Late Effects of Treatment for Childhood Cancer (PDQ®): Treatment - Health Professional Information [NCI]
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.[3,4,5]
- 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 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; 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.[3,4,5,10,11,12]
Research has demonstrated that among adults treated for cancer during childhood, late effects contribute to a high burden of morbidity, including the following:[6,8,9,13,14,15]
- 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.[15] 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).[15]
Figure 1. Figure shows 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. The cumulative burden at age 30 years and rate of cumulative burden growth is variable across cancer subtypes and organ systems. Reprinted from The Lancet, Volume 390, Issue 10112, Bhakta N, Liu Q, Ness KK, Baassiri M, Eissa H, Yeo F, Chemaitilly W, Ehrhardt MJ, Bass J, Bishop MW, Shelton K, Lu L, Huang S, Li Z, Caron E, Lanctot J, Howell C, Folse T, Joshi V, Green DM, Mulrooney DA, Armstrong GT, Krull KR, Brinkman TM, Khan RB, Srivastava DK, Hudson MM, Yasui Y, Robison LL, The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE), Pages 2569-2582, Copyright (2017), with permission from Elsevier.
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.[16] Female survivors demonstrate a steeper trajectory of age-dependent decline in health status than do male survivors.[17] 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]
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).[18] 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,[19] 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.[20] 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.
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.[21,22,23,24,25,26,27]
- An analysis of the CCSS and Surveillance, Epidemiology, and End Results (SEER) 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.[28]
Despite high premature morbidity rates, overall mortality has decreased over time.[21,29,30,31] 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:[21,29]
- 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:[32]
- 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.[33] In support of this, a CCSS investigation observed the following:[34]
- 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,[35] 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:[36]
- 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.[36,37,38]
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.[39]
- 31.5% reported receiving care that focused on their previous cancer (survivor-focused care).[39]
- 17.8% reported receiving survivor-focused care that included advice about risk reduction and discussion or ordering of screening tests.[39]
- 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.[40]
- 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.[41]
Access to health insurance appears to play an important role in risk-based survivor care.[42,43] 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.[42]
- 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 no cancer history, the proportion of uninsured survivors did not differ between the two groups.[44]
- 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.[44]
Overall, lack of health insurance remains a significant concern for survivors of childhood cancer because of health issues, unemployment, and other societal factors.[45,46] Legislation, including the Health Insurance Portability and Accountability Act (HIPAA),[47,48] 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.[49]
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.[50]
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.[51]
- 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.[52,53,54,55,56,57,58,59,60,61,62,63,64]
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.[9,65,66] 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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- Wasilewski-Masker K, Mertens AC, Patterson B, et al.: Severity of health conditions identified in a pediatric cancer survivor program. Pediatr Blood Cancer 54 (7): 976-82, 2010.
Late Effects of the Cardiovascular System
Cardiovascular disease, after recurrence of the original cancer and development of second primary cancers, has been reported to be the leading cause of premature mortality among long-term childhood cancer survivors.[1,2,3,4,5]
Evidence (excess risk of premature cardiovascular mortality):
- Among more than 20,000 North American 5-year survivors of childhood cancer (in the Childhood Cancer Survivor Study [CCSS]) treated from 1970 to 1986, participants had a standardized mortality ratio of 7.0 (95% confidence interval [CI], 5.9-8.2) for cardiac mortality, which translated to 0.36 excess deaths per 1,000 person-years.[1]
- All-cause circulatory disease was associated with an absolute excess risk of 3.4% (95% CI, 2.8%-4.2%) among nearly 18,000 5-year survivors in the British CCSS who were diagnosed with cancer between 1950 and 1991. Individual standardized mortality ratios for cardiac, cerebrovascular, and other circulatory diseases ranged from 3.5 to 5.2.[2]
By age 45 years, the overall cumulative incidence of severe, life-threatening, or fatal cardiac events has been reported to be approximately 5% for coronary artery disease and heart failure separately and 1% to 2% for valve disorders and arrhythmias.[6] Compared with siblings, 5-year survivors had relative risks (RRs) approaching, if not exceeding, tenfold for heart failure, coronary artery disease, and cerebrovascular disease.[7] The burden of subclinical disease is likely much greater.[8]
The specific late effects covered in this section include the following:
- Cardiomyopathy/heart failure.
- Ischemic heart disease.
- Pericardial heart disease.
- Valve disease.
- Conduction disorders.
- Cerebrovascular disease.
The section will also briefly discuss the influence of related conditions such as hypertension, dyslipidemia, and diabetes in relation to these late effects, but not directly review in detail those conditions as a consequence of childhood cancer treatment. A comprehensive review on long-term cardiovascular toxicity in childhood and young adult survivors of cancer, issued by the American Heart Association, has been published.[5]
Overall, there has been a wealth of studies focused on the topic of cardiac events among childhood cancer survivors. In addition to many smaller studies not covered in detail here, the literature includes very large cohort studies that are either hospital based,[6,8,9,10,11,12] clinical trial based,[13,14] or population based,[2,4] many with up to several decades of follow-up. However, even with decades of follow-up, the average age of these populations may still be relatively young (young or middle adulthood). And while the risk of serious cardiovascular outcomes may be very high relative to the age-matched general population, the absolute risk often remains low, limiting the power of many studies. Among the very large studies featuring thousands of survivors, the main limitation has been inadequate ability to clinically ascertain late cardiovascular complications, with a greater reliance on either administrative records (e.g., death registries) and/or self-report or proxy-report.
While each study design has some inherent biases, the overall literature, based on a combination of self-reported outcomes, clinical ascertainment, and administrative data sources, is robust in concluding that certain cancer-related exposures predispose survivors toward a significantly greater risk of cardiovascular morbidity and mortality. Although late effects research often lags behind changes in contemporary therapy, many therapies linked to cardiovascular late effects remain in common use today.[15,16] Ongoing research will be important to ensure that newer targeted agents being introduced today do not result in unexpected cardiovascular effects.[17]
Evidence (selected cohort studies describing cardiovascular outcomes):
- A multicenter French cohort of 3,162 5-year survivors treated between 1942 and 1986 were monitored for a median of 26 years.[12]
- The cumulative incidence of any cardiac disease (ischemic heart disease, heart failure, arrhythmia, or valve and pericardial diseases) by age 40 years was 11% (7% if restricted to those that warranted medical intervention).
- Risk increased with higher anthracycline and radiation doses, particularly anthracycline doses of 250 mg/m2 or more and heart radiation doses of 15 Gy or higher.
- A significant interaction was identified between radiation dose, anthracycline exposure, and attained age.
- A Dutch hospital-based cohort of 1,362 5-year childhood cancer survivors (median attained age, 29.1 years) were monitored from diagnosis for a median of 22.2 years.[11]
- The 30-year cause-specific cumulative incidence of symptomatic cardiac events (congestive heart failure, cardiac ischemia, valve disease, arrhythmia, and/or pericarditis) was significantly increased after treatment with both anthracyclines and cardiac radiation (12.6%; 95% CI, 4.3%-20.3%), anthracyclines alone (7.3%; 95% CI, 3.8%-10.7%), and cardiac radiation alone (4.0%; 95% CI, 0.5%-7.4%) compared with other treatments.
- A report from the CCSS that featured over 14,000 5-year survivors examined detailed dose-response to both radiation therapy and chemotherapy (anthracycline) in relation to self-reported (or death caused by) myocardial infarction, congestive heart failure, pericardial disease, and valvular abnormalities.[10]
- Cardiac radiation doses of 15 Gy or higher were associated with substantially greater risk compared with the risk seen in nonirradiated survivors, while anthracycline doses of 250 mg/m2 or more were associated with a substantially increased risk of congestive heart failure, pericardial disease, and valvular abnormalities, independent of radiation exposure.
- Overall, the cumulative incidence of adverse cardiac outcomes continued to rise more than 30 years after original cancer diagnosis.
- A follow-up study from the CCSS demonstrated that the cumulative incidence of these serious cardiac events continued to increase beyond age 45 years.[6]
- The risk of these events was potentiated (i.e., beyond what would be expected by an additive model) by the presence of concurrent, but potentially modifiable, conditions such as obesity, dyslipidemia, diabetes, and, particularly, hypertension.
- Hypertension was independently associated with all serious cardiac outcomes (RRs, sixfold to 19-fold), even after adjustment for anthracycline use and chest irradiation.
- Of 670 survivors of Hodgkin lymphoma (HL) who were treated at St. Jude Children's Research Hospital (SJCRH) and have lived 10 or more years, 348 patients were clinically assessed in the St. Jude Lifetime Cohort Study.[18]
- Overall, survivors had a higher cumulative burden (a novel measurement of disease burden that incorporates multiple health conditions and recurrent events into a single metric) than did community controls, with the total grade 3 to 5 cumulative burden among survivors at age 30 years being comparable to that of community controls at 50 years.
- At age 50 years, the cumulative incidence of those survivors experiencing at least one grade 3 to grade 5 cardiovascular condition was 45.5% (95% CI, 36.6%-54.3%), compared with 15.7% (95% CI, 7.0%-24.4%) in community controls.
- Myocardial infarction and structural heart defects were the major contributors to the excess grade 3 to grade 5 cumulative burden in survivors, whereas there was no notable difference in survivors and community controls at age 50 years for grades 3 to 5 cumulative burden of dyslipidemia and essential hypertension.
- Another St. Jude Lifetime Cohort Study compared the prevalence of major and minor electrocardiography (ECG) abnormalities among 2,715 participants and 268 community controls.[19]
- Major ECG abnormalities were significantly more prevalent in survivors (10.7%) than in controls (4.9%); the most common abnormalities included isolated ST-T wave abnormalities (7.2%), evidence of myocardial infarction (3.7%), and left ventricular hypertrophy with strain pattern (2.8%).
- Treatment exposures predicting increased risk of major abnormalities were anthracycline doses of 300 mg/m2 or greater (odds ratio [OR], 1.7; 95% CI, 1.1-2.5) and cardiac radiation (OR, 2.1; 95% CI, 1.5-2.9 [1-1,999 cGy]; OR, 2.6; 95% CI, 1.6-3.9 [2,000-2,999 cGy]; OR, 10.5; 95% CI, 6.5-16.9 [≥3,000 cGy]).
- Major ECG abnormalities were predictive of all-cause mortality (HR, 4.0; 95% CI, 2.1-7.8).
- In the Teenage and Young Adult Cancer Survivor Study, cardiac mortality was investigated in more than 200,000 5-year survivors of adolescent and young adult cancer (aged 15-39 years).[20]
- Age at diagnosis and type of cancer were identified as being important in determining risk of cardiac mortality.
- The standardized mortality ratios (SMR) for all cardiac disease combined was greatest for individuals diagnosed at age 15 to 19 years (4.2), decreasing to 1.2 for individuals aged 35 to 39 years (2P for trend < .0001). This age effect was most apparent for survivors of Hodgkin lymphoma, who were also found to be at greatest risk overall.
Using data from four large, well-annotated childhood cancer survivor cohorts (CCSS, National Wilms Tumor Study Group, the Netherlands, and SJCRH), a heart failure risk calculator based on readily available demographic and treatment characteristics has been created and validated, which may provide more individualized clinical heart failure risk estimation for 5-year survivors of childhood cancer who have recently completed therapy and up through age 40 years. One limitation of this estimator is that because of the young age of participants at the time of baseline prediction (5-year survival), information on conventional cardiovascular conditions such as hypertension, dyslipidemia, or diabetes could not be incorporated.[21]
Treatment Risk Factors
Chemotherapy (in particular, anthracyclines and anthraquinones) along with radiation therapy both independently and in combination, increase the risk of cardiovascular disease in survivors of childhood cancer and are considered to be the most important risk factors contributing to premature cardiovascular disease in this population (refer to Figure 3).[11]
Figure 3. (A, B) Marginal (Kaplan-Meier) and (C-E) cause-specific (competing risk) cumulative incidence of cardiac events (CEs) in childhood cancer survivors stratified according to different treatment groups. (A) Marginal cumulative incidence for all CEs, stratified according to potential cardiotoxic (CTX) therapy or no CTX therapy, log-rank P < .001. (B) Marginal cumulative incidence for all CEs, stratified according to different CTX therapies, log-rank P < .001. (C) Cause-specific cumulative incidence for congestive heart failure, stratified according to different treatment groups, log-rank P < .001. (D) Cause-specific cumulative incidence for cardiac ischemia, stratified according to cardiac irradiation (RTX) or no RTX, log-rank P = .01. (E) Cause-specific cumulative incidence for valvular disease, stratified according to RTX or no RTX, log-rank P < .001. The shaded colorized background areas refer to the 95% CIs. Ant, anthracycline. Helena J. van der Pal, Elvira C. van Dalen, Evelien van Delden, Irma W. van Dijk, Wouter E. Kok, Ronald B. Geskus, Elske Sieswerda, Foppe Oldenburger, Caro C. Koning, Flora E. van Leeuwen, Huib N. Caron, Leontien C. Kremer, High Risk of Symptomatic Cardiac Events in Childhood Cancer Survivors, Journal of Clinical Oncology, volume 30, issue 13, pages 1429-1437. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.
Anthracyclines and related agents
Anthracyclines (e.g., doxorubicin, daunorubicin, idarubicin, and epirubicin) and anthraquinones (e.g., mitoxantrone) are known to directly injure cardiomyocytes through the formation of reactive oxygen species and inducing mitochondrial apoptosis.[5,22] The downstream results of cell death are changes in heart structure, including wall thinning, which leads to ventricular overload and pathologic remodeling that, over time, leads to dysfunction and eventual clinical heart failure.[23,24,25,26]
Risk factors for anthracycline-related cardiomyopathy include the following:[27]
- Cumulative dose, particularly greater than 250 mg/m2 to 300 mg/m2.
- Younger age at time of exposure, particularly children younger than 5 years.
- Increased time from exposure.
Among these factors, cumulative dose appears to be the most significant (refer to Figure 4).[9] While it is not completely certain whether there is a truly safe lower dose threshold, doses in excess of 250 mg/m2 to 300 mg/m2 have been associated with a substantially increased risk of cardiomyopathy, with cumulative incidences exceeding 5% after 20 years of follow-up, and in some subgroups, reaching or exceeding 10% cumulative incidence by age 40 years.[9,10,21,24,26] Concurrent chest or heart radiation therapy also further increases risk of cardiomyopathy,[11,12,21] as does the presence of other cardiometabolic traits such as hypertension.[6,28] While development of clinical heart failure can occur within a few years after anthracycline exposure, in most survivors, even those who received very high doses, clinical manifestations may not occur for decades.
Figure 4. Risk of anthracycline-induced clinical heart failure (A-CHF) according to cumulative anthracycline dose. Reprinted from European Journal of Cancer, Volume 42, Elvira C. van Dalen, Helena J.H. van der Pal, Wouter E.M. Kok, Huib N. Caron, Leontien C.M. Kremer, Clinical heart failure in a cohort of children treated with anthracyclines: A long-term follow-up study, Pages 3191-3198, Copyright (2006), with permission from Elsevier.
Anthracycline dose equivalency
It remains unclear how best to add together doses of different anthracycline agents. A variety of anthracycline equivalence formulas (in relation to doxorubicin) have been used; however, they are largely based on hematologic toxicity equivalence, and may not necessarily be the same for cardiac toxicity.[21,29,30] Most pediatric professional societies and groups have generally considered daunorubicin equivalent, or near equivalent, to doxorubicin, although historically lower ratios have been proposed as well.[31] A large analysis of over 15,000 childhood cancer survivors who were monitored to age 40 years found that daunorubicin may be significantly less cardiotoxic than doxorubicin (equivalence ratio, 0.5 [95% CI, 0.2-0.7]).[32]
Other agents such as idarubicin, epirubicin, and mitoxantrone (an anthraquinone) were designed to reduce cardiac toxicity while maintaining similar antitumor effect, although data supporting this are primarily limited to adult cancer patients.[33] Similarly, data on whether liposomal formulations of anthracyclines reduce cardiac toxicity in children also are limited.[33]
Anthracycline cardioprotection
Cardioprotective strategies that have been explored include the following:
- New, less cardiotoxic agents and liposomal formulations.
- Prolonged infusion time. Prolonged infusion time has been associated with reduced heart failure in adult patients but not in children.[34,35]
-
Concurrent administration of cardioprotectants. A variety of agents have been tested as cardioprotectants (amifostine, acetylcysteine, calcium channel blockers, carvedilol, coenzyme Q10, and L-carnitine), but none have been definitively shown to be beneficial and are not considered standard of care.[36,37]
There are more data for dexrazoxane as a cardioprotectant, but again, mainly in adult cancer patients, for whom it is approved by the U.S. Food and Drug Administration for women with metastatic breast cancer who have received 300 mg/m2 of anthracyclines and who may benefit from further anthracycline-based therapy.[36] Pediatric data show that dexrazoxane may ameliorate some markers of early cardiac toxicity up to 5 years after therapy.[38,39,40,41] Dexrazoxane may be associated with an increased risk of acute toxicities in some regimens, however.[42] While these data suggest that dexrazoxane does protect the heart in the short term, there are not yet long-term data showing the impact of dexrazoxane on cardiac health.
As a topoisomerase inhibitor, dexrazoxane's association with secondary cancers, particularly secondary leukemia, remains controversial.[41,43] One report that described the use of concurrent etoposide and doxorubicin observed an increased risk of acute myeloid leukemia (AML) among patients treated with dexrazoxane.[44] However, all other pediatric randomized controlled and nonrandomized studies have not observed an increased risk of subsequent malignant neoplasms in conjunction with dexrazoxane,[41] and the risk of secondary AML was not increased among children treated with dexrazoxane who were registered in the Pediatric Health Information Systems database.[45] Another randomized trial reported an increased risk of secondary brain tumors among survivors treated with cranial irradiation, but this risk did not differ among patients who did and did not receive dexrazoxane.[40]
Radiation therapy
While anthracyclines directly damage cardiomyocytes, radiation therapy primarily affects the fine vasculature of affected organs.[5]
Cardiovascular disease
Late effects of radiation therapy to the heart specifically include the following:
- Delayed pericarditis, which can present abruptly or as a chronic pericardial effusion.
- Pancarditis, which includes pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
- Cardiomyopathy (in the absence of significant pericardial disease), which can occur even without anthracycline exposure.
- Ischemic heart disease.
- Functional valve injury, often aortic.
- Conduction defects.
These cardiac late effects are related to the following:
- Individual radiation fraction size.
- Volume of the heart that is exposed to radiation.
- Total radiation dose. Various studies have demonstrated a substantially increased risk of these outcomes with higher radiation doses, particularly doses to the heart exceeding 35 Gy (refer to Figure 5).[10,11,12,14,46,47] At higher radiation doses, rates of heart failure, pericardial disease, and valvular disease have been reported to exceed 10% after 20 to 30 years. Although some studies suggest that doses less than 5 Gy may be associated with an increased risk of cardiovascular disease, the RR is small (i.e., 2.5) and the 95% CI is large (i.e., 0.2-41.5); moreover, the dosimetric analyses are generally estimations of incidental cardiac exposure.[3,10,11,12] Consequently, additional confirmatory data are needed for an accurate assessment of risk at very low cardiac doses.
Figure 5. 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.
Similar to anthracyclines, manifestation of these late effects may take years, if not decades, to present. Finally, patients who were exposed to both radiation therapy affecting the cardiovascular system and cardiotoxic chemotherapy agents are at even greater risk of late cardiovascular outcomes.[12]
Cerebrovascular disease
Cerebrovascular disease after radiation therapy exposure is another potential late effect for survivors. While brain tumor survivors have had traditionally the greatest risk, other survivors exposed to cranial irradiation (≥18 Gy) and neck irradiation (≥40 Gy), such as leukemia and lymphoma survivors, have also been reported to be at increased risk.[48,49,50,51] In lymphoma survivors who only received chest and/or neck radiation therapy, cerebrovascular disease is thought to be caused by large-vessel atherosclerosis and cardiac embolism.[49]
As with cardiac outcomes, risk increases with cumulative dose received. One study (N = 325) reported that the stroke hazard increased by 5% (hazard ratio [HR], 1.05; 95% CI, 1.01-1.09; P = .02), with each 1 Gy increase in the radiation dose, leading to a cumulative incidence of 2% for the first stroke after 5 years and 4% after 10 years.[52] Survivors who experienced stroke were then at significantly greater risk of experiencing recurrent strokes.
Evidence (selected studies describing prevalence of and risk factors for cerebrovascular [CVA]/vascular disease):
- In a multicenter retrospective Dutch study, among 2,201 5-year survivors of HL diagnosed before age 51 years (25% pediatric-aged patients), with a median follow-up of 18 years, 96 patients developed cerebrovascular disease (CVA and transient ischemic attacks [TIA]).[49]
- Most ischemic events were from large-artery atherosclerosis (36%) or cardiac embolism (24%).
- The cumulative incidence of ischemic CVA or TIA 30 years after lymphoma treatment was 7%.
- The overall standardized incidence ratio (SIR) was 2.2 for CVA and 3.1 for TIA. However, SIR estimates appeared to be greater among childhood cancer survivors, with SIRs of 3.8 for CVA and 7.6 for TIA.
- Irradiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (HR, 2.5; 95% CI, 1.1-5.6) versus no radiation therapy. Treatment with chemotherapy was not associated with increased risk.
- Hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease.
- French investigators observed a significant association between radiation dose to the brain and long-term cerebrovascular mortality among 4,227 5-year childhood cancer survivors (median follow-up, 29 years).[50]
- Survivors who received more than 50 Gy to the prepontine cistern had an HR of 17.8 (95% CI, 4.4-73.0) for 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.
- A retrospective, single-center, cohort study of 325 survivors of pediatric cancer treated with cranial irradiation or cervical irradiation determined that cranial irradiation put survivors at a high risk of first and recurrent strokes.[52]
- The cumulative incidence of first stroke was 4% (95% CI, 2.0%-8.4%) at 10 years after radiation therapy. The stroke hazard increased by 5% (HR, 1.05; 95% CI, 1.01-1.09; P = .02) with each 1 Gy increase in the radiation dose.
- The cumulative incidence of recurrent stroke was 38% (95% CI, 17%-69%) at 5 years and 59% (95% CI, 27%-92%) at 10 years after the first stroke.
- CCSS investigators evaluated the rates and predictors of recurrent stroke among participants who reported a first stroke.[53]
- Among responding participants (329 of 443), 271 confirmed a first stroke (at median age, 19 years) and 70 reported a second stroke (at median age, 32 years).
- Independent predictors of recurrent stroke included treatment with a cranial radiation therapy dose of 50 Gy or higher (vs. no cranial radiation therapy), history of hypertension, and age 40 years or older at first stroke (vs. age 0-17 years).
- The 10-year cumulative incidence of late recurrent stroke was 21% overall, and 33% for those treated with 50 Gy or higher of cranial radiation therapy.
- A retrospective study of 3,172 5-year survivors of childhood cancer monitored for a mean time of 26 years was constituted from the Euro2K cohort, which included eight centers in France and the United Kingdom. Radiation doses to the Circle of Willis were estimated for each of the 2,202 children who received radiation therapy.[54]
- Patients who received radiation therapy had an 8.5-fold increased risk (95% CI, 6.3-11.0) of stroke in contrast to a nonelevated risk for patients not receiving radiation therapy.
- The RR was 15.7 (95% CI, 4.9-50.2) for doses of 40 Gy or higher.
- At age 45 years, the cumulative incidence was 11.3% (95% CI, 7.1%-17.7%) in patients who received 10 Gy or higher to the Circle of Willis, compared with 1% in the general population.
- Investigators from the Teenage and Young Adult Cancer Survivor Study (N = 178,962) evaluated the risk of hospitalization for a cerebrovascular event among 5-year survivors of cancer diagnosed between age 15 and 39 years.[55]
- The investigators found that survivors of adolescent and young adult cancers had a 40% increased risk of hospitalization for cerebrovascular event compared with the general population.
- Survivors of central nervous system (CNS) tumors (standardized hospitalization ratios [SHR], 4.6), head and neck tumors (SHR, 2.6), and leukemia (SHR, 2.5) had the highest risk of hospitalization for a cerebrovascular complication.
- Males had significantly higher absolute excess risks than did females, especially among head and neck tumor survivors. By age 60 years, 9% of CNS tumor survivors, 6% of head and neck tumor survivors, and 5% of leukemia survivors had been hospitalized for a cerebrovascular event.
- The risk of hospitalization for a cerebral infarction was particularly increased among survivors of a CNS tumor older than 60 years, whereas this risk was increased across all ages in survivors of head and neck tumors.
Conventional cardiovascular conditions
Various cancer treatment exposures may also directly or indirectly influence the development of hypertension, diabetes mellitus, and dyslipidemia.[5] These conditions remain important among cancer survivors, as they do in the general population, in that they are independent risk factors in the development of cardiomyopathy, ischemic heart disease, and cerebrovascular disease.[6,49,56,57,58]
Childhood cancer survivors should be closely screened for the development of these cardiovascular conditions because they represent potentially modifiable targets for intervention. This includes being aware of related conditions such as obesity and various endocrinopathies (e.g., hypothyroidism, hypogonadism, growth hormone deficiency) that may be more common among subsets of childhood cancer survivors; if these conditions are untreated/uncontrolled, they may be associated with a metabolic profile that increases cardiovascular risk.[8,59]
Other Risk Factors
Some, but not all, studies suggest that female sex may be associated with a greater risk of anthracycline-related cardiomyopathy.[5] In addition, there is emerging evidence that genetic factors, such as single nucleotide polymorphisms in genes regulating drug metabolism and distribution, could explain the heterogeneity in susceptibility to anthracycline-mediated cardiac injury.[60,61,62,63,64,65] However, these genetic findings still require additional validation before being incorporated into any clinical screening algorithm.[66]
Knowledge Deficits
While much knowledge has been gained over the past 20 years in better understanding the long-term burden and risk factors for cardiovascular disease among childhood cancer survivors, many areas of inquiry remain, and include the following:
- Radiation may have both direct and indirect effects on vascular endothelium, contributing to vascular damage beyond the primary radiation field.[67]
- The long-term effects of lower radiation doses, particularly in light of newer technology that allows radiation oncologists to reduce the dose to critical organs outside of the tumor field, remain to be determined.[68]
- The long-term effects of many newer anticancer agents that are based on molecular targets remains unclear, although some of them are known to have shorter-term cardiac toxicity.[17]
- The efficacy of cardioprotective strategies, including the use of alternative anthracycline formulations that appear promising in adults, requires further study in children.[37]
Screening, Surveillance, and Counseling
Various national groups, including the National Institutes of Health-sponsored COG (refer to Table 2), have published recommendations regarding screening and surveillance for cardiovascular and other late effects among childhood cancer survivors.[69,70,71,72,73] Professional groups (both pediatric and adult) have developed evidence-based health surveillance recommendations and have identified knowledge deficits to help guide future studies.[27,74] Adult oncology professional and national groups have also issued recommendations related to cardiac toxicity monitoring.[75]
At this point, there is no clear evidence (at least through age 50 years or 30-40 years posttreatment) that there is a plateau in risk that occurs after a certain time among survivors exposed to cancer treatments associated with cardiovascular late effects.[3,4,10,11,48,76] Thus, some form of life-long surveillance is recommended, even if the cost-effectiveness of certain screening strategies remains unclear.[27,77,78,79]
However, a growing amount of literature is beginning to establish the yield from these screening studies, which will help inform future guidelines.[8,80,81,82] In these studies, for example, among adult-aged survivors of childhood cancer, evidence for cardiomyopathy on the basis of echocardiographic changes was found in approximately 6% of at-risk survivors. Overall, in a cohort of more than 1,000 survivors (median age, 32 years), nearly 60% of screened at-risk survivors had some clinically ascertained cardiac abnormality identified.[8]
Given the growing evidence that conventional cardiovascular conditions such as hypertension, dyslipidemia, and diabetes substantially increase the risk of more serious cardiovascular disease among survivors, clinicians should carefully consider baseline and follow-up screening and treatment of these comorbid conditions that impact cardiovascular health (refer to Table 2).[6,49,56,57]
There is also emerging evidence that adoption of healthier lifestyle factors may decrease future cardiovascular morbidity in at-risk survivors.[83] Thus, similar to the general population, survivors are counseled about maintaining a healthy weight, participating in regular physical activity, adhering to a heart-healthy diet, and abstaining from smoking.
In addition to releasing a comprehensive, publicly available (online) set of guidelines, the COG has also put together a series of handouts on cardiovascular and related topics, including lifestyle choices written for a lay audience, available on the same website.
| Predisposing Therapy | Potential Cardiovascular Effects | Health Screening |
|---|---|---|
| a The Children's Oncology Group (COG) guidelines also cover other conditions that may influence cardiovascular risk also exist, such as obesity and diabetes mellitus/impaired glucose metabolism. | ||
| b Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
| Any anthracycline and/or any radiation to the heart | Cardiac toxicity (arrhythmia, cardiomyopathy/heart failure, pericardial disease, valve disease, ischemic heart disease) | Yearly medical history and physical exam |
| Electrocardiogram at entry into long-term follow-up | ||
| Echocardiogram at entry into long-term follow-up, periodically repeat based on previous exposures and other risk factors | ||
| Radiation to the area (≥40 Gy) | Carotid and/or subclavian artery disease | Yearly medical history and physical exam; consider Doppler ultrasound 10 years after exposure |
| Radiation to the brain/cranium (≥18 Gy) | Cerebrovascular disease (cavernomas, Moyamoya, occlusive cerebral vasculopathy, stroke) | Yearly medical history and physical exam |
| Radiation to the abdomen | Diabetes | Diabetes screen every 2 years |
| Total-body irradiation | Dyslipidemia; diabetes | Fasting lipid profile and diabetes screen every 2 years |
| Heavy metals (carboplatin, cisplatin), ifosfamide, and methotrexate exposure; radiation to the kidneys; hematopoietic cell transplantation; nephrectomy | Hypertension (as a consequence of renal toxicity) | Yearly blood pressure and urinalysis; renal function laboratory studies at entry into long-term follow-up |
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- Galper SL, Yu JB, Mauch PM, et al.: Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood 117 (2): 412-8, 2011.
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- Bowers DC, Liu Y, Leisenring W, et al.: Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J Clin Oncol 24 (33): 5277-82, 2006.
- De Bruin ML, Dorresteijn LD, van't Veer MB, et al.: Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma. J Natl Cancer Inst 101 (13): 928-37, 2009.
- Haddy N, Mousannif A, Tukenova M, et al.: Relationship between the brain radiation dose for the treatment of childhood cancer and the risk of long-term cerebrovascular mortality. Brain 134 (Pt 5): 1362-72, 2011.
- van Dijk IW, van der Pal HJ, van Os RM, et al.: Risk of Symptomatic Stroke After Radiation Therapy for Childhood Cancer: A Long-Term Follow-Up Cohort Analysis. Int J Radiat Oncol Biol Phys 96 (3): 597-605, 2016.
- Mueller S, Sear K, Hills NK, et al.: Risk of first and recurrent stroke in childhood cancer survivors treated with cranial and cervical radiation therapy. Int J Radiat Oncol Biol Phys 86 (4): 643-8, 2013.
- Fullerton HJ, Stratton K, Mueller S, et al.: Recurrent stroke in childhood cancer survivors. Neurology 85 (12): 1056-64, 2015.
- El-Fayech C, Haddy N, Allodji RS, et al.: Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries. Int J Radiat Oncol Biol Phys 97 (2): 278-286, 2017.
- Bright CJ, Hawkins MM, Guha J, et al.: Risk of Cerebrovascular Events in 178 962 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The TYACSS (Teenage and Young Adult Cancer Survivor Study). Circulation 135 (13): 1194-1210, 2017.
- Mueller S, Fullerton HJ, Stratton K, et al.: Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 86 (4): 649-55, 2013.
- Lipshultz SE, Landy DC, Lopez-Mitnik G, et al.: Cardiovascular status of childhood cancer survivors exposed and unexposed to cardiotoxic therapy. J Clin Oncol 30 (10): 1050-7, 2012.
- Chao C, Xu L, Bhatia S, et al.: Cardiovascular Disease Risk Profiles in Survivors of Adolescent and Young Adult (AYA) Cancer: The Kaiser Permanente AYA Cancer Survivors Study. J Clin Oncol 34 (14): 1626-33, 2016.
- Nandagopal R, Laverdière C, Mulrooney D, et al.: Endocrine late effects of childhood cancer therapy: a report from the Children's Oncology Group. Horm Res 69 (2): 65-74, 2008.
- Lipshultz SE, Lipsitz SR, Kutok JL, et al.: Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia. Cancer 119 (19): 3555-62, 2013.
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- Aminkeng F, Bhavsar AP, Visscher H, et al.: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat Genet 47 (9): 1079-84, 2015.
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- Davies SM: Getting to the heart of the matter. J Clin Oncol 30 (13): 1399-400, 2012.
- Brouwer CA, Postma A, Hooimeijer HL, et al.: Endothelial damage in long-term survivors of childhood cancer. J Clin Oncol 31 (31): 3906-13, 2013.
- Maraldo MV, Jørgensen M, Brodin NP, et al.: The impact of involved node, involved field and mantle field radiotherapy on estimated radiation doses and risk of late effects for pediatric patients with Hodgkin lymphoma. Pediatr Blood Cancer 61 (4): 717-22, 2014.
- Landier W, Bhatia S, Eshelman DA, et al.: Development of risk-based guidelines for pediatric cancer survivors: the Children's Oncology Group Long-Term Follow-Up Guidelines from the Children's Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol 22 (24): 4979-90, 2004.
- Skinner R, Wallace WH, Levitt GA, et al.: Long-term follow-up of people who have survived cancer during childhood. Lancet Oncol 7 (6): 489-98, 2006.
- Shankar SM, Marina N, Hudson MM, et al.: Monitoring for cardiovascular disease in survivors of childhood cancer: report from the Cardiovascular Disease Task Force of the Children's Oncology Group. Pediatrics 121 (2): e387-96, 2008.
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- Sieswerda E, Postma A, van Dalen EC, et al.: The Dutch Childhood Oncology Group guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors. Ann Oncol 23 (8): 2191-8, 2012.
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- Chen AB, Punglia RS, Kuntz KM, et al.: Cost effectiveness and screening interval of lipid screening in Hodgkin's lymphoma survivors. J Clin Oncol 27 (32): 5383-9, 2009.
- Wong FL, Bhatia S, Landier W, et al.: Cost-effectiveness of the children's oncology group long-term follow-up screening guidelines for childhood cancer survivors at risk for treatment-related heart failure. Ann Intern Med 160 (10): 672-83, 2014.
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- Jones LW, Liu Q, Armstrong GT, et al.: Exercise and risk of major cardiovascular events in adult survivors of childhood hodgkin lymphoma: a report from the childhood cancer survivor study. J Clin Oncol 32 (32): 3643-50, 2014.
Late Effects of the Central Nervous System
Neurocognitive
Neurocognitive late effects are most commonly observed after treatment of malignancies that require central nervous system (CNS)-directed therapies. While there is considerable evidence published about this outcome, its quality is often limited by small sample size, cohort selection and participation bias, cross-sectional versus longitudinal evaluations, and variable time of assessment from treatment exposures. CNS-directed therapies include the following:
- Cranial radiation therapy.
- Systemic therapy with high-dose methotrexate or cytarabine.
- Intrathecal chemotherapy.
Children with brain tumors or acute lymphoblastic leukemia (ALL) are most likely to be affected. Risk factors for the development of neurocognitive late effects include the following:[1,2,3,4,5,6,7]
- Female sex.
- Younger age at the time of treatment.
- Tumor location.
- Higher cranial radiation dose.
- Treatment with cranial radiation therapy and/or chemotherapeutic agents (systemic or intrathecal).
It should be noted that the cognitive phenotypes observed in childhood survivors of ALL and CNS tumors may differ from traditional developmental disorders. For example, the phenotype of attention problems in ALL and brain tumor survivors appears to differ from developmental attention-deficit/hyperactivity disorder in that few survivors demonstrate significant hyperactivity/impulsivity, but instead have associated difficulties with processing speed and executive function.[8,9]
Neurocognitive outcomes in brain tumor survivors
Survival rates have increased over recent decades for children with brain tumors; however, long-term cognitive effects caused by illness and associated treatments are a well-established morbidity in this group of survivors. In childhood and adolescent brain tumor survivors, risk factors for adverse neurocognitive effects include the following:
- Cranial radiation therapy. Cranial radiation therapy has been associated with the highest risk of long-term cognitive morbidity, particularly in younger children.[10] There is an established dose-response relationship, with patients who receive higher-dose cranial radiation therapy consistently performing more poorly on intellectual measures.[11] Radiation dose to specific regions of the brain, including the temporal lobes and hippocampi, have been shown to significantly impact longitudinal intelligence quotient (IQ) scores and academic achievement scores among children treated with craniospinal irradiation for medulloblastoma.[12]
- Tumor site.[10,13]
- Shunted hydrocephalus.[10,14,15]
- Postsurgical cerebellar mutism.[16]
- Auditory difficulties, including sensorineural hearing loss.[14,17]
- History of stroke.[18]
- Seizures.[13,19]
The negative impact of radiation treatment has been characterized by changes in IQ scores, which have been noted to drop about 2 to 5 years after diagnosis; the decline continues 5 to 10 years afterward, although less is known about potential stabilization or further decline of IQ scores several decades after diagnosis.[20,21,22] The decline in IQ scores over time typically reflects the child's failure to acquire new abilities or information at a rate similar to that of his or her peers, rather than a progressive loss of skills and knowledge.[11] Affected children also may experience deficits in other cognitive areas, including academic difficulties (reading and math) and problems with attention, processing speed, memory, and visual or perceptual motor skills.[21,23,24]
These changes in cognitive functioning may be partially explained by radiation-induced reduction of normal-appearing white matter volume or integrity of white matter pathways, as evaluated through magnetic resonance imaging (MRI).[25,26,27] In fact, reduced white matter integrity has been directly linked to slowed cognitive processing speed in survivors of brain tumors,[28] while greater white matter volume has been associated with better working memory, particularly in females.[27] It should be noted that data emerging from contemporary protocols show that using lower doses of cranial radiation and more targeted treatment volumes appears to reduce the severity of neurocognitive effects of therapy.[13,15,29]
Data are emerging regarding cognitive outcomes after proton radiation to the CNS.[30,31] To date, these studies largely describe IQ changes during early (less than 5 years from radiation) follow-up and are limited by retrospective analysis of cognitive outcomes among relatively small clinically heterogeneous pediatric brain tumor cohorts and use of historically treated photon patients or population standards as comparison groups. Study results demonstrating lack of difference in slopes of IQ change among photon- and proton-treated patients [30] and significant declines in cognitive processing speed among patients treated with proton radiation [31] underscore the importance of longitudinal follow-up to determine whether proton radiation provides a clinically meaningful benefit in sparing cognitive function compared with photon radiation.
In addition, studies are beginning to examine cognitive outcomes in histologically distinct subtypes of brain tumors. For example, data from a sample of 121 medulloblastoma patients demonstrated variation in cognitive outcomes by four distinct molecular subgroups and differences in patterns of change over time.[32] This study highlights the need for future research to consider neurocognitive outcomes across biologically distinct subtypes of childhood brain tumors.
Longitudinal cohort studies have provided insight into the trajectory and predictors of cognitive decline among survivors of CNS tumors.
Evidence (predictors of cognitive decline among survivors of CNS tumors):
- St. Jude Children's Research Hospital (SJCRH) studied 78 children younger than 20 years (mean, 9.7 years) diagnosed with low-grade glioma.[33]
- Cognitive decline after 54 Gy of conformal cranial radiation therapy was noted (refer to Figure 6).
- Age at time of cranial irradiation was more important than was cranial radiation dose in predicting cognitive decline, with children younger than 5 years estimated to experience the greatest cognitive decline.
Figure 6. 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.
- A study of 126 medulloblastoma survivors treated with 23.4 Gy or 36 Gy to 39.6 Gy of cranial spinal radiation (with a conformal boost dose of 55.8 Gy to the primary tumor bed) assessed processing speed, attention, and memory performance.[34]
- Processing speed scores declined significantly over time, while less decline was observed in attention and memory performance. Higher doses of radiation and younger age at diagnosis predicted slower processing speed over time.
- Studies of working memory and academic achievement in patients enrolled on the same medulloblastoma trial (St. Jude SJMB03 [NCT00085202]) indicated that performance was largely within the age-expected range up to 5 years postdiagnosis,[35,36] although in both studies, posterior fossa syndrome, higher cranial radiation dose, and younger age at diagnosis predicted worse performance over time. In addition, serious hearing loss was associated with intellectual and academic decline over time.[36]
- Canadian investigators evaluated the impact of radiation (dose and boost volume) and neurologic complications on patterns of intellectual functioning in a cohort of 113 medulloblastoma survivors (mean age at diagnosis, 7.5 years; mean time from diagnosis to last assessment, 6 years).[37]
- Survivors treated with reduced-dose craniospinal radiation therapy plus tumor bed boost showed stable intellectual functioning.
- Neurological complications, such as hydrocephalus requiring cerebrospinal fluid diversion and mutism, and treatment with higher doses and larger boost volumes of radiation resulted in intellectual declines with distinctive trajectories.
Although adverse neurocognitive outcomes observed 5 to 10 years after treatment are presumed to be pervasive, and potentially worsen over time, few empirical data are available regarding the neurocognitive functioning in very long-term survivors of CNS tumors.
- Among adult survivors participating in the Childhood Cancer Survivor Study (CCSS), CNS tumor survivors (n = 802) self-reported significantly more problems with attention/processing speed, memory, emotional control, and organization than did survivors of non-CNS malignancies (n = 5,937) and sibling controls (n = 382).[4] Moreover, a large proportion of CNS tumor survivors treated with cranial irradiation reported impairment on measures of attention/processing speed (42.9%-73.3%) and memory (14.3%-37.4%), with differences observed by diagnosis and cranial radiation dose.[38]
- A study of 224 adult survivors of pediatric brain tumors participating in the St. Jude Lifetime Cohort Study revealed that 20% to 30% of the survivors demonstrated severe neurocognitive impairment (defined as at least two standard deviations below normative mean) on tests of intelligence, memory, and executive function (e.g., planning, organization, and flexibility).[13] Among adults in the general population, the expected impairment rate at this threshold is 2%. Survivors who received whole-brain cranial irradiation were 1.5 to 3 times more likely to have severe neurocognitive impairment than were survivors who did not receive any cranial irradiation. Hydrocephalus with shunt placement and seizures were also associated with increased risk of impairment. Importantly, this study relied on direct assessment of neurocognitive skills while the previous CCSS report relied on self-report of problems.[13]
The neurocognitive consequences of CNS disease and treatment may have a considerable impact on functional outcomes for brain tumor survivors.
- In childhood and adolescence, neurocognitive deficits have been associated with poor social adjustment, including problems with peer relations, social withdrawal, and reduced social skills.[39,40]
- CNS tumor survivors are more likely to need special education services than are survivors of other malignancies.[41]
- Adult CNS tumor survivors are less likely to live independently, marry, and graduate from college than are survivors of other malignancies and siblings.[41,42,43]
Neurocognitive outcomes in acute lymphoblastic leukemia (ALL) survivors
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. To minimize the risk of late sequelae, patients are stratified for treatment according to their risk of relapse. Cranial irradiation is reserved for the fewer than 20% of children who are considered at high risk for CNS relapse.[44]
Although low-risk, standard-risk, and most high-risk patients are treated with chemotherapy-only protocols, early reports of neurocognitive late effects for ALL patients were based on heterogeneously treated groups of survivors who received combinations (simultaneously or sequentially) of intrathecal chemotherapy, radiation therapy, and high-dose chemotherapy, making it difficult to differentiate the impact of the individual treatment components. However, outcome data are increasingly available regarding the risk of neurocognitive late effects in survivors of childhood ALL treated with chemotherapy only.
ALL and cranial radiation
In survivors of ALL, cranial radiation therapy may result in clinical and radiographic neurologic late sequelae, including the following:
- Clinical leukoencephalopathy. Clinical leukoencephalopathy characterized by spasticity, ataxia, dysarthria, dysphagia, hemiparesis, and seizures is uncommon after contemporary ALL therapy. In contrast, neuroimaging frequently demonstrates white matter abnormalities among survivors treated with cranial irradiation and/or high-dose methotrexate. Radiographic leukoencephalopathy has been reported in up to 80% of children on some treatment regimens. Higher doses and more courses of intravenous methotrexate have been reported to increase risk of leukoencephalopathy.[45] In many patients, white matter anomalies are transient and decrease in prevalence, extent, and intensity with longer elapsed time from completion of therapy.[45] Leukoencephalopathy results in smaller white matter volumes that have been correlated with cognitive deficits. Although these abnormalities are mild among the irradiated patients (overall IQ fall of approximately 10 points), those who have received higher doses at a young age may have significant learning difficulties.[46,47]
- Neuropsychological deficits. Deficits in neuropsychological functions such as visual-motor integration, processing speed, attention, and short-term memory are reported in children treated with 18 Gy to 24 Gy.[46,48,49] Females and children treated at a younger age are more vulnerable to the adverse impact of cranial radiation on the developing brain.[50] The decline in intellectual functioning appears to be progressive, showing more impairment of cognitive function with increasing time since radiation therapy.[50,51] Limited studies suggest that long-term survivors of childhood ALL treated with cranial irradiation are at risk of progressive decline consistent with early-onset mild cognitive impairment; this risk is most prominent among those treated with cranial radiation doses of 24 Gy.[52,53]
ALL and chemotherapy-only CNS therapy
Because of its penetrance into the CNS, systemic methotrexate has been used in a variety of low-dose and high-dose regimens for leukemia CNS prophylaxis. Systemic methotrexate in high doses with or without radiation therapy can lead to an infrequent but well-described leukoencephalopathy, which has been linked to neurocognitive impairment.[45] When neurocognitive outcomes after radiation therapy and chemotherapy-only regimens are directly compared, the evidence suggests a better outcome for those treated with chemotherapy alone, although some studies show no significant difference.[54,55]
Compared with cranial irradiation, chemotherapy-only CNS-directed treatment produces neurocognitive deficits involving processes of attention, speed of information processing, memory, verbal comprehension, visual-spatial skills, visual-motor functioning, and executive functioning; global intellectual function is typically preserved.[48,54,56,57,58,59] Few longitudinal studies evaluating long-term neurocognitive outcome report adequate data for a decline in global IQ after treatment with chemotherapy alone.[57] 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.[54,60,61] Risk factors for poor neurocognitive outcome after chemotherapy-only CNS-directed treatment are younger age and female sex.[59,62,63]
Reduced cognitive status has been observed in association with reduced integrity in neuroanatomical regions essential in memory formation (e.g., reduced hippocampal volume with increased activation and thinner parietal cortices). However, the long-term impact of these prevalent neurocognitive and neuroimaging abnormalities on functional status in aging adults treated for childhood ALL, particularly those treated with contemporary approaches using chemotherapy alone, remains an active area of research.
Evidence (neurocognitive functioning in large pediatric cancer survivor cohorts):
- In the St. Jude Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed the following:[64]
- A higher risk for below-average performance on a measure of sustained attention but not on measures of intellectual functioning, academic skills, or memory.
- The risk of cognitive deficits correlated with treatment intensity but not with age at diagnosis or sex.
- Prolonged follow-up (average, 7.7 years from diagnosis) of this cohort demonstrated that intelligence was within normal limits compared with population expectations, but measures of executive function, processing speed, and memory were less than population means. Higher plasma methotrexate was associated with executive dysfunction, thicker cerebral cortex, and higher activity in frontal brain regions on functional MRI.
- These results underscore the need for continued follow-up as this population ages to better characterize the prevalence and magnitude of cognitive deficits after CNS-directed therapy with chemotherapy alone.[65]
- In a large prospective study of neurocognitive outcomes in children with newly diagnosed ALL, 555 children were randomly assigned to receive CNS-directed therapy according to risk group.[66]
- Low-risk group: Intrathecal methotrexate versus high-dose methotrexate.
- High-risk group: High-dose methotrexate versus 24 Gy of cranial radiation therapy.
- A significant reduction in IQ scores (4-7 points) was observed in all patient groups when compared with controls, regardless of the CNS treatment delivered.
- Children younger than 5 years at diagnosis were more likely to have IQs below 80 at 3 years posttherapy than were children older than 5 years at diagnosis, irrespective of treatment allocation, suggesting that younger children are more vulnerable to treatment-related neurologic toxic effects.
- Persistent cognitive deficits and progressive intellectual decline have been observed in cohorts of adults treated for ALL during childhood and associated with reduced educational attainment and unemployment.[47,50,53] The results of a study of more than 500 adult survivors of childhood ALL (average, 26 years postdiagnosis) showed the following:[47]
- Survivors demonstrated increased rates of impairment across all neurocognitive domains (ranging from 28.6%-58.9% for each domain).
- Rate of severe impairment increased as a function of cranial radiation dose, but was common among survivors treated with lower doses of cranial irradiation and chemotherapy only.
- Impairment in executive function skills increased with time since diagnosis in a cranial radiation dose-dependent manner; impairment in intellect, academics, and memory progressively increased with younger age at treatment in a cranial radiation dose-dependent manner; and neurocognitive impairment was related to functional outcomes as adults, including reduced likelihood of college graduation and full-time employment.
- Continued monitoring by health professionals is needed to identify neurocognitive problems that may emerge over time.
ALL and steroid therapy
The type of steroid used for ALL systemic treatment may affect cognitive functioning. In a study that involved long-term neurocognitive testing (mean follow-up, 9.8 years) of 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment, no meaningful differences in mean neurocognitive and academic performance scores were observed.[67] In contrast, in a study of 567 adult survivors of childhood leukemia (mean age, 33 years; mean time since diagnosis, 26 years) dexamethasone exposure was associated with increased risk of impairment in attention (relative risk [RR], 2.12; 95% confidence interval [CI], 1.11-4.03) and executive function (RR, 2.42; 95% CI, 1.20-4.91), independent of methotrexate exposure. Intrathecal hydrocortisone also increased risk of attention problems (RR, 1.24; 95% CI, 1.05-1.46).[47]
Other cancers
Neurocognitive abnormalities have been reported in other groups of cancer survivors. In a study of adult survivors of childhood non-CNS cancers (including ALL, n = 5,937), 13% to 21% of survivors reported impairment in task efficiency, organization, memory, or emotional regulation. This rate of impairment was approximately 50% higher than that reported in the sibling comparison group. Factors such as diagnosis before age 6 years, female sex, cranial radiation therapy, and hearing impediment were associated with impairment.[49] In addition, emerging data suggest that the development of chronic health conditions in adulthood may contribute to cognitive deficits in long-term survivors of non-CNS cancers.
Neurocognitive abnormalities have been reported for the following cancers:
- Osteosarcoma. In a study evaluating neurocognitive function among 80 long-term survivors of osteosarcoma (mean time since diagnosis, 24.7 years), survivors demonstrated lower mean scores in reading skills, attention, memory, and processing speed than did community controls. The presence of cardiac, pulmonary, and endocrine conditions were significantly associated with worse performance on measures of memory and processing speed.[68]
-
Retinoblastoma. Early studies of intellectual functioning in survivors of retinoblastoma suggested above average intelligence among bilateral survivors compared with unaffected siblings and the general population, especially those who were blind as a result of their disease.[69,70,71]
Later studies have yielded mixed results. For example, serial assessment of cognitive and adaptive functioning in a group of survivors younger than 6 years revealed declines in developmental functioning over time. The most pronounced declines were observed in patients with 13q deletion.[72] In contrast, a study of long-term adult survivors, who were on average 33 years postdiagnosis, demonstrated largely average cognitive functioning across domains of intelligence, memory, attention, and executive function.[73] These conflicting findings may be attributed, in part, to the low test-retest reliability of measures used to assess cognitive outcomes at a very young age, as well as temporal differences in treatment exposures.
- Lymphoma. Survivors of lymphoma have not historically been considered at risk of developing neurocognitive late effects. However, reports suggest that more than two-thirds of survivors of childhood non-Hodgkin lymphoma experience at least mild neurocognitive impairment, including severe deficits in executive function (13%), attention (9%), and memory (4%).[74] Similarly, in a study of 62 adult survivors of childhood Hodgkin lymphoma, survivors demonstrated worse performance on measures of sustained attention, short- and long-term memory, and cognitive fluency when compared with national normative data.[75] Importantly, measures of cardiac and pulmonary function also were associated with neurocognitive impairment in this group of survivors.
Stem cell transplantation
Cognitive and academic consequences of stem cell transplantation in children have also been evaluated and include, but are not limited to, the following:
- In a report from SJCRH in which 268 patients were treated with stem cell transplantation, minimal risk of late cognitive and academic sequelae was observed.[76]
- Subgroups of patients were at relatively higher risk, including patients who underwent unrelated donor transplantation, received total-body irradiation, and developed graft-versus-host disease (GVHD). However, these differences were small relative to differences in premorbid functioning, particularly those associated with socioeconomic status.
- In a series of 38 patients who underwent hematopoietic stem cell transplantation (HSCT) and received intrathecal chemotherapy, significant declines in visual motor skills and memory scores were noted within the first year posttransplant.[77]
- By 3 years posttransplant, there was an improvement in visual motor development scores and memory scores, but new deficits were evident in long-term memory scores.
- By 5 years posttransplant, there were progressive declines in verbal skills and performance skills, and new deficits were 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 after stem cell transplantation 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 typically associated with white matter was compared with performance on measures thought to correlate with gray matter function. Composite white matter scores were significantly lower than composite gray matter scores, thereby supporting the belief that white matter damage contributes to neurocognitive late effects in this population.[78]
Neurologic Sequelae
Risk of neurologic complications may be predisposed by the following:
- Tumor location.
- Neurosurgery.
- Cranial radiation therapy.
- 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 secondary effects such as seizures and cerebrovascular complications. Numerous reports describe abnormalities of CNS integrity and function, but such studies are typically limited by small sample size, cohort selection and participation bias, cross-sectional ascertainment of outcomes, and variable time of assessment from treatment exposures. In contrast, relatively few studies comprehensively or systematically ascertain outcomes related to peripheral nervous system function.
Neurologic complications that may occur in survivors of childhood cancer include the following:
-
Seizures. The development of seizures may occur secondary to tumor mass effect within the CNS and/or as a result of neurotoxic CNS-directed therapies.
- An early report from the CCSS estimated the prevalence of seizures to be 25% among 5-year survivors of childhood brain tumors, with 6.5% of those constituting a late first occurrence. Radiation dose of 30 Gy or higher to any cortical segment of the brain was associated with a twofold elevated risk of developing a late seizure disorder.[79] In a CCSS report of 380 5-year survivors of medulloblastoma/primitive neuroectodermal tumors, survivors who received more than 50 Gy of cranial irradiation to the temporal/frontal lobe were 2.1 times more likely to develop seizures than were survivors who received less than 50 Gy of radiation.[80]
- Among survivors of childhood leukemia in the CCSS (N = 4,151; 64.5% treated with cranial irradiation), 6.1% reported the development of a seizure disorder, and seizures occurred more than 5 years after diagnosis in 51% of these patients.[81]
- Leukoencephalopathy. Clinical or radiographic leukoencephalopathy has been reported after cranial irradiation and high-dose systemic methotrexate administration. Younger patients and those treated with cranial radiation doses higher than 24 Gy are more vulnerable to reduced white matter volumes associated with leukoencephalopathy.[48,53,82,83] White matter changes may be accompanied by other neuroimaging abnormalities, including dystrophic calcifications, cerebral lacunae, and cerebral atrophy.
-
Peripheral neuropathy. Vinca alkaloid agents (vincristine and vinblastine) and cisplatin may cause peripheral neuropathy. This condition presents during treatment and appears to improve or clinically resolve after completion of therapy.[84] 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 affect functional status in aging survivors.[85]
Among adult survivors of extracranial solid tumors of childhood (median time from diagnosis, 25 years), standardized assessment of neuromuscular function disclosed motor impairment in association with vincristine exposure and sensory impairment in association with cisplatin exposure.[86] Survivors with sensory impairment demonstrated a higher prevalence of functional performance limitations related to poor endurance and mobility restrictions. These studies underscore the importance of assessment and referral to rehabilitative services to optimize functional outcomes among long-term survivors.
- Stroke. Refer to the Cerebrovascular disease section of this summary for information on stroke.
-
Other neurologic sequelae. In a report from the CCSS that compared self-reported neurologic late effects among 4,151 adult survivors of childhood ALL with siblings, survivors were at 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 irradiation for ALL and those who suffered relapse were at increased risk for late-onset neurologic sequelae.[81]
In a cross-sectional study that evaluated neurologic morbidity and quality of life in 162 survivors of childhood ALL (median age at evaluation, 15.7 years; median time from completion of therapy, 7.4 years) in concert with a clinical neurologic exam, neurologic symptoms were present in 83% of survivors, but symptom-related morbidity was low and quality of life was high in most survivors. The most commonly reported symptoms included neuropathy (63%), headache (46.9%), dizziness (33.3%), and back pain (22.8%). Female sex, ten doses or more of intrathecal chemotherapy, cranial irradiation, CNS leukemia at diagnosis, and history of ALL relapse were associated with neurologic morbidity.[7]
Neuroimaging studies of irradiated and nonirradiated ALL survivors demonstrate a variety of CNS abnormalities, including leukoencephalopathy, cerebral lacunes, cerebral atrophy, and dystrophic calcifications (mineralizing microangiopathy). Among these, abnormalities of cerebral white matter integrity and volume have been correlated with neurocognitive outcomes.[45,53,82,83]
Cavernomas have also been observed in ALL survivors treated with cranial irradiation. They have been speculated to result from angiogenic processes as opposed to tumorigenesis.[87]
Table 3 summarizes CNS late effects and the related health screenings.
| Predisposing Therapy | Neurologic Effects | Health Screening |
|---|---|---|
| IQ = intelligence quotient; IT = intrathecal; IV = intravenous. | ||
| a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
| Platinum agents (carboplatin, cisplatin) | Peripheral sensory neuropathy | Neurologic exam |
| Plant alkaloid agents (vinblastine, vincristine) | Peripheral sensory or motor neuropathy (areflexia, weakness, foot drop, paresthesias) | Neurologic exam |
| Methotrexate (high dose IV or IT); cytarabine (high dose IV or IT); radiation impacting the brain | Clinical leukoencephalopathy (spasticity, ataxia, dysarthria, dysphagia, hemiparesis, seizures); headaches; seizures; sensory deficits | History: cognitive, motor, and/or sensory deficits, seizures |
| Neurologic exam | ||
| Radiation impacting cerebrovascular structures | Cerebrovascular complications (stroke, moyamoya, occlusive cerebral vasculopathy) | History: transient/permanent neurological events |
| Blood pressure | ||
| Neurologic exam | ||
| Neurosurgery-brain | Motor and/or sensory deficits (paralysis, movement disorders, ataxia, eye problems [ocular nerve palsy, gaze paresis, nystagmus, papilledema, optic atrophy]); seizures | Neurologic exam |
| Neurology evaluation | ||
| Neurosurgery-brain | Hydrocephalus; shunt malfunction | Abdominal x-ray |
| Neurosurgery evaluation | ||
| Neurosurgery-spine | Neurogenic bladder; urinary incontinence | History: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary stream |
| Neurosurgery-spine | Neurogenic bowel; fecal incontinence | History: chronic constipation, fecal soiling |
| Rectal exam | ||
| Predisposing Therapy | Neuropsychological Effects | Health Screening |
| Methotrexate (high-dose IV or IT); cytarabine (high-dose IV or IT); radiation impacting the brain; neurosurgery-brain | Neurocognitive deficits (executive function, memory, attention, processing speed, etc.); learning deficits; diminished IQ; behavioral change | Assessment of educational and vocational progress |
| Formal neuropsychological evaluation | ||
Psychosocial
Many childhood cancer survivors report reduced quality of life or other adverse psychosocial outcomes. Evidence for adverse psychosocial adjustment after childhood cancer has been derived from a number of sources, ranging from patient-reported or proxy-reported outcomes to data from population-based registries. The former may be limited by small sample size, cohort selection and participation bias, and variable methods and venues (clinical vs. distance-based survey) of assessments. The latter is often not well correlated with clinical and treatment characteristics that permit the identification of survivors at high risk of psychosocial deficits.
Survivors with neurocognitive deficits are particularly vulnerable to adverse psychosocial outcomes that affect achievement of expected social outcomes during adulthood.
- In a population-based study of adult survivors of CNS tumors diagnosed in childhood or adolescence, survivors had significantly poorer self-perception and self-esteem than did individuals in the general population. Female sex, persistent visible physical sequelae, specific tumor type, and treatment with cranial radiation therapy predicted poor self-perception outcomes.[88]
- In a series of CNS malignancy survivors (n = 802) reported from the CCSS, adverse outcome on multiple indicators of successful adult adjustment (educational achievement, income, employment, and marital status) were most prevalent among survivors who reported neurocognitive dysfunction.[4]
- Collectively, studies evaluating psychosocial outcomes among CNS tumor survivors indicate deficits in social competence that worsen over time.[89] This includes problems with peer rejection and isolation in childhood/adolescence, as well as the inability to develop friendships and romantic relationships as adults.
- In a CCSS study that evaluated 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 than were siblings in the comparison group.[42]
- In a St. Jude Lifetime Cohort study of 224 survivors of CNS tumors (median current age, 26 years; median time from diagnosis, 18 years), neurocognitive impairment was significantly associated with lower educational attainment, unemployment, and nonindependent living.[13]
Childhood cancer survivors are also at risk of developing symptoms of psychological distress. In a longitudinal study of more than 4,500 survivors, subgroups of survivors were found to be at risk of developing persistent and increasing symptoms of anxiety and depression during a 16-year period. Survivors who reported pain and worsening health status were at the greatest risk of developing symptoms of anxiety, depression, and somatization over time.[90]
Adult survivors of childhood cancer are also at risk of suicide ideation compared with siblings, with survivors of CNS tumors being most likely to report thoughts of suicide. In a CCSS study that evaluated the prevalence of recurrent suicidal ideation among 9,128 adult long-term survivors of childhood cancer, survivors were more likely to report late suicidal ideation (odds ratio [OR], 1.9; 95% CI, 1.5-2.5) and recurrent suicidal ideation (OR, 2.6; 95% CI, 1.8-3.8) compared with siblings. History of seizure was associated with a twofold increased likelihood of suicide ideation in survivors.[91] In a population-based study that evaluated suicide among adults treated for cancer before age 25 years, the absolute risk of suicide was low (24 cases among 3,375 deaths), but the hazard ratio (HR) of suicide was increased among individuals treated for cancer in childhood (0-14 years; HR, 2.5; 95% CI, 1.7-3.8) and in adolescence and young adulthood (15-24 years; HR, 2.3; 95% CI, 1.2-4.6).[92]
The presence of chronic health conditions can also impact aspects of psychological health. In a study that evaluated psychological outcomes among long-term survivors treated with HSCT, 22% of survivors and 8% of sibling controls reported adverse outcomes. Somatic distress was the most prevalent condition and affected 15% of HSCT survivors, representing a threefold higher risk compared with siblings. HSCT survivors with severe or life-threatening health conditions and active chronic GVHD had a twofold increased risk of somatic distress.[93] A report from the CCSS revealed that the presence of chronic pulmonary, endocrine, and cardiac conditions was associated with increased risk of psychological distress symptoms in a sample of 5,021 adult survivors of childhood cancer.[94]
Incorporation of psychological screening into clinical visits for childhood cancer survivors may be valuable; however, limiting such evaluations to those returning to long-term follow-up clinics may result in a biased subsample of survivors with more difficulties, and precise prevalence rates may be difficult to establish. A review of behavioral, emotional, and social adjustment among survivors of childhood brain tumors illustrates this point, with the prevalence of psychological maladjustment ranging from 25% to 93%.[95] In a study of 101 adult cancer survivors of childhood cancer, psychological screening was performed during a routine annual evaluation at the survivorship clinic at the Dana Farber Cancer Institute. On the Symptom Checklist 90 Revised, 32 subjects had a positive screen (indicating psychological distress), and 14 subjects reported at least one suicidal symptom. Risk factors for psychological distress included subjects' dissatisfaction with physical appearance, poor physical health, and treatment with cranial irradiation. In this study, the instrument was shown to be feasible for use in the clinic visit setting because the psychological screening was completed in less than 30 minutes. In addition, completion of the instrument itself did not appear to cause distress in the survivors in 80% of cases.[96] These data support the feasibility and importance of consistent assessment of psychosocial distress in a medical clinic setting.
(Refer to the PDQ summary on Adjustment to Cancer: Anxiety and Distress for more information about psychological distress and cancer patients.)
Post-traumatic stress after childhood cancer
Despite the many stresses associated with the diagnosis of cancer and its treatment, studies have generally shown low levels of post-traumatic stress symptoms and post-traumatic stress disorder (PTSD) in children with cancer, typically no higher than those in healthy comparison children.[97] Patient and parent adaptive style appear to be significant determinants of PTSD in the pediatric oncology setting.[98,99]
The prevalence of PTSD and post-traumatic stress symptoms has been reported in 15% to 20% of young adult survivors of childhood cancer, with estimates varying based on criteria used to define these conditions.[100]
- Survivors with PTSD reported more psychological problems and negative beliefs about their illness and health status than did those without PTSD.[101,102]
- A subset of adult survivors (9%) from the CCSS reported functional impairment and/or clinical distress in addition to the set of symptoms consistent with a full diagnosis of PTSD. This was significantly more prevalent in survivors than in sibling comparisons.[103] In this study, PTSD was significantly associated with being unmarried, having an annual income of less than $20,000, being unemployed, having a high school education or less, and being older than 30 years. Survivors who were treated with cranial irradiation before age 4 years were at particularly high risk for PTSD. Intensive cancer-directed therapy was also associated with increased risk of full PTSD.
Because avoidance of places and persons associated with the cancer is part of PTSD, the syndrome may interfere with obtaining appropriate health care. Those with PTSD perceive greater current threats to their lives or the lives of their children. Other risk factors include poor family functioning, decreased social support, and noncancer stressors.[104]
Psychosocial outcomes among childhood, adolescent, and young adult cancer survivors
Most research on late effects after cancer has focused on individuals with a cancer manifestation during childhood. Little is known about the specific impact of a cancer diagnosis with an onset in adolescence or the impact of childhood cancer on adolescent and young adult (AYA) psychosocial outcomes.
Evidence (psychosocial outcomes in AYA cancer survivors):
- Adult survivors of cancer diagnosed during adolescence (aged 15-18 years) (N = 825) were compared with an age-matched sample from the general population and a comparison group of adults without cancer.[105]
- Female survivors of adolescent cancers achieved fewer developmental milestones related to their psychosexual development, such as having their first boyfriend, or they reached these milestones later.
- Male survivors were more likely to live with their parents than were same-sex controls.
- Adolescent cancer survivors were less likely to have ever married or have had children. Survivors were significantly older at their first marriage and at the birth of their first child than were their age-matched samples.
- Survivors in this cohort were also significantly less satisfied with their general and health-related life than were people in a community-based control group. Impaired general and health-related life satisfaction were associated with somatic late effects, symptoms of depression and anxiety, and lower rates of posttraumatic growth.[106]
- A survey of 4,054 AYA cancer survivors and 345,592 respondents who had no history of cancer reported the following:[107]
- AYA cancer survivors were more likely to smoke (26% vs. 18%), be obese (31% vs. 27%), and have chronic conditions such as cardiovascular disease (14% vs. 7%), hypertension (35% vs. 9%), asthma (15% vs. 8%), disability (36% vs. 18%), and poor mental health (20% vs. 10%).
- They were also less likely to receive medical care because of cost (24% vs. 15%).
- The CCSS evaluated outcomes of 2,979 adolescent survivors and 649 siblings of childhood cancer survivors to determine the incidence of difficulty in six behavioral and social domains (depression/anxiety, being headstrong, attention deficit, peer conflict/social withdrawal, antisocial behaviors, and social competence).[108]
- Survivors were 1.5 times (95% CI, 1.1-2.1) more likely than siblings to have symptoms of depression/anxiety and 1.7 times (95% CI, 1.3-2.2) more likely than siblings to have antisocial behaviors.
- Scores in the depression/anxiety, attention deficit, and antisocial domains were significantly elevated in adolescents treated for leukemia or CNS tumors, compared with the scores in siblings.
- In addition, survivors of neuroblastoma had difficulty in the depression/anxiety and antisocial domains.
- CNS-directed treatments (cranial radiation therapy and/or intrathecal methotrexate) were specific risk factors for adverse behavioral outcomes.
- Another CCSS study evaluated psychological and neurocognitive function in 2,589 long-term cancer survivors who were diagnosed during adolescence and young adulthood.[109]
- Compared with a sibling cohort, survivors diagnosed during adolescence and young adulthood reported higher rates of depression (OR, 1.55; 95% CI, 1.04-2.30) and anxiety (OR, 2.00; 95% CI, 1.17-3.43) and reported more cognitive problems affecting task efficiency (OR, 1.72; 95% CI, 1.21-2.43), emotional regulation (OR, 1.74; 95% CI, 1.26-2.40), and memory (OR, 1.44; 95% CI, 1.09-1.89).
- Survivors of lymphoma and sarcoma diagnosed during later adolescence were at reduced risk of psychosocial and neurocognitive problems than were those diagnosed before age 11 years. These outcomes did not differ by age at diagnosis among CNS tumor and leukemia survivors.
- Survivors diagnosed during adolescence and young adulthood were also significantly less likely than sibling controls to have attained a post-high school education, be working full time, be married, or be living independently; inferior social outcomes were related to neurocognitive symptoms.
- A follow-up CCSS study evaluated profiles of symptom comorbidities in 3,993 adolescents (aged 13-17 years) treated for cancer.[110] Latent profile analysis identified four symptom profiles:
- No significant symptoms.
- Elevated internalizing symptoms (anxiety and/or depression, social withdrawal, and attention problems).
- Elevated externalizing symptoms (headstrong behavior and attention problems).
- Elevated internalizing and externalizing symptoms.
Overall results support that behavioral, emotional, and social symptoms frequently co-occur in adolescent survivors and are associated with treatment exposures (cranial radiation, corticosteroids, and methotrexate) and late effects (obesity, cancer-related pain, and sensory impairments).
It should be noted that social withdrawal in adolescence has been associated with adult obesity and physical inactivity.[111] As a result, these psychological problems may increase future risk for chronic health conditions and support the need to routinely screen and treat psychological problems after cancer therapy.
Because of the challenges experienced by adolescents and young adults at cancer diagnosis and during long-term follow-up, this group may benefit from access to programs to address the unique psychosocial, educational, and vocational issues that impact their transition to survivorship.[112,113]
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for CNS and psychosocial late effects information, including risk factors, evaluation, and health counseling.
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- Krull KR, Cheung YT, Liu W, et al.: Chemotherapy Pharmacodynamics and Neuroimaging and Neurocognitive Outcomes in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia. J Clin Oncol 34 (22): 2644-53, 2016.
- Conklin HM, Krull KR, Reddick WE, et al.: Cognitive outcomes following contemporary treatment without cranial irradiation for childhood acute lymphoblastic leukemia. J Natl Cancer Inst 104 (18): 1386-95, 2012.
- Halsey C, Buck G, Richards S, et al.: The impact of therapy for childhood acute lymphoblastic leukaemia on intelligence quotients; results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI. J Hematol Oncol 4: 42, 2011.
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- Willard VW, Qaddoumi I, Chen S, et al.: Developmental and adaptive functioning in children with retinoblastoma: a longitudinal investigation. J Clin Oncol 32 (25): 2788-93, 2014.
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- Krull KR, Sabin ND, Reddick WE, et al.: Neurocognitive function and CNS integrity in adult survivors of childhood hodgkin lymphoma. J Clin Oncol 30 (29): 3618-24, 2012.
- Phipps S, Rai SN, Leung WH, et al.: Cognitive and academic consequences of stem-cell transplantation in children. J Clin Oncol 26 (12): 2027-33, 2008.
- Shah AJ, Epport K, Azen C, et al.: Progressive declines in neurocognitive function among survivors of hematopoietic stem cell transplantation for pediatric hematologic malignancies. J Pediatr Hematol Oncol 30 (6): 411-8, 2008.
- Anderson FS, Kunin-Batson AS, Perkins JL, et al.: White versus gray matter function as seen on neuropsychological testing following bone marrow transplant for acute leukemia in childhood. Neuropsychiatr Dis Treat 4 (1): 283-8, 2008.
- Packer RJ, Gurney JG, Punyko JA, et al.: Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: childhood cancer survivor study. J Clin Oncol 21 (17): 3255-61, 2003.
- King AA, Seidel K, Di C, et al.: Long-term neurologic health and psychosocial function of adult survivors of childhood medulloblastoma/PNET: a report from the Childhood Cancer Survivor Study. Neuro Oncol 19 (5): 689-698, 2017.
- Goldsby RE, Liu Q, Nathan PC, et al.: Late-occurring neurologic sequelae in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 28 (2): 324-31, 2010.
- Khong PL, Leung LH, Fung AS, et al.: White matter anisotropy in post-treatment childhood cancer survivors: preliminary evidence of association with neurocognitive function. J Clin Oncol 24 (6): 884-90, 2006.
- Zeller B, Tamnes CK, Kanellopoulos A, et al.: Reduced neuroanatomic volumes in long-term survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 31 (17): 2078-85, 2013.
- Jain P, Gulati S, Seth R, et al.: Vincristine-induced neuropathy in childhood ALL (acute lymphoblastic leukemia) survivors: prevalence and electrophysiological characteristics. J Child Neurol 29 (7): 932-7, 2014.
- Ness KK, Hudson MM, Pui CH, et al.: Neuromuscular impairments in adult survivors of childhood acute lymphoblastic leukemia: associations with physical performance and chemotherapy doses. Cancer 118 (3): 828-38, 2012.
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- Schulte F, Barrera M: Social competence in childhood brain tumor survivors: a comprehensive review. Support Care Cancer 18 (12): 1499-513, 2010.
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- Sun CL, Francisco L, Baker KS, et al.: Adverse psychological outcomes in long-term survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study (BMTSS). Blood 118 (17): 4723-31, 2011.
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- Fuemmeler BF, Elkin TD, Mullins LL: Survivors of childhood brain tumors: behavioral, emotional, and social adjustment. Clin Psychol Rev 22 (4): 547-85, 2002.
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- Phipps S, Klosky JL, Long A, et al.: Posttraumatic stress and psychological growth in children with cancer: has the traumatic impact of cancer been overestimated? J Clin Oncol 32 (7): 641-6, 2014.
- Phipps S, Larson S, Long A, et al.: Adaptive style and symptoms of posttraumatic stress in children with cancer and their parents. J Pediatr Psychol 31 (3): 298-309, 2006.
- Phipps S, Jurbergs N, Long A: Symptoms of post-traumatic stress in children with cancer: does personality trump health status? Psychooncology 18 (9): 992-1002, 2009.
- Stuber ML, Meeske KA, Leisenring W, et al.: Defining medical posttraumatic stress among young adult survivors in the Childhood Cancer Survivor Study. Gen Hosp Psychiatry 33 (4): 347-53, 2011 Jul-Aug.
- Rourke MT, Hobbie WL, Schwartz L, et al.: Posttraumatic stress disorder (PTSD) in young adult survivors of childhood cancer. Pediatr Blood Cancer 49 (2): 177-82, 2007.
- Schwartz L, Drotar D: Posttraumatic stress and related impairment in survivors of childhood cancer in early adulthood compared to healthy peers. J Pediatr Psychol 31 (4): 356-66, 2006.
- Stuber ML, Meeske KA, Krull KR, et al.: Prevalence and predictors of posttraumatic stress disorder in adult survivors of childhood cancer. Pediatrics 125 (5): e1124-34, 2010.
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Late Effects of the Endocrine System
Endocrine dysfunction is very common among childhood cancer survivors, especially those treated with surgery or radiation therapy that involves hormone-producing organs and those receiving alkylating agent chemotherapy.
Figure 7. Prevalence of endocrine disorders at the last follow-up visit, by sex. Copyright © 2013, European Society of Endocrinology.
The prevalence of specific endocrine disorders is affected by the following:[1,2,3]
- Patient factors (e.g., age at treatment and sex).
- Treatment factors (e.g., radiation dose and treatment volume).
- Time from radiation exposure (typically increases with longer time from radiation exposure [refer to Figure 7]).
Endocrinologic late effects can be broadly categorized as those resulting from hypothalamic/pituitary injury or from peripheral glandular compromise.[4,5] The former are most common after treatment for central nervous system (CNS) tumors, where the prevalence was reported to be 24.8% in a nationwide cohort study of 718 survivors who lived longer than 2 years and all hypothalamic/pituitary axes were effected.[3]
The following sections summarize research that characterizes the clinical features of survivors at risk of endocrine dysfunction that impacts pituitary, thyroid, adrenal, and gonadal function.
Thyroid Gland
Thyroid dysfunction is a common delayed effect of radiation therapy fields that include the thyroid gland incidental to treating Hodgkin lymphoma (HL), brain tumors, head and neck sarcomas, and acute lymphoblastic leukemia (ALL). There is considerable evidence linking radiation exposure to thyroid abnormalities, but the prevalence of specific conditions varies widely because studies are limited by cohort selection and participation bias, heterogeneity in radiation treatment approach, time since radiation exposure, and method of ascertainment (e.g., self-report vs. clinical or diagnostic imaging assessment).
Thyroid abnormalities observed in excess in childhood cancer survivors include the following:
- Primary hypothyroidism.
- Hyperthyroidism.
- Goiter.
- Nodules.
Hypothyroidism
Of children treated with radiation therapy, most develop hypothyroidism within the first 2 to 5 years posttreatment, but new cases can occur later. Reports of thyroid dysfunction differ depending on the dose of radiation, the length of follow-up, and the biochemical criteria utilized to make the diagnosis.[6] The most frequently reported abnormalities include:
- Elevated thyroid-stimulating hormone (TSH).
- Depressed thyroxine (T4).
- Elevated TSH and depressed T4.
Compensated hypothyroidism includes an elevated TSH with a normal T4 and is asymptomatic. The natural history is unclear, but most endocrinologists support treatment. Uncompensated hypothyroidism includes both an elevated TSH and a depressed T4. Thyroid hormone replacement is beneficial for correction of the metabolic abnormality, and has clinical benefits for cardiovascular, gastrointestinal, and neurocognitive function.
An increased risk of hypothyroidism has been reported among childhood cancer survivors treated with head and neck radiation exposing the thyroid gland, especially among survivors of HL.
Evidence (prevalence of and risk factors for hypothyroidism):
- The German Group of Paediatric Radiation Oncology reported on 1,086 patients treated at 62 centers, including 404 patients (median age, 10.9 years) who received radiation therapy to the thyroid and/or pituitary gland.[7] Follow-up information was available for 264 patients (60.9%; median follow-up, 40 months), with 60 patients (22.7%) showing pathologic values.
- In comparison to patients treated with prophylactic cranial irradiation (median dose, 12 Gy), patients treated with radiation doses of 15 Gy to 25 Gy to the thyroid gland had a hazard ratio (HR) of 3.072 (P = .002) for the development of pathologic thyroid blood values.
- Patients treated with more than 25 Gy of radiation to the thyroid gland had an HR of 3.769 (P = .009), and patients treated with craniospinal irradiation had an HR of 5.674 (P < .001).
- The cumulative incidence of thyroid hormone substitution therapy did not differ between defined subgroups.
- In a cohort of childhood HL survivors treated between 1970 and 1986, survivors were evaluated for thyroid disease by use of a self-report questionnaire in the Childhood Cancer Survivor Study (CCSS).[8]
- Among 1,791 survivors, 34% reported that they had been diagnosed with at least one thyroid abnormality.
- For hypothyroidism, there was a clear dose response (refer to Figure 8), with a 20-year risk of:
- 20% for those who received less than 35 Gy of radiation to the thyroid gland.
- 30% for those who received 35 Gy to 44.9 Gy of radiation to the thyroid gland.
- 50% for those who received more than 45 Gy of radiation to the thyroid gland.
- Compared to a sibling control group, the relative risk (RR) was 17.1 for hypothyroidism; 8.0 for hyperthyroidism; and 27.0 for thyroid nodules.
- Elapsed time since diagnosis was a risk factor for both hypothyroidism and hyperthyroidism, with the risk increasing in the first 3 to 5 years postdiagnosis. For nodules, the risk increased beginning at 10 years postdiagnosis. Females were at increased risk for hypothyroidism and thyroid nodules.
Figure 8. Probability of developing hypothyroidism according to radiation dose in 5-year survivors of childhood cancer. Data from the Childhood Cancer Survivor Study. Sklar C, Whitton J, Mertens A, Stovall M, Green D, Marina N, Greffe B, Wolden S, Robison L: Abnormalities of the Thyroid in Survivors of Hodgkin's Disease: Data from the Childhood Cancer Survivor Study. The Journal of Clinical Endocrinology and Metabolism 85 (9): 3227-3232, September 1, 2000. Copyright 2000, The Endocrine Society. - In a more recent report from the CCSS that compared self-reported data from 14,290 survivors with data from 4,031 sibling controls.[2]
- The RR was 3.8 for hypothyroidism and 2.5 for hyperthyroidism; the RR for both remained significantly higher in survivors when compared with controls even in the absence of radiation therapy to the thyroid or pituitary.
- These results indicate the need for continued and individualized long-term monitoring strategies in childhood cancer survivors.
Thyroid nodules
Any radiation field that includes the thyroid is associated with an excess risk of thyroid neoplasms, which may be benign (usually adenomas) or malignant (most often differentiated papillary carcinoma).[2,8,9,10,11,12] The clinical manifestation of thyroid neoplasia among childhood cancer survivors ranges from asymptomatic, small, solitary nodules to large, intrathoracic goiters that compress adjacent structures. CCSS investigators performed a nested case-control study to evaluate the magnitude of risk for thyroid cancer over the therapeutic radiation dose range of pediatric cancers. The risk of thyroid cancer increased with radiation doses up to 20 Gy to 29 Gy (odds ratio [OR], 9.8; 95% confidence interval [CI], 3.2-34.8), but declined at doses higher than 30 Gy, consistent with a cell-killing effect.[12]
The following factors are linked to an increased risk of thyroid nodule development:
- Time from diagnosis, female sex, and radiation dose. In a study of HL survivors, CCSS investigators identified time from diagnosis, female sex, and radiation dose of 25 Gy or higher as significant risk factors for thyroid nodule development.[8] Based on a cohort of 3,254 2-year childhood cancer survivors treated before 1986 and monitored for 25 years, the risk of thyroid adenoma increased with the size of the radiation dose to the thyroid during childhood cancer treatment and plateaued at doses exceeding 10 Gy.[10]
- Age at time of radiation therapy. Based on the same cohort of 3,254 2-year childhood cancer survivors, the risk of thyroid adenoma per unit of radiation dose to the thyroid was higher if radiation therapy had been delivered before age 5 years; the risk was also higher in individuals who were younger than 40 years at the time of the study.[10] Younger age at radiation therapy has also been linked to an excess risk of thyroid carcinoma.[9,10,11,12]
- Exposure to iodine I 131-metaiodobenzylguanidine (131I-MIBG). During childhood and adolescence, there is an increased incidence of developing thyroid nodules, and potentially thyroid cancer, for patients exposed to 131I-MIBG. Children who have been treated with 131I-MIBG should undergo lifelong monitoring, not only for thyroid function but also for the development of thyroid nodules and thyroid cancer.[13]
-
Chemotherapy. Whereas the risk of thyroid cancer is known to be increased by exposure to radiation therapy and 131I-MIBG, an increased risk of thyroid nodules and cancer has also been observed in association with chemotherapy, independent of radiation exposure.[2,9,10]
In a pooled study of two cohorts of 16,757 survivors that included 187 patients with secondary thyroid cancer, treatments with alkylating agents, anthracyclines, or bleomycin were associated with a significantly increased risk of thyroid cancer in individuals not exposed to radiation therapy.[14] In the CCSS, the RR of developing thyroid cancer was 2.5 (P < .01) in survivors not treated with thyroid radiation when compared with sibling controls.[2] Defining the precise role of exposure to chemotherapy and developing risk prediction models for thyroid cancer in childhood cancer survivors on the basis of demographic and treatment-related risk factors are areas of active research.[15]
Several investigations have demonstrated the superiority of ultrasound to clinical exam for detecting thyroid nodules and thyroid cancers and characterized ultrasonographic features of nodules that are more likely to be malignant.[16,17,18] However, primary screening for thyroid neoplasia (beyond physical exam with thyroid palpation) remains controversial because of the lack of data indicating a survival benefit and quality-of-life benefit associated with early detection and intervention. In fact, because these lesions tend to be indolent, are rarely life-threatening, and may clinically manifest many years after exposure to radiation, there are significant concerns regarding the costs and harms of overscreening.[19] Expert panels have refrained from specifically endorsing or discouraging the use of ultrasound as a screening tool for thyroid cancer and this continues to be an active area of investigation.[20]
(Refer to the Subsequent Neoplasms section of this summary for information about subsequent thyroid cancers.)
Posttransplant thyroid dysfunction
Survivors of pediatric hematopoietic stem cell transplantation (HSCT) are at increased risk of thyroid dysfunction, with the risk being much lower (15%-16%) after fractionated total-body irradiation (TBI), as opposed to single-dose TBI (46%-48%). Non-TBI-containing regimens historically were not associated with an increased risk. However, in a report from the Fred Hutchinson Cancer Research Center, the increased risk of thyroid dysfunction did not differ between children receiving a TBI-based or busulfan-based regimen (P = .48).[21] Other high-dose therapies have not been studied.
TSH deficiency (central hypothyroidism) is discussed with late effects that affect the pituitary gland.
Table 7 summarizes thyroid late effects and the related health screenings.
| Predisposing Therapy | Endocrine/Metabolic Effects | Health Screening |
|---|---|---|
| 131I-MIBG = Iodine I 131-metaiodobenzylguanidine; T4 = thyroxine; TSH = thyroid-stimulating hormone. | ||
| a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
| Radiation impacting thyroid gland; thyroidectomy | Primary hypothyroidism | TSH level |
| Radiation impacting thyroid gland | Hyperthyroidism | Free T4 level |
| TSH level | ||
| Radiation impacting thyroid gland, including 131I-MIBG | Thyroid nodules | Thyroid exam |
| Thyroid ultrasound | ||
Pituitary Gland
Survivors of childhood cancer are at risk of developing a spectrum of neuroendocrine abnormalities, primarily because of the effect of radiation therapy on the hypothalamus. In addition, tumor development or surgical resection close to the hypothalamus and/or pituitary gland may induce direct anatomical damage to these structures and result in hypothalamic/pituitary dysfunction. Essentially all of the hypothalamic-pituitary axes are at risk.[4,22,23,24]
Although the quality of the literature regarding pituitary endocrinopathy among childhood cancer survivors is often limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment, the evidence linking this outcome with radiation therapy, surgery, and tumor infiltration is quite compelling because affected individuals typically present with metabolic and developmental abnormalities early in follow-up.
Central diabetes insipidus
Central diabetes insipidus may herald the diagnosis of craniopharyngioma, suprasellar germ cell tumor, or Langerhans cell histiocytosis.[25,26,27] In these conditions, diabetes insipidus may occur as an isolated pituitary deficiency, although additional pituitary hormone deficiencies may develop with tumor progression. More commonly, however, diabetes insipidus occurs in the context of panhypopituitarism caused by the presence of a tumor in close proximity to the sellar region or as a consequence of surgical procedures undertaken for local tumor control.
Central diabetes insipidus has not been reported as a late effect of cranial irradiation in childhood cancer survivors.
Anterior pituitary hormone deficiency
Deficiencies of anterior pituitary hormones and major hypothalamic regulatory factors are common late effects among survivors treated with cranial irradiation.
Evidence (prevalence of anterior pituitary hormone deficiency):
- In a single-institution study, 1,713 adult survivors of childhood cancers and brain tumors (median age, 32 years) were monitored for a median follow-up of 25 years.[24]
- The prevalence of hypothalamic-pituitary axis disorders was 56.4% in individuals exposed to cranial radiation therapy at doses of 18 Gy or higher.
- A study of 748 childhood cancer survivors treated with cranial irradiation and observed for a mean of 27.3 years reported the following:[5]
- The estimated point prevalence for anterior pituitary hormone deficiency was 46.5% for growth hormone deficiency, 10.8% for luteinizing/follicle stimulating hormone deficiency, 7.5% for thyroid-stimulating hormone deficiency, and 4% for adrenocorticotropin deficiency; the cumulative incidence increased with follow-up.
The six anterior pituitary hormones and their major hypothalamic regulatory factors are outlined in Table 8.
| Pituitary Hormone | Hypothalamic Factor | Hypothalamic Regulation of the Pituitary Hormone |
|---|---|---|
| (-) = inhibitory; (+) = stimulatory. | ||
| Growth hormone (GH) | Growth hormone-releasing hormone | + |
| Somatostatin | - | |
| Prolactin | Dopamine | - |
| Luteinizing hormone (LH) | Gonadotropin-releasing hormone | + |
| Follicle-stimulating hormone (FSH) | Gonadotropin-releasing hormone | + |
| Thyroid-stimulating hormone (TSH) | Thyroid-releasing hormone | + |
| Somatostatin | - | |
| Adrenocorticotropin (ACTH) | Corticotropin-releasing hormone | + |
| Vasopressin | + | |
Growth hormone deficiency
Growth hormone deficiency is the earliest hormonal deficiency associated with cranial radiation therapy in childhood cancer survivors. The risk increases with radiation dose and time since treatment. Growth hormone deficiency is sensitive to low doses of radiation. Other hormone deficiencies require higher doses, and their time to onset is much longer than for growth hormone deficiency.[28] The prevalence in pooled analysis was found to be approximately 35.6%.[29]
Growth hormone deficiency is commonly observed in these long-term survivors because of radiation doses used in the treatment of childhood brain tumors. Approximately 60% to 80% of irradiated pediatric brain tumor patients who received doses higher than 30 Gy will have impaired serum growth hormone (GH) response to provocative stimulation, usually within 5 years of treatment. The dose-response relationship has a threshold of 18 Gy to 20 Gy; the higher the radiation dose, the earlier that growth hormone deficiency will occur after treatment.
Evidence (radiation-dose response relationship of growth hormone deficiency):
- A study of conformal radiation therapy (CRT) in children with CNS tumors indicates that growth hormone insufficiency can usually be demonstrated within 12 months of radiation therapy, depending on hypothalamic dose-volume effects.[30]
- In a report featuring data from 118 patients with localized brain tumors who were treated with radiation therapy, peak growth hormone was modeled as an exponential function of time after CRT and mean radiation dose to the hypothalamus.[31]
- The average patient was predicted to develop growth hormone deficiency with the following combinations of time after CRT and mean dose to the hypothalamus: 12 months and more than 60 Gy; 36 months and 25 Gy to 30 Gy; and 60 months and 15 Gy to 20 Gy.
- A cumulative dose of 16.1 Gy to the hypothalamus would be considered the mean radiation dose required to achieve a 50% risk of growth hormone deficiency at 5 years (TD50/5) (refer to Figure 9).
Figure 9. Peak growth hormone (GH) according to hypothalamic mean dose and time after start of radiation. According to equation 2, peak GH = exp{2.5947 + time × [0.0019 − (0.00079 × mean dose)]}. Thomas E. Merchant, Susan R. Rose, Christina Bosley, Shengjie Wu, Xiaoping Xiong, and Robert H. Lustig, Growth Hormone Secretion After Conformal Radiation Therapy in Pediatric Patients With Localized Brain Tumors, Journal of Clinical Oncology, volume 29, issue 36, pages 4776-4780. Reprinted with permission. © (2011) American Society of Clinical Oncology. All rights reserved.
Children treated with CNS-directed therapy for leukemia are also at increased risk of growth hormone deficiency.
Evidence (risk of growth hormone deficiency in childhood ALL survivors):
- One study evaluated 127 patients with ALL treated with 24 Gy, 18 Gy, or no cranial radiation therapy.[32]
- The change in height, compared with population norms expressed as the standard deviation score (SDS), was significant for all three groups, with a dose response of -0.49 ± 0.14 for the group that did not receive radiation therapy, -0.65 ± 0.15 for the group that received 18 Gy of radiation therapy, and -1.38 ± 0.16 for the group that received 24 Gy of radiation therapy.
- Another study found similar results in 118 ALL survivors treated with 24 Gy of cranial radiation, in which 74% had SDS of -1 or higher and the remainder had scores of -2 or higher.[33]
- Survivors of childhood ALL who are treated with chemotherapy alone are also at increased risk for adult short stature, although the risk is highest for those treated with cranial and craniospinal radiation therapy at a young age.[34] In this cross-sectional study, attained adult height was determined for 2,434 ALL survivors participating in the CCSS.
- All survivor treatment exposure groups (chemotherapy alone and chemotherapy with cranial or craniospinal radiation therapy) had decreased adult height and an increased risk of adult short stature (height SDS < -2), compared with siblings (P < .001).
- Compared with siblings, the risk of short stature for survivors treated with chemotherapy alone was elevated (OR, 3.4; 95% CI, 1.9-6.0).
- Among survivors, significant risk factors for short stature included diagnosis of ALL before puberty, higher-dose cranial radiation therapy (≥20 Gy vs. <20 Gy), any radiation therapy to the spine, and female sex.
- The impact of chemotherapy alone on growth in 67 survivors treated with contemporary regimens for ALL was statistically significant at -0.59 SD. The loss of growth potential did not correlate with growth hormone status in this study, further highlighting the participation of other factors in the growth impairments observed in this population.[35]
Children who undergo HSCT with TBI have a significant risk of both growth hormone deficiency and the direct effects of radiation on skeletal development. The risk is increased with single-dose TBI as opposed to fractionated TBI, pretransplant cranial irradiation, female sex, and posttreatment complications such as graft-versus-host disease (GVHD).[36,37,38] Hyperfractionation of the TBI dose markedly reduces risk in patients who have not undergone pretransplant cranial irradiation for CNS leukemia prophylaxis or therapy.[39] Regimens containing busulfan and cyclophosphamide appear to increase risk in some studies,[38,40] but not others.[41]
Evidence (growth hormone deficiency in childhood HSCT survivors):
- The late effects that occur after HSCT have been studied and reviewed by the Late Effect Working Party of the European Group for Blood and Marrow Transplantation. Among 181 patients with aplastic anemia, leukemias, and lymphomas who underwent HSCT before puberty, the following results were observed:[42,43]
- An overall decrease in final height-SDS value was found, compared with height at transplant and genetic height. The mean loss of height is estimated to be approximately 1 height-SDS (6 cm), compared with the mean height at time of HSCT and mean genetic height.
- The type of transplantation, GVHD, and growth hormone or steroid treatment did not influence final height.
- TBI (single-dose radiation therapy more than fractionated-dose radiation therapy), male sex, and young age at transplant were found to be major factors for long-term height loss. Most patients (140 of 181) reached adult height within the normal range of the general population.
Growth hormone deficiency replacement therapy
Growth hormone deficiency replacement therapy provides the benefit of optimizing height outcomes among children who have not reached skeletal maturity. Treatment with recombinant growth hormone (rGH) replacement therapy is generally delayed until 12 months after successful completion of cancer or brain tumor treatments and after a multidisciplinary discussion involving the prescribing pediatric endocrinologist, the primary oncologist, and other providers selected by the patient or family.[44] Safety concerns pertaining to the use of rGH in childhood cancer survivors have primarily been related to the mitogenic potential of the growth hormone stimulating tumor growth in a population with an increased risk of second neoplasms.[45] Most studies that report these outcomes, however, are limited by selection bias and small sample size.
The following study results have been reported in survivors who did or did not receive treatment with growth hormone.
Evidence (growth hormone deficiency replacement therapy):
- One study evaluated 361 growth hormone-treated cancer survivors enrolled in the CCSS and compared risk of recurrence, risk of subsequent neoplasm, and risk of death among survivors who did and did not receive treatment with growth hormone.[46]
- The RR of disease recurrence was 0.83 (95% CI, 0.37-1.86) for growth hormone-treated survivors. Growth hormone-treated subjects were diagnosed with 15 subsequent neoplasms, all solid tumors, for an overall RR of 3.21 (95% CI, 1.88-5.46), mainly because of a small excess number of subsequent neoplasms observed in survivors of acute leukemia.[46] With prolonged follow-up, the elevation of subsequent cancer risk resulting from growth hormone diminished.[47]
- Compared with survivors not treated with growth hormone, those who were treated had a twofold excess risk of developing a subsequent neoplasm (RR, 2.15; 95% CI, 1.33-3.47; P < .002); meningiomas were the most commonly observed neoplasms (9 of 20 tumors).[46]
- A review of existing data suggests that treatment with growth hormone is not associated with an increased risk of CNS tumor progression or recurrence, or new or recurrent leukemia.[48]
- A study from the CCSS reported specifically on the risk of subsequent CNS neoplasms after a longer period of follow-up.[49]
- The adjusted rate ratio of meningioma and gliomas in growth hormone-treated survivors of CNS tumors was 1.0 (95% CI, 0.6-1.8; P = .94) when compared with CNS tumor survivors who were not treated with growth hormone, thus indicating negligible differences between the two groups for this particular risk.
In general, the data addressing subsequent malignancies should be interpreted with caution given the small number of events.[44,45,46]
Disorders of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
Pubertal development can be adversely affected by cranial radiation therapy. Doses higher than 18 Gy can result in central precocious puberty, while doses higher than 30 Gy to 40 Gy may result in LH and FSH deficiency.[50]
Central precocious puberty
Central precocious puberty is defined by the onset of pubertal development before age 8 years in girls and 9 years in boys as a result of the premature activation of the hypothalamic-pituitary-gonadal axis. Aside from the adjustment and psychosocial challenges associated with early pubertal development, precocious puberty can lead to the rapid closure of the skeletal growth plates and short stature. This deleterious effect can be further potentiated by growth hormone deficiency.[51,52] The increased growth velocity induced by pubertal development can mask concurrent growth hormone deficiency with seemingly normal growth velocity; this occurrence may mislead care providers. It is also important to note that the assessment of puberty cannot be performed using testicular volume measurements in boys exposed to chemotherapy or direct radiation to the testes, given the toxic effect of these treatments on germ cells and repercussions on gonadal size. The staging of puberty in males within this population relies on the presence of other signs of virilization, such as the presence of pubic hair and the measurement of plasma testosterone levels.[51]
Children who have tumors that grow near the hypothalamus/pituitary or optic pathways (including those with neurofibromatosis type 1) have the highest risk of developing central precocious puberty.[52,53] Hydrocephalus also seems to increase the risk of this complication.[53] Central precocious puberty has been reported in some children receiving cranial irradiation in doses of 18 Gy or higher.[52,54,55] The impact of central precocious puberty on linear growth can be ascertained by assessing the degree of skeletal maturation (or bone age) using an x-ray of the left hand.[56]
When appropriate, delaying the progression of puberty relies on the use of various gonadotropin-releasing hormone agonist preparations, an approach that has been shown to improve growth prospects-especially when other pituitary abnormalities, including growth hormone deficiency, are concurrently treated.[57]
LH/FSH deficiency
LH/FSH deficiency (also referred to as hypogonadotropic hypogonadism) can manifest through pubertal delay, arrested puberty, or symptoms of decreased sex hormone production, depending on age and pubertal status at the time of diagnosis. The risk of LH/FSH deficiency is highest among patients treated with cranial radiation at doses greater than or equal to 30 Gy; LH/FSH deficiency following the exposure to lower doses can occur at delayed time points.[5] With higher doses of cranial radiation therapy (>35 Gy), deficiencies in LH/FSH can be seen, with a cumulative incidence of 10% to 20% at 5 to 10 years posttreatment.[58,59]
The treatment of LH/FSH deficiency relies on sex-hormone replacement therapy adjusted to age and pubertal status.
TSH deficiency
TSH deficiency (also referred to as central hypothyroidism) in survivors of childhood cancer can have profound clinical consequences and be underappreciated. Symptoms of central hypothyroidism (e.g., asthenia, edema, drowsiness, and skin dryness) may have a gradual onset and go unrecognized until thyroid replacement therapy is initiated. In addition to delayed puberty and slow growth, hypothyroidism may cause fatigue, dry skin, constipation, increased sleep requirement, and cold intolerance. Individuals with TSH deficiency have low plasma free T4 levels and either low or inappropriately normal TSH levels.
The risk of TSH deficiency is highest among patients treated with cranial radiation at doses greater than or equal to 30 Gy; TSH deficiency following the exposure to lower doses can occur at delayed time points.[5] Radiation dose to the hypothalamus in excess of 42 Gy is associated with an increased risk of developing TSH deficiency (44% ± 19% for dose of ≥42 Gy and 11% ± 8% for dose of <42 Gy).[60] It occurs in as many as 65% of survivors of brain tumors, 43% of survivors of childhood nasopharyngeal tumors, 35% of bone marrow transplant recipients, and 10% to 15% of leukemia survivors.[61,62]
Mixed primary and central hypothyroidism can also occur and reflects separate injuries to the thyroid gland and the hypothalamus (e.g., radiation injury to both structures). TSH values may be elevated and, in addition, the secretory dynamics of TSH are abnormal, with a blunted or absent TSH surge or a delayed peak response to TSH-releasing hormone (TRH).[63] In a study of 208 childhood cancer survivors referred for evaluation of possible hypothyroidism or hypopituitarism, mixed hypothyroidism was present in 15 patients (7%).[63] Among patients who received TBI (fractionated total doses of 12-14.4 Gy) or craniospinal radiation therapy (fractionated total cranial doses higher than 30 Gy), 15% had mixed hypothyroidism. In one study of 32 children treated for medulloblastoma, 56% developed hypothyroidism, including 38% with primary hypothyroidism and 19% with central hypothyroidism.[64]
Thyroid hormone replacement therapy using levothyroxine represents the mainstay of treatment of TSH deficiency. The dose of levothyroxine needs to be adjusted solely using plasma free T4 levels; the levels of TSH are expected to remain low during therapy, given the central nature of this deficiency.
Adrenal-corticotropin (ACTH) deficiency
ACTH deficiency is less common than other neuroendocrine deficits but should be suspected in patients who have a history of brain tumor (regardless of therapy modality), cranial radiation therapy, growth hormone deficiency, or central hypothyroidism.[28,60,65,66,67] Although uncommon, ACTH deficiency can occur in patients treated with intracranial radiation doses of less than 24 Gy and has been reported to occur in fewer than 3% of patients after chemotherapy alone.[67]
The diagnosis should be suspected when low plasma levels of morning cortisol are measured (a screening cortisol level collected at 8 a.m. that is 10 µg/dL or more is reassuring for ACTH sufficiency, whereas a value of 5 µg/dL or lower is suspicious for insufficiency). Confirmation is necessary using dynamic testing such as the low-dose ACTH stimulation test.[66] Because of the substantial risk of central adrenal insufficiency among survivors treated with cranial radiation doses exceeding 30 Gy to the hypothalamic-pituitary axis, endocrine monitoring with periodic dynamic testing as clinically indicated is recommended for this high-risk group.
Patients with partial ACTH deficiency may have only subtle symptoms unless they become ill. Illness can disrupt these patients' usual homeostasis and cause a more severe, prolonged, or complicated course than expected. As in complete ACTH deficiency, incomplete or unrecognized ACTH deficiency can be life-threatening during concurrent illness.
The treatment of ACTH deficiency relies on replacement with hydrocortisone, including stress dosing in situations of illness to adjust to the body's physiologically increased need for glucocorticoids.
Hyperprolactinemia
Hyperprolactinemia has been described in patients who received radiation therapy to the hypothalamus in doses higher than 50 Gy or who underwent surgery that disrupted the integrity of the pituitary stalk. Primary hypothyroidism may lead to hyperprolactinemia as a result of hyperplasia of thyrotrophs and lactotrophs, presumably due to TRH hypersecretion. The prolactin response to TRH is usually exaggerated in these patients.[28,68]
In general, hyperprolactinemia may result in delayed puberty, galactorrhea, menstrual irregularities, loss of libido, hot flashes, infertility, and osteopenia. However, hyperprolactinemia resulting from cranial radiation therapy is rarely symptomatic and, given its frequent associations with hypogonadism (both central and primary).
Hyperprolactinemia rarely requires treatment.
Table 9 summarizes pituitary gland late effects and the related health screenings.
| Predisposing Therapy | Endocrine/Metabolic Effects | Health Screening |
|---|---|---|
| BMI = body mass index; FSH = follicle-stimulating hormone; LH = luteinizing hormone; T4 = thyroxine; TSH = thyroid-stimulating hormone. | ||
| a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
| b Testicular volume measurements are not reliable in the assessment of pubertal development in boys exposed to chemotherapy or direct radiation to the testes. | ||
| c Appropriate only at diagnosis. TSH levels are not useful for follow-up during replacement therapy. | ||
| Tumor or surgery affecting hypothalamus/pituitary. Radiation impacting hypothalamic-pituitary axis. | Growth hormone deficiency | Assessment of nutritional status |
| Height, weight, BMI, Tanner stageb | ||
| Tumor or surgery affecting hypothalamus/pituitary or optic pathways; hydrocephalus. Radiation impacting hypothalamic-pituitary axis. | Precocious puberty | Height, weight, BMI, Tanner stageb |
| FSH, LH, estradiol, or testosterone levels | ||
| Tumor or surgery affecting hypothalamus/pituitary. Radiation impacting hypothalamic-pituitary axis. | Gonadotropin deficiency | History: puberty, sexual function |
| Exam: Tanner stageb | ||
| FSH, LH, estradiol or testosterone levels | ||
| Tumor or surgery affecting hypothalamus/pituitary. Radiation impacting hypothalamic-pituitary axis. | Central adrenal insufficiency | History: failure to thrive, anorexia, episodic dehydration, hypoglycemia, lethargy, unexplained hypotension |
| Endocrine consultation for those with radiation dose ≥30 Gy | ||
| Radiation impacting hypothalamic-pituitary axis. | Hyperprolactinemia | History/exam: galactorrhea |
| Prolactin level | ||
| Radiation impacting hypothalamic-pituitary axis. | Overweight/obesity | Height, weight, BMI |
| Blood pressure | ||
| Components of metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism) | Fasting blood glucose level and lipid profile | |
| Tumor or surgery affecting hypothalamus/pituitary. Radiation impacting hypothalamic-pituitary axis. | Central hypothyroidism | TSHc free thyroxine (free T4) level |
Testis and Ovary
Testicular and ovarian hormonal functions are discussed in the Late Effects of the Reproductive System section of this summary.
Metabolic Syndrome
An increased risk of metabolic syndrome or its components has been observed among cancer survivors. The evidence for this outcome ranges from clinically manifested conditions that are self-reported by survivors to retrospectively assessed data in medical records and hospital registries to systematic clinical evaluations of clinically well-characterized cohorts. Studies have been limited by cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment. Despite these limitations, compelling evidence indicates that metabolic syndrome is highly associated with cardiovascular events and mortality.
Definitions of metabolic syndrome are evolving but generally include a combination of central (abdominal) obesity with at least two of the following features:
- Hypertension.
- Atherogenic dyslipidemia (elevated triglycerides, reduced high-density lipoprotein [HDL] cholesterol).
- Abnormal glucose metabolism (fasting hyperglycemia, hyperinsulinism, insulin resistance, diabetes mellitus type 2).[69]
Evidence (prevalence of and risk factors for metabolic syndrome in childhood cancer survivors):
- A study monitored 784 long-term childhood ALL survivors (median age, 31.7 years) for a median follow-up of 26.1 years.[70]
- The prevalence of metabolic syndrome was 33.6%, which was significantly higher than that in a cohort of age-, sex-, and race-matched controls (n = 777) from the National Health and Nutrition Examination Survey (RR, 1.43; 95% CI, 1.22-1.69).
- Risk factors associated with metabolic syndrome in this study included older age and past exposures to cranial radiation therapy.
- Components of metabolic syndrome with significantly higher prevalence in ALL survivors than in controls included obesity, insulin resistance, hypertension, and decreased HDL levels.
- French investigators evaluated the overall and age-specific prevalence of and risk factors for metabolic syndrome and its components among 650 adult survivors of childhood leukemia treated without hematopoietic stem cell transplantation.[71]
- The overall prevalence of the condition was 6.9%, with the following age-specific cumulative prevalence:
- 20 years-1.3%.
- 25 years-6.1%.
- 30 years-10.8%.
- 35 years-22.4%.
- The prevalence of individual components of the metabolic syndrome was as follows:
- Increased fasting glucose-5.8%.
- Increased triglycerides-11.7%.
- Increased abdominal circumference-16.7%.
- Decreased high-density lipoprotein cholesterol-26.8%.
- Increased blood pressure-36.7%.
- Clinical factors significantly predicting the risk of metabolic syndrome included male sex (OR, 2.64; 95% CI, 1.32-5.29), age at last evaluation (OR, 1.10; 95% CI, 1.04-1.17) and body mass index at diagnosis (OR, 1.15; 95% CI, 1.01-1.32), but not cumulative steroid dose. Irradiated and nonirradiated patients exhibited different patterns of metabolic abnormalities, with more frequent abdominal obesity in irradiated patients and more frequent hypertension in nonirradiated patients.
- The overall prevalence of the condition was 6.9%, with the following age-specific cumulative prevalence:
- Abdominal irradiation is an additional risk factor for metabolic syndrome. Survivors of developmental or embryonal tumors treated with abdominal irradiation are also at an increased risk of developing components of metabolic syndrome. In a prospective study of 164 long-term survivors (median follow-up, 26 years), nephroblastoma (OR, 5.2) and neuroblastoma (OR, 6.5) survivors had more components of metabolic syndrome than did controls.[72]
- Compared with nonirradiated survivors, survivors treated with abdominal irradiation had higher blood pressure, triglycerides, low-density lipoprotein (LDL) cholesterol, and total fat percentage, which were assessed by dual-energy x-ray absorptiometry.
Long-term survivors of ALL, especially those treated with cranial radiation therapy, may have a higher prevalence of some potentially modifiable risk factors for cardiovascular disease such as impaired glucose tolerance or overt diabetes mellitus, dyslipidemia, hypertension, and obesity.[70,73,74,75,76,77,78] The contribution of modifiable risk factors associated with metabolic syndrome to the risk of major cardiac events suggests that survivors are good candidates for targeted screening and lifestyle counseling regarding risk-reduction measures.[79]
Several studies have provided support for the potential benefits of lifestyle modifications in reducing cardiovascular disease risk.
Evidence (lifestyle modifications to reduce cardiovascular risk in childhood cancer survivors):
- Survivors participating in the St. Jude Lifetime Cohort Study who were adherent to a heart-healthy lifestyle had a lower risk of metabolic syndrome. Females (RR, 2.4; 95% CI, 1.7-3.3) and males (RR, 2.2; 95% CI, 1.6-3.0) in the cohort who did not follow recommended dietary and physical activity guidelines had a more than twofold excess risk of having clinical features of the metabolic syndrome.[80]
- In a CCSS investigation evaluating the impact of exercise on cardiovascular disease risk among survivors of HL, vigorous exercise was associated with a lower risk of cardiovascular events in a dose-dependent manner, independent of cardiovascular risk profile and treatment. Survivors who were adherent to national vigorous-intensity exercise guidelines had a 51% reduction in the risk of any cardiovascular event compared with those not meeting the guidelines.[81]
Abnormal glucose metabolism
Abdominal radiation therapy and TBI are increasingly recognized as independent risk factors for diabetes mellitus in childhood cancer survivors.[2,72,74,78,82,83,84,85,86]
Evidence (risk factors for diabetes mellitus in childhood cancer survivors):
- A single-center cohort study of 532 long-term (median follow-up, 17.9 years) adult (median age, 25.6 years) survivors observed the following:[84]
- Treatment, but not genetic variation, was strongly associated with the occurrence of the components of metabolic syndrome.
- Metabolic syndrome was more frequent in cranially (23.3%, P = .002) and abdominally (23.4%, P = .009) irradiated survivors than in nonirradiated survivors (10.0%).
- A cross-sectional study evaluated cardiovascular risk factors and insulin resistance in a clinically heterogeneous cohort of 319 childhood cancer survivors 5 or more years since diagnosis and 208 sibling controls.[87]
- Insulin resistance was significantly higher in survivors treated with cisplatin plus cranial irradiation (92% brain tumors) and in those who received steroids but no cisplatin (most leukemia survivors), compared with siblings.
- Insulin resistance did not differ between survivors treated with surgery alone and siblings.
- Among survivors, analysis of individual chemotherapy agents failed to find associations with cardiovascular risk factors or insulin resistance. However, compared with siblings, nearly all chemotherapeutic agents, when examined individually, seemed to be associated with a high cardiovascular risk profile, characterized by lower total lean body mass, higher percentage fat mass, and insulin resistance.
- In a European multicenter cohort of 2,520 childhood cancer survivors (median follow-up, 28 years), significant associations were found between diabetes mellitus and increasing doses of radiation therapy to the tail of the pancreas. These data support the contribution of radiation-induced islet cell injury to impairments of glucose homeostasis in this population.[85]
- A report from the CCSS compared 8,599 childhood cancer survivors with 2,936 randomly selected sibling controls, and adjusted for age, body mass index (BMI), and several demographic factors.[88]
- The risk of diabetes mellitus was 1.8 times higher in survivors (95% CI, 1.3-2.5; P < .001).
- Significant associations were found between diabetes mellitus and young age at diagnosis (0-4 years), the use of alkylating agents and abdominal radiation therapy or TBI.
- Survivors were significantly more likely to be receiving medication for hypertension, dyslipidemia, and/or diabetes mellitus than were sibling controls.
Table 10 summarizes metabolic syndrome late effects and the related health screenings.
| Predisposing Therapy | Potential Late Effects | Health Screening |
|---|---|---|
| BMI = body mass index. | ||
| a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
| Abdominal irradiation. Total-body irradiation. | Components of metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, impaired glucose metabolism) | Height, weight, BMI, blood pressure |
| Labs: fasting glucose and lipids | ||
Body Composition: Underweight, Overweight, and Obesity
Childhood cancer survivors are at risk of experiencing abnormal body composition, which includes being underweight (BMI, <18.5), overweight (BMI, >25.0 to BMI, <30.0), or obese (BMI, ≥30.0). BMI at diagnosis has been identified as a significant predictor of being underweight or overweight at follow-up, suggesting that genetic or environmental factors contribute to the development or persistence of abnormal body composition.[89,90]
CCSS investigators identified treatment-related risk factors for being underweight, including TBI (females) or abdominal irradiation (males), use of alkylating agents, and use of anthracyclines.[90] Among a cohort of 893 Dutch childhood cancer survivors monitored for a median of almost 15 years, being underweight was linked to a high prevalence of moderate to extreme adverse health statuses and reports of a major medical condition.[89]
To date, cancer patients with an increased incidence of being overweight and obese are primarily ALL [89,91,92,93,94,95,96,97] and CNS tumor [4,22] survivors who were treated with cranial radiation therapy.[90,98] The development of obesity after cranial radiation therapy is multifactorial and includes the following:[94,99,100]
- Growth hormone deficiency.
- Leptin sensitivity.
- Reduced levels of physical activity and energy expenditure.
Also, craniopharyngioma survivors have a substantially increased risk of extreme obesity because of the tumor location and the hypothalamic damage resulting from surgical resection.[101,102,103,104,105,106]
In addition to treatment factors, lifestyle factors and medication use can also contribute to the risk of obesity. CCSS investigators reported the following independent risk factors for obesity in childhood cancer survivors:[107]
- Cancer diagnosed at ages 5 to 9 years (RR, 1.12; 95% CI, 1.01-1.24).
- Abnormal physical functioning (RR, 1.19; 95% CI, 1.06-1.33).
- Hypothalamic/pituitary radiation dose of 20 Gy to 30 Gy (RR, 1.17; 95% CI, 1.05-1.3; P = .01).
- Specific antidepressant use (paroxetine) (RR, 1.29; 95% CI, 1.08-1.54).
Survivors who adhered to the U.S. Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82-0.97; P = .01) and who had a medium amount of anxiety (RR, 0.86; 95% CI, 0.75-0.99; P = .04) had a lower risk of obesity.[107]
Body composition alterations after childhood ALL
Moderate-dose cranial radiation therapy (18-24 Gy) among ALL survivors is associated with obesity, particularly in females treated at a young age.[75,92,94,108] Female adult survivors of childhood ALL who were treated with cranial radiation therapy of 24 Gy before age 5 years are four times more likely to be obese than are women who have not been treated for a cancer.[92] In addition, women treated with 18 Gy to 24 Gy cranial radiation therapy before age 10 years have a substantially greater rate of increase in their BMI through their young adult years than do women who were treated for ALL with only chemotherapy or women in the general population.[94] It appears that these women also have a significantly increased visceral adiposity and associated insulin resistance.[109,110]
These outcomes are attenuated in males. However, a study of long-term male survivors of ALL (mean age, 29 years) observed significantly higher body adiposity than in age-matched controls, despite normal weight and BMI. Potential indicators of increased adiposity included high leptin and low sex hormone-binding globulin levels. Serum testicular endocrine markers (testosterone, FSH, or inhibin B) did not correlate with body adiposity.[111]
ALL therapy regimens are associated with increases in BMI shortly after completion of therapy, and possibly with a higher risk of obesity in the long term.[95,96,97,112,113] Several studies have reported that survivors of childhood ALL treated with chemotherapy alone also exhibit long-term changes in body composition, with relative increases in body fat [110,114,115,116] and visceral adiposity in comparison to lean mass.[109] These changes cannot be detected if BMI alone is used in the assessment of metabolic risk in this population.
Evidence (body composition changes in adult survivors of childhood ALL):
- A cohort study of 365 adult survivors of ALL (149 treated with cranial radiation therapy and 216 treated without cranial radiation therapy) compared body composition, energy balance, and fitness with age-, sex-, and race-matched peers.[117]
- Female survivors who were not exposed to cranial irradiation had comparable body composition values to that of peers. However, waist circumference, waist-to-height ratio, and total and percent fat mass were higher among male survivors and cranial radiation-exposed female survivors than among comparison group members.
- Survivors of both sexes exposed to cranial radiation therapy had higher BMI and percent body fat than did survivors not exposed to cranial radiation therapy.
- Although survivors who did not receive cranial radiation therapy had energy balance similar to the matched peer group, they had significantly higher measures of impaired fitness (impaired flexibility, peripheral sensorimotor deficits, proximal muscle weakness, and poor exercise tolerance).
- These results suggest that elimination of cranial radiation from ALL therapy has improved, but not eliminated, adverse body composition outcomes and underscores the importance of attention to interventions to preserve function in this group as they age.
- In contrast, in a report from the CCSS, adult survivors of childhood ALL treated with chemotherapy alone did not have significantly higher rates of obesity than did sibling controls,[92] nor were there differences in BMI changes between these groups after a subsequent period of follow-up that averaged 7.8 years.[94]
Results from the CCSS, however, were based on self-reported height and weight measurements. Likewise, Children's Oncology Group investigators also did not observe an increased risk of being overweight and obese based on BMI measurements in 269 patients with standard-risk ALL (age, 3.5 years at diagnosis and 13.3 years at follow-up) compared with peers without cancer. Again, these variable outcomes likely relate to the use of BMI as the metric for abnormal body composition, which does not adequately assess visceral adiposity that can contribute to metabolic risk in this population.[118]
Body composition alterations after treatment for CNS tumors
Among brain tumor survivors treated with higher doses of cranial radiation therapy, only females treated at a younger age appear to be at increased risk for obesity.[119]
Body composition alterations after hematopoietic cell transplantation
Survivors of childhood cancer treated with TBI in preparation for an allogeneic HSCT have increased measures of body fatness (percent fat) while often having a normal BMI.[82,86,120] Longitudinal decline in BMI related to substantial decrease in lean mass has been observed among survivors of hematological malignancies treated with allogeneic HSCT. This finding was largely attributable to TBI conditioning and severity of chronic GVHD.[121]
Body composition and frailty
Young adult childhood cancer survivors have a higher-than-expected prevalence of frailty, a phenotype characterized by low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Individuals are termed prefrail if they have two of these five characteristics and frail if they have three or more of these characteristics. The frailty phenotype increases in prevalence with aging, and has been associated with excess risk of mortality and onset of chronic conditions.[122] Ongoing research aims to elucidate the pathophysiology of frailty and develop/test interventions to prevent or reverse this condition.
Table 11 summarizes body composition late effects and the related health screenings.
| Predisposing Therapy | Potential Late Effects | Health Screening |
|---|---|---|
| BMI = body mass index. | ||
| a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
| Cranial radiation therapy | Overweight/obesity | Height, weight, BMI, blood pressure |
| Labs: fasting glucose and lipids | ||
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for endocrine and metabolic syndrome late effects information, including risk factors, evaluation, and health counseling.
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- Surapolchai P, Hongeng S, Mahachoklertwattana P, et al.: Impaired glucose tolerance and insulin resistance in survivors of childhood acute lymphoblastic leukemia: prevalence and risk factors. J Pediatr Hematol Oncol 32 (5): 383-9, 2010.
- Veringa SJ, van Dulmen-den Broeder E, Kaspers GJ, et al.: Blood pressure and body composition in long-term survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 58 (2): 278-82, 2012.
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- Gurney JG, Ness KK, Sibley SD, et al.: Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia. Cancer 107 (6): 1303-12, 2006.
- Oudin C, Simeoni MC, Sirvent N, et al.: Prevalence and risk factors of the metabolic syndrome in adult survivors of childhood leukemia. Blood 117 (17): 4442-8, 2011.
- Armstrong GT, Oeffinger KC, Chen Y, et al.: Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 31 (29): 3673-80, 2013.
- Smith WA, Li C, Nottage KA, et al.: Lifestyle and metabolic syndrome in adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study. Cancer 120 (17): 2742-50, 2014.
- Jones LW, Liu Q, Armstrong GT, et al.: Exercise and risk of major cardiovascular events in adult survivors of childhood hodgkin lymphoma: a report from the childhood cancer survivor study. J Clin Oncol 32 (32): 3643-50, 2014.
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- Baker KS, Chow EJ, Goodman PJ, et al.: Impact of treatment exposures on cardiovascular risk and insulin resistance in childhood cancer survivors. Cancer Epidemiol Biomarkers Prev 22 (11): 1954-63, 2013.
- Meacham LR, Chow EJ, Ness KK, et al.: Cardiovascular risk factors in adult survivors of pediatric cancer--a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev 19 (1): 170-81, 2010.
- van Santen HM, Geskus RB, Raemaekers S, et al.: Changes in body mass index in long-term childhood cancer survivors. Cancer 121 (23): 4197-204, 2015.
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- Mayer EI, Reuter M, Dopfer RE, et al.: Energy expenditure, energy intake and prevalence of obesity after therapy for acute lymphoblastic leukemia during childhood. Horm Res 53 (4): 193-9, 2000.
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- Sklar CA, Mertens AC, Walter A, et al.: Changes in body mass index and prevalence of overweight in survivors of childhood acute lymphoblastic leukemia: role of cranial irradiation. Med Pediatr Oncol 35 (2): 91-5, 2000.
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- Dalton VK, Rue M, Silverman LB, et al.: Height and weight in children treated for acute lymphoblastic leukemia: relationship to CNS treatment. J Clin Oncol 21 (15): 2953-60, 2003.
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- Oeffinger KC: Are survivors of acute lymphoblastic leukemia (ALL) at increased risk of cardiovascular disease? Pediatr Blood Cancer 50 (2 Suppl): 462-7; discussion 468, 2008.
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Late Effects of the Reproductive System
Surgery, radiation therapy, or chemotherapy that negatively affects any component of the hypothalamic-pituitary axis or gonads may compromise reproductive outcomes in childhood cancer survivors. Evidence for this outcome in childhood cancer survivors is limited by studies characterized by small sample size, cohort selection and participation bias, cross-sectional assessment, heterogeneity in treatment approach, time since treatment, and method of ascertainment. In particular, the literature is deficient regarding hard outcomes of reproductive potential (e.g., semen analysis in men, primordial follicle count in women) and outcomes after contemporary risk-adapted treatment approaches.[1,2]
The risk of infertility is generally related to the tissues or organs involved by the cancer and the specific type, dose, and combination of cytotoxic therapy.
- Orchiectomy or oophorectomy performed for the management of pediatric germ cell tumors may reduce germ cell numbers.
- Alkylating agents and similar DNA interstrand cross-linking agents used in the treatment of pediatric cancers are the primary chemotherapeutic agents associated with a high risk of infertility. Factors influencing the risk of gonadal injury in children treated with alkylating agent chemotherapy include the following:
- Cumulative dose.
- The specific alkylating agent.
- The length of treatment.
- Age at treatment.
- Sex.
- The risk of radiation injury to the hypothalamic-pituitary axis or gonads is related to the treatment volume, total dose, fractionation schedule, and age at treatment.
In addition to anticancer therapy, age at treatment, and sex, it is likely that genetic factors influence the risk of permanent infertility. It should be noted that pediatric cancer treatment protocols often prescribe combined-modality therapy; thus, the additive effects of gonadotoxic exposures may need to be considered in assessing reproductive potential. Detailed information about the specific cancer treatment modalities including specific surgical procedures, the type and cumulative doses of chemotherapeutic agents, and radiation treatment volumes and doses are needed to estimate risks for gonadal dysfunction and infertility.
Testis
Cancer treatments that may impair testicular and reproductive function include the following:
- Surgery (orchiectomy, retroperitoneal lymph node dissection, extensive pelvic dissection).
- Radiation therapy (exposing the hypothalamic-pituitary axis or testes).
- Chemotherapy (alkylating agents and similar DNA interstrand cross-linking agents such as procarbazine).
- Hematopoietic stem cell transplantation (HSCT).
Surgery affecting testicular function
Patients who undergo unilateral orchiectomy for testicular torsion may have subnormal sperm counts at long-term follow-up.[3,4] Retrograde ejaculation is a frequent complication of bilateral retroperitoneal lymph node dissection performed on males with testicular neoplasms,[5,6] and impotence may occur after extensive pelvic dissections to remove a rhabdomyosarcoma of the prostate.[7]
Radiation affecting testicular function
Among men treated for childhood cancer, the potential for gonadal injury exists if radiation treatment fields include the pelvis, gonads, or total body. The germinal epithelium is more sensitive to radiation injury than are the androgen-producing Leydig cells. A decrease in sperm counts can be seen 3 to 6 weeks after such irradiation, and depending on the dosage, recovery may take 1 to 3 years. The germinal epithelium is damaged by much lower dosages (<1 Gy) of radiation than are Leydig cells (20-30 Gy). Irreversible germ cell failure may occur with fractionated radiation doses of greater than 2 Gy to 4 Gy.[8] Administration of higher radiation doses, such as 24 Gy, which was used for the treatment of testicular relapse of acute lymphoblastic leukemia (ALL), results in both germ cell failure and Leydig cell dysfunction.[9]
Radiation injury to Leydig cells is related to the dose delivered and age at treatment. Testosterone production may be normal in prepubertal boys treated with less than 12 Gy fractionated testicular irradiation, but elevated plasma concentrations of luteinizing hormone observed in this group suggest subclinical injury. Gonadal failure typically results when prepubertal boys are treated with more than 20 Gy of radiation to the testes; androgen therapy is required for masculinization. Leydig cell function is usually preserved in sexually mature male patients if radiation doses do not exceed 30 Gy. Although available data suggest that Leydig cells are more vulnerable when exposed to radiation before puberty, confounding factors, such as the age at testing and the effects of both orchiectomy and chemotherapy, limit the reliability of this observation.[10]
Chemotherapy affecting testicular function
Cumulative alkylating agent (e.g., cyclophosphamide, mechlorethamine, dacarbazine) dose is an important factor in estimating the risk of testicular germ cell injury, but limited data are available that correlate results of semen analyses in clinically well-characterized cohorts.[11] In general, Leydig cell function is preserved, but germ cell failure is common in men treated with high cumulative doses of cyclophosphamide (7,500 mg/m2 or more) and more than 3 months of combination alkylating agent therapy. Most studies suggest that prepubertal males are not at lower risk for chemotherapy-induced testicular damage than are postpubertal patients.[12,13,14,15]
Studies of testicular germ cell injury, as evidenced by oligospermia or azoospermia, after alkylating agent administration with or without radiation therapy, have reported the following:
-
Cyclophosphamide:
- Male survivors of non-Hodgkin lymphoma who received a cumulative cyclophosphamide dose of greater than 9.5 g/m2 and underwent pelvic radiation therapy were at increased risk for failure to recover spermatogenesis.[16]
- In survivors of Ewing sarcoma and soft tissue sarcoma, treatment with a cumulative cyclophosphamide dose of greater than 7.5 g/m2 was correlated with persistent oligospermia or azoospermia.[17]
- Cyclophosphamide doses exceeding 7.5 g/m2 and ifosfamide doses exceeding 60 g/m2 produced oligospermia or azoospermia in most exposed individuals.[18,19,20]
- A small cohort study reported normal semen quality in adult long-term survivors of childhood ALL treated with 0 to 10 g/m2 of cyclophosphamide and cranial irradiation, whereas no spermatozoa were detected in semen samples from survivors treated with more than 20 g/m2 of cyclophosphamide.[21]
- Treatment with a cyclophosphamide equivalent dose of less than 4 g/m2 results in infrequent azoospermia or oligospermia, with 88.6% of 31 men treated being normospermic.[22]
- Spermatogenesis was present in 67% of 15 men who received 200 mg/kg of cyclophosphamide before undergoing HSCT for aplastic anemia.[23]
-
Dacarbazine:
- The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) produced oligospermia or azoospermia in adults frequently during the course of treatment. However, recovery of spermatogenesis occurred after treatment was completed, in contrast to the experience reported after treatment with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP).[24]
-
Alkylating agent plus procarbazine:
- Most studies suggest that combination chemotherapy with an alkylating agent and procarbazine causes severe damage to the testicular germinal epithelium that is irreversible at high cumulative doses.[12,25,26,27,28]
- Azoospermia occurred less frequently in adults after treatment with two, rather than six, cycles of MOPP.[29]
- Elevation of the basal follicle-stimulating hormone (FSH) level, which may reflect impaired spermatogenesis, was less frequent among patients receiving two courses of vincristine, procarbazine, prednisone, and doxorubicin (OPPA) than among those who received two courses of OPPA in combination with two or more courses of cyclophosphamide, vincristine, procarbazine and prednisone (COPP).[30]
Testicular function after hematopoietic stem cell transplantation (HSCT)
The risk of gonadal dysfunction and infertility related to conditioning with total-body irradiation (TBI), high-dose alkylating agent chemotherapy, or both is substantial. Because transplantation is often undertaken for relapsed or refractory cancer, previous treatment with alkylating agent chemotherapy or hypothalamic-pituitary axis or gonadal radiation therapy may confer additional risks. Age at treatment also influences the risk of gonadal injury. Young boys and adolescents treated with high-dose cyclophosphamide (200 mg/kg) will generally maintain Leydig cell function and testosterone production, but germ cell failure is common. After TBI conditioning, most male patients retain their ability to produce testosterone but will experience germ cell failure.[31]
Limited data suggest that a greater proportion of boys will retain germinal function or recovery of spermatogenesis (based on pubertal progress and gonadotropin levels) after reduced-intensity conditioning with fludarabine/melphalan than will those treated with myeloablative conditioning with busulfan/cyclophosphamide.[32]
Recovery of gonadal function
Recovery of gonadal function after cytotoxic chemotherapy and radiation therapy is possible. Dutch investigators used inhibin B as a surrogate marker of gonadal function in a cross-sectional, retrospective study of 201 male survivors of childhood cancer, with a median follow-up of 15.7 years (range, 3-37 years) from diagnosis. The median inhibin B level among the cohort increased based on serial measurements performed over a median of 3.3 years (range, 0.7-11.3 years). The probability of recovery of the serum inhibin B level was significantly influenced by baseline inhibin B level, but not age at diagnosis, age at study evaluation, interval between discontinuation of treatment and study evaluation, gonadal irradiation, and alkylating agent dose score. These results suggest that recovery can occur but not if inhibin B is already at a critically low level.[33]
Inhibin B and FSH levels are correlated with sperm concentration and often used to estimate the presence of spermatogenesis; however, limitations in the specificity and positive predictive value of these tests have been reported.[34] Hence, male survivors should be advised that semen analysis is the most accurate assessment of adequacy of spermatogenesis.
Ovary
Cancer treatments that may impair ovarian function/reserve include the following:
- Surgery (oophorectomy).
- Radiation therapy (exposing the hypothalamic-pituitary axis or ovaries).
- Chemotherapy (alkylating agents, similar DNA interstrand cross-linking agents like procarbazine).
- HSCT.
Surgery affecting ovarian function
Oophorectomy performed for the management of germ cell tumors may reduce ovarian reserve. Contemporary treatments utilize fertility-sparing surgical procedures combined with systemic chemotherapy to reduce this risk.[35]
Radiation affecting ovarian function
In women treated for childhood cancer, the potential for primary gonadal injury exists if treatment fields involve the lumbosacral spine, abdomen, pelvis, or total body. The frequency of ovarian failure after abdominal radiation therapy is related to both the age of the woman at the time of irradiation and the radiation therapy dose received by the ovaries. The ovaries of younger individuals are more resistant to radiation damage than are those of older women because of their greater complement of primordial follicles.
Whole-abdomen irradiation at doses of 20 Gy or greater is associated with the highest risk of ovarian dysfunction. Seventy-one percent of women in one series failed to enter puberty, and 26% had premature menopause after receiving whole-abdominal radiation therapy doses of 20 Gy to 30 Gy.[36] Other studies reported similar results in women treated with whole-abdomen irradiation [37] or craniospinal irradiation [38,39] during childhood.
Chemotherapy affecting ovarian function
Ovarian function may be impaired after treatment with combination chemotherapy that includes an alkylating agent and procarbazine. In general, girls maintain gonadal function at higher cumulative alkylating agent doses than do boys. Most female childhood cancer survivors who are treated with risk-adapted combination chemotherapy retain or recover ovarian function. However, the risk of acute ovarian failure and premature menopause is substantial if treatment includes combined-modality therapy with alkylating agent chemotherapy and abdominal or pelvic radiation therapy or dose-intensive alkylating agents for myeloablative conditioning before HSCT.[40,41,42,43]
Premature ovarian failure
Premature ovarian failure is well documented in childhood cancer survivors, especially in women treated with both an alkylating agent and abdominal radiation therapy.[40,44,45] Studies have associated the following factors with an increased rate of premature ovarian failure (acute ovarian failure and premature menopause):
- Age at the time of treatment and attained age.
- Increasing doses of abdominal-pelvic radiation therapy.
- Exposure to alkylating agents and/or procarbazine.
- Oophorectomy.
The presence of apparently normal ovarian function at the completion of chemotherapy should not be interpreted as evidence that no ovarian injury has occurred.
Evidence (acute ovarian failure and premature menopause in childhood cancer survivors):
- Of 3,390 eligible participants in the Childhood Cancer Survivor Study (CCSS), 215 (6.3%) developed acute ovarian failure (defined as never having menses or ceased having menses within 5 years of diagnosis).[41]
- Survivors with acute ovarian failure were older (aged 13-20 years vs. aged 0-12 years) at cancer diagnosis and more likely to have been diagnosed with Hodgkin lymphoma or to have received abdominal or pelvic radiation therapy than were survivors without acute ovarian failure.
- Of survivors who developed acute ovarian failure, 75% had received abdominal-pelvic radiation therapy. Radiation doses to the ovary of at least 20 Gy were associated with the highest rate of acute ovarian failure, with over 70% of such patients developing acute ovarian failure.
- In a multivariable logistic regression model, increasing doses of ovarian radiation, exposure to procarbazine at any age, and exposure to cyclophosphamide at ages 13 to 20 years were independent risk factors for acute ovarian failure.
- A total of 126 childhood cancer survivors and 33 control siblings who participated in the CCSS developed premature menopause, defined as cessation of menses before 40 years.[40]
- The cumulative incidence of nonsurgical premature menopause was substantially higher for survivors than for siblings (8.0% vs. 0.8%; relative risk [RR], 13.21; 95% confidence interval [CI], 3.26-53.51; P < .001) (refer to Figure 10).
- A multiple Poisson regression model showed that risk factors for nonsurgical premature menopause included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent dose score, and a diagnosis of Hodgkin lymphoma.
- For survivors who were treated with alkylating agents plus abdominal-pelvic radiation therapy, the cumulative incidence of nonsurgical premature menopause approached 30%.
Figure 10. Cumulative incidence curves of nonsurgical premature menopause in survivors (solid line) compared with siblings (broken line). Vertical bars indicate 95% confidence intervals. Sklar C A et al. JNCI J Natl Cancer Inst 2006;98:890-896. ©Sklar 2006. Published by Oxford University Press.
- A French cohort study of 1,109 female survivors of childhood solid cancer identified the following risk factors for nonsurgical menopause:[45]
- Exposure to and dose of alkylating agents, especially during adolescence.
- Radiation dose to the ovaries.
- Oophorectomy.
- Women treated with alkylating agents after the onset of puberty, either alone (RR, 9.0; 95% CI, 2.7-28.0; P = .0003) or associated with even a low dose of radiation to the ovaries (RR, 29; 95% CI, 8-108; P < .0001), had the highest risk ratio for nonsurgical menopause.
- The overall rate of nonsurgical menopause by age 40 years was only 2.1% and substantially lower than the CCSS and European Organization for Research and Treatment of Cancer cohort studies that include survivors of hematological malignancies.
- Unilateral oophorectomy was associated with a 7-year-earlier age at menopause.
- In Europe, survivors of Hodgkin lymphoma treated between the ages 15 years and 40 years and who were not receiving hormonal contraceptives were surveyed for the occurrence of premature ovarian failure.[44]
- In 460 women, premature ovarian failure was mainly influenced by alkylating chemotherapy use with a linear dose relationship between alkylating chemotherapy and premature ovarian failure occurrence. Premature ovarian failure risk increased by 23% per year of age at treatment. In women treated without alkylating chemotherapy before age 32 years and at age 32 years or older, cumulative premature ovarian failure risks were 3% and 9%, respectively.
- If menstruation returned after treatment, cumulative premature ovarian failure risk was independent of age at treatment.
- Among women who ultimately developed premature ovarian failure, 22% had one or more children after treatment, compared with 41% of women without premature ovarian failure who had one or more children after treatment. This report indicates that women with proven fertility after treatment can still face infertility problems at a later stage.
Ovarian function after HSCT
The preservation of ovarian function among women treated with HSCT is related to age at treatment, receipt of pretransplant alkylating agent chemotherapy and abdominal-pelvic radiation therapy, and transplant conditioning regimen.[42,46]
Evidence (ovarian function among women treated with HSCT):
- Girls and young women conditioned with TBI or busulfan-based regimens appear to be at equally high risk of declining ovarian function and premature menopause compared with patients conditioned with cyclophosphamide only.[42] All women who received high-dose (50 mg/kg/day x 4 days) cyclophosphamide before HSCT for aplastic anemia developed amenorrhea after transplantation.
- In another series, 36 of 43 women with aplastic anemia conditioned with cyclophosphamide (200 mg/kg) had recovery of normal ovarian function 3 to 42 months after transplantation, including all of the 27 patients who were between ages 13 and 25 years at the time of HSCT.[43]
- TBI is especially damaging when given in a single fraction.[42] Most postpubertal women who receive TBI before HSCT develop amenorrhea.
- In one series, recovery of normal ovarian function occurred in only 9 of 144 patients and was highly correlated with age at time of radiation therapy in patients younger than 25 years.[43]
- Among women with leukemia, cranial irradiation before transplantation further decreased the possibility of retaining ovarian function.[42]
- Ovarian function may be better preserved (based on pubertal progress and gonadotropin levels) in females undergoing HSCT with reduced-intensity conditioning using fludarabine/melphalan than in those undergoing conditioning with myeloablative busulfan/cyclophosphamide.[32]
Fertility
Infertility remains one of the most common life-altering treatment effects experienced by long-term childhood survivors. Pediatric cancer cohort studies have demonstrated the impact of cytotoxic therapy on reproductive outcomes. CCSS investigations have elucidated factors contributing to subfertility among childhood cancer survivors.[47,48]
Fertility was evaluated in 10,938 CCSS participants (5,640 males, 5,298 females) and 3,949 siblings.[47]
- At a median follow-up of 8 years from cohort entry, 38% of survivors reported having or siring a pregnancy, resulting in at least one live birth in 83% of those survivors. Among siblings monitored for a median of 10 years, 62% reported having or siring a pregnancy, resulting in at least one live birth in 90% of those siblings. Multivariable analysis confirmed that survivors had significantly decreased likelihood of siring or having a pregnancy (hazard ratio [HR], 0.63 in males and 0.87 in females) or of having a live birth (HR, 0.63 in males and 0.82 in females) than did siblings.
- Greater doses of alkylating drugs (HR, 0.82 per 5,000 mg/m2 increments) and cisplatin reduced the likelihood of siring pregnancy among male survivors, but only busulfan and higher doses (>411 mg/m2) of lomustine significantly reduced pregnancy among females. Reassuringly, the risk of reduced likelihood of pregnancy in women was observed only at the highest cyclophosphamide equivalent dose (HR, 0.85 for upper quartile [≥11,295 mg/m2] vs. no exposure).
- HRs (95% CIs) for the likelihood of reporting first pregnancy by cyclophosphamide equivalent dose for male and female survivors are summarized in Table 14:
Table 14. Cyclophosphamide Equivalent Dose by Tertile and Sex Cyclophosphamide Equivalent Dose by Tertile Male Female HR (95% CI) P Value HR (95% CI) P Value CI = confidence interval; HR = hazard ratio. Lower (<4,897 mg/m2) 1.14 (1.00-1.30) .045 0.97 (0.86-1.08) .55 Middle (4,897-9,638 mg/m2) 0.79 (0.68-0.91) .0010 0.98 (0.87-1.11) .76 Upper (≥9,639 mg/m2) 0.55 (0.47-0.64) <.0001 0.90 (0.79-1.01) .07 - Similar relationships were observed for live birth outcomes.
Fertility may be impaired by factors other than the absence of sperm and ova. Conception requires delivery of sperm to the uterine cervix, patency of the fallopian tubes for fertilization to occur, and appropriate conditions in the uterus for implantation.[5,6,49]
- Retrograde ejaculation occurs with a significant frequency in men who undergo bilateral retroperitoneal lymph node dissection.[5,6]
- Uterine structure may be affected by abdominal irradiation. A study demonstrated that uterine length was significantly shorter in ten women with ovarian failure who had been treated with whole-abdomen irradiation. Endometrial thickness did not increase in response to hormone replacement therapy in three women who underwent weekly ultrasound examination. No flow was detectable with Doppler ultrasound through either uterine artery of five women, and through one uterine artery in three additional women.[49]
Reproduction
For survivors who maintain fertility, numerous investigations have evaluated the prevalence of and risk factors for pregnancy complications in adults treated for cancer during childhood. Pregnancy complications including hypertension, fetal malposition, fetal loss/spontaneous abortion, preterm labor, and low birth weight have been observed in association with specific diagnostic and treatment groups.[50,51,52,53,54]
Evidence (pregnancy complications in adults treated for childhood cancer):
- In a study of 4,029 pregnancies among 1,915 women followed in the CCSS, there were 63% live births, 1% stillbirths, 15% miscarriages, 17% abortions, and 3% unknown or in gestation.[50]
- Risk of miscarriage was 3.6-fold higher in women treated with craniospinal irradiation and 1.7-fold higher in those treated with pelvic irradiation. Chemotherapy exposure alone did not increase risk of miscarriage.
- Survivors were less likely to have live births, more likely to have medical abortions, and more likely to have low-birth-weight babies than were siblings.
- Disruption of normal uterine function after radiation therapy or other treatment that results in reduced uterine volume and impaired uterine blood flow appears to be the underlying pathophysiology for many of these adverse obstetrical events.[55]
- In the National Wilms Tumor Study, records were obtained for 1,021 pregnancies of more than 20 weeks duration. In this group, there were 955 single live births.[56]
- Hypertension complicating pregnancy, early or threatened labor, malposition of the fetus, lower birth weight (<2,500 g), and premature delivery (<36 weeks) were more frequent among women who had received flank irradiation, in a dose-dependent manner.
- Another CCSS study evaluated pregnancy outcomes of partners of male survivors.[51]
- Among 4,106 sexually active males, 1,227 reported they sired 2,323 pregnancies, which resulted in 69% live births, 13% miscarriages, 13% abortions, and 5% unknown or in gestation at the time of analysis.
- Compared with partners of male siblings, there was a decreased incidence of live births (RR, 0.77), but no significant differences of pregnancy outcome by treatment.
- Results from a Danish study confirm the association of uterine irradiation with spontaneous abortion, but not other types of abortion. Thirty-four thousand pregnancies were evaluated in a population of 1,688 female survivors of childhood cancer in the Danish Cancer Registry. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in the population were identified.[52]
- No significant differences were seen between survivors and comparison women in the proportions of live births, stillbirths, or all types of abortions combined.
- Survivors with a history of neuroendocrine or abdominal radiation therapy had an increased risk of spontaneous abortion.
- Thus, the pregnancy outcomes of survivors were similar to those of comparison women with the exception of spontaneous abortion.
- In a retrospective cohort analysis from the CCSS of 1,148 men and 1,657 women who had survived cancer, there were 4,946 pregnancies.[53]
- Irradiation of the testes in men and pituitary gland in women and chemotherapy with alkylating drugs were not associated with an increased risk of stillbirth or neonatal death.
- Uterine and ovarian irradiation significantly increased the risk of stillbirth and neonatal death at doses higher than 10 Gy.
- For girls treated before menarche, irradiation of the uterus and ovaries at doses as low as 1 Gy to 2.49 Gy significantly increased the risk of stillbirth or neonatal death.
- Most pregnancies reported by HSCT survivors and their partners result in live births.[54]
- In female HSCT survivors who were exposed to TBI, there appears to be an increased risk of preterm delivery of low-birth-weight infants.
- Female HSCT survivors are at higher risk of needing cesarean delivery than are the normal population (42% vs. 16%).
- Preservation of fertility and successful pregnancies may occur after HSCT, although the conditioning regimens that include TBI, cyclophosphamide, and busulfan are highly gonadotoxic. One study evaluated pregnancy outcomes in a group of females treated with HSCT.[57]
- Among 708 women who were postpubertal at the time of transplant, 116 regained normal ovarian function and 32 became pregnant.
- Among 82 women who were prepubertal at the time of transplant, 23 had normal ovarian function and nine became pregnant.
- Of the 72 pregnancies in these 41 women, 16 occurred in those treated with TBI and 50% resulted in early termination.
- Among the 56 pregnancies in women treated with cyclophosphamide without either TBI or busulfan, 21% resulted in early termination.
- There were no pregnancies among the 73 women treated with busulfan and cyclophosphamide, and only one retained ovarian function.
- A German study demonstrated that the rate of childbearing for female survivors of Hodgkin lymphoma was similar to that of the general population, although the rate of childbearing was lower for survivors who received pelvic radiation therapy.[58]
- British CCSS investigators evaluated pregnancy and labor complications among female survivors of childhood cancer treated with abdominal radiation by linking British CCSS cohort data to a national hospital registry.[59]
- Survivors treated with abdominal radiation had a significantly higher risk (RR, 2.1) of pregnancy complications than did survivors who did not receive abdominal radiation.
- Risks were elevated for hypertension complicating pregnancy among Wilms tumor survivors (RR, 3.29) treated with abdominal radiation and for gestational diabetes mellitus (RR, 3.35) and anemia (RR, 2.10) among all survivors treated with abdominal radiation.
Fertility preservation
Progress in reproductive endocrinology has resulted in the availability of several options for preserving or permitting fertility in patients about to receive potentially toxic chemotherapy or radiation therapy.[60] For males, cryopreservation of spermatozoa before treatment is an effective method to circumvent the sterilizing effect of therapy. Although pretreatment semen quality in patients with cancer has been shown to be less than that noted in healthy donors, the percentage decline in semen quality and the effect of cryodamage to spermatozoa from patients with cancer is similar to that of normal donors.[61,62] For those unable to bank sperm, newer technologies such as testicular sperm extraction may be an option. Further micromanipulative technologic advances such as intracytoplasmic sperm injection and similar techniques may be able to render sperm extracted surgically, or even poor-quality cryopreserved spermatozoa from cancer patients, capable of successful fertilization.[63]
For females, the most successful assisted-reproductive techniques depend on harvesting and banking the postpubertal patient's oocytes and cryopreserving unfertilized oocytes or embryos before gonadotoxic therapy.[64] Options for prepubertal patients are limited to investigational ovarian tissue cryopreservation for later autotransplantation, which may be offered to girls with nonovarian, nonhematologic cancers.[65]
Offspring of childhood cancer survivors
For childhood cancer survivors who have offspring, there is concern about congenital anomalies, genetic disease, or risk of cancer in the offspring. Children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parents' exposure to mutagenic cancer treatments.
Evidence (children of cancer survivors not at significantly increased risk of congenital anomalies):
- A retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female participants of the CCSS observed the following:[66]
- No significant associations between gonadal radiation therapy or cumulative exposure to alkylating agents and congenital anomalies in offspring.
- A study compared 2,198 offspring of adult survivors treated for childhood cancer between 1945 and 1975 with 4,544 offspring of sibling controls.[67]
- There were no differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations.
- There was similarly no effect of type of childhood cancer treatment on the occurrence of genetic disease in the offspring.
- A population-based study of 2,630 live-born offspring of childhood cancer survivors versus 5,504 live-born offspring of the survivors' siblings found no differences in proportion of abnormal karyotypes or incidence of Down syndrome or Turner syndrome between survivor and sibling offspring.[68]
In the same population-based cohort, survivors treated with abdominal radiation therapy and/or alkylating agents did not have an increased risk of offspring with genetic disease, compared with survivors not exposed to these agents.
- In a study of 5,847 offspring of survivors of childhood cancers treated in five Scandinavian countries, in the absence of a hereditary cancer syndrome (such as hereditary retinoblastoma), there was no increased risk of cancer.[69] Data from the five-center study also indicated no excess risk of single-gene disorders, congenital malformations, or chromosomal syndromes among the offspring of former patients compared with the offspring of siblings.[70]
- In a study that evaluated pregnancy outcomes in 19,412 allogeneic and 17,950 autologous transplant patients, European Group for Blood and Marrow Transplantation investigators did not observe an increased risk of birth defects, developmental delay, or cancer among offspring of male and female HSCT recipients.[54]
- A nationwide Finnish population-based registry study compared the risk of congenital anomalies in the offspring of 6,862 long-term survivors of childhood, adolescent, and young adult cancer treated between 1953 and 2004 with the risk of congenital anomalies in the offspring of 35,690 siblings.[71]
- The study did not find a significant excess risk of congenital anomalies among childhood and adolescent survivors (prevalence ratio [PR], 1.17; 95% CI, 0.92-1.49) and young adult survivors (PR, 1.17; 95% CI, 0.83-1.23) compared with siblings.
- There was an association between parent cancer and congenital anomalies in the offspring of survivors who were diagnosed in the earlier decades (1955-1964: PR, 2.77; 95% CI, 1.26-6.11; and 1965-1974: PR, 1.55; 95% CI, 0.94-2.56).
Table 15 summarizes reproductive late effects and the related health screenings.
| Predisposing Therapy | Reproductive Late Effects | Health Screening |
|---|---|---|
| AMH = anti-mullerian hormone; FSH = follicle-stimulating hormone; LH = luteinizing hormone. | ||
| a Adapted from theChildren's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. | ||
| Alkylating agents; gonadal irradiation | Testicular hormonal dysfunction: Testosterone deficiency/insufficiency; delayed/arrested puberty | Tanner stage |
| Morning testosterone | ||
| LH | ||
| Impaired spermatogenesis: Reduced fertility; oligospermia; azoospermia; infertility | Semen analysis | |
| FSH | ||
| Inhibin B | ||
| Ovarian hormone deficiencies: Delayed/arrested puberty; premature ovarian insufficiency/premature menopause. Reduced ovarian follicular pool: Diminished ovarian reserve; infertility. | Tanner stage | |
| Menstrual cycle history | ||
| Estradiol | ||
| FSH | ||
| LH | ||
| AMH | ||
| Antral follicle count | ||
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for reproductive late effects information including risk factors, evaluation, and health counseling.
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