Neurocognitive outcomes in adult survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study.

11563 Background: Long-term survivors of neuroblastoma may be at risk for neurocognitive impairment due to young age at diagnosis and intensive multimodal therapies. Methods: 837 survivors of neuroblastoma (57% female; median [range] age 25 [17-58] years, age at diagnosis 1 [0-21] years) and 728 siblings (56% female; age 32[16-43] years) self-reported neurocognitive problems using a neurocognitive questionnaire. Impairment was defined as scores ≥90th percentile of siblings in emotional regulation (ER), organization, task efficiency (TE), and memory. Multivariable log-binomial models evaluated associations with treatment exposures, era and chronic conditions (Grade 2-4 CTCAE v5) adjusting for sex, age, and race. Analyses were stratified by age at diagnosis (≤1 and > 1 year) as proxy for risk group. Results: Rates of impairment were 19.7% (ER), 25.3% organization, 21.9% TE and 19.4% for memory. Survivors had 50% higher risk of impaired TE (≤1 year relative risk [RR] 1.48, 95% confidence interval [CI] 1.08-2.03; > 1 year: RR 1.58, CI 1.22-2.06) and ER (≤1 year RR 1.51, CI 1.07-2.12; > 1 year RR 1.44, CI 1.06-1.95) versussiblings. Among survivors ≤1 year at diagnosis, treatment with platinum (RR 1.74, CI 1.01-2.97), hearing loss (RR 1.95, CI 1.26-3.00), cardiovascular (RR 1.83, CI 1.15-2.89) and neurologic (RR 2.00, CI 1.32-3.03) conditions were associated with higher risk of impaired TE. Female sex (RR = 1.54, CI, 1.02-2.33), cardiovascular (RR 1.71, CI 1.08-2.70) and respiratory (RR 1.99, CI 1.14-3.49) conditions were associated with higher risk of impaired ER. Among survivors > 1 year at diagnosis those treated in 1970-79 vs. 1990-99 had 80% higher risk of impaired ER (RR 1.77, CI 1.02-3.06). Hearing loss (RR 1.56 (1.09-2.24), respiratory (RR 2.35, CI 1.60-3.45) and cardiovascular (RR 1.74, CI 1.12-2.69) conditions were associated with higher risk of impaired TE. Conclusions: Adult survivors of neuroblastoma are at-risk for neurocognitive impairment. Differences associated with age at diagnosis, chronic disease and treatment exposures may inform risk-stratified inventions to improve neurocognitive outcomes. Reduced risk in later eras may reflect improved supportive care and knowledge of late effects.

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Prevalence and Predictors of Neurocognitive Impairment in Long-Term Survivors of Childhood Hodgkin Lymphoma: A Report from the Childhood Cancer Survivor Study

Blood ◽

10.1182/blood-2020-136339 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-15

Author(s):

Annalynn M Williams ◽

Mengqi Xing ◽

Sedigheh Mirzaei Salehabadi ◽

Yutaka Yasui ◽

Matt J. Ehrhardt ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Emotional Regulation ◽

Neurocognitive Impairment ◽

Elevated Risk ◽

Chronic Health Conditions ◽

Health Conditions ◽

Chronic Health ◽

Childhood Cancer Survivor Study ◽

Task Efficiency ◽

Long Term Survivors

Background: Long-term survivors of childhood Hodgkin lymphoma (HL) are at significant risk for cardiovascular, pulmonary, and endocrine morbidity in addition to subsequent cancers. Emerging evidence suggests that HL survivors may also experience persistent neurocognitive impairment, however the prevalence of neurocognitive impairment has not been well characterized. Further, little work has been done to examine how specific treatments or comorbidities are associated with these impairments. Methods: The current study included 1,760 survivors (52.0% female, mean[sd] 37.5 [6.0] years old, 23.6 [4.7] years from diagnosis) of childhood Hodgkin lymphoma and 3,180 sibling controls (54.5% female, 33.2 [8.5] years old) from the Childhood Cancer Survivor Study. Participants completed questionnaires assessing four domains of neurocognitive impairment (task efficiency, emotional regulation, organization, and memory). Impairment for each domain was defined as a score worse than the 90th percentile of community controls. Treatment exposures were abstracted from the medical record. Second malignancies (SMN) were self-reported and subsequently confirmed by pathology findings or medical record review. Chronic health conditions were self-reported and systematically graded according to the NCI CTCAE v4.3 (Grade 1 mild, Grade 2 moderate, Grade 3 severe/disabling, Grade 4 life-threatening). Generalized estimating equations were used to calculate risk of impairment in survivors compared with siblings adjusted for age, sex, and race. Among HL survivors, multivariable log-binomial regression was used to calculate risk of impairment associated with demographic, clinical, and treatment factors. Separate models examined risk associated with Grade 2+ chronic health conditions adjusted for age, sex, and race. Results: 10.8% of HL survivors reported impaired task efficiency (vs. 7.7% in siblings), 16.6% emotional regulation (vs. 11.5% in siblings), 12.1% organization (vs. 10.3% in siblings), and 8.1% memory (vs. 5.7% in siblings). Compared with siblings, survivors reported significantly higher risk of impairment in each of the four neurocognitive domains after adjusting for age, sex, and race (Table). Female survivors had elevated risk of impairment on emotional regulation (RR [95%CI] 1.4 [1.1,1.9)) and memory (2.0 [1.3,3.0]). Compared with white survivors (91.8% of the population), non-white survivors had higher risk of impairment in task efficiency (2.1 [1.2, 3.5]) and emotional regulation (1.7 [1.0,2.7]). Current smokers (12.3%) had higher risk of impairment in task efficiency (1.9 [1.2, 3.1]), emotional regulation (2.5 [1.7,3.7]), and memory (1.7 [1.0,3.0]). Having a late-relapse (>5 years from diagnosis) or a second malignancy (20.0%) was associated with elevated risk of impairment in task efficiency (1.6 [1.06,2.3]). While not statistically significant, anthracycline exposure (39.8%) was associated with higher risk of impairment in task efficiency (1.3 [0.7,2.2]) and memory (1.6 [0.9,3.0]). No statistically significant associations were noted for bleomycin, corticosteroids, or chest radiation. HL survivors with pulmonary morbidity (8.5%) had a higher risk of impairment on task efficiency (1.9 [1.2,3.0]) compared to those without. Cardiovascular conditions (32.9%) were associated with elevated risk of impairment in all domains (RR range from 1.5 to 2.1, all p<0.05, Table). Endocrine (54.3%) and neurologic conditions (6.6%) were associated with an increased risk of task efficiency, emotional regulation, and memory impairments (RR range from 1.4 to 5.5, all p<0.05, Table). Conclusions: Survivors experienced significantly more neurocognitive impairment compared to sibling controls. Among survivors, potentially modifiable risk factors such as smoking and chronic health conditions were associated with neurocognitive impairment while treatment exposures showed little association. Mitigation or prevention of smoking and chronic health conditions may improve neurocognitive functioning in HL survivors Table Disclosures No relevant conflicts of interest to declare.

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Consistent Physical Activity and Future Neurocognitive Problems in Adult Survivors of Childhood Cancers: A Report From the Childhood Cancer Survivor Study

Journal of Clinical Oncology ◽

10.1200/jco.19.02677 ◽

2020 ◽

Vol 38 (18) ◽

pp. 2041-2052

Author(s):

Emily Barlow-Krelina ◽

Yan Chen ◽

Yutaka Yasui ◽

Christine Till ◽

Todd M. Gibson ◽

...

Keyword(s):

Physical Activity ◽

Childhood Cancer ◽

Adult Survivors ◽

Age At Diagnosis ◽

Moderate Activity ◽

Mediation Effects ◽

Childhood Cancer Survivor Study ◽

Small Change ◽

Survivors Of Childhood Cancer ◽

Task Efficiency

PURPOSE To investigate longitudinal associations between physical activity (PA) and neurocognitive problems in adult survivors of childhood cancer. METHODS A total of 12,123 5-year survivors diagnosed between 1970 and 1999 (median [range] age at diagnosis, 7 [0-21] years, time since diagnosis at baseline, 16 [6-30] years) and 720 siblings self-reported PA and neurocognitive problems. PA was collected at baseline, and PA and neurocognitive data were obtained 7 (1-12) years and 12 (9-14) years later. PA consistency was defined as any combination of ≥ 75 minutes of vigorous or 150 minutes of moderate activity per week on all surveys. Multiple linear regressions, conducted separately for CNS and non-CNS survivors, identified associations between PA consistency and neurocognitive outcomes (expected mean, 50; standard deviation [SD], 10). Mediating effects of body mass index (BMI) and chronic health conditions (CHCs) were evaluated. RESULTS Survivors were less likely than siblings to report consistent PA (28.1% v 33.6%) and more likely to report problems in Task Efficiency (T-scores mean ± SD: siblings, 50.0 ± 0.4; CNS, 61.4 ± 0.4; non-CNS, 53.3 ± 0.3), Emotion Regulation (siblings, 51.4 ± 0.4; CNS, 54.5 ± 0.3; non-CNS 53.4 ± 0.2), and Memory (siblings, 50.8 ± 0.4; CNS, 58.9 ± 0.4; non-CNS, 53.5 ± 0.2; all P < .001). Survivors of CNS cancers (52.8 ± 0.3) also reported poorer Organization than siblings (49.9 ± 0.4; P < .001). After adjusting for age at diagnosis, age at questionnaire, emotional distress, and cancer treatment exposures, consistent PA was associated with fewer neurocognitive problems compared with consistent inactivity for both CNS and non-CNS groups (T-score differences ranging from −7.9 to −2.2) and larger neurocognitive improvements over time (−6.0 to −2.5), all P ≤ .01. BMI and severe CHCs partially mediated the PA-neurocognitive associations, but the mediation effects were small (change in β ≤ 0.4). CONCLUSION Adult survivors of childhood cancer who report more consistent PA have fewer neurocognitive problems and larger improvements in these concerns many years after treatment.

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Psychosocial and Neurocognitive Outcomes in Adult Survivors of Adolescent and Early Young Adult Cancer: A Report From the Childhood Cancer Survivor Study

Journal of Clinical Oncology ◽

10.1200/jco.2014.57.7528 ◽

2015 ◽

Vol 33 (23) ◽

pp. 2545-2552 ◽

Cited By ~ 66

Author(s):

Pinki K. Prasad ◽

Kristina K. Hardy ◽

Nan Zhang ◽

Kim Edelstein ◽

Deokumar Srivastava ◽

...

Keyword(s):

Childhood Cancer ◽

Cancer Survivor ◽

Emotional Regulation ◽

Adult Survivors ◽

Brief Symptom Inventory ◽

Childhood Cancer Survivor ◽

Logistic Regression Models ◽

Childhood Cancer Survivor Study ◽

Employment Education ◽

Task Efficiency

Purpose To characterize psychological and neurocognitive function in long-term cancer survivors diagnosed during adolescence and early young adulthood (AeYA). Methods Six thousand one hundred ninety-two survivors and 390 siblings in the Childhood Cancer Survivor Study completed the Brief Symptom Inventory-18 and a Neurocognitive Questionnaire. Treatment and demographic predictors were examined, and associations with social attainment (employment, education, and living independently) were evaluated. Logistic regression models were used to compute odds ratios (ORs) and corresponding 95% CIs. Results Among survivors, 2,589 were diagnosed when AeYA (11 to 21 years old). Adjusted for current age and sex, these survivors, compared with siblings, self-reported higher rates of depression (11.7% v 8.0%, respectively; OR, 1.55; 95% CI, 1.04 to 2.30) and anxiety (7.4% v 4.4%, respectively; OR, 2.00; 95% CI, 1.17 to 3.43) and more problems with task efficiency (17.2% v 10.8%, respectively; OR, 1.72; 95% CI, 1.21 to 2.43), emotional regulation (19.1% v 14.1%, respectively; OR, 1.74; 95% CI, 1.26 to 2.40), and memory (25.9% v 19.0%, respectively; OR, 1.44; 95% CI, 1.09 to 1.89). Few differences were noted between survivors diagnosed with leukemia or CNS tumor before 11 years old versus during later adolescence, although those diagnosed with lymphoma or sarcoma during AeYA were at reduced risk for self-reported psychosocial and neurocognitive problems. Unemployment was associated with self-reports of impaired task efficiency (OR, 2.93; 95% CI, 2.28 to 3.77), somatization (OR, 2.29; 95% CI, 1.77 to 2.98), and depression (OR, 1.94; 95% CI, 1.43 to 2.63). Conclusion We demonstrated that risk for poor functional outcome is not limited to survivors' diagnoses in early childhood. AeYA is a critical period of development, and cancer during this period can impact neurocognitive and emotional function and disrupt vocational attainment.

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Sex-Specific Associations Between Chemotherapy, Chronic Conditions, and Neurocognitive Impairment in Acute Lymphoblastic Leukemia Survivors: A Report From the Childhood Cancer Survivor Study

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djaa136 ◽

2020 ◽

Author(s):

Ellen van der Plas ◽

Weiyu Qiu ◽

Brian J Nieman ◽

Yutaka Yasui ◽

Qi Liu ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Childhood Cancer ◽

Chronic Conditions ◽

Lymphoblastic Leukemia ◽

Neurocognitive Impairment ◽

Chronic Health Conditions ◽

Health Conditions ◽

Impaired Memory ◽

Childhood Cancer Survivor Study ◽

Task Efficiency

Abstract Background The purpose was to examine associations between treatment and chronic health conditions with neurocognitive impairment survivors of acute lymphoblastic leukemia (ALL) treated with chemotherapy only. Methods This cross-sectional study included 1207 ALL survivors (54.0% female; mean age 30.6 years) and 2273 siblings (56.9% female; mean age 47.6 years), who completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire. Multivariable logistic regression compared prevalence of neurocognitive impairment between survivors and siblings by sex. Associations between neurocognitive impairment with treatment exposures and chronic conditions (graded according to Common Terminology Criteria for Adverse Events) were also examined. Statistical tests were 2-sided. Results Relative to same-sex siblings, male and female ALL survivors reported increased prevalence of impaired task efficiency (males: 11.7% vs 16.9%; adjusted odds ratio [OR] = 1.89, 95% confidence interval [CI] = 1.31 to 2.74; females: 12.5% vs 17.6%; OR = 1.50, 95% CI = 1.07 to 2.14), as well as impaired memory (males: 11.6% vs 19.9%, OR = 1.89, CI = 1.31 to 2.74; females: 14.78% vs 25.4%, OR = 1.96, 95% CI = 1.43 to 2.70, respectively). Among male survivors, impaired task efficiency was associated with 2-4 neurologic conditions (OR = 4.33, 95% CI = 1.76 to 10.68) and with pulmonary conditions (OR = 4.99, 95% CI = 1.51 to 16.50), and impaired memory was associated with increased cumulative dose of intrathecal methotrexate (OR = 1.68, 95% CI = 1.16 to 2.46) and with exposure to dexamethasone (OR = 2.44, 95% CI = 1.19 to 5.01). In female survivors, grade 2-4 endocrine conditions were associated with higher risk of impaired task efficiency (OR = 2.19, 95% CI = 1.20 to 3.97) and memory (OR = 2.26, 95% CI = 1.31 to 3.92). Conclusion Neurocognitive impairment is associated with methotrexate, dexamethasone, and chronic health conditions in a sex-specific manner, highlighting the need to investigate physiological mechanisms and monitor impact through survivorship.

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Corticosteriods, Neurocognition and Stress In Adult Survivors of Childhood Leukemia

Blood ◽

10.1182/blood.v116.21.738.738 ◽

2010 ◽

Vol 116 (21) ◽

pp. 738-738

Author(s):

Kevin R. Krull ◽

Leslie L. Robison ◽

Robert J. Ferry ◽

Melissa M. Hudson

Keyword(s):

Emotional Regulation ◽

Childhood Leukemia ◽

Adult Survivors ◽

Dexamethasone Suppression Test ◽

Group Comparison ◽

Increased Risk ◽

Morning Cortisol ◽

Neurocognitive Outcomes ◽

Suppression Test ◽

Dexamethasone Suppression

Abstract Abstract 738 While recent research has demonstrated comparable neurocognitive outcomes in survivors of childhood leukemia (ALL) treated with different types of corticosteroids during induction therapy, the long-term impact of prolonged corticosteroid therapy has not been investigated. We compared neurocognitive and physiologic outcomes in 37 adult survivors of childhood leukemia who were treated with only chemotherapy (i.e., no cranial radiation therapy) on one of two standard therapy protocols (21 treated with 20 g/m2 HD-IV methotrexate and repeated cycles of prednisone for two years; 16 treated with either 20 or 24 g/m2 HD-IV methotrexate and repeated cycles of dexamethasone for two years). Patients underwent neurocognitive evaluations, physical exams, and laboratory tests after overnight fasting. Morning cortisol was assessed at baseline and 12 h after 1 mg dexamethasone (standard dexamethasone suppression test). Groups were similar for male:female ratio (p=0.73), current age (p=0.90), and cumulative HD-IV methotrexate exposure (p=0.68). No differences were detected in final adult height (p=0.85), body mass index (p=0.43), HDL (p=0.86) or LDL (p=0.99) cholesterol, heart rate (p=0.49), triglycerides (p=0.59), serum glucose (p=0.84), insulin (p=0.63), HgA1C (p=0.62), free T4 (p=0.78), IGF-I (p=0.77), or basal morning cortisol (p=0.72). Survivors treated with dexamethasone displayed significantly higher systolic blood pressure compared to the prednisone exposure group (mean=128.5 ± SD 11.71 vs. 117.7±13.78; p=0.02), and a trend for higher diastolic BP (mean=75.1±9.33 vs. 68.7±10.55; p=0.08). Survivors originally treated with dexamethasone displayed significantly less suppression of cortisol following the dexamethasone suppression test (mean 3.82±6.41 μg/dL) compared to those originally treated with prednisone (0.94 ± 0.75 μg/dL; p=0.05). The dexamethasone group demonstrated significantly lower performance on multiple measures neurocognitive function (Tables 1), including mathematical problem solving (p=0.002), semantic verbal memory (p=0.006) and cognitive flexibility (p=0.02). They also reported more difficulty with emotional regulation (p=0.04). These results suggest that adult survivors of childhood leukemia treated with dexamethasone are at increased risk for neurocognitive impairment and poor emotional regulation. These problems may occur in the presence of symptoms of physical stress. Surprisingly, these survivors appear to display persistent late signs of increased reactivity within the hypothalamic-pituitary-adrenal axis. Table 1. Group comparison on neurocognitive outcomes. Neurocognitive Outcomes Prednisone (n=21) Dexamethasone (n=16) Group Comparison p-value Mean SD Mean SD Intellect 1 Vocabulary 100.2 15.56 86.4 18.72 0.02 Matrices 103.2 15.08 103.1 7.50 0.99 Academics 2 Reading 100.2 6.62 86.8 16.48 0.002 Mathematics 100.8 9.72 86.6 15.53 0.002 Processing Speed Reaction time3 45.0 9.35 50.5 10.97 0.12 Visual-Motor Speed4 11.6 3.29 8.8 3.44 0.02 Attention Focused5 102.1 17.98 96.1 19.01 0.35 Span6 101.1 11.11 97.4 16.68 0.43 Sustained3 56.2 20.41 54.3 12.73 0.76 Memory 7 Immediate Semantic 11.0 3.24 8.6 2.34 0.02 Delay Semantic 11.5 2.60 8.9 2.43 0.006 Spatial Locations 9.9 2.99 8.6 3.29 0.25 Facial Memory 10.7 3.16 9.6 2.79 0.31 Executive Function Working Memory6 101.3 9.97 94.5 14.66 0.11 Cognitive Flexibility5 103.1 14.63 84.0 31.89 0.02 Cognitive Fluency8 9.7 2.83 8.5 2.95 0.25 1 Wechsler Abbreviated Test of Intelligence; 2 Woodcock-Johnson-III; 3 Connors Continuous Performance Test-II; 4 Weschler Coding/Digit Symbol subtest; 5 Trail Making Test; 6 Wechsler Digit Span subtest (Forward=Span, Backward=Working Memory); 7 Test of Memory and Learning-II; 8 Controlled Oral Word Test. Disclosures: No relevant conflicts of interest to declare.

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Neurocognitive Outcomes and Interventions in Long-Term Survivors of Childhood Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2017.76.4696 ◽

2018 ◽

Vol 36 (21) ◽

pp. 2181-2189 ◽

Cited By ~ 51

Author(s):

Kevin R. Krull ◽

Kristina K. Hardy ◽

Lisa S. Kahalley ◽

Ilse Schuitema ◽

Shelli R. Kesler

Keyword(s):

At Risk ◽

Childhood Cancer ◽

Lymphoblastic Leukemia ◽

Tumor Location ◽

Neurocognitive Impairment ◽

High Dose ◽

Treatment Type ◽

Survivors Of Childhood Cancer ◽

Long Term Survivors

Recent research has demonstrated that survivors of childhood cancer are at risk for a myriad of late effects that affect physical and mental quality of life. We discuss the patterns and prevalence of neurocognitive problems commonly experienced by survivors of CNS tumors and acute lymphoblastic leukemia, the two most commonly researched cancer diagnoses. Research documenting the direct effects of tumor location and treatment type and intensity is presented, and patient characteristics that moderate outcomes (eg, age at diagnosis and sex) are discussed. Potential biologic mechanisms of neurotoxic treatment exposures, such as cranial irradiation and intrathecal and high-dose antimetabolite chemotherapy, are reviewed. Genetic, brain imaging, and neurochemical biomarkers of neurocognitive impairment are discussed. Long-term survivors of childhood cancer are also at risk for physical morbidity (eg, cardiac, pulmonary, endocrine) and problems with health behaviors (eg, sleep); research is reviewed that demonstrates these health problems contribute to neurocognitive impairment in survivors with or without exposure to neurotoxic therapies. We conclude this review with a discussion of literature supporting specific interventions that may be beneficial in the treatment of survivors who already experience neurocognitive impairment, as well as in the prevention of impairment manifestation.

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Accelerated cognitive decline in adult survivors of pediatric central nervous system (CNS) tumors: A report from the Childhood Cancer Survivor Study (CCSS).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10049 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10049-10049

Author(s):

Nicholas Steve Phillips ◽

Kayla Stratton ◽

AnnaLynn M. Williams ◽

Wei Liu ◽

Tim Ahles ◽

...

Keyword(s):

Cognitive Decline ◽

Group Treatment ◽

Emotional Regulation ◽

Chronic Conditions ◽

Linear Models ◽

Adult Survivors ◽

Elevated Risk ◽

Cns Tumors ◽

Cns Tumor ◽

Task Efficiency

10049 Background: Survivors of pediatric CNS tumors may be at elevated risk for accelerated cognitive decline as they age through adulthood relative to the general population, which may be an early risk factor for dementia. Methods: Longitudinal analysis of 512 CNS tumor survivors (52.3% female, mean [SD] 30.6 [7.1] years at T1) and 232 siblings (57.8% female, mean [SD] 34.2 [8.4] years at T1) from the CCSS was conducted using the Neurocognitive Questionnaire (NCQ) to assess task efficiency, emotional regulation, organization and memory at two timepoints separated by a mean of 11.6 [0.7] years. Impairment in each NCQ domain was defined as a score ≥ 90th percentile of the CCSS sibling distribution at each survey, with decline defined as moving from unimpaired at T1 to impaired at T2. Treatment exposures were abstracted from medical records. Chronic health conditions were self-reported at T1 and graded according to CTCAE v4.3. Relative risk of decline for group, treatment and chronic condition predictors was estimated using generalized linear models with robust variance estimates. Mediation analysis examined direct effects of treatments and mediating effects of chronic conditions. All models were adjusted for age, sex, and race. Results: At T1, survivors demonstrated higher frequency of impaired memory (24.5% vs. 6.5%, p < 0.001), emotional regulation (14.3 % vs. 5.6%, p < 0.001), task efficiency (43.3% vs. 13.8%, p < 0.001) and organization (17.7% vs. 10.8%, p = 0.015) than siblings. Among those unimpaired at T1, more survivors vs. siblings declined in memory (34.7% vs. 7.8; RR 4.2, 95% CI 2.6-6.9), emotional regulation (15.5% vs. 5.0%; RR 2.8, 95% CI 1.5-5.3), task efficiency (22.7% vs. 7.0%; RR 2.9, 95% CI 1.7-5.2), and organization (14.5% vs. 2.9%; RR 4.9, 95% CI 2.1-11.0) by T2. Decline in survivor memory was associated with exposure to craniospinal irradiation (RR 1.9, 95% CI 1.3-2.8) and focal irradiation (RR 1.6, 95% CI 1.1-2.3) compared with no radiation, and exposure to Ara-C (RR 1.7, 95% CI 1.0-2.8) and cyclophosphamide (RR 1.7, 95% CI 1.01-2.8). Independent of therapy, serious/disabling or life-threatening cardiopulmonary conditions at T1 predicted future decline in memory (RR 1.5, 95% CI 1.02-2.2) and organization (RR 2.0, 95% CI 1.1-3.6), with the presence of 2 or more cardiopulmonary conditions associated with even higher risk (memory RR 2.6, 95% CI 2.0-3.1; organization RR 3.4, 95% CI 1.1-10.5). Chronic conditions did not mediate associations between treatment exposures and cognitive decline. Conclusions: CNS tumor survivors are at elevated risk for impairment and accelerated cognitive decline compared to siblings. Cranial radiation, Ara-C, cyclophosphamide, and cardiopulmonary morbidity are risk factors for decline. Survivors with these exposures/conditions may benefit from interventions to prevent additional future cognitive decline.

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