Biomarkers and Cognitive Function in Children and Adolescents During Maintenance Therapy for Leukemia.

OBJECTIVES: To explore the relationship between biomarkers of oxidative stress and inflmmation in cerebrospinal fluid (CSF) and cognitive function in children receiving maintenance therapy for acute lymphocytic leukemia (ALL). SAMPLE & SETTING: 30 participants aged 4-17 years receiving ALL maintenance therapy at two pediatric cancer centers in the United States. METHODS & VARIABLES: F2-isoprostane (F2-ISoP) and interleukin-8 (IL-8) were evaluated in CSF samples, and cognitive function measures were completed during the first and last cycles of ALL maintenance. The Flanker Inhibitory Control and Attention Test (Flanker) and Dimensional Change Card Sort were completed during the last cycle. RESULTS: During maintenance therapy, IL-8 decreased, and parent reports of children's cognitive function improved. Higher IL-8 was associated with better parent reports of children's cognitive function at each timepoint. Higher F2-ISoP levels were associated with lower Flanker scores. IMPLICATIONS FOR NURSING: F2-ISoP may be a useful biomarker in evaluating cognitive dysfunction in children with ALL and merits further investigation.

Childhood Cancer Symptom Cluster: Leukemia and Health-Related Quality of Life.

OBJECTIVES: To examine the relationship of the Childhood Cancer Symptom Cluster-Leukemia (CCSC-L) with health-related quality of life (HRQOL). SAMPLE & SETTING: 327 children receiving treatment for acute lymphoblastic leukemia from four pediatric oncology programs across the United States. METHODS & VARIABLES: Participants completed fatigue, sleep disturbance, pain, nausea, and depression symptom questionnaires at four time points; these symptoms comprised the CCSC-L. HRQOL was measured at the start of postinduction therapy and then at the start of maintenance therapy. Relationships between the CCSC-L and HRQOL scores were examined with longitudinal parallel-process modeling. RESULTS: The mean HRQOL significantly increased over time (p < 0.001). The CCSC-L had a significant negative association with HRQOL scores at the start of postinduction therapy (beta = -0.53, p < 0.005) and the start of maintenance therapy (beta = -0.33, p < 0.015). Participants with more severe symptoms in the CCSC-L over time had significantly lower HRQOL at the start of maintenance therapy (beta = -0.42, p < 0.005). IMPLICATIONS FOR NURSING: Nurses are pivotal in providing management strategies to minimize symptom severity that may improve HRQOL.

Patterns of Internet-based health information seeking in adult survivors of childhood cancer.

BACKGROUND: To assess where, when, and why survivors of childhood cancer seek health information. PROCEDURE: Data from the Childhood Cancer Survivor Study (CCSS) cohort (n = 1386) and Health Information National Trends Survey (n = 2385) were analyzed to determine the health information seeking strategies of childhood cancer survivors. Descriptive frequencies, χ2 analyses, t-tests, and multivariable logistic regression models were used. RESULTS: To seek health-related information for themselves, 54% (n = 742) of the childhood survivors reported using the Internet in the past 12 months, compared to 45% of the general population (adjusted OR: 2.76; 95% CI: 2.40-3.19). Childhood cancer survivors who used the Internet for health information were more likely to be female, between the ages of 18-34, have received some college education or be a college graduate, and report being in poor health. Although survivors were less likely than the general population to trust health information from the Internet (P < 0.01), they indicated that they would like a secure website that uses information from their medical records to provide individualized health-related information. CONCLUSION: The use of the Internet to access health information among the childhood cancer survivors was over 50%. Information on late effects was a high priority for most survivors, as was their interest in websites related to late effects and a website on patient information tailored to personal situations. Identification of factors associated with searching the Internet for cancer information may provide direction for development of effective cancer communication interventions for this at-risk population.

Health and well-being in adolescent survivors of early childhood cancer: a report from the Childhood Cancer Survivor Study.

OBJECTIVE: With the growing number of childhood cancer survivors in the US, it is important to assess the well-being of these individuals, particularly during the transitional phase of adolescence. Data about adolescent survivors' overall health and quality of life will help identify survivor subgroups most in need of targeted attention to successfully transition to adulthood. PARTICIPANTS AND METHODS: This ancillary study to the Childhood Cancer Survivor Study focused on children 15-19 years of age who had been diagnosed with cancer before the age of 4 years. A cohort of siblings of pediatric cancer survivors of the same ages served as a comparison sample. Adolescent health was assessed using the Child Health and Illness Profile-Adolescent Edition (CHIP-AE) survey. RESULTS: The teen survey was sent to 444 survivor teens and 189 siblings. Of these, 307(69%) survivors and 97 (51%) siblings completed and returned the survey. The overall health profiles of siblings and survivors were similar. Among survivors, females scored significantly below males on satisfaction, discomfort, and disorders domains. Survivors diagnosed with central nervous system tumors scored less favorably than leukemia survivors in the global domains of satisfaction and disorders. CONCLUSION: In general, adolescent survivors fare favorably compared to healthy siblings. However, identification of the subset of pediatric cancer survivors who are more vulnerable to medical and psychosocial disorders in adolescence provides the opportunity for design and implementation of intervention strategies that may improve quality of life.

Increasing rates of breast cancer and cardiac surveillance among high-risk survivors of childhood Hodgkin lymphoma following a mailed, one-page survivorship care plan.

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 27-55 years, 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 2 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 6 months after the intervention. RESULTS: The survivor participation (62/72; 86%) and 6-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 6 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.

Characteristics of responders to a request for a buccal cell specimen among survivors of childhood cancer and their siblings.

PURPOSE: Analysis of biological samples in large cohort studies may provide insight into the mechanism of, and risk factors for, disease onset and progression. METHODS: This study describes the methods used to collect biological samples from a large multi-center cohort of childhood cancer survivors and siblings of childhood cancer survivors and evaluates the predictors of a positive response among these individuals. RESULTS: Among survivors, female sex, white race/ethnicity, college graduation, never smoking, accessing the healthcare system in the past 2 years, and having a second malignant neoplasm were the strongest predictors of returning a sample. Among siblings, a similar demographic profile defined those likely to submit the requested sample. CONCLUSION: To reduce selection bias and increase the value of these samples for future analysis, additional phone calls and reminders targeting non-responders are needed to improve response rates among those least likely to respond to a single mailed request.

Behaviors associated with ultraviolet radiation exposure in a cohort of adult survivors of childhood and adolescent cancer: a report from the Childhood Cancer Survivor Study.

BACKGROUND: Previous research from the Childhood Cancer Survivor Study (CCSS) has shown that risk of skin cancer is strongly associated with exposure to radiation therapy. The potential role of ultraviolet radiation exposure in survivors has not been described. METHODS: The CCSS is a retrospective cohort study designed to investigate late effects among 5-year survivors of children and adolescents diagnosed with cancer between 1970-1986. Data regarding current sun protection behavior were collected on 9298 survivors and 2950 sibling controls. Median age at follow-up was 31 years (range, 17-54). RESULTS: In this cohort, childhood cancer survivors and siblings showed similar patterns of sunscreen use (67% vs 66%). Survivors were significantly less likely to report having sunbathed in the previous year (none vs any in previous year: relative risk (RR)=0.92; 95% confidence interval (CI)=0.89-0.95) or use artificial tanning (none vs any in previous year: RR=0.76; 95% CI=0.70-0.83). Compared with survivors without radiation therapy, survivors with radiation exposure showed increased use of sunscreen (RR=1.06; 95% CI=1.03-1.10), and less sunbathing (none vs any in previous year: RR=0.89; 95% CI=0.86-0.92) or artificial tanning (none vs any in previous year: RR=0.62; 95% CI=0.56-0.69). In adjusted multivariable analysis, statistically significant factors for regular sunscreen use in the past summer (vs never/rarely) in the survivor population were being female, having lighter skin complexions, having previously been examined for skin cancer, and having skin that burned when in the sun unprotected. CONCLUSIONS: Survivors of childhood cancer self-reported lower tanning practices than siblings. However, because of the potential increased risk of skin cancer from therapy-related exposures, future research should be directed at intervention studies to further reduce UV exposures.

Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study.

Second primary malignancies and premature death are a concern for patients surviving treatment for childhood lymphomas. We assessed mortality and second malignant neoplasms (SMNs) among 1082 5-year survivors of non-Hodgkin lymphoma (NHL) in the Childhood Cancer Survivor Study, a multi-institutional North American retrospective cohort study of cancer survivors diagnosed from 1970 to 1986. Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) were calculated using US population rates. Relative risks for death and solid tumor SMNs were calculated based on demographic, clinical, and treatment characteristics using Poisson regression models. There were 87 observed deaths (SMR = 4.2; 95% CI, 1.8-4.1) with elevated rates of death from solid tumors, leukemia, cardiac disease, and pneumonia. Risk for death remained elevated beyond 20 years after NHL. Risk factors for death from causes other than NHL included female sex (rate ratio [RR] = 3.4) and cardiac radiation therapy exposure (RR = 1.9). There were 27 solid tumor SMNs (SIR = 3.9; 95% CI, 2.6-5.7) with 3% cumulative incidence between 5 and 20 years after NHL diagnosis. Risk factors were female sex (RR = 3.1), mediastinal NHL disease (RR = 5.2), and breast irradiation (RR = 4.3). Survivors of childhood NHL, particularly those treated with chest RT, are at continued increased risk of early mortality and solid tumor SMNs.

Stroke as a late treatment effect of Hodgkin's Disease: a report from the Childhood Cancer Survivor Study.

PURPOSE: The objectives of this report are to examine the incidence of and risk factors for stroke among childhood Hodgkin's disease (HD) survivors. PATIENTS AND METHODS: The Childhood Cancer Survivor Study is a multi-institutional cohort study of more than 5-year cancer survivors diagnosed between 1970 and 1986 and a sibling comparison group. Incidence rates of stroke among HD survivors (n = 1,926) and siblings (n = 3,846) were calculated and compared. Cox proportional hazards models were used to estimate the hazard ratios, reported as relative risks (RR), of developing stroke between HD survivors and siblings. RESULTS: Nine siblings reported a stroke, for an incidence of 8.00 per 100,000 person-years (95% CI, 3.85 to 14.43 per 100,000 person-years). Twenty-four HD survivors reported a stroke. The incidence of late-occurring stroke among HD survivors was 83.6 per 100,000 person-years (95% CI, 54.5 to 121.7 per 100,000 person-years). The RR of stroke among HD survivors was 4.32 (95% CI, 2.01 to 9.29; P = .0002). All 24 survivors received mantle radiation exposure (median dose, 40 Gy). The incidence of late-occurring stroke among HD survivors treated with mantle radiation was 109.8 per 100,000 person-years (95% CI, 70.8 to 161.1 per 100,000 person-years). The RR of late-occurring stroke among HD survivors treated with mantle radiation was 5.62 (95% CI, 2.59 to 12.25; P < .0001). CONCLUSION: Survivors of childhood HD are at increased risk of stroke. Mantle radiation exposure is strongly associated with subsequent stroke. Potential mechanisms may include carotid artery disease or cardiac valvular disease.

Nonmelanoma skin cancer in survivors of childhood and adolescent cancer: a report from the childhood cancer survivor study.

PURPOSE: Nonmelanoma skin cancer (NMSC) has become the most common type of cancer in many populations throughout the world. Ultraviolet and ionizing radiation are known risk factors. Because NMSCs are rarely lethal and most cancer registries do not routinely report data regarding these cancers, they have received little attention in studies evaluating long-term effects of cancer therapy. This article reports on the occurrence of secondary NMSC as a long-term effect of cancer therapy in survivors of childhood cancer. PATIENTS AND METHODS: The Childhood Cancer Survivor Study (CCSS) is a cohort study of 5-year survivors of childhood and adolescent cancer from 25 participating institutions in North America. NMSC patients were defined by a history of basal cell or squamous cell carcinoma of the skin after primary malignancy treatment. Demographic and treatment data were collected and analyzed. RESULTS: Among the 13,132 eligible CCSS participants, 213 have reported NMSC; 99 patients (46%) have had multiple occurrences. Median age of occurrence was 31 years (range, 7 to 46 years). Location of NMSC included head and neck (43%), back (24%), chest (22%), abdomen and pelvis (5%), extremity (3%), and unknown (4%). Ninety percent of patients had previously received radiation therapy (RT); 90% of tumors occurred within the RT field. RT was associated with a 6.3-fold increase in risk (95% CI, 3.5- to 11.3-fold). CONCLUSION: Long-term survivors of childhood and adolescent cancer who were treated with RT are at highest risk for developing NMSC. Educational efforts need to be directed to this population to facilitate early diagnosis of NMSC and reduction in sun exposure.

Characteristics of childhood cancer survivors predicted their successful tracing.

OBJECTIVE: The Childhood Cancer Survivor Study is a retrospective cohort study that was initiated to explore late effects of childhood cancer and its therapies. We evaluated the characteristics of those requiring tracing and factors that influenced tracing success. STUDY DESIGN AND SETTING: Medical record review identified 20,051 eligible individuals from 25 institutions in the United States and Canada. Of these, 13,021 had a current address in the medical record at the treating institution, and 7,030 had an incorrect address and required tracing by a commercial firm. RESULTS: Tracing was successful for 4,188 persons (60%). Younger age at contact, shorter length of time since last contact, having a middle initial available, an uncommon last name, and socioeconomic factors were found to predict successful tracing. Compared to those with a current address available in medical records, subjects successfully traced were less likely to have accessed health care during the previous 2 years; and more likely to be current smokers, obese, and to report moderate to severe impairments (pain, functional status, and activity). CONCLUSION: These findings provide an empirical basis concerning determinants and predictors of tracing success. If tracing had not been performed in this cohort, spurious associations may have been obtained for some health outcomes of interest.

XRCC1 and glutathione-S-transferase gene polymorphisms and susceptibility to radiotherapy-related malignancies in survivors of Hodgkin disease.

BACKGROUND: One of the most serious late effects of treatment for childhood cancer is the occurrence of subsequent malignancy. Survivors of Hodgkin disease (HD), in particular, have been shown to be at high risk of subsequent malignancy, the occurrence of which has been associated strongly with exposure to radiotherapy. METHODS: In the current study, the authors investigated the association between polymorphisms in 3 genes--glutathione-S-transferase M1 (GSTM1), glutathione-S-transferase T1 (GSTT1), and XRCC1, with roles in protection from a variety of DNA-damaging agents-and the risk of subsequent malignancy in 650 survivors of HD enrolled in the Childhood Cancer Survivor Study who had received radiotherapy. RESULTS: Individuals lacking GSTM1 but not GSTT1 were at increased risk of any subsequent malignancy (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.0-2.3), and for subsequent cancer within the radiation field (OR, 1.4; 95% CI, 0.9-2.1). A nonsignificant increased risk of thyroid carcinoma was observed in individuals lacking either GSTM1 (OR, 2.9; 95% CI, 0.8-10.9) or GSTT1 (OR, 3.7; 95% CI, 0.6-23.5). Individuals having the genotype of the arginine/glutamine polymorphism at codon 399 in the XRCC1 gene (R399) showed a nonsignificant increased risk of breast carcinoma compared with those without (OR, 1.4; 95% CI, 0.7-2.7), and a nonsignificant decreased risk against a subsequent thyroid carcinoma (OR, 0.6; 95% CI, 0.2-1.6). No differences in genotype frequencies were observed between survivors with basal cell carcinoma when compared with survivors without a subsequent cancer. CONCLUSIONS: These data illustrated the potential value of incorporating the collection of genomic DNA in longitudinal cohort studies of populations with well defined, potentially carcinogenic exposures. Evaluation of additional genetic polymorphisms in this cohort may help define genes that influence individual sensitivity to radiotherapy.

Factors that affect final height and change in height standard deviation scores in survivors of childhood cancer treated with growth hormone: a report from the childhood cancer survivor study.

GH deficiency is a common late complication in survivors of pediatric malignancies, particularly those who are treated with radiation (RT) to the hypothalamic-pituitary region. Nonetheless, few reports have assessed final height outcomes in survivors treated with GH. In the present study, we investigated which patient and treatment variables correlate with final height and change in height sd score (SDS) in a large cohort of cancer survivors treated with GH. We previously identified 361 participants in the multicenter Childhood Cancer Survivor Study who were treated with GH. Final height data were available in 183 survivors (120 males). Diagnoses included: central nervous system tumors (n = 90), acute leukemia (n = 64), soft tissue sarcomas (n = 23), and miscellaneous (n = 6). The median age at diagnosis of the primary cancer was 4.6 yr, and the median age at start of GH treatment was 11.3 yr. Mean height SDS at start of GH therapy was -2.03 +/- 0.8, and the mean final height SDS was -1.48 +/- 0.10 (P < 0.001). Final height SDS was positively associated with target height and dose of GH but negatively associated with the presence of concomitant endocrinopathies and dose of spinal RT. Change in height SDS (start of GH-final height) was positively associated with male gender, younger bone age at start of GH, and dose of GH; presence of concomitant endocrinopathies and dose of spinal RT were negatively associated with change in height SDS. Risk factors associated with a final height of -2.0 sd or less included lower doses of GH and exposure to higher doses of spinal RT. Thus, to maximize final height, our findings emphasize the importance of beginning GH therapy at the earliest bone age that is clinically feasible; treating with conventional higher doses of GH; and, when possible, minimizing the dose of spinal RT.

An examination of the dental utilization practices of adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

OBJECTIVES: This study characterized the self-reported dental utilization practice of long-term survivors of childhood cancer, a group at increased risk for treatment-induced dental abnormalities. METHODS: 9,434 survivors and a comparison group of 3,858 siblings completed a 289-item survey that included a question on when their last dental visit occurred. RESULTS: Within the last year 60.4 percent of survivors reported a dental visit. The groups less likely to report a recent dental visit include minority subjects, subjects with low levels of educational attainment, subjects with annual household incomes < dollar 20,000, and those without health insurance. No significant differences between survivors and siblings were seen. Male survivors exposed to cranial radiation were slightly more likely than other male survivors to report a recent dental visit (OR = 1.27, 95% CI = 1.12, 1.44). CONCLUSIONS: The dental utilization practices among survivors of childhood cancer are below recommended levels, even among those at highest risk for dental abnormalities.

Utilization of special education services and educational attainment among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

BACKGROUND: The objective of the current report was to compare the self-reported rates of special education (SE) and educational attainment among specific groups of childhood cancer survivors and a random sample of sibling controls. METHODS: The Childhood Cancer Survivor Study is a retrospective cohort of individuals who were diagnosed with a cancer in childhood and survived at least 5 years postdiagnosis. This analysis includes 12,430 survivors and 3410 full siblings. Reported use of SE services and educational attainment were analyzed within subgroups defined by type of cancer, age at diagnosis, and type of treatment. RESULTS: The use of SE services was reported in 23% of survivors and 8% of siblings, with the greatest differences observed among survivors who were diagnosed before age 6 years, most notably survivors of central nervous system (CNS) tumors (odds ratio [OR], 18.8; 95% confidence interval [95%CI], 15.01-23.49), leukemia (OR, 4.4; 95%CI, 3.75-5.16), and Hodgkin disease (OR, 4.4; 95%CI, 2.64-7.24). It was found that intrathecal methotrexate (IT MTX) and cranial radiation (CRT), administered alone or in combination, significantly increased the likelihood that a survivor would use SE (IT MTX only: OR, 1.3; 95%CI, 1.09-1.78; CRT only: OR, 7.2; 95%CI, 6.14-8.39; IT MTX and CRT combined: OR, 2.6; 95%CI, 2.30-2.95). A positive dose response was identified between higher doses of CRT and use of SE. It was determined that survivors of leukemia (OR, 1.6; 95%CI, 1.23-2.16), CNS tumors (OR, 2.7; 95%CI, 1.92-3.81), non-Hodgkin lymphoma (OR, 1.8; 95%CI, 1.15-2.78), and neuroblastoma (OR, 1.7; 95%CI, 1.14-2.61) were significantly less likely to finish high school compared with siblings; however, when survivors received SE services, risk estimates approximated those of the sibling SE population. CONCLUSIONS: Children who are diagnosed with cancer should be followed closely during and after treatment to identify early signs of learning disabilities and to maximize intervention strategies for the successful completion of scholastic goals.