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1.  Solid Tumor Second Primary Neoplasms: Who is at Risk, What Can We Do? 
Seminars in oncology  2013;40(6):676-689.
Eighteen percent of incident malignancies in the U.S. are a second (or subsequent) cancer. Second primary neoplasms (SPN), particularly solid tumors, are a major cause of mortality and serious morbidity among cancer survivors successfully cured of their first cancer. Multiple etiologies may lead to a cancer survivor subsequently being diagnosed with an SPN, including radiotherapy for the first cancer, unhealthy lifestyle behaviors, germline and somatic mutations, aging, or an interaction between any of these factors. In this article, we discuss these factors and synthesize this information for use in clinical practice, including preventive strategies and screening recommendations for SPNs.
doi:10.1053/j.seminoncol.2013.09.012
PMCID: PMC3921623  PMID: 24331190
2.  Modifiable Risk Factors and Major Cardiac Events Among Adult Survivors of Childhood Cancer 
Journal of Clinical Oncology  2013;31(29):3673-3680.
Purpose
To evaluate the relative contribution of modifiable cardiovascular risk factors on the development of major cardiac events in aging adult survivors of childhood cancer.
Patients and Methods
Among 10,724 5-year survivors (median age, 33.7 years) and 3,159 siblings in the Childhood Cancer Survivor Study, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity was determined, along with the incidence and severity of major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmia. On longitudinal follow-up, rate ratios (RRs) of subsequent cardiac events associated with cardiovascular risk factors and cardiotoxic therapy were assessed in multivariable Poisson regression models.
Results
Among survivors, the cumulative incidence of coronary artery disease, heart failure, valvular disease, and arrhythmia by 45 years of age was 5.3%, 4.8%, 1.5%, and 1.3%, respectively. Two or more cardiovascular risk factors were reported by 10.3% of survivors and 7.9% of siblings. The risk for each cardiac event increased with increasing number of cardiovascular risk factors (all Ptrend < .001). Hypertension significantly increased risk for coronary artery disease (RR, 6.1), heart failure (RR, 19.4), valvular disease (RR, 13.6), and arrhythmia (RR, 6.0; all P values < .01). The combined effect of chest-directed radiotherapy plus hypertension resulted in potentiation of risk for each of the major cardiac events beyond that anticipated on the basis of an additive expectation. Hypertension was independently associated with risk of cardiac death (RR, 5.6; 95% CI, 3.2 to 9.7).
Conclusion
Modifiable cardiovascular risk factors, particularly hypertension, potentiate therapy-associated risk for major cardiac events in this population and should be the focus of future interventional studies.
doi:10.1200/JCO.2013.49.3205
PMCID: PMC3804290  PMID: 24002505
3.  Reduced Cardiorespiratory Fitness in Adult Survivors of Childhood Acute Lymphoblastic Leukemia 
Pediatric blood & cancer  2013;60(8):10.1002/pbc.24492.
Background
Adult survivors of childhood acute lymphoblastic leukemia (ALL) are at increased cardiovascular risk. Studies of factors including treatment exposures that may modify risk of low cardiorespiratory fitness in this population have been limited.
Procedure
To assess cardiorespiratory fitness, maximal oxygen uptake (VO2max) was measured in 115 ALL survivors (median age, 23.5 years; range 18–37). We compared VO2max measurements for ALL survivors to those estimated from submaximal testing in a frequency-matched (age, gender, race/ethnicity) 2003–2004 National Health and Nutritional Examination Survey (NHANES) cohort. Multivariable linear regression models were constructed to evaluate the association between therapeutic exposures and outcomes of interest.
Results
Compared to NHANES participants, ALL survivors had a substantially lower VO2max (mean 30.7 vs 39.9 ml/kg/min; adjusted P<0.0001). For any given percent total body fat, ALL survivors had an 8.9 ml/kg/min lower VO2max than NHANES participants. For key treatment exposure groups (cranial radiotherapy [CRT], anthracycline chemotherapy, or neither), ALL survivors had substantially lower VO2max compared with NHANES participants (all comparisons, P<0.001). Almost two-thirds (66.7%) of ALL survivors were classified as low cardiorespiratory fitness compared with 26.3% of NHANES participants (adjusted P<0.0001). In multivariable models including only ALL survivors, treatment exposures were modestly associated with VO2max. Among females, CRT was associated with low VO2max (P=0.02), but anthracycline exposure was not (P=0.58). In contrast, among males, anthracycline exposure ≥100 mg/m2 was associated with low VO2max (P=0.03), but CRT was not (P=0.54).
Conclusion
Adult survivors of childhood ALL have substantially lower levels of cardiorespiratory fitness compared with a similarly aged non-cancer population.
doi:10.1002/pbc.24492
PMCID: PMC3725590  PMID: 23418044
childhood cancer; acute lymphoblastic leukemia; survivor; cardiorespiratory fitness
4.  Contribution of diet and physical activity to metabolic parameters among survivors of childhood leukemia 
Cancer causes & control : CCC  2012;24(2):313-321.
Purpose
Determine the relationship between diet and metabolic abnormalities among adult survivors of childhood acute lymphoblastic leukemia (ALL).
Methods
We surveyed 117 adult survivors of childhood ALL using the Harvard Food Frequency Questionnaire. Physical activity energy expenditure (PAEE) was measured with the SenseWear Pro2 Armband. Insulin resistance was estimated using the Homeostasis Model for Insulin Resistance (HOMA-IR). Visceral and subcutaneous adiposity were measured by abdominal CT. Adherence to a Mediterranean diet pattern was calculated using the index developed by Trichopoulou. Subjects were compared using multivariate analysis adjusted for age and gender.
Results
Greater adherence to a Mediterranean diet pattern was associated with lower visceral adiposity (P=0.07), subcutaneous adiposity (P<0.001), waist circumference (P=0.005), and body mass index (P=0.04). For each point higher on the Mediterranean Diet Score, the odds of having the metabolic syndrome fell by 31% (OR 0.69; 95% CI 0.50, 0.94; P = 0.019). Higher dairy intake was associated with higher HOMA-IR (P =0.014), but other individual components of the Mediterranean diet, such as low intake of meat or high intake of fruits and vegetables, were not significant. PAEE was not independently associated with metabolic outcomes, although higher PAEE was associated with lower body mass index.
Conclusions
Adherence to a Mediterranean diet pattern was associated with better metabolic and anthropometric parameters in this cross-sectional study of ALL survivors.
doi:10.1007/s10552-012-0116-6
PMCID: PMC3557541  PMID: 23187859
insulin resistance; leukemia; Mediterranean diet; obesity; survivorship
5.  Abdominal radiation and diabetes: one more piece in the puzzle 
The Lancet. Oncology  2012;13(10):961-962.
doi:10.1016/S1470-2045(12)70340-6
PMCID: PMC4280844  PMID: 22921662
6.  Recommendations for Breast Cancer Surveillance for Female Childhood, Adolescent and Young Adult Cancer Survivors Treated with Chest Radiation: A Report from the International Late Effects of Childhood Cancer Guideline Harmonization Group 
The Lancet. Oncology  2013;14(13):e621-e629.
Summary
Female childhood, adolescent and young adult (CAYA) cancer survivors treated with radiation to fields that include breast tissue (chest radiation) have an increased risk of breast cancer. Clinical practice guidelines are essential to ensure that these survivors receive optimum care, and thereby reduce the detrimental consequences of cancer treatment. However, surveillance recommendations vary among the existing long-term follow-up guidelines. This guideline provides international harmonized breast cancer surveillance recommendations for female CAYA cancer survivors treated with chest radiation prior to age 30 years. We applied evidence-based methods to develop the international harmonized recommendations. The recommendations were formulated by an international multidisciplinary guideline panel and categorized according to a 4-level colour grading schema adapted from existing level of evidence criteria. The harmonized breast cancer surveillance recommendations are based on a transparent process and are intended to be scientifically rigorous, positively influence health outcomes, and facilitate care for CAYA cancer survivors.
doi:10.1016/S1470-2045(13)70303-6
PMCID: PMC4257601  PMID: 24275135
7.  Increasing Rates of Breast Cancer and Cardiac Surveillance Among High Risk Survivors of Childhood Hodgkin Lymphoma Following a Mailed, One-Page Survivorship Care Plan 
Pediatric blood & cancer  2010;56(5):818-824.
Background
Hodgkin lymphoma (HL) survivors face substantially elevated risks of breast cancer and cardiovascular disease. They and their physicians are often unaware of these risks and surveillance recommendations.
Procedure
A prospective one-arm study was conducted among a random sample of 72 HL survivors, ages 27 to 55, participating in the Childhood Cancer Survivor Study (CCSS) who were at increased risk for breast cancer and/or cardiomyopathy and had not had a screening mammogram or echocardiogram, respectively, within the prior two years. A one-page survivorship care plan with recommendations for surveillance was mailed to participants. In addition, survivors’ primary physicians were contacted and provided patient-specific information and a web-based Virtual Information Center was made available for both survivors and physicians. Outcomes were assessed by telephone six months after the intervention.
Results
The survivor participation (62/72; 86%) and six-month retention (56/61; 92%) rates were high. Tension and anxiety, measured by the Profile of Mood States, did not increase following risk notification; 91% of survivors described their reactions to receiving the information in positive terms. At six months, 41% of survivors reported having completed the recommended mammogram; 20% reported having an echocardiogram (females 30%, males 10%). Only 29% of survivors visited the website. Nine physicians enrolled, and none used the study resources.
Conclusion
A mailed, personalized survivorship care plan was effective in communicating risk and increasing compliance with recommended medical surveillance. Internet- and telephone-based strategies to communicate risk were not utilized by survivors or physicians.
doi:10.1002/pbc.22696
PMCID: PMC3749088  PMID: 21370417
cancer survivor; late effects; survivorship care plan
8.  SECONDARY GASTROINTESTINAL MALIGNANCIES IN CHILDHOOD CANCER SURVIVORS: A COHORT STUDY 
Annals of internal medicine  2012;156(11):757-260.
Background
Childhood cancer survivors develop gastrointestinal malignancies more frequently and at a younger age than the general population, but risk factors for their development have not been well characterized.
Objective
To determine the risk and associated risk factors for gastrointestinal subsequent malignant neoplasms (SMN) in childhood cancer survivors.
Design
Retrospective cohort study.
Setting
The Childhood Cancer Survivor Study, a multi-center study of childhood cancer survivors diagnosed between 1970 and 1986.
Patients
14,358 survivors of a malignancy diagnosed at < 21 years who had survived for 5 or more years from initial diagnosis.
Measurements
Standardized incidence ratios (SIR) for gastrointestinal SMN were calculated using age-specific population data. Multivariate Cox regression models identified associations between risk factors and gastrointestinal SMN development.
Results
At median follow-up of 22.8 years (range: 5.5-30.2), 45 gastrointestinal malignancies were identified. Gastrointestinal SMN risk was 4.6-fold higher in childhood cancer survivors than the general population (95% confidence interval [CI]: 3.5-6.1). Colorectal cancer SIR was 4.2 (95% CI: 2.8-6.3). The highest gastrointestinal SMN risk was associated with abdominal radiation (SIR=11.2, 95% CI: 7.6-16.4). However, survivors not exposed to radiation had a significantly increased risk (SIR=2.4, 95% CI-1.4-3.9). In addition to abdominal radiation, high dose procarbazine (RR=3.2, 95% CI 1.1-9.4) and platinum drugs (RR 7.6, 95% CI: 2.3-25.5) independently increased the gastrointestinal SMN risk.
Limitations
This cohort has not yet attained an age at which gastrointestinal malignancy risk is greatest.
Conclusions
Childhood cancer survivors, particularly those exposed to abdominal radiation, are at increased risk for gastrointestinal SMN. These findings suggest that surveillance of at-risk childhood cancer survivors should commence at a younger age than recommended for the general population.
doi:10.1059/0003-4819-156-11-201206050-00002
PMCID: PMC3554254  PMID: 22665813
9.  Risk Factors for Obesity in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2011;30(3):246-255.
Purpose
Many Childhood Cancer Survivor Study (CCSS) participants are at increased risk for obesity. The etiology of their obesity is likely multifactorial but not well understood.
Patients and Methods
We evaluated the potential contribution of demographic, lifestyle, treatment, and intrapersonal factors and self-reported pharmaceutical use to obesity (body mass index ≥ 30 kg/m2) among 9,284 adult (> 18 years of age) CCSS participants. Independent predictors were identified using multivariable regression models. Interrelationships were determined using structural equation modeling (SEM).
Results
Independent risk factors for obesity included cancer diagnosed at 5 to 9 years of age (relative risk [RR], 1.12; 95% CI, 1.01 to 1.24; P = .03), abnormal Short Form–36 physical function (RR, 1.19; 95% CI, 1.06 to 1.33; P < .001), hypothalamic/pituitary radiation doses of 20 to 30 Gy (RR, 1.17; 95% CI, 1.05 to 1.30; P = .01), and paroxetine use (RR, 1.29; 95% CI, 1.08 to 1.54; P = .01). Meeting US Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82 to 0.97; P = .01) and a medium amount of anxiety (RR, 0.86; 95% CI, 0.75 to 0.99; P = .04) reduced the risk of obesity. Results of SEM (N = 8,244; comparative fit index = 0.999; Tucker Lewis index = 0.999; root mean square error of approximation = 0.014; weighted root mean square residual = 0.749) described the hierarchical impact of the direct predictors, moderators, and mediators of obesity.
Conclusion
Treatment, lifestyle, and intrapersonal factors, as well as the use of specific antidepressants, may contribute to obesity among survivors. A multifaceted intervention, including alternative drug and other therapies for depression and anxiety, may be required to reduce risk.
doi:10.1200/JCO.2010.34.4267
PMCID: PMC3269951  PMID: 22184380
10.  Adipokines, Body Fatness, and Insulin Resistance Among Survivors of Childhood Leukemia 
Pediatric blood & cancer  2011;58(1):31-36.
Background
Following our previous reports of an increased prevalence of insulin resistance and adiposity among acute lymphoblastic leukemia (ALL) survivors, particularly women treated with cranial radiotherapy (CRT), we aimed to (1) assess the relationships between adipokines (leptin and adiponectin), CRT, and measures of body fatness, and (2) determine correlates of insulin resistance, by gender.
Methods
We conducted cross-sectional evaluation of 116 ALL survivors (median age, 23.0 years; range, 18–37; average time from treatment: 17.5 years), including fasting laboratory testing (adiponectin, leptin, insulin, glucose), anthropometric measurements (weight, height, waist circumference), DXA (total body fat, truncal-to-lower-body-fat ratio), and abdominal CT (visceral fat). We estimated insulin resistance using the homeostasis model for assessment of insulin resistance (HOMA-IR). Analytic approaches included regression models and Wilcoxon rank sum testing.
Results
Mean leptin per kilogram fat mass was higher for females (0.7 ng/mL/kg) than males (0.4 ng/mL/kg, P<0.01), and among subjects who had received CRT compared to those who had not received CRT (females CRT =0.9 ng/mL/kg, no CRT=0.7 ng/mL/kg; P=0.1; males CRT=0.5 ng/mL/kg, no CRT=0.3 ng/mL/kg; P<0.01). Elevated HOMA-IR was nearly uniformly present, even among subjects with BMI<25 kg/m2, and was associated with higher leptin:adiponectin ratio (P<0.01).
Conclusions
Among survivors of childhood leukemia, higher leptin levels were associated with measures of body fat and insulin resistance. Anthropomorphic and metabolic changes many years after ALL treatment remain a major health problem facing survivors and may be related to central leptin resistance.
doi:10.1002/pbc.22964
PMCID: PMC3520427  PMID: 21254377
ALL; adiponectin; insulin resistance; leptin; leukemia
11.  Diabetes Mellitus in Long-Term Survivors of Childhood Cancer: Increased Risk Associated with Radiation Therapy A Report for the Childhood Cancer Survivor Study (CCSS) 
Archives of internal medicine  2009;169(15):1381-1388.
Background
Childhood cancer survivors are at increased risk of morbidity and mortality. To further characterize this risk, this study aimed to compare the prevalence of diabetes mellitus (DM) in childhood cancer survivors and their siblings.
Methods
Participants included 8599 survivors in the Childhood Cancer Survivor Study (CCSS), a retrospectively ascertained North American cohort of long-term survivors who were diagnosed 1970–1986, and 2936 randomly selected siblings of CCSS survivors. The main outcome was self-reported DM.
Results
Survivors and siblings had mean ages of 31.5 years (range, 17.0–54.1) and 33.4 years (range, 9.6–58.4), respectively. DM was reported in 2.5% of survivors and 1.7% of siblings. Adjusting for body mass index (BMI), age, sex, race/ethnicity, household income, and insurance, survivors were 1.8 times more likely to report DM (95% confidence interval [CI], 1.3–2.5; P<0.001) than siblings, with survivors who received total body irradiation (odds ratio [OR], 12.6; 95% CI, 6.2–25.3; P<0.001), abdominal irradiation (OR, 3.4; 95% CI, 2.3–5.0; P<0.001) and cranial irradiation (OR, 1.6; 95% CI 1.0–2.3; P=0.03) at increased risk. In adjusted models, increased risk of DM was associated with: total body irradiation (OR 7.2; 95% CI, 3.4–15.0; P<0.001); abdominal irradiation (OR 2.7; 95% CI, 1.9–3.8; P<0.001); alkylating agents (OR 1.7; 95% CI, 1.2–2.3; P<0.01); and younger age at diagnosis (0–4 years; OR 2.4; 95% CI 1.3–4.6; P<0.01).
Conclusions
Childhood cancer survivors treated with total body or abdominal irradiation have an increased risk of diabetes that appears unrelated to BMI or physical inactivity.
doi:10.1001/archinternmed.2009.209
PMCID: PMC3529471  PMID: 19667301
Childhood cancer survivor; diabetes mellitus; abdominal radiation; total body irradiation
12.  Whole-body magnetic resonance imaging (WB-MRI) as surveillance for subsequent malignancies in survivors of hereditary retinoblastoma: a pilot study 
Pediatric blood & cancer  2013;61(8):1440-1444.
Background
Individuals with hereditary retinoblastoma (RB) are at very high risk of developing subsequent malignant neoplasms (SMN) of which osteosarcoma (OS) is one of the most common. We hypothesized that annual surveillance using whole-body magnetic resonance imaging (WB-MRI) in asymptomatic survivors of hereditary RB would detect SMN of the bone and soft tissues at an early stage.
Procedure
Retrospective review of the results of a WB-MRI screening program in hereditary RB survivors from February 2008 – August 2012. The primary outcome was to determine the sensitivity and specificity of WB-MRI in detecting SMNs.
Results
Twenty-five patients had at least one WB-MRI performed (range: 1 – 5). First WB- MRI was performed at a median age of 16 years (range: 8 – 25 years). WB-MRI detected new osseous abnormalities suspicious for malignancy in 5 patients: 2 were diagnosed with localized high-grade OS of the extremity and 3 were found to have benign osseous abnormalities after dedicated imaging (n=5/5) and/or biopsy (n=3/5). One patient was diagnosed with secondary OS three months after a normal screening WB- MRI exam. Among a total of 41 WB-MRI screening tests performed in survivors of hereditary RB, the sensitivity of detecting SMN was 66.7% and the specificity was 92.1%.
Conclusions
Preliminary results suggest that annual WB-MRI surveillance detects SMN in survivors of hereditary RB, but with modest sensitivity. Further study is needed to assess the performance of annual surveillance WB-MRIs and whether this modality decreases SMN-related mortality in RB survivors.
doi:10.1002/pbc.24835
PMCID: PMC4007376  PMID: 24402721
Retinoblastoma; survivors; screening; whole-body MRI; pediatric oncology
13.  Survivor Typologies Predict Medical Surveillance Participation: The Childhood Cancer Survivor Study 
Psycho-oncology  2012;22(7):1534-1542.
Objective
Adult survivors of childhood cancer adhere poorly to recommended medical surveillance. We sought to identify modifiable factors that contribute to non-adherence.
Methods
Latent class analysis categorized survivors (ages 18–52 years) at risk of cardiac, breast, or bone late sequelae on the basis of their health-related concerns, fears, and motivation. These classifications were compared at two time points for self-reported adherence to recommended echocardiography, mammography, and bone densitometry screening.
Results
Three classes (worried, collaborative, self-controlling) characterized survivors in each of the 3 risk groups: cardiac (N=564; BIC=10,824.66; LRMLRT P=.002), breast (N=584; BIC=11,779.97, LRMLRT P<.001), and bone (N=613; BIC=11,773.56; LMRLRT P=.028). Only 9% of at-risk survivors in the self-controlling class reported undergoing bone density screening in 2005, compared to 17.2% in the collaborative class (P=.034). Thirteen percent of the self-controlling, 24% of the collaborative (P=.025), and 34% of the worried (P=.010) classes reported undergoing bone densitometry in 2009. While 73% of at-risk survivors in the worried class reported having had an echocardiogram in 2009, only 57% of the collaborative (P=.040) and 43% of the self-controlling (P<.001) classes did. In 2005 and 2009, respectively, fewer survivors in the self-controlling class (37% and 53%) than in the collaborative (51%, P=.038 and 70%, P=.01) and worried (58%, P=0.002 and 69%, P=0.025) classes reported undergoing mammograms.
Conclusions
Modifiable intrapersonal characteristics associated with these 3 classes predict self-reported participation in medical surveillance. Continued observation and validation of these survivor profiles may inform tailored interventions to enhance survivors’ screening participation.
doi:10.1002/pon.3167
PMCID: PMC3548022  PMID: 22968964
childhood cancer; screening; late effects; pediatric oncology
14.  A Worldwide Collaboration To Harmonize Guidelines For The Long-Term Follow-Up Of Childhood And Young Adult Cancer Survivors: A Report From The International Late Effects Of Childhood Cancer Guideline Harmonization Group 
Pediatric blood & cancer  2012;60(4):10.1002/pbc.24445.
Childhood and young adult cancer survivors should receive optimum care to reduce the consequences of late effects and improve quality of life. We can facilitate achieving this goal by international collaboration in guideline development. In 2010 the International Late Effects of Childhood Cancer Guideline Harmonization Group was initiated. The aim of the harmonization endeavor is to establish a common vision and integrated strategy for the surveillance of late effects in childhood and young adult cancer survivors. With the implementation of our evidence-based methods we provide a framework for the harmonization of guidelines for the long-term follow-up of childhood and young adult cancer survivors.
doi:10.1002/pbc.24445
PMCID: PMC3819170  PMID: 23281199
Guidelines; Late effects; Childhood and young adult cancer survivors; Collaboration
15.  Knowledge of Hepatitis C Virus Screening in Long-Term Pediatric Cancer Survivors: A Report from the Childhood Cancer Survivor Study 
Cancer  2010;116(4):974-982.
Background
Pediatric cancer survivors who were treated before routine hepatitis C virus (HCV) screening of blood donors in 1992 have an elevated risk of transfusion-acquired HCV.
Methods
To assess long-term pediatric cancer survivors’ knowledge of HCV testing and blood transfusion history, a questionnaire was administered to 9,242 participants in the Childhood Cancer Survivor Study (CCSS) who are at risk for transfusion-acquired HCV following cancer therapy from 1970–1986.
Results
More than 70% of survivors reported either no prior HCV testing (41%) or uncertainty about testing (31%), with only 29% reporting prior testing. One-half recalled having a treatment-related blood transfusion; those who recalled a transfusion were more likely to report HCV testing (39%) than those who did not (18%) or were unsure (20%). In multivariate models, survivors who reported no prior HCV testing were more likely to be older (odds ratio [OR] per five-year increase, 1.1; 95% confidence interval [95% CI], 1.0–1.1) and to report no care at a cancer center within the past two years (OR, 1.2; 95% CI, 1.0–1.4), no cancer treatment summary (OR, 1.3; 95% CI, 1.2–1.5), and no transfusions (OR, 2.6; 95% CI, 2.3–3.0) or uncertainty about transfusions (OR, 2.2; 95% CI, 1.9–2.6), and less likely to be racial/ethnic minorities (OR, 0.9; 95% CI, 0.8–1.0) or survivors of acute myeloid leukemia (OR, 0.7; 95% CI, 0.5–1.0).
Conclusions
Many pediatric cancer survivors at risk for transfusion-acquired HCV are unaware of their transfusion history and prior testing for HCV and would benefit from programs to increase HCV knowledge and screening.
doi:10.1002/cncr.24810
PMCID: PMC2819650  PMID: 20041485
cancer screening; late effects; survivorship; adverse treatment effects; chronic disease
16.  American Cancer Society Lung Cancer Screening Guidelines 
Findings from the National Cancer Institute’s National Lung Screening Trial established that lung cancer mortality in specific high-risk groups can be reduced by annual screening with low-dose computed tomography. These findings indicate that the adoption of lung cancer screening could save many lives. Based on the results of the National Lung Screening Trial, the American Cancer Society is issuing an initial guideline for lung cancer screening. This guideline recommends that clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about screening with apparently healthy patients aged 55 years to 74 years who have at least a 30-pack-year smoking history and who currently smoke or have quit within the past 15 years. A process of informed and shared decision-making with a clinician related to the potential benefits, limitations, and harms associated with screening for lung cancer with low-dose computed tomography should occur before any decision is made to initiate lung cancer screening. Smoking cessation counseling remains a high priority for clinical attention in discussions with current smokers, who should be informed of their continuing risk of lung cancer. Screening should not be viewed as an alternative to smoking cessation.
doi:10.3322/caac.21172
PMCID: PMC3632634  PMID: 23315954
humans; lung neoplasms; mortality; radiography; radiation dosage; randomized controlled trials as topic; risk; risk reduction behavior; x-ray; computed tomography; adverse effects; lung cancer screening
17.  Insulin Resistance and Risk Factors for Cardiovascular Disease in Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia 
Journal of Clinical Oncology  2009;27(22):3698-3704.
Purpose
To determine the prevalence of insulin resistance and other risk factors for cardiovascular disease (CVD) in young adult survivors of childhood acute lymphoblastic leukemia (ALL).
Patients and Methods
In this cross-sectional evaluation of 118 survivors of childhood ALL (median age, 23.0 years; range, 18 to 37 years), insulin resistance was estimated using the homeostasis model for assessment of insulin resistance (HOMA-IR). Sex-specific comparisons were made with a cohort of 30- to 37-year-old individuals from the same region participating in the Dallas Heart Study (DHS, N = 782). ALL survivors were stratified by treatment with and without cranial radiotherapy (CRT).
Results
Female ALL survivors had a significantly higher HOMA-IR (CRT, mean 4.6, 95% CI, 3.6 to 5.7; no CRT, mean 3.3, 95% CI, 2.8 to 3.8) in comparison with DHS women (mean 2.4, 95% CI, 2.2 to 2.7). Eighty percent of women treated with CRT had at least three of six CVD risk factors, and they were significantly more likely to have three or more risk factors compared with DHS women (odds ratio [OR], 5.96; 95% CI, 2.15 to 16.47). Male ALL survivors had a significantly higher HOMA-IR (CRT, mean 4.0, 95% CI, 2.8 to 5.6; no CRT, mean 3.4, 95% CI, 2.9 to 3.9) in comparison with DHS men (mean 2.3, 95% CI, 2.1 to 2.6), but were not more likely to have multiple CVD risk factors.
Conclusion
ALL survivors had an increased prevalence of insulin resistance in comparison with a cohort of older individuals from the same community. Importantly, women treated with CRT seem to have an increased prevalence of multiple CVD risk factors, warranting close monitoring and risk-reducing strategies.
doi:10.1200/JCO.2008.19.7251
PMCID: PMC2720083  PMID: 19564534
18.  Health Behaviors, Medical Care, and Interventions to Promote Healthy Living in the Childhood Cancer Survivor Study Cohort 
Journal of Clinical Oncology  2009;27(14):2363-2373.
Childhood cancer survivors are at risk for medical and psychosocial late effects as a result of their cancer and its therapy. Promotion of healthy lifestyle behaviors and provision of regular risk-based medical care and surveillance may modify the evolution of these late effects. This manuscript summarizes publications from the Childhood Cancer Survivor Study (CCSS) that have examined health behaviors, risk-based health care, and interventions to promote healthy lifestyle practices. Long-term survivors use tobacco and alcohol and have inactive lifestyles at higher rates than is ideal given their increased risk of cardiac, pulmonary, and metabolic late effects. Nearly 90% of survivors report receiving some form of medical care. However, only 18% report medical visits related to their prior cancer that include discussion or ordering of screening tests or counseling on how to reduce the specific risks arising from their cancer. One low-cost, peer-driven intervention trial has been successful in improving smoking cessation within the CCSS cohort. On the basis of data from CCSS investigations, several trials to promote improved medical surveillance among high-risk groups within the cohort are underway. Despite their long-term risks, many survivors of childhood cancer engage in risky health behaviors and do not receive adequate risk-based medical care.
doi:10.1200/JCO.2008.21.1441
PMCID: PMC2738646  PMID: 19255308
19.  Surveillance for Breast Cancer in Women Treated with Chest Radiation for a Childhood, Adolescent or Young Adult Cancer: A Report from the Children's Oncology Group 
Annals of internal medicine  2010;152(7):444-W154.
Background
Women treated with therapeutic chest radiation may develop breast cancer.
Purpose
Summarize breast cancer risk and breast cancer surveillance in women following chest radiation for a pediatric or young adult cancer.
Data Sources
Studies from MEDLINE, EMBASE, Cochrane Library, and CINAHL (1966 through December 2008).
Study Selection
Articles selected to answer any of 3 questions: 1) What is the incidence and excess risk of breast cancer in women following chest radiation for a pediatric or young adult cancer? 2) For these women, are the clinical characteristics of the breast cancer and the outcomes following therapy different than for women with sporadic breast cancer in the general population? 3) What are the potential benefits and harms associated with breast cancer surveillance among women exposed to chest radiation?
Data Extraction
Three investigators independently extracted data and assessed study quality.
Data Synthesis
Standardized incidence ratios ranged from 13.3 to 55.5; cumulative incidence of breast cancer by 40–45 years of age ranged from 13–20%. Risk of breast cancer increased linearly with chest radiation dose. Available limited evidence suggests that the characteristics of the breast cancers in these women and the outcomes following diagnosis are similar to those in the general population; these breast cancers can be detected by mammography, though sensitivity is limited.
Limitations
Limitations include study heterogeneity, design and small sample size.
Conclusions
Women treated with chest radiation have a substantially elevated risk of breast cancer at a young age, which does not appear to plateau. Among this high risk population, there appears to be a benefit associated with early detection. Further research is required to better define the harms and benefits of lifelong surveillance.
doi:10.1059/0003-4819-152-7-201004060-00009
PMCID: PMC2857928  PMID: 20368650
20.  Longitudinal Changes in Obesity and Body Mass Index Among Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2008;26(28):4639-4645.
Purpose
We examined the rate of increase in the body mass index (BMI; kg/m2) after final height attainment in survivors of acute lymphoblastic leukemia (ALL) and a noncancer comparison group.
Methods
Childhood Cancer Survivor Study (CCSS) is a retrospectively ascertained cohort study that prospectively tracks the health status of adults who were diagnosed with childhood cancer between 1970 and 1986 and a comparison group of siblings. Changes in BMI from baseline enrollment to time of completion of follow-up (mean interval, 7.8 years) were calculated for 1,451 ALL survivors (mean age, 32.3 years at follow-up) and 2,167 siblings of childhood cancer survivors (mean age, 35.9 years).
Results
The mean BMI of the CCSS sibling comparison group increased with age (women, 0.25 units/yr, 95% CI, 0.22 to 0.28 units; men, 0.23 units/yr, 95% CI, 0.20 to 0.25 units). Compared with CCSS siblings, ALL survivors who were treated with cranial radiation therapy (CRT) had a significantly greater increase in BMI (women, 0.41 units/yr, 95% CI, 0.37 to 0.45 units; men, 0.29 units/yr; 95% CI, 0.26 to 0.32 units). The rate of BMI increase was not significantly increased for ALL survivors who were treated with chemotherapy alone. Younger age at CRT exposure significantly modified risk.
Conclusion
CRT used in the treatment of childhood ALL is associated with a greater rate of increasing BMI, particularly among women treated with CRT during the first decade of life. Health care professionals should be aware of this risk and interventions to reduce or manage weight gain are essential in this high-risk population.
doi:10.1200/JCO.2008.16.3527
PMCID: PMC2653124  PMID: 18824710
21.  Breast Cancer Surveillance Practices Among Women Previously Treated With Chest Radiation for a Childhood Cancer 
Context
Women treated with chest radiation for a pediatric malignancy have a significantly increased risk of breast cancer at a young age and are recommended to have an annual screening mammogram starting at age 25 or 8 years after radiation, whichever occurs last.
Objective
Characterize the breast cancer surveillance practices among female pediatric cancer survivors who were treated with chest radiation and identify correlates of screening.
Design, Setting, Participants
Between June 2005 and August 2006, a 114-item questionnaire was administered to a random sample of 625 female pediatric cancer survivors who had been treated with chest radiation and were age 25–50 and participating in the Childhood Cancer Survivor Study (CCSS), a North American cohort of long-term survivors diagnosed from 1970–1986. Comparisons were made with similarly aged pediatric cancer survivors not treated with chest radiation (N=639) and the CCSS siblings cohort (N=712).
Main Outcome Measure
Screening mammogram within the previous two years.
Results
Of 1976 cancer survivors and siblings who were contacted, 87.9% participated. Among the 551 women with a history of chest radiation, 55% reported a screening mammogram in the past two years (ages 25–39, 36.5%; 95% confidence interval [CI], 31.0%–42.0%; ages 40–50, 76.5%; 95% CI, 71.3%–81.7%). In comparison, 40.5% of survivors without chest radiation and 37.0% of CCSS siblings reported a screening mammogram in the same time interval. Notably, among women with a history of chest radiation, 47.3% (95% CI, 41.6%–53.0%) of those under age 40 had never had a mammogram and only 52.6% (95% CI, 46.4%–58.8%) of women ages 40–50 were being regularly screened (two mammograms within four years). Screening rates were higher among women who reported a physician recommendation compared to those who did not (ages 25–39, 76.0% vs. 17.6%; ages 40–50, 87.3% vs. 58.3%). In multivariable models, the association was particularly strong for younger women (ages 25–39, prevalence ratio [PR] = 3.0, 95% CI, 2.0–4.0; ages 40–50, PR = 1.3, 95% CI, 1.1–1.6).
Conclusions
In this study cohort of women who had childhood cancer treated with chest radiation, 63.5% of those aged 25–39 years and 23.5% of those aged 40–50 years had not undergone mammography screening for breast cancer, as recommended by current guidelines for survivors of childhood cancer.
doi:10.1001/jama.2008.1039
PMCID: PMC2676434  PMID: 19176442
22.  Hospitalization Rates Among Survivors of Childhood Cancer in the Childhood Cancer Survivor Study Cohort 
Pediatric blood & cancer  2011;59(1):126-132.
Background
Chronic health conditions are common among long-term childhood cancer survivors, but hospitalization rates have not been reported. The objective of this study was to determine overall and cause-specific hospitalization rates among survivors of childhood cancer and compare rates to the U.S. population.
Procedure
The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of 5+ year survivors of childhood malignancies treated at 26 participating centers. Self-reported hospitalizations from 10,366 survivors (diagnosed 1970–1986) were compared to U.S. population rates using age-and sex-stratified standardized incidence ratios (SIRs). Reasons for hospitalization were evaluated and associations between demographic, cancer and treatment-related risk factors with hospitalization were investigated.
Results
Survivors were, on average, 20.9 years from cancer diagnosis (SD: 4.6, range: 13–32) and 28.6 years of age (SD: 7.7, range: 13–51). Survivor hospitalization rates were 1.6 times the U.S. population (95% CI: 1.6; 1.7). Increased hospitalization rates were noted irrespective of gender, age at follow-up and cancer diagnosis, with highest SIRs noted among male (SIR=2.6, 95% CI: 2.2; 3.0) and female (SIR=2.7, 95% CI: 2.4; 3.1) survivors aged 45–54. Female gender, an existing chronic health condition and/or a second neoplasm, and prior treatment with radiation were associated with an increased risk of non-obstetrical hospitalization.
Conclusions
Survivors of childhood cancer demonstrate substantially higher hospitalization rates. Additional research is needed to further quantify the healthcare utilization and economic impact of treatment-related complications as this population ages.
doi:10.1002/pbc.24017
PMCID: PMC3359936  PMID: 22180128
childhood cancer; cancer survivor; hospitalization
23.  Survivorship care plans in research and practice 
CA: a cancer journal for clinicians  2012;10.3322/caac.20142.
Background
The Institute of Medicine (IOM) recommends the use of survivorship care plans (SCPs) for all cancer survivors. Developing useful SCPs requires understanding what survivors and their providers need and how SCPs can be implemented in practice.
Methods
We reviewed published studies investigating the perspectives of stakeholders (survivors, primary care providers, and oncology providers) regarding the content and use of SCPs. We surveyed all NCI-designated cancer centers about the extent to which SCPs for breast and colorectal cancer survivors are in use, their concordance with the IOM's recommendation, and details about SCP delivery.
Results
Survivors and primary care providers typically lack the information the IOM suggested should be included in SCPs. Oncology providers view SCPs favorably but express concerns about feasibility of their implementation. Fewer than half (43%) of NCI-designated cancer centers deliver SCPs to their breast or colorectal cancer survivors. Of those that do, none deliver SCPs that include all components recommended by the IOM.
Conclusion
Survivors’ and providers’ opinions about the use of SCPs are favorable, but there are barriers to implementation. SCPs are not widely used in NCI-designated cancer centers. Variation in practice is substantial, and many components recommended by the IOM framework are rarely included.
doi:10.3322/caac.20142
PMCID: PMC3330140  PMID: 22241452
24.  Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2011;30(13):1415-1421.
Purpose
Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors.
Patients and Methods
One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques.
Results
A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m2: reference; 1 to 100 mg/m2: odds ratio [OR], 1.65; 101 to 150 mg/m2: OR, 3.85; 151 to 200 mg/m2: OR, 3.69; 201 to 250 mg/m2: OR, 7.23; 251 to 300 mg/m2: OR, 23.47; > 300 mg/m2: OR, 27.59; Ptrend < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m2) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m2) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status.
Conclusion
This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m2. Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.
doi:10.1200/JCO.2011.34.8987
PMCID: PMC3383117  PMID: 22124095
25.  Survivor Profiles Predict Health Behavior Intent: The Childhood Cancer Survivor Study 
Psycho-oncology  2011;21(5):469-478.
Objectives
To determine whether unique groups of adult childhood cancer survivors could be defined on the basis of modifiable cognitive, affective and motivation indicators. Secondary objectives were to examine to what extent group membership covaried with more static variables (e.g., demographics, disease, and treatment) and predicted intent for subsequent medical follow-up.
Methods
Using latent class analysis of data from 978 participants (ages 18–52 years; mean, 31; SD, 8) in the Childhood Cancer Survivor Study, we classified survivors according to their worries about health, perceived need for follow-up care, health motivation, and background variables. Intent to participate in medical follow-up, as a function of class membership, was tested using equality of proportions.
Results
The best-fitting model (BIC=18,540.67, BLMRT=<0.001) was characterized by three distinctive survivor classes (worried, 19%; self-controlling, 26%; collaborative, 55%) and three significant class covariates (gender, perceptions of health and severity of late effects). A smaller proportion of survivors in the self-controlling group [81%] than in the worried [90%] (P=0.015) and collaborative [88%] (P=0.015) groups intended to obtain a routine medical checkup. A smaller proportion of survivors in the self-controlling group [32%] than in the collaborative [65%] (P=<0.001) and worried [86%] (P=<0.001) groups planned a cancer-related check-up. A smaller proportion of survivors in the collaborative group [65%] than in the worried group [86%] (P=<0.001) were likely to obtain a cancer-related check-up.
Conclusions
Childhood cancer survivors can be classified according to modifiable indicators. The classification is distinctive, predicts intent for future medical follow-up, and can inform tailored interventions.
doi:10.1002/pon.1935
PMCID: PMC3563242  PMID: 21381147
childhood cancer; survivorship; late effects; medical follow-up; pediatric oncology

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