Carmen L. Wilson

Physiologic Frailty As a Sign of Accelerated Aging Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study

PURPOSE Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality. METHODS Participants included 1,922 CCS at least 10 years from original cancer diagnosis (men, 50.3%; mean age, 33.6 ± 8.1 years) and a comparison population of 341 participants without cancer histories. Prefrailty and frailty were defined as two and ≥ three of the following conditions: low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Morbidity was defined as grade 3 to 4 chronic conditions (Common Terminology Criteria for Adverse Events version 4.0). Fishers exact tests were used to compare, by frailty status, percentages of those with morbidity. In a subset of 162 CCS who returned for a second visit, Poisson regression was used to evaluate associations between frailty and new onset morbidity. Cox proportional hazards regression was used to evaluate associations between frailty and death. RESULTS The prevalence of prefrailty and frailty were 31.5% and 13.1% among women and 12.9% and 2.7% among men, respectively, with prevalence increasing with age. Frail CCS were more likely than nonfrail survivors to have a chronic condition (82.1% v 73.8%). In models adjusted for existing chronic conditions, baseline frailty was associated with risk of death (hazard ratio, 2.6; 95% CI, 1.2 to 6.2) and chronic condition onset (relative risk, 2.2; 95% CI, 1.2 to 4.2). CONCLUSION The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.

Bone mineral density among long-term survivors of childhood acute lymphoblastic leukemia: Results from the St. Jude Lifetime Cohort Study

The prevalence of low bone mineral density (BMD) in adult survivors of childhood acute lymphoblastic leukemia (ALL), and the degree of recovery or decline, are not well elucidated.

Chemotherapy-related neuropathic symptoms and functional impairment in adult survivors of extracranial solid tumors of childhood: results from the St. Jude Lifetime Cohort Study.

OBJECTIVES To ascertain prevalence of peripheral sensory and motor neuropathy, and to evaluate impairments in relation to function. DESIGN St. Jude Lifetime Cohort Study, a clinical follow-up study designed to evaluate adverse late effects in adult survivors of childhood cancer. SETTING A childrens research hospital. PARTICIPANTS Eligibility required treatment for an extracranial solid malignancy between 1962 and 2002, age ≥ 18 years, ≥ 10 years postdiagnosis, and no history of cranial radiation. Survivors (N=531) were included in the evaluation with a median age of 32 years and a median time from diagnosis of 25 years. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Primary exposure measures were cumulative doses of vinca-alkaloid and platinum-based chemotherapies. Survivors with scores ≥ 1 on the sensory subscale of the Modified Total Neuropathy Score were classified with prevalent sensory impairment. Those with sex-specific z scores of ≤-1.3 for dorsiflexion strength were classified with prevalent motor impairment. Participants completed the 6-minute walk test (endurance), the Timed Up & Go test (mobility), and the Sensory Organization Test (balance). RESULTS The prevalence of sensory and motor impairment was 20% and 17.5%, respectively. Vinca-alkaloid exposure was associated with an increased risk of motor impairment (adjusted odds ratio [OR]=1.66; 95% confidence interval [CI], 1.04-2.64) without evidence for a dose response. Platinum exposure was associated with increased risk of sensory impairment (adjusted OR=1.62; 95% CI, .97-2.72) without evidence of a dose response. Sensory impairment was associated with poor endurance (OR=1.99; 95% CI, .99-4.0) and mobility (OR=1.65; 95% CI, .96-2.83). CONCLUSIONS Vincristine and cisplatin exposure may increase risk for long-term motor and sensory impairment, respectively. Survivors with sensory impairment are at increased risk for functional performance limitations.

Approach for Classification and Severity-grading of Long-term and Late-onset Health Events among Childhood Cancer Survivors in the St. Jude Lifetime Cohort

Characterization of toxicity associated with cancer and its treatment is essential to quantify risk, inform optimization of therapeutic approaches for newly diagnosed patients, and guide health surveillance recommendations for long-term survivors. The NCI Common Terminology Criteria for Adverse Events (CTCAE) provides a common rubric for grading severity of adverse outcomes in cancer patients that is widely used in clinical trials. The CTCAE has also been used to assess late cancer treatment-related morbidity but is not fully representative of the spectrum of events experienced by pediatric and aging adult survivors of childhood cancer. Also, CTCAE characterization does not routinely integrate detailed patient-reported and medical outcomes data available from clinically assessed cohorts. To address these deficiencies, we standardized the severity grading of long-term and late-onset health events applicable to childhood cancer survivors across their lifespan by modifying the existing CTCAE v4.03 criteria and aligning grading rubrics from other sources for chronic conditions not included or optimally addressed in the CTCAE v4.03. This article describes the methods of late toxicity assessment used in the St. Jude Lifetime Cohort Study, a clinically assessed cohort in which data from multiple diagnostic modalities and patient-reported outcomes are ascertained. Cancer Epidemiol Biomarkers Prev; 26(5); 666–74. ©2016 AACR.

Fractures among long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study

Although reductions in bone mineral density are well documented among children during treatment for cancer and among childhood cancer survivors, little is known about the long‐term risk of fracture. The objective of this study was to ascertain the prevalence of and risk factors for fractures among individuals participating in the Childhood Cancer Survivor Study (CCSS).

Decline in physical activity level in the Childhood Cancer Survivor Study cohort

Background: We aimed to identify demographic and health-related predictors of declining physical activity levels over a four-year period among participants in the Childhood Cancer Survivor Study. Methods: Analyses included 7,287 ≥5-year childhood cancer survivors and 2,107 siblings who completed multiple follow-up questionnaires. Participants were classified as active if they met the Centers for Disease Control and Prevention guidelines for physical activity. Generalized linear models were used to compare participants whose physical activity levels declined from active to inactive over the study to those who remained active. In addition, selected chronic conditions (CTCAE v4.03 Grade 3 and 4) were evaluated as risk factors in an analysis limited to survivors only. Results: The median age at last follow-up among survivors and siblings was 36 (range, 21–58) and 38 (range, 21–62) years, respectively. The rate of decline did not accelerate over time among survivors when compared with siblings. Factors that predicted declining activity included body mass index ≥30 kg/m2 [RR = 1.32; 95% confidence interval (CI), 1.19–1.46, P < 0.01], not completing high school (RR = 1.31; 95% CI, 1.08–1.60, P < 0.01), and female sex (RR = 1.33; 95% CI, 1.22–1.44, P < 0.01). Declining physical activity levels were associated with the presence of chronic musculoskeletal conditions (P = 0.034), but not with the presence of cardiac (P = 0.10), respiratory (P = 0.92), or neurologic conditions (P = 0.21). Conclusions: Interventions designed to maximize physical activity should target female, obese, and less educated survivors. Survivors with chronic musculoskeletal conditions should be monitored, counseled, and/or referred for physical therapy. Impact: Clinicians should be aware of low activity levels among subpopulations of childhood cancer survivors, which may heighten their risk for chronic illness. Cancer Epidemiol Biomarkers Prev; 23(8); 1619–27. ©2014 AACR.

Bone Mineral Density Deficits and Fractures in Survivors of Childhood Cancer

Although substantial increases in survival rates among children diagnosed with cancer have been observed in recent decades, survivors are at risk of developing therapy-related chronic health conditions. Among children and adolescents treated for cancer, acquisition of peak bone mass may be compromised by cancer therapies, nutritional deficiencies, and reduced physical activity. Accordingly, failure to accrue optimal bone mass during childhood may place survivors at increased risk for deficits in bone density and fracture in later life. Current recommendations for the treatment of bone density decrements among cancer survivors include dietary counseling and supplementation to ensure adequate calcium and vitamin D intake. Few strategies exist to prevent or treat bone loss. Moving forward, studies characterizing the trajectory of changes in bone density over time will facilitate the development of interventions and novel therapies aimed at minimizing bone loss among survivors of childhood cancer.

Renal Carcinoma After Childhood Cancer: A Report From the Childhood Cancer Survivor Study

Adult survivors of childhood cancer are known to be at increased risk of subsequent malignancy, but only limited data exist describing the incidence and risk factors for secondary renal carcinoma. Among 14 358 5-year survivors diagnosed between 1970 and 1986, we estimated standardized incidence ratios (SIRs) for subsequent renal carcinoma and identified associations with primary cancer therapy using Poisson regression. Twenty-six survivors were diagnosed with renal carcinoma (median = 22.6 years from diagnosis; range = 6.3-35.7 years), reflecting a statistically significant excess (SIR = 8.0, 95% confidence interval [CI] = 5.2 to 11.7) compared with the general population. Highest risk was observed among neuroblastoma survivors (SIR = 85.8, 95% CI = 38.4 to 175.2) and, in multivariable analyses, with renal-directed radiotherapy of 5 Gy or greater (relative risk [RR] = 3.8, 95% CI = 1.6 to 9.3) and platinum-based chemotherapy (RR = 3.5, 95% CI = 1.0 to 11.2). To our knowledge, this is the first report of an association between cisplatin and subsequent renal carcinoma among survivors of childhood cancer.

Premature Ovarian Insufficiency in Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort

Context Long-term follow-up data on premature ovarian insufficiency (POI) in childhood cancer survivors are limited. Objective To describe the prevalence of POI, its risk factors, and associated long-term adverse health outcomes. Design Cross-sectional. Setting The St. Jude Lifetime Cohort Study, an established cohort in a tertiary care center. Patients Nine hundred twenty-one participants (median age, 31.7 years) were evaluated at a median of 24.0 years after cancer diagnosis. Main Outcome Measure POI was defined by persistent amenorrhea combined with a follicle-stimulating hormone level >30 IU/L before age 40. Multivariable Cox regression was used to study associations between demographic or treatment-related risk factors and POI. Multivariable logistic regression was used to study associations between POI and markers for cardiovascular disease, bone mineral density (BMD), and frailty. Exposure to alkylating agents was quantified using the validated cyclophosphamide equivalent dose (CED). Results The prevalence of POI was 10.9%. Independent risk factors for POI included ovarian radiotherapy at any dose and CED ≥8000 mg/m2. Patients with a body mass index ≥30 kg/m2 at the time of the St. Jude Lifetime Cohort assessment were less likely to have a diagnosis of POI. Low BMD and frailty were independently associated with POI. Conclusion High-dose alkylating agents and ovarian radiotherapy at any dose are associated with POI. Patients at the highest risk should be offered fertility preservation whenever feasible. POI contributes to poor general health outcomes in childhood cancer survivors; further studies are needed to investigate the role of sex hormone replacement in improving such outcomes.

Genetic and clinical factors associated with obesity among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort.

The objective of this study was to identify treatment and genetic factors associated with obesity among childhood cancer survivors.