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1.  Renal function in survivors of non-syndromic Wilms tumor treated with unilateral radical nephrectomy 
Cancer  2015;121(14):2449-2456.
Purpose
Partial nephrectomy is being considered by some for children with unilateral Wilms tumor (UWT) to avoid the theoretical complication of renal insufficiency. We evaluated the prevalence of hypertension and impaired renal function in long-term survivors of non-syndromic UWT treated without nephrotoxic chemotherapy or ionizing radiation.
Patients and Methods
Eligibility included: age ≤15 years at diagnosis of non-syndromic UWT, treatment prior to 2002 and maintenance of remission following unilateral nephrectomy without abdominal irradiation or nephrotoxic chemotherapy. Renal function was assessed by urinalysis and estimated glomerular filtration rate (eGFR). Patients on anti-hypertensive medication or with blood pressure >140/90mmHg were defined as hypertensive.
Results
Seventy-five patients with median age at diagnosis of 3.2 (range: 0.2-12.1) years met eligibility criteria. The median length of follow-up was 19.6 (range: 10.0-32.8) years. All but one patient had stage 1/2 disease. Sixty-eight (90.7%) patients had favorable histology WT; seven had anaplastic histology. Sixteen (21.3%) patients had an eGFR <90 ml/min/1.73m2, two of whom also had proteinuria (12.5%). No patient had an eGFR<60 ml/min/1.73m2. Five (6.7%) patients had hypertension, three of whom were taking anti-hypertensive medications. No patient has developed end-stage renal disease.
Conclusions
Patients with UWT treated with unilateral radical nephrectomy without nephrotoxic chemotherapy or ionizing radiation are at low risk for significant long-term renal dysfunction. For this patient population, routine use of partial nephrectomy does not appear justified. However, monitoring and counseling are important for identifying the rare patient who develops subtle renal insufficiency and so might be at increased risk for adverse cardiovascular sequelae.
doi:10.1002/cncr.29373
PMCID: PMC5161342  PMID: 25832759
Renal function; Wilms tumor; Long-term; Nephrectomy; Non-syndromic
2.  Lack of Specificity of Plasma Concentrations of Inhibin B and Follicle-Stimulating Hormone for Identification of Azoospermic Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(10):1324-1328.
Purpose
Many male survivors of childhood cancer are at risk for azoospermia. Although both the levels of follicle-stimulating hormone (FSH) and inhibin B are correlated with sperm concentration, their ability to predict azoospermia in survivors of childhood cancer remains uncertain.
Patients and Methods
Semen analysis was performed and serum levels of FSH and inhibin B were measured in 275 adult male survivors of childhood cancer who had received gonadotoxic therapy. Receiver operating characteristic (ROC) analysis was performed to determine the optimal inhibin B and FSH values for identifying patients with azoospermia. The patient sample was divided into a learning set and a validation set. Sensitivity, specificity, and positive and negative predictive value were calculated.
Results
Inhibin B was dichotomized as ≤ 31 ng/L or more than 31 ng/L and FSH was dichotomized as ≤ 11.5 mIU/mL or more than 11.5 mIU/mL based on results of the ROC analysis. Using these values, the specificity of the serum level of inhibin B for identifying azoospermic survivors was 45.0%, and the positive predictive value was 52.1%. The specificity for FSH was 74.1%, and the positive predictive value was 65.1%.
Conclusion
Neither serum inhibin B nor FSH is a suitable surrogate for determination of sperm concentration in a semen sample. Young men and their physicians should be aware of the limitations of these measures for assessment of fertility potential.
doi:10.1200/JCO.2012.43.7038
PMCID: PMC3607671  PMID: 23423746
3.  Equivalence Ratio for Daunorubicin to Doxorubicin in Relation to Late Heart Failure in Survivors of Childhood Cancer 
Journal of Clinical Oncology  2015;33(32):3774-3780.
Purpose
Cumulative anthracycline dose is one of the strongest predictors of heart failure (HF) after cancer treatment. However, the differential risk for cardiotoxicity between daunorubicin and doxorubicin has not been rigorously evaluated among survivors of childhood cancer. These risks, which are based on hematologic toxicity, are currently assumed to be approximately equivalent.
Patients and Methods
Data from 15,815 survivors of childhood cancer who survived at least 5 years were used. Survivors were from the Emma Children's Hospital/Academic Medical Center (n = 1,349), the National Wilms Tumor Study (n = 364), the St Jude Lifetime Cohort Study (n = 1,695), and the Childhood Cancer Survivor Study (n = 12,407). The hazard ratio (HR) for clinical HF through age 40 years for doses of daunorubicin and doxorubicin (per 100-mg/m2 increments) was estimated by using Cox regression adjusted for sex, age at diagnosis, treatment with other anthracycline agents and chest radiation, and cohort membership.
Results
In total, 5,144 (32.5%) patients received doxorubicin as part of their cancer treatment, whereas 2,243 (14.7%) received daunorubicin. On the basis of 271 occurrences of HF during a median follow-up time after cohort entry of 17.3 years (range, 0.0 to 35.0 years), the cumulative incidence of HF at age 40 years was 3.2% (95% CI, 2.8% to 3.7%). The average ratio of HRs for daunorubicin to doxorubicin was 0.45 (95% CI, 0.23 to 0.73). A similar ratio was obtained by using a linear dose-response model, which yielded an HR of 0.49 (95% CI, 0.28 to 0.70).
Conclusion
Compared with doxorubicin, daunorubicin was less cardiotoxic among survivors of childhood cancer than most current guidelines suggest. This may have implications for follow-up guidelines. The feasibility of substitution of doxorubicin with daunorubicin in childhood cancer treatment protocols to reduce cardiotoxicity should be additionally investigated.
doi:10.1200/JCO.2015.61.5187
PMCID: PMC4737860  PMID: 26304888
4.  Collaborative Research in Childhood Cancer Survivorship: The Current Landscape 
Journal of Clinical Oncology  2015;33(27):3055-3064.
Survivors of childhood cancer carry a substantial burden of morbidity and are at increased risk for premature death. Furthermore, clear associations exist between specific therapeutic exposures and the risk for a variety of long-term complications. The entire landscape of health issues encountered for decades after successful completion of treatment is currently being explored in various collaborative research settings. These settings include large population-based or multi-institutional cohorts and single-institution studies. The ascertainment of outcomes has depended on self-reporting, linkage to registries, or clinical assessments. Survivorship research in the cooperative group setting, such as the Children's Oncology Group, has leveraged the clinical trials infrastructure to explore the molecular underpinnings of treatment-related adverse events, and to understand specific complications in the setting of randomized risk-reduction strategies. This review highlights the salient findings from these large collaborative initiatives, emphasizing the need for life-long follow-up of survivors of childhood cancer, and describing the development of several guidelines and efforts toward harmonization. Finally, the review reinforces the need to identify populations at highest risk, facilitating the development of risk prediction models that would allow for targeted interventions across the entire trajectory of survivorship.
doi:10.1200/JCO.2014.59.8052
PMCID: PMC4567704  PMID: 26304891
5.  Medical Care in Long-Term Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2008;26(27):4401-4409.
Purpose
To evaluate whether childhood cancer survivors receive regular medical care focused on the specific morbidities that can arise from their therapy.
Patients and Methods
We conducted a cross-sectional survey of health care use in 8,522 participants in the Childhood Cancer Survivor Study, a multi-institutional cohort of childhood cancer survivors. We assessed medical visits in the preceding 2 years, whether these visits were related to the prior cancer, whether survivors received advice about how to reduce their long-term risks, and whether screening tests were discussed or ordered. Completion of echocardiograms and mammograms were assessed in patients at high risk for cardiomyopathy or breast cancer. We examined the relationship between demographics, treatment, health status, chronic medical conditions, and health care use.
Results
Median age at cancer diagnosis was 6.8 years (range, 0 to 20.9 years) and at interview was 31.4 years (range, 17.5 to 54.1 years). Although 88.8% of survivors reported receiving some form of medical care, only 31.5% reported care that focused on their prior cancer (survivor-focused care), and 17.8% reported survivor-focused care that included advice about risk reduction or discussion or ordering of screening tests. Among survivors who received medical care, those who were black, older at interview, or uninsured were less likely to have received risk-based, survivor-focused care. Among patients at increased risk for cardiomyopathy or breast cancer, 511 (28.2%) of 1,810 and 169 (40.8%) of 414 had undergone a recommended echocardiogram or mammogram, respectively.
Conclusion
Despite a significant risk of late effects after cancer therapy, the majority of childhood cancer survivors do not receive recommended risk-based care.
doi:10.1200/JCO.2008.16.9607
PMCID: PMC2653112  PMID: 18802152
6.  Longitudinal smoking patterns in survivors of childhood cancer: an update from the Childhood Cancer Survivor Study 
Cancer  2015;121(22):4035-4043.
Background
Survivors of pediatric cancer have elevated risks of mortality and morbidity. Many adverse late effects associated with cancer treatment (e.g. second cancers, cardiac and pulmonary disease) are also associated with cigarette smoking, suggesting survivors who smoke may be at high risk for these conditions.
Methods
We examined self-reported smoking status in 9,397 adult survivors of childhood cancer across 3 questionnaires (median time interval 13 years). Smoking prevalence among survivors was compared to siblings and expected prevalence based on age-, sex-, race-, and calendar time-specific U.S. population rates. Multivariable regression models examined characteristics associated with longitudinal smoking patterns across all three questionnaires.
Results
At baseline, 19% of survivors were current smokers, compared with 24% of siblings and 29% expected based on U.S. rates. Current smoking among survivors dropped to 16% and 14% on follow-up questionnaires, with similar decreases in siblings and expected prevalence. Characteristics associated with consistent never smoking included higher household income (relative risk 1.16, 95% confidence interval 1.08–1.25), higher education (1.32, 1.22–1.43), and receipt of cranial radiation therapy (1.08, 1.03–1.14). Psychological distress (0.86, 0.80–0.92) and heavy alcohol drinking (0.64, 0.58–0.71) were inversely associated. Among ever smokers, higher income (1.17, 1.04–1.32) and education (1.23, 1.10–1.38) were associated with quitting, whereas cranial radiation (0.86, 0.76–0.97) and psychological distress (0.80, 0.72–0.90) were associated with not having quit (0.85, 0.76–0.96). Development of adverse health conditions was not associated with smoking patterns.
Conclusion
Despite modest declines in smoking prevalence, the substantial number of consistent current smokers reinforces the need for continued development of effective smoking interventions for survivors.
doi:10.1002/cncr.29609
PMCID: PMC4635054  PMID: 26287647
childhood cancer survivors; smoking; prevalence; smoking patterns; cancer treatment; longitudinal studies
7.  Age-Dependent Changes in Health Status in the Childhood Cancer Survivor Cohort 
Journal of Clinical Oncology  2014;33(5):479-491.
Purpose
To compare age-dependent changes in health status among childhood cancer survivors and a sibling cohort.
Methods
Adult survivors of childhood cancer and siblings, all participants of the Childhood Cancer Survivor Study, completed three surveys assessing health status. At each of three time points, participants were classified as having poor outcomes in general health, mental health, function, or daily activities if they indicated moderate to extreme impairment. Generalized linear mixed models were used to compare survivors with siblings for each outcome as a function of age and to identify host- and treatment-related factors associated with age-dependent worsening health status.
Results
Adverse health status outcomes were more frequent among survivors than siblings, with evidence of a steeper trajectory of age-dependent change among female survivors with impairment in at least one health status domain (P = .01). In adjusted models, survivors were more likely than siblings to report poor general health (prevalence ratio [PR], 2.37; 95% CI, 2.09 to 2.68), adverse mental health (PR, 1.66; 95% CI, 1.52 to 1.80), functional impairment (PR, 4.53; 95% CI, 3.91 to 5.24), activity limitations (PR, 2.38; 95% CI, 2.12 to 2.67), and an adverse health status outcome in any domain (PR, 2.10; 95% CI, 1.97 to 2.23). Cancer treatment and health behaviors influence the magnitude of differences by age groups. Chronic conditions were associated with adverse health status outcomes across organ systems.
Conclusion
The prevalence of poor health status is higher among survivors than siblings, increases rapidly with age, particularly among female participants, and is related to an increasing burden of chronic health conditions.
doi:10.1200/JCO.2014.57.4863
PMCID: PMC4314595  PMID: 25547510
8.  CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children’s Oncology Group Genome-Wide Association Study 
Journal of Clinical Oncology  2016;34(8):863-870.
Purpose
Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests that genetic susceptibility could play a role. The current study uses an agnostic approach to identify genetic variants that could modify cardiomyopathy risk.
Methods
A genome-wide association study was conducted in childhood cancer survivors with and without cardiomyopathy (cases and controls, respectively). Single-nucleotide polymorphisms (SNPs) that surpassed a prespecified threshold for statistical significance were independently replicated. The possible mechanistic significance of validated SNP(s) was sought by using healthy heart samples.
Results
No SNP was marginally associated with cardiomyopathy. However, SNP rs1786814 on the CELF4 gene passed the significance cutoff for gene-environment interaction (Pge = 1.14 × 10−5). Multivariable analyses adjusted for age at cancer diagnosis, sex, anthracycline dose, and chest radiation revealed that, among patients with the A allele, cardiomyopathy was infrequent and not dose related. However, among those exposed to greater than 300 mg/m2 of anthracyclines, the rs1786814 GG genotype conferred a 10.2-fold (95% CI, 3.8- to 27.3-fold; P < .001) increased risk of cardiomyopathy compared with those who had GA/AA genotypes and anthracycline exposure of 300 mg/m2 or less. This gene-environment interaction was successfully replicated in an independent set of anthracycline-related cardiomyopathy. CUG-BP and ETR-3-like factor proteins control developmentally regulated splicing of TNNT2, the gene that encodes for cardiac troponin T (cTnT), a biomarker of myocardial injury. Coexistence of more than one cTnT variant results in a temporally split myofilament response to calcium, which causes decreased contractility. Analysis of TNNT2 splicing variants in healthy human hearts suggested an association between the rs1786814 GG genotype and coexistence of more than one TNNT2 splicing variant (90.5% GG v 41.7% GA/AA; P = .005).
Conclusion
We report a modifying effect of a polymorphism of CELF4 (rs1786814) on the dose-dependent association between anthracyclines and cardiomyopathy, which possibly occurs through a pathway that involves the expression of abnormally spliced TNNT2 variants.
doi:10.1200/JCO.2015.63.4550
PMCID: PMC5070560  PMID: 26811534
9.  Identifying Predictors of Longitudinal Decline in the Level of Medical Care Received by Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Health Services Research  2015;50(4):1021-1042.
Objectives
Characterize longitudinal changes in the use of medical care in adult survivors of childhood cancer.
Data Sources
The Childhood Cancer Survivor Study, a retrospective cohort study of 5+ year survivors of childhood cancer.
Study Design
Medical care was assessed at entry into the cohort (baseline) and at most recent questionnaire completion. Care at each time point was classified as no care, general care, or survivor-focused care.
Data Collection
There were 6,176 eligible survivors. Multivariable models evaluated risk factors for reporting survivor-focused care or general medical care at baseline and no care at follow-up; and survivor-focused care at baseline and general care at follow-up.
Principal Findings
Males (RR, 2.3; 95 percent CI 1.8–2.9), earning <$20,000/year (RR, 1.6; 95 percent CI 1.2–2.3) or ≤high school education (RR, 2.5; 95 percent CI 1.6–3.8 and RR 2.0; 95 percent CI 1.5–2.7 for
Conclusions
While the incidence of late effects increases over time for survivors, the likelihood of receiving survivor-focused care decreases for vulnerable populations.
doi:10.1111/1475-6773.12282
PMCID: PMC4545345  PMID: 25600956
Childhood cancer survivors; health insurance; health care access; survivorship; delivery of health care
Journal of Clinical Oncology  2016;34(12):1358-1367.
Purpose
To assess the prevalence and severity of neurocognitive impairment in adult survivors of pediatric CNS tumors and to examine associated treatment exposures.
Patients and Methods
Participants included 224 survivors of CNS tumors who were treated at St Jude Children's Research Hospital (current median age [range], 26 years [19 to 53 years]; time from diagnosis, 18 years [11 to 42 years]) and completed neurocognitive testing. Information on cranial radiation therapy (CRT) doses and parameters of delivery were abstracted from medical records. The prevalence of severe impairment (ie, at least two standard deviations below normative mean) was compared across radiation treatment groups (no CRT, focal irradiation, craniospinal irradiation) using the χ2 test. Log-binomial models were used to estimate risk ratios (RRs) and corresponding 95% CIs for severe impairment.
Results
In multivariable models, craniospinal irradiation was associated with a 1.5- to threefold increased risk of severe impairment compared with no CRT (eg, intelligence: RR = 2.70; 95% CI, 1.37 to 5.34; memory: RR = 2.93; 95% CI, 1.69 to 5.08; executive function: RR = 1.74; 95% CI, 1.24 to 2.45). Seizures were associated with impaired academic performance (RR = 1.48; 95% CI, 1.02 to 2.14), attention (RR = 1.54; 95% CI, 1.12 to 2.13), and memory (RR = 1.44; 95% CI, 1.04 to 1.99). Hydrocephalus with shunt placement was associated with impaired intelligence (RR = 1.78; 95% CI, 1.12 to 2.82) and memory (RR = 1.42; 95% CI, 1.03 to 1.95). Differential follow-up time contributed to variability in prevalence estimates between survivors treated with older nonconformal and those treated with more contemporary conformal radiation therapy methods. Neurocognitive impairment was significantly associated with lower educational attainment, unemployment, and nonindependent living.
Conclusion
Survivors of pediatric CNS tumors are at risk of severe neurocognitive impairment in adulthood. The prevalence of severe impairment is greater than expected in the general population, even in the absence of CRT, and is associated with disrupted attainment of adult social milestones.
doi:10.1200/JCO.2015.62.2589
PMCID: PMC4933131  PMID: 26834063
Journal of Clinical Oncology  2014;32(35):3974-3981.
Purpose
To determine whether the addition of advanced-practice nurse (APN) telephone counseling to a printed survivorship care plan (SCP) significantly increases the proportion of at-risk survivors who complete cardiomyopathy screening.
Patients and Methods
Survivors age ≥ 25 years participating in the Childhood Cancer Survivor Study who received cardiotoxic therapy and reported no history of cardiomyopathy screening in the previous 5 years were eligible for enrollment. The 472 participants (mean age, 40.1 years; range, 25.0 to 59.0; 53.3% women) were randomly assigned to either standard care, consisting of an SCP summarizing cancer treatment and cardiac health screening recommendations (n = 234), or standard care plus two APN telephone counseling sessions (n = 238). The primary outcome—completion of cardiomyopathy screening within 1 year—was validated by medical records and compared between the two arms using adjusted relative risks (RRs) with 95% CIs.
Results
Participants in the standard and APN counseling groups were not statistically different by demographic or clinical characteristics. At the time of 1-year follow-up, 107 (52.2%) of 205 survivors in the APN group completed screening compared with 46 (22.3%) of 206 survivors in the non-APN group (P < .001). With adjustment for sex, age (< 30 v ≥ 30 years), and Children's Oncology Group–recommended screening frequency group (annual, 2 years, or 5 years), survivors in the APN group were > 2× more likely than those in the control group to complete the recommended cardiomyopathy screening (RR, 2.31; 95% CI, 1.74 to 3.07).
Conclusion
The addition of telephone counseling to an SCP with cardiac health screening recommendations increases cardiomyopathy screening in at-risk survivors.
doi:10.1200/JCO.2014.57.3493
PMCID: PMC4251960  PMID: 25366684
Annals of internal medicine  2016;164(2):93-101.
Background
Studies of cardiac disease among adult survivors of childhood cancer have generally relied upon self-reported or registry-based data.
Objective
Systematically assess cardiac outcomes among childhood cancer survivors
Design
Cross-sectional
Setting
St. Jude Children's Research Hospital
Patients
1,853 adult survivors of childhood cancer, ≥18 years old, and ≥10 years from treatment with cardiotoxic therapy for childhood cancer.
Measurements
History/physical examination, fasting metabolic and lipid panels, echocardiogram, electrocardiogram (ECG), 6-minute walk test (6MWT) all collected at baseline evaluation.
Results
Half (52.3%) of the survivors were male, median age 8.0 years (range: 0-24) at cancer diagnosis, 31.0 years (18-60) at evaluation. Cardiomyopathy was present in 7.4% (newly identified at the time of evaluation in 4.7%), coronary artery disease (CAD) in 3.8% (newly identified in 2.2%), valvular regurgitation/stenosis in 28.0% (newly identified in 24.8%), and conduction/rhythm abnormalities in 4.6% (newly identified in 1.4%). Nearly all (99.7%) were asymptomatic. The prevalences of cardiac conditions increased with age at evaluation, ranging from 3-24% among those 30-39 years to 10-37% among those ≥40 years. On multivariable analysis, anthracycline exposure ≥250 mg/m2 increased the odds of cardiomyopathy (odds ratio [OR] 2.7, 95% CI 1.1-6.9) compared to anthracycline unexposed survivors. Radiation to the heart increased the odds of cardiomyopathy (OR 1.9 95% CI 1.1-3.7) compared to radiation unexposed survivors. Radiation >1500 cGy with any anthracycline exposure conferred the greatest odds for valve findings.
Limitations
61% participation rate of survivors exposed to cardiotoxic therapies, which were limited to anthracyclines and cardiac-directed radiation. A comparison group and longitudinal assessments are not available.
Conclusions
Cardiovascular screening identified considerable subclinical disease among adult survivors of childhood cancer.
Funding
Cancer Center Support Grant (CA21765), U01 CA195547 1, American Lebanese Syrian Associated Charities
doi:10.7326/M15-0424
PMCID: PMC4809016  PMID: 26747086
Nature reviews. Clinical oncology  2014;11(12):740-750.
Survivors of childhood cancer are at risk of long-term adverse effects and late effects of the disease and/or its treatment. In response to national recommendations to improve evidence-based follow-up care, a web-based support system for clinical decision making, the Passport for Care (PFC), was developed for use at the point of care to produce screening recommendations individualized to the survivor. To date, the PFC has been implemented in over half of the nearly 200 clinics affiliated with the Children's Oncology Group across the USA. Most clinician users report that the PFC has been integrated into clinic workflows, and that it fosters improved conversations with survivors about the potential late effects a survivor might experience and about the screening and/or behavioural interventions recommended to improve health status. Furthermore, clinicians using the PFC have indicated that they adhered more closely to follow-up care guidelines. Perspectives on the challenges encountered and lessons learned during the development and deployment of the PFC are reviewed and contrasted with other nationwide approaches to the provision of guidance on survivor follow-up care; furthermore, the implications for the care of childhood cancer survivors are discussed.
doi:10.1038/nrclinonc.2014.175
PMCID: PMC5142740  PMID: 25348788
Craniopharyngiomas are the third most common pediatric brain tumor and most common pediatric suprasellar tumor. Contemporary treatment of craniopharyngiomas utilizes limited surgery and radiation in an effort to minimize morbidity, but the long-term health status of patients treated in this fashion has not been well described. The purpose of this study was to analyze the health status of long-term survivors of pediatric craniopharyngioma treated primarily with radiation and conservative surgical resection. Medical records of all long-term survivors of craniopharyngioma treated at St. Jude Children's Research Hospital and then transferred to the long-term follow-up clinic were reviewed. The initial cohort comprised 55 patients. Of these, 51 (93%) were alive at the time of this analysis. The median age at diagnosis was 7.1 years (range, 1.2–17.6 years), and 29 (57%) were male. At the time of analysis, the median survival was 7.6 years (range, 5.0–21.3 years). Diagnosis and treatment included surgical biopsy, resection (n=50), and radiation therapy (n=48). Only one patient received chemotherapy. Polyendocrinopathy was the most common morbidity, with hypothyroidism (96%), adrenocorticotropic hormone deficiency (84%), and diabetes insipidus (53%) occurring most frequently. Half were hypogonadal, and 33 (65%) were overweight or obese. The most common neurologic problems included shunt dependence (37%), seizures (28%), and headaches (39%). Psychological and educational deficits were also identified in a significant number of these individuals. Despite efforts to reduce morbidity in these patients, many survivors remain burdened with significant medical complications. In a small percentage of patients, these may result in death even during extended remission of craniopharyngioma. Due to the broad spectrum or morbidities experienced, survivors of craniopharyngioma continue to benefit from multidisciplinary care.
PMCID: PMC4895693  PMID: 21207770
health status; craniopharyngioma; pediatric; survivors
The New England journal of medicine  2016;374(9):833-842.
Background
Previously, eighteen percent of childhood cancer patients who survived five years died within the subsequent 25 years. In recent decades, cancer treatment regimens have been modified with the goal of reducing risk for life-threatening late effects.
Methods
Late mortality was evaluated in 34,033 five-year survivors of childhood cancer (diagnosed <21 years of age from 1970-1999, median follow-up 21 years, range 5-38). Demographic and disease factors associated with mortality due to health-related causes, which exclude recurrence/progression of the original cancer but include deaths that reflect late effects of cancer therapy, were evaluated using cumulative incidence and piecewise exponential models estimating relative rates (RRs) and 95% confidence intervals (CI).
Results
1,618 (41%) of the 3,958 deaths were attributable to health-related causes, including 746 subsequent neoplasm, 241 cardiac, and 137 pulmonary deaths. Reduction in 15-year mortality was observed for all-cause (12.4% to 6.0%, P for trend <0.001) and health-related mortality (3.5% to 2.1%, P for trend <0.001), attributable to reductions in subsequent neoplasm (P<0.001), cardiac (P<0.001) and pulmonary death (P<0.001). Changes in therapy by decade included reduced rates of: cranial radiotherapy for acute lymphoblastic leukemia (1970s 85%, 1980s 51%, 1990s 19%), abdominal radiotherapy for Wilms’ tumor (78%, 53%, 43%), chest radiotherapy for Hodgkin's lymphoma (87%, 79%, 61%), and anthracycline exposure. Reduction in treatment exposure was associated with reduced late mortality among lymphoblastic leukemia and Wilms’ tumor survivors.
Conclusion
The strategy of lowering therapeutic exposure has successfully translated to an observed decline in late mortality among 5-year survivors of childhood cancer.
doi:10.1056/NEJMoa1510795
PMCID: PMC4786452  PMID: 26761625
Pediatric; Cancer; Survivor; Mortality
Pediatric blood & cancer  2015;62(9):1630-1636.
Background
Among those 9-26 years of age, vaccination can prevent specific types of genital human papillomavirus (HPV), the most common sexually transmitted infection and cause of cervical and other cancers. The objective of this study was to estimate the prevalence of and factors associated with HPV vaccine initiation and completion among females surviving childhood cancer.
Procedure
One-hundred fourteen young adults and 230 mothers with daughters surviving childhood cancer completed surveys querying HPV vaccination history along with medical and sociodemographic factors potentially associated with vaccination outcomes. Vaccination rate differences by age necessitated analysis of outcomes by age group: 9-13 years (preadolescents), 14-17 years (adolescents), and 18-26 years (young adults). Multivariable logistic regression was utilized to identify factors associated with HPV vaccination outcomes.
Results
Overall, 34.6% (119/344) of survivors initiated and 20.9% (72/344) completed HPV vaccination. Preadolescents were least likely to have initiated vaccination (P<0.001). Physician recommendation was associated with initiation across age groups (OR=6.81–11.96, Ps<0.001-.01), whereas older age at diagnosis (≥12 years of age) was associated with lower vaccination initiation among young adults only (OR=0.28; 95% CI, 0.10–0.76, P=0.012). Physician recommendation (OR=7.54; 95% CI, 1.19–47.69, P=0.032; adolescent group) and greater treatment intensity (OR=5.25; 95% CI, 1.00–27.61, P=0.050; young adult group) were associated with vaccine completion, whereas being non-White was associated with decreased vaccination completion (OR=0.17; 95% CI, 0.05–0.66, P=0.010; adolescent group).
Conclusions
A minority of youths surviving childhood cancer have initiated or completed HPV vaccination. Strategies to increase vaccination among survivors are discussed.
doi:10.1002/pbc.25539
PMCID: PMC4834844  PMID: 25900433
Oncology; Adolescents; Young Adults; Human Papillomavirus; Vaccination
Cancer  2015;121(22):4053-4061.
Background
Survivors of childhood cancer treated with platinum-based chemotherapy and/or cranial radiation are at risk of treatment-induced hearing loss; however, the effects of such hearing loss on adult social attainment have not been well elucidated.
Methods
Adult survivors of pediatric central nervous system (CNS; n=180) and non-CNS solid tumors (n=226) treated with potentially ototoxic cancer therapy completed audiologic evaluations and questionnaires assessing perception of social functioning and social attainment (i.e. independent living, marriage, employment). Audiograms were graded with the Chang Ototoxicity Grading Scale. Analyses were stratified by tumor type (i.e. CNS vs. non-CNS). Multivariable logistic regression models were conducted with adjustment for age, sex, chronic health conditions, and for the CNS group, IQ. Adjusted odds ratios (OR) and 95% confidence intervals (CI) are reported.
Results
Serious hearing loss (requiring a hearing aid or deafness) was detected in 36% of CNS and 39% of non-CNS tumor survivors. Serious hearing loss was associated with increased risk for perceived negative impact in one or more areas of social functioning (non-CNS: OR=1.83, 95% CI, 1.00-3.34). Among non-CNS tumor survivors, serious hearing loss was associated with 2-fold increased risk of non-independent living (OR=2.19, 95% CI, 1.19-4.04) and unemployment or not graduating from high school (OR=1.85, 95% CI, 1.00-3.34).
Conclusions
A substantial proportion of adult survivors of childhood cancer treated with potentially ototoxic therapy have serious hearing loss. Treatment-induced hearing loss was associated with reduced social attainment, both perceived and actual, in this study sample.
doi:10.1002/cncr.29604
PMCID: PMC4635051  PMID: 26287566
Background
Women with a history of chest radiotherapy (RT) have an increased risk of breast cancer however many do not undergo annual recommended screening mammography. We sought to characterize the relationship between mammography and potentially modifiable factors, with the goal of identifying targets for intervention to improve utilization.
Methods
Of 625 female participants sampled from the Childhood Cancer Survivor Study who were treated with chest RT, 551 responded to a survey about breast cancer screening practices. We used multivariate Poisson regression to assess several lifestyle and emotional factors, health care practices, and perceived breast cancer risk, in relation to reporting a screening mammogram within the last two years.
Results
Women who had a Papanicolaou test (Prevalence Ratio [PR]: 1.77, 95% confidence interval [CI]; 1.26–2.49), and who perceived their breast cancer risk as higher than the average woman were more likely to have had a mammogram (PR: 1.26, 95% CI: 1.09–1.46). We detected an attenuated effect of echocardiogram screening (PR: 0.70 (0.52–0.95) on having a mammogram among older women compared to younger women. Smoking, obesity, physical activity, coping, and symptoms of anxiety, depression and somatization were not associated with mammographic screening.
Conclusion
Our findings suggest that compliance with routine and risk-based screening can be an important indicator of mammography in childhood cancer survivors. Additionally, there is a need to ensure women understand their increased breast cancer risk, as a means to encouraging them to follow breast surveillance guidelines.
Impact
Screening encounters could be used to promote mammography compliance in this population.
doi:10.1158/1055-9965.EPI-14-1377
PMCID: PMC4633330  PMID: 26304504
Journal of Clinical Oncology  2014;32(7):641-646.
Purpose
To examine posttraumatic stress disorder and posttraumatic stress symptoms (PTSD/PTSS) in children with cancer using methods that minimize focusing effects and allow for direct comparison to peers without a history of cancer.
Patients and Methods
Children with cancer (n = 255) stratified by time since diagnosis, and demographically matched peers (n = 101) were assessed for PTSD using structured diagnostic interviews by both child and parent reports, and survey measures of PTSS and psychological benefit/growth by child report.
Results
Cancer was identified as a traumatic event by 52.6% of children with cancer, declining to 23.8% in those ≥ 5 years from diagnosis. By diagnostic interview, 0.4% of children with cancer met criteria for current PTSD, and 2.8% met lifetime criteria by self-report. By parent report, 1.6% of children with cancer met current criteria and 5.9% met lifetime criteria for PTSD. These rates did not differ from controls (all Ps >.1). PTSS levels were descriptively lower in children with cancer but did not differ from controls when all were referring to their most traumatic event (P = .067). However, when referring specifically to cancer-related events, PTSS in the cancer group were significantly lower than in controls (P = .002). In contrast, perceived growth was significantly higher in the cancer group when referring to cancer (P < .001).
Conclusion
These findings suggest no evidence of increased PTSD or PTSS in youths with cancer. Although childhood cancer remains a significant and challenging event, these findings highlight the capacity of children to adjust, and even thrive, in the face of such challenge.
doi:10.1200/JCO.2013.49.8212
PMCID: PMC3927732  PMID: 24449230
Background
Anthracyclines are widely used in the treatment of childhood cancer. One of the well-recognized side-effects of anthracycline therapy is dose-dependent cardiomyopathy that may progress to heart failure (HF) years after completion of cancer-directed therapy. This study will evaluate the efficacy of low-dose beta-blocker (carvedilol) for HF risk reduction in childhood cancer survivors at highest risk for HF. The proposed intervention has the potential to significantly reduce chronic cardiac injury via interruption of neurohormonal systems responsible for left ventricular (LV) remodeling, resulting in improved cardiac function and decreased risk of HF. The intervention is informed by previous studies demonstrating efficacy in pediatric and adult non-oncology populations, yet remains unstudied in the pediatric oncology population.
Methods/Design
The primary objective of the trial is to determine impact of the intervention on echocardiographic markers of cardiac remodeling and HF risk, including: LV wall thickness/ dimension ratio (LVWT/D; primary endpoint), as well as LV ejection fraction, volume, and blood biomarkers (natriuretic peptides, galectin-3) associated with HF risk. Secondary objectives are to establish safety and tolerability of the 2-year course of carvedilol using: 1) objective measures: hepatic and cardiovascular toxicity, treatment adherence, and 2) subjective measures: participant self-reported outcomes. Two hundred and fifty survivors of childhood cancer (diagnosed <21 years of age), and previously treated with high-dose (≥300 mg/m2) anthracyclines will be enrolled in a randomized, double-blind, placebo controlled trial. After baseline assessments, participants will be randomized in a 1:1 ratio to low-dose carvedilol (maximum dose: 12.5 mg/day) or placebo. Carvedilol or placebo is up-titrated (starting dose: 3.125 mg/day) according to tolerability.
Discussion
When completed, this study will provide much-needed information regarding a physiologically plausible pharmacological risk-reduction strategy for childhood cancer survivors at high risk for developing anthracycline-related HF.
Trial registration
ClinicalTrials.gov; NCT02717507
doi:10.1186/s12872-016-0364-6
PMCID: PMC5050602  PMID: 27716152
Childhood cancer; Survivors; Cardiomyopathy; Heart failure; Anthracyclines; Risk reduction; Carvedilol
Background
Pediatric cancer patients who received blood transfusions were potentially exposed to hepatitis C virus (HCV) prior to second-generation HCV screening of blood products in 1992. Limited evidence is available about long-term incident cirrhosis in this population.
Objectives
We aimed to estimate the overall and sex-specific incidence of cirrhosis among HCV-seropositive survivors of pediatric cancer.
Study design
We identified 113 HCV-seropositive pediatric cancer patients treated at St. Jude Children’s Research Hospital between 1962 and 1997, who survived ≥5 years post-diagnosis, and were followed through 2014. Our outcome was cirrhosis determined by liver biopsy or diagnostic imaging. We used a competing-risk framework to estimate the overall and sex-specific cumulative incidence and 95% confidence limits (CL) of cirrhosis at 10-year follow-up intervals.
Results
The median duration of follow-up was 30 years (interquartile range=28 – 36) post-cancer diagnosis. Cumulative incidence of cirrhosis increased at each 10-year interval from 0% after 10 years to 13% after 40 years (Ptrend<0.001). The median age at diagnosis of cirrhosis was 30 years (interquartile range=24 – 38). We observed a linear trend in incidence for males (Ptrend<0.001), with a cumulative incidence of 18% (95% CL: 6.1%, 34%) after 40 years. The cumulative incidence for females was 6.5% (95% CL: 0.42%, 26%) after 40 years, but we did not observe a linear trend (Ptrend=0.99).
Conclusion
Our results suggest that the incidence of cirrhosis is similar between HCV-seropositive pediatric cancer survivors and the general population given similar duration of follow-up, but survivors may be diagnosed with cirrhosis at an earlier age.
doi:10.1016/j.jcv.2015.07.306
PMCID: PMC4570969  PMID: 26370309
Journal of Clinical Oncology  2014;33(5):394-402.
Purpose
To create clinically useful models that incorporate readily available demographic and cancer treatment characteristics to predict individual risk of heart failure among 5-year survivors of childhood cancer.
Patients and Methods
Survivors in the Childhood Cancer Survivor Study (CCSS) free of significant cardiovascular disease 5 years after cancer diagnosis (n = 13,060) were observed through age 40 years for the development of heart failure (ie, requiring medications or heart transplantation or leading to death). Siblings (n = 4,023) established the baseline population risk. An additional 3,421 survivors from Emma Children's Hospital (Amsterdam, the Netherlands), the National Wilms Tumor Study, and the St Jude Lifetime Cohort Study were used to validate the CCSS prediction models.
Results
Heart failure occurred in 285 CCSS participants. Risk scores based on selected exposures (sex, age at cancer diagnosis, and anthracycline and chest radiotherapy doses) achieved an area under the curve of 0.74 and concordance statistic of 0.76 at or through age 40 years. Validation cohort estimates ranged from 0.68 to 0.82. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups, corresponding to cumulative incidences of heart failure at age 40 years of 0.5% (95% CI, 0.2% to 0.8%), 2.4% (95% CI, 1.8% to 3.0%), and 11.7% (95% CI, 8.8% to 14.5%), respectively. In comparison, siblings had a cumulative incidence of 0.3% (95% CI, 0.1% to 0.5%).
Conclusion
Using information available to clinicians soon after completion of childhood cancer therapy, individual risk for subsequent heart failure can be predicted with reasonable accuracy and discrimination. These validated models provide a framework on which to base future screening strategies and interventions.
doi:10.1200/JCO.2014.56.1373
PMCID: PMC4314592  PMID: 25287823
Journal of Clinical Oncology  2015;33(5):492-500.
Purpose
To estimate the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulatin hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after cranial radiotherapy (CRT) in childhood cancer survivors (CCS) and assess the impact of untreated deficiencies.
Patients and Methods
Retrospective study in an established cohort of CCS with 748 participants treated with CRT (394 men; mean age, 34.2 years [range, 19.4 to 59.6 years] observed for a mean of 27.3 years [range, 10.8 to 47.7 years]). Multivariable logistic regression was used to study associations between demographic and treatment-related risk factors and pituitary deficiencies, as well as associations between untreated deficiencies and cardiovascular health, bone mineral density (BMD), and physical fitness.
Results
The estimated point prevalence was 46.5% for GHD, 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD, and the cumulative incidence increased with follow-up. GHD and LH/FSHD were not treated in 99.7% and 78.5% of affected individuals, respectively. Male sex and obesity were significantly associated with LH/FSHD; white race was significant associated with LH/FSHD and TSHD. Compared with CRT doses less than 22 Gy, doses of 22 to 29.9 Gy were significantly associated with GHD; doses ≥ 22 Gy were associated with LH/FSHD; and doses ≥ 30 Gy were associated with TSHD and ACTHD. Untreated GHD was significantly associated with decreased muscle mass and exercise tolerance; untreated LH/FSHD was associated with hypertension, dyslipidemia, low BMD, and slow walking; and both deficits, independently, were associated with with abdominal obesity, low energy expenditure, and muscle weakness.
Conclusion
Anterior pituitary deficits are common after CRT. Continued development over time is noted for GHD and LH/FSHD with possible associations between nontreatment of these conditions and poor health outcomes.
doi:10.1200/JCO.2014.56.7933
PMCID: PMC4314596  PMID: 25559807
Psycho-oncology  2014;24(9):1116-1123.
Objective
The current study investigated the occurrence of emotional distress in parents of long-term survivors of childhood acute lymphoblastic leukemia (ALL) and identified factors associated with parent emotional distress symptoms.
Methods
Parents of 127 long-term survivors of childhood ALL treated on a chemotherapy-only protocol at St. Jude Children’s Research Hospital participated in the study. Parents completed standard ratings of emotional distress, caregiver strain, and child physical, emotional, and psychosocial functioning. Multivariable hierarchical linear regression analyses were used to examine associations between symptoms of caregiver strain, survivor functioning, and parent emotional distress. Covariates included parent education, survivor age, survivor sex, and time since childhood cancer diagnosis.
Results
On average, few parents reported significant symptoms of emotional distress. Clinically significant levels of anxiety and depression were reported by 7.1% and 3.1% of parents, respectively. Only 3.9% of parents endorsed significant symptoms of posttraumatic stress. Perceived caregiver strain was significantly associated with symptoms of parent anxiety, depression, and posttraumatic stress. Parent-report of child emotional functioning was significantly associated with symptoms of parent anxiety.
Conclusions
Most parents of long-term survivors of ALL exhibit low levels of emotional distress in the context of rates observed in the general population. Perceived caregiver strain was significantly associated with parent emotional distress. Further research is required to examine specific sources of caregiver strain, as well as other risk and protective factors associated with parent emotional distress symptoms.
doi:10.1002/pon.3732
PMCID: PMC4485981  PMID: 25557175
ALL; survivorship; parents; emotional distress
Journal of Clinical Oncology  2014;32(21):2217-2223.
Purpose
The risk of breast cancer is high in women treated for a childhood cancer with chest irradiation. We sought to examine variations in risk resulting from irradiation field and radiation dose.
Patients and Methods
We evaluated cumulative breast cancer risk in 1,230 female childhood cancer survivors treated with chest irradiation who were participants in the CCSS (Childhood Cancer Survivor Study).
Results
Childhood cancer survivors treated with lower delivered doses of radiation (median, 14 Gy; range, 2 to 20 Gy) to a large volume (whole-lung field) had a high risk of breast cancer (standardized incidence ratio [SIR], 43.6; 95% CI, 27.2 to 70.3), as did survivors treated with high doses of delivered radiation (median, 40 Gy) to the mantle field (SIR, 24.2; 95% CI, 20.7 to 28.3). The cumulative incidence of breast cancer by age 50 years was 30% (95% CI, 25 to 34), with a 35% incidence among Hodgkin lymphoma survivors (95% CI, 29 to 40). Breast cancer–specific mortality at 5 and 10 years was 12% (95% CI, 8 to 18) and 19% (95% CI, 13 to 25), respectively.
Conclusion
Among women treated for childhood cancer with chest radiation therapy, those treated with whole-lung irradiation have a greater risk of breast cancer than previously recognized, demonstrating the importance of radiation volume. Importantly, mortality associated with breast cancer after childhood cancer is substantial.
doi:10.1200/JCO.2013.54.4601
PMCID: PMC4100937  PMID: 24752044

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