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1.  Breast Cancer After Chest Radiation Therapy for Childhood Cancer 
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
2.  Childhood Cancer, Endocrine Disorders, and Cohort Studies 
Lancet  2014;383(9933):1950-1952.
doi:10.1016/S0140-6736(14)60114-8
PMCID: PMC4094362  PMID: 24556021
3.  Pain in Cancer Survivors 
Journal of Clinical Oncology  2014;32(16):1739-1747.
Pain is a common problem in cancer survivors, especially in the first few years after treatment. In the longer term, approximately 5% to 10% of survivors have chronic severe pain that interferes with functioning. The prevalence is much higher in certain subpopulations, such as breast cancer survivors. All cancer treatment modalities have the potential to cause pain. Currently, the approach to managing pain in cancer survivors is similar to that for chronic cancer-related pain, pharmacotherapy being the principal treatment modality. Although it may be appropriate to continue strong opioids in survivors with moderate to severe pain, most pain problems in cancer survivors will not require them. Moreover, because more than 40% of cancer survivors now live longer than 10 years, there is growing concern about the long-term adverse effects of opioids and the risks of misuse, abuse, and overdose in the nonpatient population. As with chronic nonmalignant pain, multimodal interventions that incorporate nonpharmacologic therapies should be part of the treatment strategy for pain in cancer survivors, prescribed with the aim of restoring functionality, not just providing comfort. For patients with complex pain issues, multidisciplinary programs should be used, if available. New or worsening pain in a cancer survivor must be evaluated to determine whether the cause is recurrent disease or a second malignancy. This article focuses on patients with a history of cancer who are beyond the acute diagnosis and treatment phase and on common treatment-related pain etiologies. The benefits and harms of the various pharmacologic and nonpharmacologic options for pain management in this setting are reviewed.
doi:10.1200/JCO.2013.52.4629
PMCID: PMC4031191  PMID: 24799477
4.  Aging and Risk of Severe, Disabling, Life-Threatening, and Fatal Events in the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2014;32(12):1218-1227.
Purpose
The first generation of childhood cancer survivors is now aging into their fourth and fifth decades of life, yet health risks across the aging spectrum are not well established.
Methods
Analyses included 14,359 5-year survivors from the Childhood Cancer Survivor Study, who were first diagnosed when they were younger than 21 years old and who received follow-up for a median of 24.5 years after diagnosis (range, 5.0 to 39.3 years) along with 4,301 of their siblings. Among the survivors, 5,604 were at least 35 years old (range, 35 to 62 years) at last follow-up. Severe, disabling, life-threatening, and fatal health conditions more than 5 years from diagnosis were classified using the Common Terminology Criteria for Adverse Events, grades 3 to 5 (National Cancer Institute).
Results
The cumulative incidence of a severe, disabling, life-threatening, or fatal health condition was greater among survivors than siblings (53.6%; 95% CI, 51.5 to 55.6; v 19.8%; 95% CI, 17.0 to 22.7) by age 50 years. When comparing survivors with siblings, hazard ratios (HR) were significantly increased within the age group of 5 to 19 years (HR, 6.8; 95% CI, 5.5 to 8.3), age group of 20 to 34 years (HR, 3.8; 95% CI, 3.2 to 4.5), and the ≥ 35 years group (HR, 5.0; 95% CI, 4.1 to 6.1), with the HR significantly higher among those ≥ 35 years versus those 20 to 34 years old (P = .03). Among survivors who reached age 35 years without a previous grade 3 or 4 condition, 25.9% experienced a subsequent grade 3 to 5 condition within 10 years, compared with 6.0% of siblings (P < .001).
Conclusion
Elevated risk for morbidity and mortality among survivors increases further beyond the fourth decade of life, which affects the future clinical demands of this population relative to ongoing surveillance and interventions.
doi:10.1200/JCO.2013.51.1055
PMCID: PMC3986385  PMID: 24638000
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  Decline in physical activity level in the Childhood Cancer Survivor Study cohort 
Background
We aimed to identify demographic and health-related predictors of declining physical activity levels over a four year period among participants in the Childhood Cancer Survivor Study.
Methods
Analyses included 7287 ≥5 year childhood cancer survivors and 2107 siblings who completed multiple follow-up questionnaires. Participants were classified as active if they met the Centers for Disease Control and Prevention guidelines for physical activity. Generalized linear models were used to compare participants whose physical activity levels declined from active to inactive over the study to those who remained active. Additionally, selected chronic conditions (CTCAE v4.03 Grade 3 and 4) were evaluated as risk factors in an analysis limited to survivors only.
Results
The median age at last follow-up among survivors and siblings was 36 (range: 21–58) and 38 (range: 21–62) years, respectively. The rate of decline did not accelerate over time among survivors when compared with siblings. Factors that predicted declining activity included BMI ≥30kg/m2 (RR=1.32, 95%CI=1.19–1.46, p<0.01), not completing high school (RR=1.31, 95%CI=1.08–1.60, p<0.01), and female sex (RR=1.33, 95%CI=1.22–1.44, p<0.01). Declining physical activity levels were associated with the presence of chronic musculoskeletal conditions (p=0.034), but not with the presence of cardiac (p=0.10), respiratory (p=0.92) or neurological conditions (p=0.21).
Conclusions
Interventions designed to maximize physical activity should target female, obese, and less educated survivors. Survivors with chronic musculoskeletal conditions should be monitored, counseled and/or referred for physical therapy.
Impact
Clinicians should be aware of low activity levels among sub-populations of childhood cancer survivors which may heighten their risk for chronic illness.
doi:10.1158/1055-9965.EPI-14-0213
PMCID: PMC4119523  PMID: 24842624
children; cancer; survivor; physical; activity
12.  Identifying and Addressing the Needs of Adolescents and Young Adults With Cancer: Summary of an Institute of Medicine Workshop 
The Oncologist  2015;20(2):186-195.
The Institute of Medicine’s National Cancer Policy Forum convened a public workshop to examine the needs of the nearly 70,000 adolescents and young adults (AYAs) between the ages of 15 and 39 that are diagnosed with cancer each year. This article highlights potential action items to improve the care and outcomes for AYA patients with cancer.
Cancer is the leading disease-related cause of death in adolescents and young adults (AYAs). This population faces many short- and long-term health and psychosocial consequences of cancer diagnosis and treatment, but many programs for cancer treatment, survivorship care, and psychosocial support do not focus on the specific needs of AYA cancer patients. Recognizing this health care disparity, the National Cancer Policy Forum of the Institute of Medicine convened a public workshop to examine the needs of AYA patients with cancer. Workshop participants identified many gaps and challenges in the care of AYA cancer patients and discussed potential strategies to address these needs. Suggestions included ways to improve access to care for AYAs, to deliver cancer care that better meets the medical and psychosocial needs of AYAs, to develop educational programs for providers who care for AYA cancer survivors, and to enhance the evidence base for AYAs with cancer by facilitating participation in research.
doi:10.1634/theoncologist.2014-0265
PMCID: PMC4319626  PMID: 25568146
Adolescent; Young adult; Cancer survivorship; Psychosocial aspects; Fertility preservation; Adverse effects
13.  Predicting Adverse Health Outcomes in Long-Term Survivors of a Childhood Cancer 
Children (Basel, Switzerland)  2014;1(2):63-73.
More than 80% of children and young adults diagnosed with invasive cancer will survive five or more years beyond their cancer diagnosis. This population has an increased risk for serious illness- and treatment-related morbidity and premature mortality. A number of these adverse health outcomes, such as cardiovascular disease and some second primary neoplasms, either have modifiable risk factors or can be successfully treated if detected early. Absolute risk models that project a personalized risk of developing a health outcome can be useful in patient counseling, in designing intervention studies, in forming prevention strategies, and in deciding upon surveillance programs. Here, we review existing absolute risk prediction models that are directly applicable to survivors of a childhood cancer, discuss the concepts and interpretation of absolute risk models, and examine ways in which these models can be used applied in clinical practice and public health.
doi:10.3390/children1020063
PMCID: PMC4521414
clinical prediction tool; risk prediction model; late effects; second cancers
14.  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
15.  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
16.  Colorectal Cancer Survivors' Needs and Preferences for Survivorship Information 
Journal of Oncology Practice  2014;10(4):e277-e282.
In the absence of a survivorship care plan, colorectal cancer survivors still generally understood their cancer history; however, many lacked knowledge of ongoing risks and prevention.
Purpose:
Before developing a survivorship care plan (SCP) that colorectal cancer (CRC) survivors will value, understanding the informational needs of CRC survivors is critical.
Methods:
We surveyed survivors treated for nonmetastatic CRC at two hospitals in New York about their needs and preferences for survivorship information. Participants completed treatment 6 to 24 months before the interview and had not received an SCP. We evaluated whether survivors knew their treatment history (10 topics), whether they understood ongoing risks (four topics), and their preferences for receiving 16 topics of survivorship information.
Results:
One hundred seventy-five survivors completed the survey. Most survivors remembered information about past treatment (98% to 99% for each treatment). Fewer survivors knew their risks of local recurrence, distant recurrence, or developing a new CRC (69%, 77%, and 40%, respectively). Most participants reported receiving information about their cancer history and ongoing oncology visits (77% to 86% across topics). Across all topics, 93% to 99% of those who reported receiving information found the information useful. A minority of survivors reported they received information about symptoms to report to doctors, returning to work, or financial or legal issues (5% to 48% across topics), but those who did found the information useful (89% to 100% across topics).
Conclusions:
In the absence of an SCP, CRC survivors still generally understood their cancer history. However, many lacked knowledge of ongoing risks and prevention. Most survivors stated that they found the survivorship information they received useful. SCPs for CRC survivors should focus less on past care and more on helping survivors understand their risks and plan for the future.
doi:10.1200/JOP.2013.001312
PMCID: PMC4094649  PMID: 24893610
17.  Estimating the risk for late effects of therapy in children newly diagnosed with standard risk acute lymphoblastic leukemia using an historical cohort: A report from the Childhood Cancer Survivor Study 
The Lancet. Oncology  2014;15(8):841-851.
Summary
Background
Pediatric acute lymphoblastic leukemia (ALL) therapy has evolved such that the risk for late effects in ALL survivors treated on contemporary protocols is likely different from that observed in survivors treated in prior eras. We estimated the risk for late effects in children with standard-risk ALL treated in the current era using data from similarly treated members of the Childhood Cancer Survivor Study (CCSS) cohort.
Methods
The CCSS is a multi-centre North American study of five-year survivors of childhood cancer diagnosed between 1970 and1986. Cohort members were eligible for this analysis if they were aged 1·0–9·9 years at the time of ALL diagnosis and received therapy consistent with contemporary standard-risk ALL protocols. Outcomes were compared to a sibling cohort (n=2788) and the general United States population.
Findings
556/5980 cohort members treated for ALL met the inclusion criteria. After a median follow up of 18·4 years (range 0·0–33·0) from cohort entry, 28/556 (5%) had died (standardized mortality ratio, 3·5; 95% CI, 2·3–5·0). Sixteen deaths were due to causes other than ALL recurrence. Among 556 survivors, six (1%) developed a subsequent malignant neoplasm (standardized incidence ratio, 2·6; 95% CI, 1·0–5·7). 107 subjects in each group would need to be followed for one year in order to observe one extra chronic health condition in the ALL group compared to the sibling group (95% CI, 81–193). 415 subjects in each group would need to be followed for one year to observe one extra severe, life-threatening or fatal condition in the ALL group (95% CI, 376–939) Survivors did not differ from siblings in their educational attainment, rate of marriage or independent living.
Interpretation
Overall, the expected prevalence of adverse long-term outcomes among children treated for standard risk ALL on contemporary protocols is low, but regular care from a knowledgeable primary care practitioner is warranted.
Funding
National Cancer Institute, Cancer Center Support, American Lebanese-Syrian Associated Charities, Cancer Research Switzerland.
doi:10.1016/S1470-2045(14)70265-7
PMCID: PMC4142216  PMID: 24954778
18.  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
19.  Sociodemographic Disparities in Quality of Life for Survivors of Adolescent and Young Adult Cancers in the Behavioral Risk Factor Surveillance System 
Purpose: Survivors of cancer diagnosed during adolescence and young adulthood (AYA; aged 15–39) may experience quality of life (QOL) limitations; however, little is known about QOL for AYA survivors who are now middle-aged or among racial/ethnic minority survivors. We evaluated QOL outcomes for AYA cancer survivors relative to a non-cancer comparison group by gender, race/ethnicity, and current age.
Methods: Using the 2009 Behavioral Risk Factor Surveillance System (BRFSS) data, we identified 8375 individuals diagnosed with cancer while aged 15–39 years old and 334,759 controls. Participants were currently ≥20 years of age. QOL was measured using four items from the Center for Disease Control's Healthy Days Measure (general health, number of days of poor physical and mental health, and activity limitation days). Multivariable regressions compared these measures for survivors and controls by gender, race/ethnicity, and age, and among survivors to determine cancer-related factors associated with poor QOL.
Results: Survivors were more likely to report fair/poor general health than controls (relative risk=1.92; 95% confidence interval: 1.77–2.10; p<0.001). QOL limitations existed by gender and race/ethnicity for survivors. Approximately 30% of survivors currently in their 40s, 50s, and early 60s were in poor health, compared to less than 20% of same-aged controls (both p<0.001). Of survivors with two or more cancers, 41.0% reported poor health, compared to 26.2% with one cancer (p<0.001).
Conclusion: AYA cancer survivors have worse QOL compared to the general population and these limitations persist across gender, race/ethnicity, and age. Targeted interventions are essential for improving AYA cancer survivors' health status.
doi:10.1089/jayao.2013.0035
PMCID: PMC4048978  PMID: 24940530
quality of life; survivor; BRFSS; population
20.  Causes of Death in Long-term Survivors of Head and Neck Cancer 
Cancer  2014;120(10):1507-1513.
Background
Survivors of head and neck squamous cell carcinoma (HNSCC) face excess mortality from multiple causes.
Methods
We used population-based Surveillance, Epidemiology, and End Results (SEER) cancer registry data to evaluate the causes of death in patients with non-metastatic HNSCC diagnosed between 1992 and 2005 who survived at least three years from diagnosis (long-term survivors). We used competing-risks proportional hazards regression to estimate probabilities of death from causes: HNSCC, second primary malignancy (SPM) excluding HNSCC, cardiovascular disease (CVD), and other causes.
Results
We identified 35,958 3-year survivors of HNSCC with a median age at diagnosis of 60 years (range 18 to 100 years) and a median follow-up of 7.7 years (range 3 to 18 years). There were 13,120 deaths during the study period. Death from any cause at 5 and 10 years was 15.4% (95% confidence interval [CI], 15.0% to 15.8%) and 41.0% (95% CI, 40.4% to 41.6%), respectively. There were 3,852 HNSCC deaths including both primary and subsequent head and neck tumors. The risk of death from HNSCC was greater in patients with nasopharynx or hypopharynx cancer and in patients with locally advanced disease. SPM was the leading cause of non-HNSCC death, and the most common sites of SPM death were lung (53%), esophagus (10%), and colorectal (5%) cancer.
Conclusion
Many long-term HNSCC survivors die from cancers other than HNSCC and from non-cancer causes. Routine follow-up care for HNSCC survivors should expand beyond surveillance for recurrence and new head and neck cancers.
doi:10.1002/cncr.28588
PMCID: PMC4101810  PMID: 24863390
competing mortality; head and neck cancer; survivorship; second primary malignancy; competing risk
21.  CHRONIC HEALTH CONDITIONS AND HEALTH-RELATED QUALITY OF LIFE IN SURVIVORS OF CHILDHOOD ACUTE MYELOID LEUKEMIA (AML): A Report from the Children's Oncology Group 
Pediatric blood & cancer  2013;61(4):729-736.
Background
Therapy for childhood acute myeloid leukemia (AML) has historically included chemotherapy with or without autologous bone marrow transplant (autoBMT) or allogeneic hematopoietic stem cell transplantation (alloBMT). We sought to compare health-related quality-of-life (HRQOL) outcomes between these treatment groups.
Procedure
Five-year survivors of AML diagnosed before age 21 and enrolled and treated from 1979 to 1995 on one of 4 national protocols were interviewed. These survivors or proxy caregivers completed a health questionnaire and an HRQOL measure.
Results
Of 180 survivors, 100 were treated with chemotherapy only, 26 with chemotherapy followed by autoBMT, and 54 with chemotherapy followed by alloBMT. Median age at interview was 20 years (range 8 to 39). Twenty-one percent reported a severe or life-threatening chronic health condition (chemotherapy-only 16% vs. autoBMT 21% vs. alloBMT 33%; p=0.02 for chemotherapy-only vs. alloBMT). Nearly all (95%) reported excellent, very good or good health. Reports of cancer-related pain and anxiety did not vary between groups. HRQOL scores among 136 participants ≥ 14 years of age were similar among groups and to the normative population, though alloBMT survivors had a lower physical mean summary score (49.1 alloBMT vs. 52.2 chemotherapy-only; p=0.03). Multivariate analyses showed the presence of severe chronic health conditions to be a strong predictor of physical but not mental mean summary scores.
Conclusions
Overall HRQOL scores were similar among treatment groups, although survivors reporting more health conditions or cancer-related pain had diminished HRQOL. Attention to chronic health conditions and management of cancer-related pain may improve QOL.
doi:10.1002/pbc.24881
PMCID: PMC4190066  PMID: 24285698
pediatric; bone marrow transplantation; acute myeloid leukemia; late effects; chronic health condition; quality of life
22.  Survivorship care plans: Is there buy-in from community oncology providers? 
Cancer  2013;120(5):722-730.
Background
The Institute of Medicine recommended that cancer survivors and their primary care providers receive survivorship care plans (SCPs) to summarize cancer treatment and plan ongoing care. However, the use of SCPs remains limited.
Methods
Oncology providers at 14 National Cancer Institute Community Cancer Centers Program (NCCCP) hospitals completed a survey regarding their perceptions of SCPs, including barriers to implementation, strategies for implementation, the role of oncology providers, and the importance of topics in SCPs (diagnosis, treatment, recommended ongoing care, and the aspects of ongoing care that the oncology practice will provide).
Results
Among 245 providers (70% response rate), 52% reported ever providing any component of an SCP to patients. The most widely reported barriers were lack of personnel and time to create SCPs (69% and 64% of respondents, respectively). The most widely endorsed strategy among those using SCPs was the use of a template with pre-specified fields; 94% of those who used templates found them helpful. For each topic of an SCP, while 87%-89% of oncology providers felt it was very important for primary care providers to receive the information, only 58%-65% of respondents felt it was very important for patients to receive the information. Further, 33%-38% of respondents had mixed feelings about whether it was oncology providers’ responsibility to provide SCPs.
Conclusions
Practices need additional resources to overcome barriers to implementing SCPs. We found resistance toward SCPs, particularly the perceived value for the survivor and the idea that oncology providers are responsible for SCP dissemination.
doi:10.1002/cncr.28472
PMCID: PMC3949150  PMID: 24327371
oncologist; survivorship; communication; quality of healthcare; primary healthcare
23.  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
24.  General Internists’ Preferences and Knowledge About the Care of Adult Survivors of Childhood Cancer 
Annals of internal medicine  2014;160(1):11-17.
Background
Adult childhood cancer survivors (CCSs) are at high risk for illness and premature death. Little is known about the physicians who provide their routine medical care.
Objective
To determine general internists’ self-reported attitudes and knowledge about the care of CCSs.
Design
Cross-sectional survey.
Setting
Mailed survey delivered between September 2011 and August 2012.
Participants
Random sample of 2000 U.S. general internists.
Measurements
Care preferences, comfort levels with caring for CCSs (7-point Likert scale: 1 = very uncomfortable, 7 = very comfortable), familiarity with available surveillance guidelines (7-point Likert scale: 1 = very unfamiliar, 7 = very familiar), and concordance with Children’s Oncology Group Long-Term Follow-Up Guidelines in response to a clinical vignette.
Results
The response rate was 61.6% (1110 of 1801). More than half the internists (51.1%) reported caring for at least 1 CCS; 72.0% of these internists never received a treatment summary. On average, internists were “somewhat uncomfortable” caring for survivors of Hodgkin lymphoma, acute lymphoblastic leukemia, and osteosarcoma. Internists reported being “somewhat unfamiliar” with available surveillance guidelines. In response to a clinical vignette about a young adult survivor of Hodgkin lymphoma, 90.6% of respondents did not appropriately recommend yearly breast cancer surveillance, 85.1% did not appropriately recommended cardiac surveillance, and 23.6% did not appropriately recommend yearly thyroid surveillance. Access to surveillance guidelines and treatment summaries were identified as the most useful resources for caring for CCSs.
Limitation
Findings, based on self-report, may not reflect actual clinical practice.
Conclusion
Although most general internists report involvement in the care of CCSs, many seem unfamiliar with available surveillance guidelines and would prefer to follow patients in collaboration with a cancer center.
Primary Funding Source
National Cancer Institute.
doi:10.7326/M13-1941
PMCID: PMC4337806  PMID: 24573662
25.  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

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