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.
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.[3-7] Research has clearly demonstrated that late effects contribute to a high burden of morbidity among adults treated for cancer during childhood, with 60% to more than 90% developing one or more chronic health conditions and 20% to 80% experiencing severe or life-threatening complications during adulthood.[2,8-12] The variability in prevalence is related to differences in age and follow-up time of the cohorts studied and the methods and consistency of assessment (e.g., self-reported vs. risk-based medical evaluations). 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.Mortality
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.[13-19]; [Level of evidence: 3iA] Despite high premature morbidity rates, overall mortality has decreased over time.[21,22] 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.[21,22] 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:
- Tumor location.
- Direct tissue effects.
- Tumor-induced organ dysfunction.
- Mechanical effects.
- Radiation therapy: total dose, fraction size, organ or tissue volume, type of machine energy.
- Chemotherapy: agent type, dose-intensity, cumulative dose, schedule.
- Surgery: technique, site.
- Use of combined modality therapy.
- Blood product transfusion.
- Hematopoietic cell transplantation.
- Age at diagnosis.
- Time from diagnosis/therapy.
- Developmental status.
- Genetic predisposition.
- Inherent tissue sensitivities and capacity for normal tissue repair.
- Function of organs not affected by cancer treatment.
- Premorbid health state.
- Socioeconomic status.
- Health habits.
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.[24,25] 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.[29-32] 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.[33-35]
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 than 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.[39,40]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.[43-51] Information concerning late effects is summarized in tables throughout this summary.References
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