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Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version - National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version

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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:
  • Population-based registries.[3-5]
  • Self-reported outcomes (provided through large-scale cohort studies).[6,7]
  • Medical assessments.[8,9]
Studies reporting outcomes in survivors who have been well characterized regarding clinical status and treatment exposures, and comprehensively ascertained for specific effects through medical assessments, typically provide the highest quality data to establish the occurrence and risk profiles for late cancer treatment–related toxicity. Regardless of study methodology, it is important to consider selection and participation bias of the cohort studies in the context of the findings reported.

Prevalence of Late Effects in Childhood Cancer Survivors

Late effects are commonly experienced by adults who have survived childhood cancer; the prevalence of late effects increases as time from cancer diagnosis elapses. Population-based studies support excess hospital-related morbidity among childhood and young adult cancer survivors compared with age- and sex-matched controls.[3-5,10-14]
Research has demonstrated that among adults treated for cancer during childhood, late effects contribute to a high burden of morbidity, including the following:[6,8,9,15-18]
  • 60% to more than 90% develop one or more chronic health conditions.
  • 20% to 80% experience severe or life-threatening complications during adulthood.
Using the cumulative burden metric—which incorporates multiple health conditions and recurrent events into a single metric that takes into account competing risks—by age 50 years, survivors in the St. Jude Lifetime Cohort experienced an average of 17.1 chronic health conditions, 4.7 of which were severe/disabling, life threatening, or fatal.[17] This is in contrast to the cumulative burden in matched community controls who experienced 9.2 chronic health conditions, 2.3 of which were severe/disabling, life threatening, or fatal (refer to Figure 1).[17]
ENLARGECharts showing distribution of cumulative burden by age among childhood cancer survivors of specific pediatric cancer subtypes and community controls participating in St. Jude Lifetime Cohort Study.
Figure 1. Figure shows distribution of cumulative burden by age among childhood cancer survivors of specific pediatric cancer subtypes and community controls participating in the St. Jude Lifetime Cohort Study. The cumulative burden at age 30 years and rate of cumulative burden growth is variable across cancer subtypes and organ systems. Reprinted from The LancetExit Disclaimer, Volume 390, Issue 10112, Bhakta N, Liu Q, Ness KK, Baassiri M, Eissa H, Yeo F, Chemaitilly W, Ehrhardt MJ, Bass J, Bishop MW, Shelton K, Lu L, Huang S, Li Z, Caron E, Lanctot J, Howell C, Folse T, Joshi V, Green DM, Mulrooney DA, Armstrong GT, Krull KR, Brinkman TM, Khan RB, Srivastava DK, Hudson MM, Yasui Y, Robison LL, The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE), Pages 2569–2582, Copyright (2017), with permission from Elsevier.
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).
  • Treatment intensity and treatment era.
Childhood Cancer Survivor Study (CCSS) investigators demonstrated that the elevated risk of morbidity and mortality among aging survivors in the cohort increases beyond the fourth decade of life. By age 50 years, the cumulative incidence of a self-reported severe, disabling, life-threatening, or fatal health condition was 53.6% among survivors, compared with 19.8% among a sibling control group. Among survivors who reached age 35 years without a previous severe, disabling, life-threatening, or fatal health condition, 25.9% experienced a new grade 3 to grade 5 health condition within 10 years, compared with 6.0% of healthy siblings (refer to Figure 2).[6]
The presence of serious, disabling, and life-threatening chronic health conditions adversely affects the health status of aging survivors, with the greatest impact on functional impairment and activity limitations. Predictably, chronic health conditions have been reported to contribute to a higher prevalence of emotional distress symptoms in adult survivors than in population controls.[19] Female survivors demonstrate a steeper trajectory of age-dependent decline in health status than do male survivors.[20] 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.[9]
ENLARGECharts showing the cumulative incidence of chronic health conditions by age among survivors and siblings.
Figure 2. Cumulative incidence of chronic health conditions for (A) grades 3 to 5 chronic health conditions, (B) multiple grade 3 to 5 conditions in survivors, (C) multiple grade 3 to 5 conditions in siblings, (D) conditioned based on no previous grade 3 to 5 conditions among survivors by ages 25, 35, or 45, and (E) conditioned based on no previous grade 3 to 5 conditions among siblings by ages 25, 35, or 45. Gregory T. Armstrong, Toana Kawashima, Wendy Leisenring, Kayla Stratton, Marilyn Stovall, Melissa M. Hudson, Charles A. Sklar, Leslie L Robison, Kevin C. Oeffinger; Aging and Risk of Severe, Disabling, Life-Threatening, and Fatal Events in the Childhood Cancer Survivor Study; Journal of Clinical Oncology, volume 32, issue 12, pages 1218-1227. Reprinted with permission. © (2014) American Society of Clinical Oncology. All rights reserved.
CCSS investigators also evaluated the impact of race and ethnicity on late outcomes by comparing late mortality, subsequent neoplasms, and chronic health conditions in Hispanic (n = 750) and non-Hispanic black (n = 694) participants with non-Hispanic white participants (n = 12,397).[21] The following results were observed:
  • Cancer treatment did not account for disparities in mortality, chronic health conditions, or subsequent neoplasms observed among the groups.
  • Differences in socioeconomic status and cardiovascular risk factors affected risk. All-cause mortality was higher among non-Hispanic black participants than among other groups, but this difference disappeared after adjustment for socioeconomic status.
  • Risk of developing diabetes was elevated among racial/ethnic minority groups even after adjustment for socioeconomic status and obesity.
  • Non-Hispanic blacks had a higher likelihood of reporting cardiac conditions, but this risk diminished after adjusting for cardiovascular risk factors.
  • Nonmelanoma skin cancer was not reported by non-Hispanic blacks, a finding that has been replicated by others,[22] and Hispanic participants had a lower risk than did non-Hispanic white participants.
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. The CCSS reported that with decreased cumulative dose and frequency of therapeutic radiation use over treatment decades from 1970 to 1999, survivors have experienced a significant decrease in risk of subsequent neoplasms.[23] With the exception of survivors requiring intensive multimodality therapy, sometimes including hematopoietic cell transplantation, 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.
A CCSS investigation examined temporal patterns in the cumulative incidence of severe to fatal chronic health conditions among survivors treated from 1970 to 1999. The 20-year cumulative incidence of at least one grade 3 to 5 chronic condition decreased significantly, from 33.2% for survivors diagnosed between 1970 and 1979, to 29.3% for those diagnosed between 1980 and 1989, to 27.5% for those diagnosed between 1990 and 1999, compared with a 4.6% incidence in a sibling cohort. The overall decrease in incidence of chronic conditions across the three treatment decades was, in part, because of a substantial reduction of endocrinopathies, subsequent malignant neoplasms, musculoskeletal conditions, and gastrointestinal conditions, whereas the cumulative incidence of hearing loss increased during this time. Declines in morbidity were not uniform across the diagnosis groups or condition types because of differences in treatment and survival patterns over time (refer to Figure 3 for more information).[24]
ENLARGEGraphs showing the cumulative incidence of grade 3–5 chronic health conditions in 5-year survivors of childhood cancer by diagnosis decade and siblings.
Figure 3. Cumulative incidence of grade 3–5 chronic health conditions in 5-year survivors of childhood cancer by diagnosis decade and siblings. (A) Cumulative incidence of a first grade 3–5 condition. (B) Cumulative incidence of two or more grade 3–5 conditions. The shaded area represents the 95% confidence interval (CI). The number of participants at risk (number censored) at each 5-year interval post-diagnosis is listed below the x-axis. The number censored does not include those who experienced a competing risk event (death from a cause other than a grade 5 chronic condition). Reprinted from The Lancet OncologyExit Disclaimer, Volume 19, Issue 12, Todd M Gibson, Sogol Mostoufi-Moab, Kayla L Stratton, Wendy M Leisenring, Dana Barnea, Eric J Chow, Sarah S Donaldson, Rebecca M Howell, Melissa M Hudson, Anita Mahajan, Paul C Nathan, Kirsten K Ness, Charles A Sklar, Emily S Tonorezos, Christopher B Weldon, Elizabeth M Wells, Yutaka Yasui, Gregory T Armstrong, Leslie L Robinson, Kevin C Oeffinger, Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970–99: a report from the Childhood Cancer Survivor Study cohort. Pages 1590-1601, Copyright (2018), with permission from Elsevier.

Mortality

Late effects also contribute to an excess risk of premature death among long-term survivors of childhood cancer as observed in the following:
  • Several studies of very large cohorts of survivors have reported early mortality among individuals treated for childhood cancer compared with age- and sex-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.[25-31]
  • An analysis of the CCSS and Surveillance, Epidemiology, and End Results (SEER) data that evaluated conditional survival demonstrated a subsequent 5-year survival rate of 92% or higher among most diagnoses at 5 years, 10 years, 15 years, and 20 years. Among those who had survived at least 5 years from diagnosis, the probability of all-cause mortality in the next 10 years was 8.8% in the CCSS and 10.6% in the SEER study, with neoplasms accounting for cause of death in approximately 75% of survivors.[32]
Despite high premature morbidity rates, overall mortality has decreased over time.[25,33-36] 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.

Survivors of adolescent and young adult cancers

Little information is available on the conditional probabilities of death among adolescent and young adult cancer patients who survive more than 5 years after their diagnosis. Using SEER data, conditional relative survival up to 25 years after diagnosis was studied in a cohort of adolescent and young adult patients (N = 205,954) diagnosed with a first malignant cancer (thyroid, melanoma, testicular, breast, lymphoma, leukemia, and central nervous system [CNS] tumors). For all cancer types combined, among individuals who survived up to 5 years, subsequent 5-year relative survival exceeded 95% by 7 years after diagnosis. According to this study, most adolescent and young adult cancer patients who survived at least 7 years after diagnosis experienced little difference in survival from that of the general population. For specific cancer types, including CNS tumors, female breast cancer, Hodgkin lymphoma, and leukemia, evidence of excess mortality risk persisted, or re-emerged, more than 10 years after a cancer diagnosis. Conditional relative survival was lowest for adolescent and young adult patients with CNS tumors, although patients aged 15 to 29 years demonstrated a higher survival rate than did patients aged 30 to 39 years at the time of diagnosis of their CNS tumors.[37]

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:[25,33]
  • 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 the following:
  • 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-related factors
  • Tumor location.
  • Direct tissue effects.
  • Tumor-induced organ dysfunction.
  • Mechanical effects.
Treatment-related factors
  • 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.
Host-related factors
  • Sex.
  • 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

Risk-based screening

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:[38]
  • Previous cancer.
  • Cancer therapy.
  • Genetic predisposition.
  • Lifestyle behaviors.
  • Comorbid conditions.
  • Sex.
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.[39] In support of this, a CCSS investigation observed the following:[40]
  • 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,[41] 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:[42]
  • Abstinence from 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.[42-44]

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.[45]
  • 31.5% reported receiving care that focused on their previous cancer (survivor-focused care).[45]
  • 17.8% reported receiving survivor-focused care that included advice about risk reduction and discussion or ordering of screening tests.[45]
  • 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.[46]
  • Sociodemographic factors have been linked to declining rates of follow-up care over time from diagnosis. CCSS participants who were male, had a household income of less than $20,000 per year, and had lower educational attainment (high school education or less) were more likely to report no care at their most recent follow-up survey. This trend is of concern because the prevalence of chronic health conditions increases with longer elapsed time from cancer diagnosis in adults treated for cancer during childhood.[47]
  • An ancillary study that included 975 adult survivors of childhood cancer identified factors associated with having the recommended risk-based, cancer-related medical visits. The relative risk of having a cancer-related visit was higher among survivors who:[48]
    • Assigned a greater importance to these visits.
    • Perceived a greater susceptibility to health problems.
    • Had experienced a cancer-related chronic health problem that was moderate to life-threatening.
    • Were seeing a primary care provider for a cancer-related problem.
    • Had received a cancer treatment summary.
    • Expressed greater confidence in physicians’ abilities to address questions and concerns.
Access to health insurance appears to play an important role in risk-based survivor care.[49,50] Lack of access to health insurance affects the following:
  • Cancer-related visits. In the CCSS, 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.[49]
  • Health care outcomes. In a study comparing health care outcomes for long-term survivors of adolescent and young adult (AYA) cancer with young adults who have no cancer history, the proportion of uninsured survivors did not differ between the two groups.[51]
  • 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.[51]
Overall, lack of health insurance remains a significant concern for survivors of childhood cancer because of health issues, unemployment, and other societal factors.[52,53] Legislation, including the Health Insurance Portability and Accountability Act (HIPAA),[54,55] 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 to Survivor Care

Long-term follow-up programs

Transition of care from the pediatric to adult health care setting is necessary for most childhood cancer survivors in the United States.
When available, multidisciplinary long-term follow-up programs in the pediatric cancer center work collaboratively with community physicians to provide care for childhood cancer survivors. This type of shared care has been proposed as the optimal model to facilitate coordination between the cancer center oncology team and community physician groups providing survivor care.[56]
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.
A CCSS investigation that evaluated perceptions of future health and cancer risk highlighted the importance of continuing education of survivors during long-term follow-up evaluations. A substantial subgroup of adult survivors reported a lack of concern about future health (24%) and subsequent cancer risks (35%), even after exposure to treatments associated with increased risks. These findings present concerns that survivors may be less likely to engage in beneficial screenings and risk-reduction activities.[57]
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 1Exit Disclaimer).

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.[58]
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 CancersExit Disclaimer 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.[59]
  • 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.[60-72]
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.[9,73,74] 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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