Publishing Group.
Compared with siblings, survivors of childhood cancer were significantly more likely to report CHF (hazard ratio [HR] = 5.9; 95% confidence interval [CI], 3.4–9.6), MI (HR = 5.0; 95% CI, 2.3–10.4), pericardial disease (HR = 6.3; 95 % CI, 3.3–11.9), or valvular abnormalities (HR = 4.8; 95 % CI, 3.0–7.6). Cardiac radiation exposure of 15 Gy or more increased the risk of CHF, MI, pericardial disease, and valvular abnormalities by twofold to sixfold compared with nonirradiated survivors. There was no evidence for increased risk following doses less than 5 Gy, and slight elevations in risk were not statistically significant following doses between 5 to 15 Gy. Exposure to 250 mg/m2 or more of anthracyclines also increased the risk of CHF, pericardial disease, and valvular abnormalities by two to five times compared with survivors who had not been exposed to anthracyclines. The cumulative incidence of adverse cardiac outcomes in childhood cancer survivors continued to increase up to 30 years after diagnosis and ranged from about 2% to slightly over 4% overall, but to much higher cumulative percentages for those receiving the highest cardiac radiation doses and the highest cumulative dose of anthracyclines.
A study of 4,122 5-year survivors of childhood cancer diagnosed before 1986 in France and the United Kingdom also provides evidence for an association between radiation dose and risk of cardiovascular disease. After 86,453 person-years of follow-up (average, 27 years), 603 deaths had occurred. The overall standardized mortality ratio was 8.3-fold (95% CI, 7.6–9.0) higher in relation to the general populations in France and the United Kingdom. Thirty-two patients had died of cardiovascular diseases, which is fivefold (95% CI, 3.3–6.7) more than expected. The risk of dying of cardiac diseases (n = 21) was significantly higher in individuals who had received a cumulative dose of anthracyclines greater than 360 mg/m2 (relative risk [RR] = 4.4; 95% CI, 1.3–15.3) and following an average radiation dose exceeding 5 Gy (RR = 12.5 for 5–14.9 Gy and RR = 25.1 for >15 Gy) to the heart. A linear relationship was found between the average dose of radiation to the heart and the risk of cardiac mortality (excess RR at 1 Gy, 60%).
Subclinical cardiac function was evaluated by a group from the Netherlands. Of 601 eligible adult 5-year childhood cancer survivors, 525 (87%) had an echocardiogram performed, of which 514 were evaluable for assessment of the left ventricular shortening fraction (LVSF). The median overall LVSF in the whole group of childhood cancer survivors was 33.1% (range, 13.0%–56.0%). Subclinical cardiac dysfunction (LVSF <30%) was identified in 139 patients (27%). In a multivariate linear regression model, LVSF was reduced with younger age at diagnosis, higher cumulative anthracycline dose, and radiation to the thorax. High-dose cyclophosphamide and ifosfamide were not associated with a reduction of LVSF.
Cardiovascular Disease in Select Cancer Subgroups
Hodgkin lymphoma (HL) continues to be the pediatric malignancy associated with the greatest risk of cardiovascular disease, with a 13.1 excess absolute risk per 10,000 person years for cardiovascular death. Newer treatment approaches are specifically designed to reduce exposure to cardiotoxic agents (e.g., total anthracycline dose) and radiation dose and volume. Moreover, newer trials explore the safe elimination of radiation from primary therapy.
Data from the German-Austrian DAL-HD studies show a dose response for cardiac diseases in children treated for HL with combined radiation and anthracycline-based chemotherapy (cumulative doxorubicin dose was uniformly 160 mg/m2). The 25-year cumulative incidence of cardiac diseases was 3% with no radiation therapy, 5% after 20 Gy, 6% after 25 Gy, 10% after 30 Gy, and 21% after 36 Gy. An older study of 635 patients treated for childhood HL confirms the risks that occur after higher-dose radiation therapy. The actuarial risk of pericarditis requiring pericardiectomy was 4% at 17 years posttreatment (occurring only in children treated with higher radiation doses). Only 12 patients died of cardiac disease, including seven deaths from acute MI; however, these deaths occurred only in children treated with 42 Gy to 45 Gy. In an analysis of 48 asymptomatic patients treated for HL from 1970 to 1991 with mediastinal therapy (median dose 40 Gy) and screened for the presence of subclinical cardiac abnormalities, 43% had unsuspected valvular abnormalities, 75% had a conduction abnormality or arrhythmia, and 30% had reduced VO2 during exercise tests. These abnormalities were noted at a mean of 15.5 years posttherapy suggesting that survivors of HL treated with high doses of mediastinal radiation therapy require long-term cardiology follow-up. Among children treated with 15 Gy to 26 Gy, none developed radiation-associated cardiac problems.
The risk of delayed valvular and CAD after lower radiation doses requires additional study of patients followed for longer periods of time to definitively ascertain lifetime risk. Nontherapeutic risk factors for CAD—such as family history, obesity, hypertension, smoking, diabetes, and hypercholesterolemia—are likely to impact the frequency of disease.[7,8,56]
Brain tumor: A study of self-reported late effects among 1,607 survivors of childhood brain tumors  showed that 18% of survivors reported a heart or circulatory late effect. Risk was highest among those treated with surgery, radiation therapy, and chemotherapy compared with surgery and radiation therapy alone, suggesting a potential additive vascular injury from chemotherapy. Children who receive spinal radiation for treatment of central nervous system tumors have been demonstrated to show low maximal cardiac index on exercise testing and pathologic Q-waves in inferior leads on ECG testing, and higher posterior-wall stress.
Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML): In a study of ALL survivors reporting a chronic medical condition in the CCSS cohort, the risk of a cardiac condition was nearly sevenfold higher compared with the siblings. No significant association was identified based on radiation exposure. A similar analysis among AML survivors in the cohort found the 20-year cumulative incidence of cardiac disease to be 4.7%. It is noteworthy that adult survivors of childhood ALL have an increased prevalence of obesity and insulin resistance and may be at risk for developing diabetes, dyslipidemia, and metabolic syndrome, all known to be potent risk factors for premature cardiovascular disease.
Wilms tumor: A long-term follow-up study of Wilms tumor survivors reported a cumulative risk of CHF of 4.4% at 20 years for those who received doxorubicin as part of their initial therapy and 17.4% at 20 years when doxorubicin was received as part of therapy for relapsed disease. Risk factors for CHF in this cohort included female gender, lung irradiation with doses 20 Gy or higher, left-sided abdominal irradiation, and doxorubicin dosage of 300 mg/m2 or more.
Hematopoietic cell transplantation (HCT): Cardiac complications after bone marrow transplantation may occur, with arrhythmia, pericarditis, and cardiomyopathy predominating, although many are either acute or subacute effects. High-dose cyclophosphamide clearly is a causative agent; total-body irradiation is a secondary contributing factor.[41,56,60] In a report from the Bone Marrow Transplant Survivors Study that compared 145 HCT survivors, 7,207 conventionally treated survivors, and 4,020 siblings from the CCSS cohort, median time from HCT to study participation was 11.0 years (range, 2.3–25.9 years). The prevalence of cardiovascular conditions (grades 3–5) was 4.8% in HCT survivors, versus 3.2% in conventionally treated CCSS survivors, and it was 0.5% (for grades 3–4) in the sibling control CCSS cohort. The RR was 0.5 (95% CI, 0.1–2.5) for the conventionally treated survivors versus HCT survivors, and 12.7 (95% CI, 5.4–30.0) for the HCT survivors versus siblings.
Vascular Disease/Cerebrovascular Accident
A spectrum of vascular morbidities may occur after radiation therapy used to treat malignancies such as lymphomas, head and neck cancers, and brain tumors. Specifically, carotid artery and cerebrovascular injury occur after cervical and central nervous system irradiation. French investigators observed a significant association with radiation dose to the brain and long-term cerebrovascular mortality among 4,227 five-year childhood cancer survivors (median follow-up, 29 years). Survivors who received more than 50 Gy to the prepontine cistern had an HR of 17.8 (95% CI, 4.4–73) of death from cerebrovascular disease compared with those who had not received radiation therapy or who had received less than 0.1 Gy in the prepontine cistern region. The RR for cerebrovascular accident (CVA [stroke]) in the CCSS cohort was almost tenfold higher compared with the sibling control group; notably, risks were highest among the adult survivors of childhood ALL, brain tumors, and HL.[63,64] Leukemia survivors were six times more likely to suffer a CVA compared with their siblings, whereas brain tumor survivors were 29 times more likely to suffer a CVA. Of the brain tumor cohort, 69 of 1,411 patients who had a history of radiation therapy reported a CVA (4.9%), with a cumulative incidence of 6.9% (95% CI, 4.47–9.33) at 25 years. Survivors exposed to cranial radiation therapy greater than 30 Gy had an increased risk for CVA, with the highest risk among those treated with greater than 50 Gy. Adult survivors of childhood HL who were treated with thoracic radiation therapy, including mediastinal and neck, had a 5.6-fold increased risk for CVA than their siblings (median dose 40 Gy). In another study from the Netherlands of 2,201 5-year survivors of HL (of whom 547 were younger than 21 years), and with median follow-up of 17.5 years, 96 patients developed cerebrovascular disease (55 CVA, 31 transient ischemic attacks [TIA], and 10 both CVA and TIA), with a median age at diagnosis of 52 years. Most ischemic events were from large-artery atherosclerosis (36%) or cardioembolism (24%). The standardized incidence ratio (SIR) for CVA was 2.2, and for TIA it was 3.1. The cumulative incidence of ischemic CVA or TIA 30 years after HL treatment was 7%. For patients younger than 21 years, the SIR for CVA was 3.8, and for TIA it was 7.6. Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (HR = 2.5; 95% CI, 1.1–5.6) versus without radiation therapy. Treatment with chemotherapy was not associated with increased risk. It is noteworthy that hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease, whereas smoking and overweight were not. 
In general, survivors should be counseled regarding the cardiovascular benefits of maintaining healthy weight, adhering to a heart-healthy diet, participating in regular physical activity, and abstaining from smoking. Survivors should obtain medical clearance before engaging in extreme exercise programs. Clinicians should consider baseline and follow-up screening as needed for comorbid conditions that impact cardiovascular health.
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for cardiovascular late effects information including risk factors, evaluation, and health counseling.
Neurocognitive late effects most commonly follow treatment of malignancies that require central nervous system (CNS)-directed therapies, such as cranial radiation, systemic therapy with high-dose methotrexate or cytarabine, or with intrathecal chemotherapy. Children with brain tumors or acute lymphoblastic leukemia are most likely to be affected. Risk factors for the development of neurocognitive side effects are female gender, young age at the time of treatment, higher radiation dose, and treatment with both cranial radiation and chemotherapy (systemic or intrathecal).[1,2,3,4]
Survival rates have increased over recent decades for children with brain tumors; however, long-term cognitive effects due to their illness and associated treatments are emerging. In childhood and adolescent brain tumor survivors, tumor site, treatment of hydrocephalus with a shunt, paralysis, auditory difficulties, or history of a stroke have emerged as risk factors for adverse neurocognitive effects.[5,6]
Cranial radiation therapy has been associated with the highest risk of long-term cognitive morbidity particularly in younger children. There is an established dose-response relationship with those getting higher-dose cranial radiation therapy consistently performing more poorly on intellectual measures. The negative impact of radiation treatment has been characterized by changes in intelligence quotient (IQ) scores, which have been noted to drop about 2 to 5 years after diagnosis and an attenuation of the decline 5 to 10 years afterward, followed by stabilization of the IQ scores 20 to 40 years after diagnosis.[8,9,10] The decline over time is typically reflective of the child's failure to acquire new abilities or information at a rate similar to peers, rather than a progressive loss of skills and knowledge. Affected children may experience information-processing deficits resulting in academic difficulties, and are prone to problems with receptive and expressive language, attention span, and visual and perceptual motor skills.[9,11,12] These changes in intellectual functioning may be partially explained by radiation-induced or chemotherapy-induced reduction of normal white matter volume as evaluated through magnetic resonance imaging (MRI). Using lower doses of radiation and more targeted volumes have demonstrated improved results in neurocognitive effects of therapy. In this regard, a report from St. Jude Children's Research Hospital showed cognitive decline after conformal radiation therapy in 78 children younger than 20 years (mean, 9.7 years) with low-grade glioma treated with 54 Gy (see Figure 3). In fact, age at time of irradiation was more important than radiation dose in predicting cognitive decline. Children younger than 5 years showed the most cognitive decline.
Figure 3. 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.
Glutathione S-transferase M1 and T1 gene polymorphisms may predict patients with medulloblastoma who are more likely to experience neurocognitive toxicity secondary to radiation.
Acute lymphoblastic leukemia (ALL)
One of the great medical success stories of the past generation is how advances in the treatment of ALL have dramatically improved survival. With the recognition that CNS relapse was common among children in bone marrow remission, presymptomatic CNS radiation and intrathecal chemotherapy were introduced into the treatment of children with ALL in the 1960s and 1970s. The increase in cure rates for children with ALL over the past decades has resulted in greater attention to the neurocognitive morbidity and quality of life of survivors. The goal of current ALL treatment is to minimize adverse late effects while maintaining high survival rates. Patients are stratified for treatment according to their risk of relapse. Cranial radiation is reserved for children (less than 20%) considered at high risk for CNS relapse.
Although low-, standard- and most high-risk patients currently are treated with chemotherapy-only protocols, the described neurocognitive effects for ALL patients are based on a heterogeneous treatment group of survivors in the past who were treated with combinations (simultaneously or sequentially) of intrathecal chemotherapy, radiation, and high-dose chemotherapy making it difficult to differentiate the impact of the individual components. In the future, more accurate data will be available as to the neurocognitive effects on survivors of childhood ALL treated with chemotherapy only.
In a large prospective study (N = 555) of neurocognitive outcomes in children with newly diagnosed ALL randomly assigned to CNS-directed therapy according to risk group (low: intrathecal methotrexate vs. high-dose methotrexate; high: high-dose methotrexate vs. cranial radiation therapy), a significant reduction in IQ scores (4 to 7 points) was observed between all patient groups when compared with controls (P < .002), regardless of the CNS treatment delivered. Children younger than 5 years were more likely to have IQs below 80 at 3 years compared with children older than 5 years at diagnosis, irrespective of treatment allocation, suggesting that younger children are more vulnerable to treatment-related neurologic toxic effects.
ALL and cranial radiation
In survivors of ALL, cranial radiation therapy does lead to identifiable neurodevelopment late sequelae. Although these abnormalities are mild in some patients (overall IQ fall of approximately 10 points), those who have received higher doses at a young age may have significant learning difficulties.[19,20] Deficits in neuropsychological functions, such as visual-motor integration, processing speed, attention, and short-term memory are reported in children treated with 1800 cGy to 2400 cGy.[21,22] Girls and younger children are more vulnerable to cranial irradiation.[23,24,25] The decline in intellectual functioning appears to be progressive, showing more impairment of cognitive function with increasing time since radiation therapy. When the neurocognitive outcome of radiation therapy and chemotherapy-only CNS regimens are directly compared, the evidence suggests a better outcome for those treated with chemotherapy alone although some studies show no significant difference.[27,28,29]
It should be noted that the phenotype of attention problems in ALL survivors appears to differ from developmental attention-deficit disorder, as few survivors demonstrate significant hyperactivity/impulsivity. By contrast, impairments in cognitive efficiency (information processing and short-term memory) and executive functioning (organization and planning) have been more often observed among ALL survivors treated with cranial radiation therapy, and have been observed in children at lower frequency among those treated with chemotherapy alone.
ALL and chemotherapy–only CNS therapy
Most studies of chemotherapy-only CNS-directed treatment display good neurocognitive long-term outcomes. However, one review suggests modest effects on processes of attention, speed of information processing, memory, verbal comprehension, visual-spatial skills, and visual-motor functioning; global intellectual function was found to be preserved.[21,27,31,32,33] Few longitudinal studies evaluating long-term neurocognitive outcome report adequate data for a decline in global IQ after treatment with chemotherapy alone.[32,34] The academic achievement of ALL survivors in the long term seems to be generally average for reading and spelling with deficits mainly affecting arithmetic performance.[27,35,36] Further risk factors for poor neurocognitive outcome after chemotherapy-only CNS-directed treatment are younger age and female gender.[34,37] Time since diagnosis or treatment does not appear to have a similar influence on neurocognitive functioning as observed following cranial irradiation.
Because of its penetrance into the CNS, systemic methotrexate has been used in a variety of low-dose and high-dose regimens for leukemia CNS prophylaxis. Systemic methotrexate in high doses and combined with radiation therapy can lead to an infrequent but well-described leukoencephalopathy, in which severe neurocognitive deficits are obvious.
The type of steroid used for ALL systemic treatment does not affect cognitive functioning. This is based on long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment that observed no meaningful differences in cognitive functioning based on corticosteroid randomization.
Treatment intensity and duration can also adversely affect cognitive performance, because of absences from school and interruption of studies. In the Childhood Cancer Survivor Study (CCSS), treatment-related neurocognitive impairment resulted in decreased educational attainment and greater utilization of special education services. Those ALL survivors who were provided with special educational services had comparable educational attainment to siblings, whereas those not reporting use of special education had lower educational attainment.
Infants with ALL
Infants with ALL are considered to be at high risk for CNS disease. In the past, infants diagnosed before age 2 years were treated with cranial irradiation. As a result, significant deficits in overall intellectual function were noted as compared with cancer controls. Currently, most ALL treatment protocols do not specify cranial irradiation for infants or very young children. When cranial radiation is avoided, neurodevelopmental outcome improves. One long-term study of infants who received high-dose systemic methotrexate combined with intrathecal cytarabine and methotrexate for CNS leukemia prophylaxis and were tested 3 to 9 years posttreatment showed cognitive function was in the average range.
Neurocognitive abnormalities have been reported in other groups of cancer survivors besides patients with CNS tumors and ALL. In a study of adult survivors of childhood non-CNS cancers (including ALL, n = 5,937), 13% to 21% of survivors had impairment in task efficiency, organization, memory, or emotional regulation. This rate of impairment was approximately 50% higher than that in the sibling comparison. Factors such as diagnosis before age 6 years, female gender, cranial radiation therapy, and hearing impediment were associated with impairment.
Stem cell transplantation
Cognitive and academic consequences of stem cell transplantation in children have also been evaluated. In a report from the St. Jude Children's Research Hospital in which 268 patients were treated with stem cell transplant, minimal risk of late cognitive and academic sequelae was seen. Subgroups of patients were at relatively higher risk, including those undergoing unrelated donor transplantation, receiving total-body irradiation, and developing graft-versus-host disease (GVHD). However, these differences were small relative to differences in premorbid functioning, particularly those associated with socioeconomic status.
Neurocognitive function of pediatric patients with hematologic malignancies who had undergone hematopoietic stem cell transplantation (HSCT) was evaluated prior to HSCT and then at 1, 3, and 5 years post-HSCT. In this series of 38 patients who had all received intrathecal chemotherapy as part of their treatment, significant declines in visual motor skills and memory test scores were noted within the first year posttransplant. By 3 years posttransplant, there was an improvement in the visual motor development scores and memory scores, but there were new deficits seen in long-term memory scores. By 5 years posttransplant, there were progressive declines in verbal skills, performance skills, and new deficits seen in long-term verbal memory scores. The greatest decline in neurocognitive function occurred in patients who received cranial irradiation either as part of their initial therapy or as part of their HSCT conditioning.
Most neurocognitive late effects are thought to be related to white matter damage in the brain. This was investigated in children with leukemia who were treated with HSCT. In a series of 36 patients, performance on neurocognitive measures associated with white matter was compared with performance on measures associated with gray matter. Composite white matter scores were significantly lower than composite gray matter scores.
Neurologic complications may be predisposed by tumor location, neurosurgery, radiation therapy, or specific neurotoxic chemotherapeutic agents. In children with CNS tumors, mass effect, tumor infiltration, and increased intracranial pressure may result in motor or sensory deficits, cerebellar dysfunction, and such secondary effects as seizures and cerebrovascular complications.
Clinical or radiographic leukoencephalopathy has been reported after cranial irradiation and high-dose systemic methotrexate administration. Younger patients and those given radiation doses greater than 24 Gy are more vulnerable to this complication. White matter changes may be accompanied by such neuroimaging abnormalities as dystrophic calcifications, cerebral lacunae, and cerebral atrophy.
Vinca alkaloid agents (vincristine and vinblastine) and cisplatin may cause peripheral neuropathy. This condition presents during treatment and appears to clinically resolve after completion of therapy. However, higher cumulative doses of vincristine and/or intrathecal methotrexate have been linked to neuromuscular impairments in long-term survivors of childhood ALL, which suggests that persistent effects of these agents may impact functional status in aging survivors.
In a report from the CCSS that compared 4,151 adult survivors of childhood ALL with their siblings, survivors were at an elevated risk for late-onset coordination problems, motor problems, seizures, and headaches. The overall cumulative incidence was 44% at 20 years. Serious headaches were most common, with a cumulative incidence of 25.8% at 20 years followed by focal neurologic dysfunction (21.2%) and seizures (7%). Children who were treated with regimens that included cranial radiation for ALL and those who suffer relapse were at increased risk for late-onset neurologic sequelae.
Many childhood cancer survivors have adverse quality of life or other adverse psychological outcomes. Incorporation of psychological screening into clinical visits for childhood cancer survivors may be valuable; however, limiting such evaluations to those returning to long-term follow-up clinics may result in a biased subsample of those with more difficulties, and precise prevalence rates may be difficult to establish. A review of behavioral, emotional, and social adjustment among survivors of childhood brain tumors illustrates this point, in whom rates of psychological maladjustment range from 25% to 93%. In a series of CNS malignancy survivors (n = 802) reported from the CCSS, adverse outcome indicators of successful adult adaptation (educational attainment, income, employment, and marital status) were most likely in survivors who report neurocognitive dysfunction. Collectively, studies evaluating psychosocial outcomes among CNS tumor survivors indicate deficits in social competence in the level of social adjustment that worsen over time. In a CCSS study evaluating predictors of independent living status across diagnostic groups, adult survivors of childhood cancer with neurocognitive, psychological, or physical late effects were less likely to live independently as adults compared with a sibling control group. The presence of chronic health conditions can also impact other aspects of psychological health. In a study evaluating psychological outcomes among long-term survivors treated with hematopoietic cell transplantation (HCT), 22% of survivors reported adverse outcomes compared with 8% of sibling controls. Somatic distress was the most prevalent among the domains studied and affected 15% of HCT survivors, representing a threefold higher risk compared with siblings. HCT survivors with severe/life-threatening conditions and active chronic GVHD had a twofold increased risk for somatic distress.
The CCSS has shown that adolescents who are long-term survivors of childhood cancer demonstrate significantly higher rates of inattention, social withdrawal, emotional problems, and externalizing problems compared with their siblings. Social withdrawal was associated with adult obesity and physical inactivity. As a result, these psychological problems may increase future risk for chronic health conditions and subsequent neoplasms and