Abstract
Objective
To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)‐directed therapies.
Methods
A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS‐treated]; median age [range] = 25.5 years [18–48]; time since diagnosis = 17.7 years [6.8–30.2]) and 8039 without CNS‐directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal care needs, ability to work/attend school, attainment of driver's license, marital/partner status). Multivariable regression models, adjusted for age, sex, race/ethnicity, and chronic health conditions, estimated odds ratios (OR) or relative risks (RR) for associations between neurologic morbidity, functional independence, and emotional distress.
Results
Among CNS‐treated survivors, three classes of independence were identified: (1) moderately independent, never married, and non‐independent living (78.7%); (2) moderately independent, unable to drive (15.6%); and (3) non‐independent (5.7%). In contrast to 50% of non‐CNS‐treated survivors and 60% of siblings, a fourth fully independent class of CNS‐treated survivors was not identified. History of stroke (OR = 2.50, 95% CI: 1.70–3.68), seizure (OR = 9.70, 95% CI: 7.37–12.8), neurosensory deficits (OR = 2.67, 95% CI: 2.16–3.31), and focal neurologic dysfunction (OR = 3.05, 95% CI: 2.40–3.88) were associated with non‐independence among CNS‐treated survivors. Non‐independence was associated with emotional distress symptoms.
Interpretation
CNS‐treated survivors do not attain full independence comparable to non‐CNS‐treated survivors or siblings. Interventions to promote independence may be beneficial for survivors with treatment‐related neurological sequalae.
Introduction
Improvements in treatment and supportive care have resulted in over 500,000 childhood cancer survivors living in the United States, 1 many of whom face long‐term medical and psychosocial sequelae. 2 , 3 , 4 , 5 , 6 , 7 Treatment directed at the developing central nervous system (CNS), including cranial radiation therapy (CRT) and intrathecal methotrexate (IT MTX), has been associated with a number of late neurologic morbidities in childhood cancer survivors. For example, CRT exposure during childhood has been associated with increased risk of stroke in a dose‐dependent manner, 8 , 9 and with an increased risk of hearing loss, seizures, and tinnitus in adulthood. 10 Intrathecal methotrexate also has been associated with the development of seizures 11 and leukoencephalopathy. 12 , 13 Leukoencephalopathy has been subsequently associated with increased neurocognitive deficits in survivors. 12 , 14
Treatment‐related neurologic morbidities have the potential to impact survivors' ability to attain independence in adulthood. A recent report from the Childhood Cancer Survivor Study (CCSS) showed that survivors with a history of stroke were more likely to live with a caregiver compared to stroke‐free survivors. 15 Independent living, however, is only a single indicator of independence. The ability to establish social relationships, work, commute, and complete activities of daily living are additional factors that contribute to independence in adulthood. A multicomponent construct of functional independence has previously been described among adult survivors of CNS tumors; 16 however, the contribution of prevalent treatment‐related neurologic morbidities to independence has not been considered, nor has functional independence been examined in non‐CNS tumor survivors treated with CNS‐directed therapies. Finally, neurological late effects and functional independence each have the potential to impact psychological health. For example, past CCSS reports have indicated that seizures were associated with a two‐fold to three‐fold increased odds of suicidal ideation in adult survivors of childhood cancer. 17 , 18 Potential associations between neurologic morbidity, functional independence, and emotional distress have not been comprehensively investigated in adult survivors of childhood cancer treated with CNS‐directed therapies.
Methods
Study sample
The CCSS is a multi‐institutional, retrospective cohort study with longitudinal follow‐up of survivors of childhood cancer recruited from 31 institutions across North America. 19 The Institutional Review Board at each participating institution approved the CCSS protocol, and all participants provided informed consent. Eligible participants (herein referred to as “CNS‐treated survivors”) included adult survivors of childhood cancer who (1) were treated between 1970 and 1999; (2) survived at least 5 years from date of original diagnosis; (3) were at least 18 years of age at cohort entry; (4) received CNS‐directed cancer therapy (CRT or IT MTX; irrespective of whether they received a CNS diagnosis); and (5) self‐completed baseline study questionnaires (Fig. 1). The CRT dose was taken as the sum of the prescribed doses from all overlapping brain‐directed radiotherapy fields. 20 Participants used in two comparison groups included survivors who met all study criteria except for having received CNS‐directed cancer therapy (“non‐CNS‐treated survivors”), and siblings of survivors who were at least 18 years of age at cohort entry and self‐completed study measures (“siblings”).
Figure 1.
Study participant flow diagram for CNS‐treated and non‐CNS‐treated survivors.
Neurologic conditions
Participants self‐reported neurologic morbidity at CCSS baseline assessments. Neurologic chronic health conditions (CHCs) were graded for severity per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, which uses the following grading schema: mild (grade 1), moderate (grade 2), severe or disabling (grade 3), or life‐threatening (grade 4). 21 The following neurologic conditions were examined: (1) stroke; (2) seizure; (3) auditory, vestibular, or visual sensory deficits (including sensory neuropathy; hearing loss with or without a hearing aid; deafness in one or both ears not completely corrected by a hearing aid; persistent dizziness or vertigo; legal blindness in one or both eyes; problems with double vision); (4) focal neurologic dysfunction (including deficits related to balance, equilibrium, or ability to reach for or manipulate objects; tremors or movements; weakness or inability to move arms/legs); and (5) migraines or severe headaches. Neurologic conditions were defined as having a minimum CTCAE grade of 2, except for sensory deficits and migraines or severe headaches, which were defined using CTCAE grade 1 or greater.
Functional independence
Six indicators were used to assess functional independence: (1) dependent living (living with parents, other adults/caregivers vs. living alone or with spouse/children); (2) inability to hold a job or attend school (yes vs. no); (3) assistance with routine care needs (yes vs. no); (4) assistance with personal care needs (yes vs. no); (5) driver's license (yes vs. no); and (6) marital/partner status (never married or lived with partner as married vs. history of marriage/partnership).
Emotional distress
The Brief Symptom Inventory‐18 (BSI‐18) 22 was used to measure symptoms of emotional distress. Using sex‐specific normative data, depression, anxiety, and somatization were defined as scores falling ≥90th percentile (equivalent to T‐score ≥ 63) for each subscale. Consistent with past CCSS reports, suicidal ideation was defined dichotomously as any positive endorsement of a single item (“thoughts of ending your life”). 18
Statistical analyses
Latent class analysis (LCA) was used to identify classes of functional independence for CNS‐treated survivors, non‐CNS‐treated survivors, and siblings, separately. LCA uses observed variables to identify subgroups of survivors who share similar response patterns. The grouping variable (e.g., class membership) is not directly observed but is derived from the observed data; thus, survivors are assigned to classes based on statistical probability. We used six observed indicators to identify latent classes of functional independence. Analyses were performed using Mplus (Muthen & Muthen, Los Angeles, CA) and utilized the Full Information Maximum Likelihood Estimation. Optimal model class solutions were evaluated using the Bayesian information criterion (BIC), entropy, and substantive meaning. For CNS‐treated survivors, we required the smallest class size be ≥5% to permit sufficient numbers to undertake subsequent multivariable analyses.
To examine the association between neurologic morbidity and classes of functional independence, multinomial logistic regression models adjusted for age, age at diagnosis, sex, race, and CHCs (i.e., cardiac, pulmonary, endocrine, and musculoskeletal) were used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CIs). For associations between functional independence and emotional distress, where functional independence was considered the exposure, relative risks (RR) were calculated by using modified Poisson regression models adjusting for age, age at diagnosis, sex, and race. All statistical analyses were weighted by inverse probability of sampling to account for the under‐sampling of leukemia survivors in the expansion cohort of CCSS. Analyses were completed using Statistical Analysis System software (SAS 9.4, Cary, NC).
Results
CNS‐treated survivors were a median of 25.5 years of age (range, 18.0–48.0 years) at baseline assessment, and 17.7 years (range, 6.8–30.2 years) from their primary childhood cancer diagnosis. Approximately half of participants were treated with CRT (48.0%), two‐thirds with IT MTX (65.4%), and nearly one‐third (26.8%) with both. Participants were primarily survivors of leukemia (58.5%), CNS tumors (26.7%), and non‐Hodgkin lymphoma (11.4%). Table 1 shows demographic and treatment characteristics of CNS‐treated survivors as well as non‐CNS‐treated survivors and siblings.
Table 1.
Demographic and treatment characteristics of CNS‐treated survivors, non‐CNS‐treated survivors, and siblings.
| CNS‐treated survivors (n = 7881) | non‐CNS‐treated survivors (n = 8039) | Siblings (n = 3994) | ||||
|---|---|---|---|---|---|---|
| M | SD | M | SD | M | SD | |
| Age at evaluation, years | 25.5 | 5.8 | 27.9 | 6.2 | 29.6 | 7.2 |
| Age at diagnosis, years | 7.8 | 5.4 | 9.9 | 6.1 | – | – |
| Time since diagnosis, years | 17.7 | 4.5 | 18 | 4.4 | – | – |
| n | % | n | % | n | % | |
|---|---|---|---|---|---|---|
| Sex | ||||||
| Female | 3641 | 47.0 | 3960 | 49.2 | 2143 | 53.7 |
| Male | 4240 | 53.0 | 4079 | 50.8 | 1847 | 46.3 |
| Race/Ethnicity | ||||||
| White/non‐Hispanic | 6567 | 85.4 | 6561 | 84.0 | 3509 | 91.1 |
| Black | 377 | 5.6 | 592 | 7.7 | 111 | 2.9 |
| Hispanic | 412 | 5.7 | 440 | 5.6 | 132 | 3.4 |
| Other | 247 | 3.4 | 214 | 2.8 | 98 | 2.5 |
| Diagnosis | ||||||
| Leukemia | 3712 | 58.5 | 833 | 11.2 | – | – |
| CNS tumor | 2684 | 26.7 | 0 | 0 | – | – |
| Hodgkin's lymphoma | 26 | 0.3 | 2627 | 32.4 | – | – |
| Non‐Hodgkin's lymphoma | 1144 | 11.4 | 440 | 5.4 | – | – |
| Neuroblastoma | 53 | 0.5 | 726 | 8.9 | – | – |
| Wilms tumor | 4 | 0.0 | 1189 | 14.7 | – | – |
| Osteosarcoma | 47 | 0.5 | 1617 | 19.9 | – | – |
| Soft tissue sarcoma | 211 | 2.1 | 607 | 7.5 | – | – |
| CRT | ||||||
| None | 3398 | 52.0 | 0 | 0 | – | – |
| <20 Gy | 1192 | 16.6 | 0 | 0 | – | – |
| ≥20 Gy to <30 Gy | 1257 | 14.5 | 0 | 0 | – | – |
| ≥30 Gy | 1602 | 16.9 | 0 | 0 | – | – |
| IT Methotrexate | ||||||
| None | 3285 | 34.6 | 0 | 0 | – | – |
| <175 mg/m2 | 2915 | 36.1 | 0 | 0 | – | – |
| ≥175 mg/m2 | 1278 | 29.3 | 0 | 0 | – | – |
CNS, central nervous system; CRT, cranial radiation therapy; Gy, Gray; IT, intrathecal; M, mean; mg/m2, milligram/square meter; n, number; SD, standard deviation; <, less than; ≥, greater than or equal to; %, percent.
Neurologic morbidity
In comparisons adjusted for age, sex, and race/ethnicity, CNS‐treated survivors had a higher prevalence of moderate, severe, or life‐threatening neurologic conditions than non‐CNS‐treated survivors (stroke: 2.4% vs. 0.9%, RR = 1.02 [95% CI = 1.01–1.02]; seizure: 4% vs. 0.8%, RR = 1.03 [95% CI = 1.03–1.04]; neurosensory deficits, 26.5% vs. 23.7%, RR = 1.20 [95% CI = 1.13–1.27]; focal neurologic dysfunction, 9.1% vs. 4.8%, RR = 1.05 [95% CI = 1.04–1.05]; and migraines, 22.8% vs. 21.8%, RR = 1.01 [95% CI = 1.00–1.02]).
Functional independence
For each individual indicator of independence, a larger proportion of CNS‐treated survivors reported the outcome associated with non‐independence versus independence compared to non‐CNS‐treated survivors and siblings (non‐independent living: 54.5% [CNS‐treated] vs. 45.4% [non‐CNS‐treated] vs. 33.0% [siblings]; no history of marriage/partnership: 61.1% vs. 43.5% vs. 35.1%; unable to work/attend school: 11.3% vs. 8.1% vs. 2.1%; assistance with routine needs: 6.8% vs. 4.7% vs. 1.6%; assistance with personal care needs: 2.2% vs. 1.3% vs. 0.6%; no driver's license: 17.4% vs. 9.5% vs. 5.4%, all p‐values <0.001). Results of the LCA yielded three classes of functional independence for CNS‐treated survivors: (1) moderately independent, never married, and non‐independent living (78.7%); (2) moderately independent, unable to drive (15.6%); and (3) non‐independent (5.7%). In the non‐CNS‐treated comparison group, LCA supported a four‐class solution: (1) independent (49.1%); (2) moderately independent, never married, and non‐independent living (37.0%); (3) moderately independent, unable to drive (9.4%); and (4) non‐independent (4.5%). Among siblings, three classes emerged: (1) independent (59.3%); (2) moderately independent, never married, and non‐independent living (39.0%); (3) non‐independent (1.7%). Model fit indices for 2 through 5 class solutions are shown in Table S1. Characteristics of class membership are shown in Fig. 2, separately for siblings, non‐CNS‐treated survivors and CNS‐treated survivors.
Figure 2.
Latent classes of functional independence for siblings, non‐CNS‐treated survivors, and CNS‐treated survivors.
Among CNS‐treated survivors, in multivariable analyses adjusted for age, sex, race/ethnicity, and age at diagnosis, ≥30 Gy CRT was associated with a nearly four‐fold increased odds of non‐independence (OR = 3.81, 95% CI: 2.95–4.94) and 2.6‐fold increased odds of moderate independence, unable to drive (OR = 2.61; 95% CI: 2.14–3.18) compared to moderate independence, never married, and non‐independent living (Table 2). Figure 3 shows the prevalence of neurological morbidity by each class of functional independence for CNS‐treated survivors. In multivariable models adjusted for the presence of other CHCs (i.e., endocrine, pulmonary, cardiac, and musculoskeletal), neurologic conditions were associated with significantly increased odds of non‐independence (stroke: OR = 2.5, 95% CI: 1.70–3.68; seizure: OR = 9.7, 95% CI: 7.37–12.8; neurosensory deficits: OR = 2.67, 95% CI: 2.16–3.31; focal neurologic dysfunction: OR = 3.05; 95% CI: 2.40–3.88; Table 3) and moderate independence, unable to drive (seizure: OR = 2.79, 95% CI: 2.09–3.73; neurosensory deficits: OR = 1.73, 95% CI: 1.49–2.01; focal neurologic dysfunction: OR = 1.93; 95% CI: 1.57–2.37) compared to moderately independent, never married, and non‐independent living.
Table 2.
Associations between treatment exposures and classes of functional independence among CNS‐treated survivors.
| Moderately independent, never married, and non‐independent living vs. moderately independent, unable to drive (Referent) | Moderately independent, never married, and non‐independent living vs. non‐independent (Referent) | |
|---|---|---|
| OR (95% CI) | OR (95% CI) | |
| Age at survey, per 5 years | 0.75 (0.69–0.83) | 1.29 (1.14–1.46) |
| Age at diagnosis, per 5 years | 0.80 (0.72–0.88) | 0.65 (0.57–0.75) |
| Male sex | 0.81 (0.71–0.93) | 0.72 (0.60–0.88) |
| Race/ethnicity | ||
| White, non‐Hispanic vs. other | 0.40 (0.35–0.47) | 0.66 (0.57–0.75) |
| Cranial radiation | ||
| <20 Gy vs. none | 1.06 (0.86–1.30) | 1.31 (0.96–1.80) |
| ≥20 Gy to <30 Gy vs. none | 1.04 (0.83–1.30) | 1.07 (0.77–1.50) |
| ≥30 Gy vs. none | 2.61 (2.14–3.18) | 3.81 (2.95–4.94) |
| IT MTX | ||
| <175 mg/m2 vs. none | 0.73 (0.60–0.89) | 0.65 (0.50–0.84) |
| ≥175 mg/m2 vs. none | 0.66 (0.54–0.80) | 0.27 (0.19–0.38) |
CI, confidence interval; CNS, central nervous system; Gy, Gray; IT MTX, intrathecal methotrexate; mg/m2, milligram/square meter; OR, odds ratio; vs, versus; <, less than; ≥, greater than or equal to; %, percent.
Figure 3.
Prevalence of neurologic conditions by classes of functional independence among CNS‐treated survivors.
Table 3.
Associations between neurologic conditions and classes of functional independence among CNS‐treated survivors.
| Moderately independent, never married, and non‐independent living vs. moderately independent, unable to drive (Referent) | Moderately independent, never married, and non‐independent living vs. non‐independent (Referent) | |
|---|---|---|
| OR (95% CI) | OR (95% CI) | |
| Migraines/Severe headaches | 0.93 (0.80–1.09) | 0.91 (0.73–1.13) |
| Focal neurological dysfunction a | 1.93 (1.57–2.37) | 3.05 (2.40–3.88) |
| Neurosensory deficits b | 1.73 (1.49–2.01) | 2.67 (2.16–3.31) |
| Seizure | 2.79 (2.09–3.73) | 9.70 (7.37–12.8) |
| Stroke | 1.47 (1.00–2.17) | 2.50 (1.70–3.68) |
Multivariable model adjusted for age, sex, race/ethnicity, and ≥Grade 2 CTCAE endocrine, pulmonary, cardiac, and musculoskeletal conditions.
CI, confidence interval; CNS, central nervous system; CTCAE, Common Terminology Criteria for Adverse Events; OR, odds ratio; vs, versus; %, percent.
Includes deficits related to balance/equilibrium, tremors or movements, weakness or inability to move arms/legs.
Include sensory neuropathy, hearing loss, deafness, persistent dizziness/vertigo, legal blindness, double vision.
Emotional distress
Among CNS‐treated survivors, neurologic conditions were associated with greater risk of emotional distress (e.g., focal neurologic dysfunction: depression RR = 1.57, 95% CI: 1.28–1.91; anxiety RR = 1.75, 95% CI: 1.35–2.27; somatization RR = 1.56, 95% CI, 1.26–1.93; suicidal ideation RR = 1.33, 95% CI, 1.04–1.70; neurosensory deficits: depression RR = 1.61, 95% CI: 1.37–1.89; anxiety RR = 1.73, 95% CI: 1.40–2.14; somatization RR = 2.26, 95% CI, 1.87–2.73; suicidal ideation RR = 1.40, 95% CI, 1.15–1.70; migraines/severe headaches: depression RR = 1.73, 95% CI: 1.48–2.03; anxiety RR = 1.81, 95% CI: 1.46–2.24; somatization RR = 1.75, 95% CI, 1.45–2.11; and suicidal ideation RR = 1.51, 95% CI, 1.24–1.84). In multivariable models restricted to CNS‐treated survivors, non‐independent survivors had a minimum two‐fold higher risk of elevated distress symptoms compared to survivors in the moderately independent, never married, and non‐independent living class (depression: RR = 2.42, 95% CI: 2.00–2.94; anxiety: RR = 3.17, 95% CI: 2.47–4.06; somatization: RR = 3.36, 95% CI: 2.75–4.11; suicidal ideation: RR = 2.05, 95% CI: 1.62–2.59; Table 4).
Table 4.
Associations between classes of functional independence and psychological distress symptoms among CNS‐treated survivors.
| Depression a | Anxiety a | Somatization a | Suicidal ideation b | |
|---|---|---|---|---|
| RR (95% CI) | RR (95% CI) | RR (95% CI) | RR (95% CI) | |
| Moderately independent, never married, and non‐independent living vs. Moderately independent, unable to drive (Referent) | 1.38 (1.11–1.71) | 1.35 (1.00–1.83) | 1.63 (1.28–2.07) | 1.37 (1.07–1.76) |
| Moderately independent, never married, and non‐independent living vs. non‐independent (Referent) | 2.42 (2.00–2.94) | 3.17 (2.47–4.06) | 3.36 (2.75–4.11) | 2.05 (1.62–2.59) |
Multivariable models adjusted for age, sex, race/ethnicity.
CI, confidence interval; CNS, central nervous system; RR, relative risk; vs, versus; %, percent.
Defined as scores >90th percentile of sex‐specific normative data.
Defined as any positive endorsement of “thoughts of ending your life”.
Discussion
In a large cohort of adult survivors of childhood cancer, we identified distinct patterns of functional independence among survivors treated with CNS‐directed therapies compared to survivors who were not exposed to CNS‐directed treatments and a comparison sibling cohort. Among CNS‐treated survivors, neurological morbidities were associated with reduced functional independence that, in turn, conferred increased risk of emotional distress. These analyses identified a subgroup of survivors who may benefit from targeted rehabilitative and/or mental health interventions as well as increased surveillance. This is particularly true as growing numbers of survivors reach and transition into adulthood when the demands for independence increase.
We observed three classes of functional independence among CNS‐treated survivors that reflect varying degrees of independence: (1) moderately independent, never married, and non‐independent living; (2) moderately independent, unable to drive; and (3) non‐independent. In our population, non‐independence was characterized by the inability to work/attend school, absence of a driver's license, non‐independent living, requiring assistance with routine and personal care needs, and no history of marriage/partnership. We did not identify a class of fully independent CNS‐treated survivors, whereas nearly 50% of non‐CNS‐treated survivors and 60% of siblings were classified as independent. This emphasizes the substantial negative impact of CNS‐directed therapies on multiple aspects of social and functional independence in long‐term survivors. A previous report on functional independence restricted to adult survivors of pediatric CNS tumors also revealed three classes of independence; 16 however, because the study did not include a comparison group, the absence of a fully independent class was not identified. Our results expand upon this past work by including non‐CNS tumor survivors who were treated with CNS‐directed therapies and by demonstrating that CNS‐treated survivors do not attain levels of independence consistent with their non‐CNS‐treated or sibling counterparts. These findings underscore the importance of early identification of survivors at risk for non‐independence and targeted interventions to promote independence.
Our results suggest that the inability of CNS‐treated survivors to attain independence in adulthood may be due, in part, to the high burden of neurologic morbidity they experience. Survivors treated with CNS‐directed therapies are at known risk for treatment‐related neurological morbidities. 10 In our sample, CNS‐treated survivors were significantly more likely to report strokes, seizures, neurosensory deficits, and focal neurologic dysfunction compared to non‐CNS‐treated survivors; in turn, these treatment‐induced neurological morbidities had a profound impact on survivors' ability to achieve independence. Specifically, CNS‐treated survivors with neurologic conditions had 3‐ to 10‐fold increased risk of non‐independence. While a recent report from CCSS demonstrated that survivors with a history of stroke were more likely to live with a caregiver compared to stroke‐free survivors, 15 our results extend these findings by indicating that survivors are not only less likely to live independently but also more likely to require assistance with other personal and routine care needs. Thus, survivors who experience adverse neurologic events may be a subgroup who could benefit from interventions targeted at promoting independence. Several intervention approaches including vocational rehabilitation 23 and physical rehabilitation, 24 and those that include exercise, 25 have been shown to increase social and functional independence in adults with neurologic conditions. Nonetheless, because some aspects of independence may not be attainable for long‐term survivors treated with CNS‐directed therapies (e.g., due to cognitive impairment), 26 intervention efforts may need to expand to include caregivers of survivors. Models for such approaches have been developed to improve the psychosocial health of caregivers of patients with dementia. 27
Survivors with neurologic toxicities also had a greater prevalence of emotional distress. Specifically, sensory deficits, focal neurologic deficits, and migraines/severe headaches were associated with 30 to 60% increased risk of elevated symptoms of anxiety, depression, and suicidal ideation. It is important to note that these associations may be bidirectional. While mood disturbances may develop poststroke, 28 emotional symptoms such as depression or anxiety may trigger migraines/severe headaches. 29 In the general population, depression is prevalent and highly comorbid in patients with neurological conditions, 30 and a recent nationwide study from Denmark revealed a higher rate of death by suicide among individuals diagnosed with neurologic disorders. 31 Unique to childhood cancer survivors, CNS‐directed therapies targeting the developing nervous system and subsequent insult from neurological events (e.g., stroke/seizure) may create a diathesis for “organic” psychopathology via neurostructural and/or neurobiological alterations, 32 which may be subsequently exacerbated by life stressors that accompany poor functioning in adulthood. Given the heightened vulnerability of CNS‐treated survivors to developing neurologic conditions, routine surveillance and screening for psychological symptoms for this subgroup of survivors is warranted.
Lastly, we found that non‐independence was itself associated with emotional distress symptoms in survivors, even while accounting for the contribution of neurological conditions. Among CNS‐treated survivors, non‐independence was associated with a nearly two‐fold increased risk of elevated symptoms of depression, anxiety, and somatization and a 15% increased risk of suicidal ideation. Reduced functional independence may result in limited social integration that subsequently contributes to increased emotional symptomatology among survivors. For example, social isolation poststroke has been associated with higher levels of depressive symptoms and decreased ability to manage daily activities. 33
The results of our study should be considered in the context of several limitations. Available indicators of functional independence in the CCSS cohort (i.e., living independently and being unmarried) may not provide optimal measurement of independence for younger adults as many are choosing to delay marriage and reside with their parents. Unfortunately, marital status/partnership is the only potential proxy available for social functioning in the cohort. However, because we used the same indicators of independence across groups, this should not differentially impact observed classes. Latent class analysis does not consider differential weights of observed variables, and we acknowledge that some considered indicators (i.e., assistance with personal care needs) may contribute more strongly to the attainment of independence than others (i.e., marital status). Nonetheless, LCA is robust method for identifying patterns of responses within large datasets where subgroups are hypothesized to exist. Although all treatment‐related data were abstracted from medical records, neurologic conditions were self‐reported and sub‐clinical events including strokes may not have been detected or reported. While cumulative dose of MTX was available, information related to high dose IV MTX was not available for the entire cohort and thus we were unable to consider this as a potential CNS treatment exposure. Survivors in our analysis were treated between 1970 and 1999. While front line therapies have evolved, IT MTX remains a curative treatment for ALL and most CNS tumor patients still receive CRT, although advancements have been made including increased availability of proton beam radiation. Future research should consider the impact of contemporary CNS‐directed therapies, including surgical advances, and advances in supportive care, on the attainment of independence. Our analyses were cross‐sectional and preclude inference about temporal or causal associations, particularly between neurologic conditions, functional independence, and emotional distress symptoms. Lastly, as neurocognitive functioning was not assessed at baseline in the CCSS cohort, we were unable to examine the impact of neurocognitive function on functional independence. Neurocognitive impairment is a prevalent consequence of CNS‐directed therapies and likely contributes to reduced independence, though neurocognitive impairment may be partially confounded with neurologic morbidities.
These limitations notwithstanding, our results demonstrate that adult survivors of childhood cancer treated with CNS‐directed therapies do not achieve independence at rates comparable to their non‐CNS‐treated survivor or sibling counterparts. The importance of this cannot be overstated, as attainment of independence is a primary goal of childhood cancer survivors and their caregivers. Among CNS‐treated survivors, neurologic late effects were associated with risk of not achieving independence in adulthood. Survivors who develop neurological morbidities and associated functional impairments will benefit from routine mental health screening of their emotional health. Assessment of and interventions for functional independence should be developmentally tailored, as evidence of non‐independence may not manifest until early adulthood, when levels of adaptive functioning prove insufficient to meet the intensified environmental demands that are required to achieve independence in adulthood.
Author Contributions
Stefanie C. Vuotto, M. Fatih Okcu, Daniel C. Bowers, Nicole J. Ullrich, Kirsten K. Ness, Todd M. Gibson, Kevin C. Oeffinger, Leslie L. Robison, Gregory T. Armstrong, Kevin R. Kull, and Tara M. Brinkman contributed to the conception and design of the study. Mingjuan Wang, Kirsten K. Ness, Chenghong Li, Deo Kumar Srivastava, Rebecca M. Howell, and Wendy M. Leisenring contributed to the acquisition and analysis of data. Stefanie C. Vuotto, Mingjuan Wang, Deo Kumar Srivastava, Kevin R. Kull, and Tara M. Brinkman contributed to drafting a significant portion of the manuscript or figures.
Disclosures
The authors have nothing to report.
Supporting information
Supplemental Table 1. Latent class analysis model fit indices for classes of functional independence for siblings, non‐CNS‐treated survivors, and CNS‐treated survivors.
Acknowledgements
This study was supported by the National Cancer Institute (U24 CA55727, GTA; P30 CA21765, CR) and the American Lebanese‐Syrian Associated Charities (ALSAC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Statement
This work was funded by National Cancer Institute grant U24 CA55727.
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Associated Data
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Supplementary Materials
Supplemental Table 1. Latent class analysis model fit indices for classes of functional independence for siblings, non‐CNS‐treated survivors, and CNS‐treated survivors.