General Information About Late Effects of Treatment for Childhood Cancer
During the past five decades, dramatic progress has been made in the development of curative therapy for pediatric malignancies. Long-term survival into adulthood is the expectation for more than 80% of children with access to contemporary therapies for pediatric malignancies.[1,2] The therapy responsible for this survival can also produce adverse long-term health-related outcomes, referred to as late effects, which manifest months to years after completion of cancer treatment.
A variety of approaches have been used to advance knowledge about the very long-term morbidity associated with childhood cancer and its contribution to early mortality. These initiatives have utilized a spectrum of resources including investigation of data from the following:
Studies reporting outcomes in survivors who have been well characterized in regards to clinical status and treatment exposures, and comprehensively ascertained for specific effects through medical assessments, typically provide the highest quality of data to establish the occurrence and risk profiles for late cancer treatment–related toxicity. Regardless of study methodology, it is important to consider selection and participation bias of the cohort studies in the context of the findings reported.
Prevalence of Late Effects in Childhood Cancer Survivors
Late effects are commonly experienced by adults who have survived childhood cancer and demonstrate an increasing prevalence associated with longer time elapsed from cancer diagnosis. Population-based studies support excess hospital-related morbidity among childhood and young adult cancer survivors compared with age- and gender-matched controls.[3-5,10-12]
- 60% to more than 90% develop one or more chronic health conditions.
- 20% to 80% experience severe or life-threatening complications during adulthood.
The variability in prevalence is related to differences in the following:
- Age and follow-up time of the cohorts studied.
- Methods and consistency of assessment (e.g., self-reported vs. risk-based medical evaluations).
Childhood Cancer Survivor Study (CCSS) investigators demonstrated that the elevated risk of morbidity and mortality among aging survivors in the cohort increases beyond the fourth decade of life. By age 50 years, the cumulative incidence of a self-reported severe, disabling, life-threatening, or fatal health condition was 53.6% among survivors, compared with 19.8% among a sibling control group. Among survivors who reached age 35 years without a previous severe, disabling, life-threatening, or fatal health condition, 25.9% experienced a new grade 3 to grade 5 condition within 10 years, compared with 6.0% of healthy siblings. The even higher prevalence of late effects among clinically ascertained cohorts is related to the subclinical and undiagnosed conditions detected by screening and surveillance measures.
Recognition of late effects, concurrent with advances in cancer biology, radiological sciences, and supportive care, has resulted in a change in the prevalence and spectrum of treatment effects. In an effort to reduce and prevent late effects, contemporary therapy for most pediatric malignancies has evolved to a risk-adapted approach that is assigned based on a variety of clinical, biological, and sometimes genetic factors. 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.[14-18]; [Level of evidence: 3iA]
Despite high premature morbidity rates, overall mortality has decreased over time.[14,20] This reduction is related to a decrease in deaths from the primary cancer without an associated increase in mortality from subsequent cancers or treatment-related toxicities. The former reflects improvements in therapeutic efficacy, and the latter reflects changes in therapy made subsequent to studying the causes of late effects. The expectation that mortality rates in survivors will continue to exceed those in the general population is based on the long-term sequelae that are likely to increase with attained age. If patients treated on therapeutic protocols are followed up for long periods into adulthood, it will be possible to evaluate the excess lifetime mortality in relation to specific therapeutic interventions.
Monitoring for Late Effects
Recognition of both acute and late modality–specific toxicity has motivated investigations evaluating the pathophysiology and prognostic factors for cancer treatment–related effects. The results of these studies have played an important role in the following areas:[14,20]
- Changing pediatric cancer therapeutic approaches to reduce treatment-related mortality among survivors treated in more recent eras.
- The development of risk counseling and health screening recommendations for long-term survivors by identifying the clinical and treatment characteristics of those at highest risk of 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.
- Secondary carcinogenesis.
- 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.
- Hematopoietic cell transplantation.
- Use of combined modality therapy.
- Blood product transfusion.
- Management of chronic graft-versus-host disease.
- Genetic predisposition.
- Premorbid health state.
- Developmental status.
- Age at diagnosis.
- Time from diagnosis/therapy.
- Inherent tissue sensitivities and capacity for normal tissue repair.
- Hormonal milieu.
- Function of organs not affected by cancer treatment.
- Socioeconomic status.
- Health habits.
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. 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:[21,22]
- Previous cancer.
- Cancer therapy.
- Genetic predisposition.
- Lifestyle behaviors.
- Comorbid conditions.
Part of long-term follow-up is also focused on appropriate screening of educational and vocational progress. Specific treatments for childhood cancer, especially those that directly impact nervous system structures, may result in sensory, motor, and neurocognitive deficits that may have adverse consequences on functional status, educational attainment, and future vocational opportunities. In support of this, a CCSS investigation observed the following:
- 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 is also emphasized. Health-promoting behaviors are stressed for survivors of childhood cancer. Targeted educational efforts appear to be worthwhile in the following areas:
- Smoking, excess alcohol use, and illicit drug use to reduce the risk of organ toxicity and, potentially, subsequent neoplasms.
- Healthy dietary practices and active lifestyle to reduce 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.[26-28]
Access to risk-based survivor care
Most childhood cancer survivors do not receive recommended risk-based care. The CCSS observed the following:
- 88.8% of survivors reported receiving some form of medical care.
- 31.5% reported receiving care that focused on their previous cancer (survivor-focused care).
- 17.8% reported receiving survivor-focused care that included advice about risk reduction and discussion or ordering of screening tests.
- Surveillance for new cases of cancer was very low in survivors at the highest risk of colon, breast, or skin cancer, suggesting that survivors and their physicians need education about the risk of subsequent neoplasms and recommended surveillance.
Access to health insurance appears to play an important role in risk-based survivor care. Lack of access to health insurance affects the following:
- Cancer-related visits. In a 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.
- Health outcomes. In a study comparing health care outcomes for long-term survivors of adolescent and young adult (AYA) cancer with young adults who have a cancer history, the proportion of uninsured survivors did not differ between the two groups.
- Financial burden. Subgroups of AYA survivors may be at additional risk of 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.[33,34] Legislation, like the Health Insurance Portability and Accountability Act legislation,[35,36] has improved access and retention of health insurance among survivors, although the quality and limitations associated with these policies have not been well studied.
Transition of Survivor Care
Long-term follow-up programs
Transition of care from the pediatric to adult health care setting is necessary for most childhood cancer survivors in the United States.
When available, multidisciplinary long-term follow-up programs in the pediatric cancer center work collaboratively with community physicians to provide care for childhood cancer survivors. This type of shared-care has been proposed as the optimal model to facilitate coordination between the cancer center oncology team and community physician groups providing survivor care.
An essential service of long-term follow-up programs is the organization of an individualized survivorship care plan that includes the following:
- Details about therapeutic interventions undertaken for childhood cancer and their potential health risks (e.g., chemotherapy type and cumulative dose, radiation treatment fields and dose, surgical procedures, blood product transfusions, and hematopoietic cell transplantation).
- Personalized health screening recommendations.
- 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 (refer to the COG Survivorship Guidelines, Appendix 1).
COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers
To facilitate survivor and provider access to succinct information to guide risk-based care, COG investigators have organized a compendium of exposure- and risk-based health surveillance recommendations, with the goal of standardizing the care of childhood cancer survivors.
The compendium of resources includes the following:
- Long-Term Follow-Up Guidelines. 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 evaluation 2 or more years after completion of therapy.
- Health Links. 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.
- Comprehensive reviews. 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 published several comprehensive reviews that address specific late effects of childhood cancer.[39-50]
Information concerning late effects is summarized in tables throughout this summary.
Several groups have undertaken research to evaluate the yield from risk-based screening as recommended by the COG and other pediatric oncology cooperative groups.[9,51,52] Pertinent considerations in interpreting the results of these studies include:
- Variability in the cohort’s age at treatment.
- Age at screening.
- Time from cancer treatment.
- Participation bias.
Collectively, these studies demonstrate that screening identifies a substantial proportion of individuals with previously unrecognized, treatment-related health complications of varying degrees of severity. Study results have also identified low-yield evaluations that have encouraged revisions of screening recommendations. Ongoing research is evaluating cost effectiveness of screening in the context of consideration of benefits, risks, and harms.
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- Armstrong GT, Kawashima T, Leisenring W, et al.: Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol 32 (12): 1218-27, 2014. [PUBMED Abstract]
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- Yeh JM, Nekhlyudov L, Goldie SJ, et al.: A model-based estimate of cumulative excess mortality in survivors of childhood cancer. Ann Intern Med 152 (7): 409-17, W131-8, 2010. [PUBMED Abstract]
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