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1.  Relevance of Historical Therapeutic Approaches to the Contemporary Treatment of Pediatric Solid Tumors 
Pediatric blood & cancer  2013;60(7):10.1002/pbc.24487.
Children with solid tumors, most of which are malignant, have an excellent prognosis when treated on contemporary regimens. These regimens, which incorporate chemotherapeutic agents and treatment modalities used for many decades, have evolved to improve relapse-free survival and reduce long-term toxicity. This review discusses the evolution of the treatment regimens employed for management of the most common solid tumors, emphasizing the similarities between contemporary and historical regimens. These similarities allow the use of historical patient cohorts to identify the late effects of successful therapy and to evaluate remedial interventions for these adverse effects.
PMCID: PMC3810072  PMID: 23418018
Childhood cancer therapy; late effects; long-term follow-up
2.  Parental nutrient intake and risk of retinoblastoma resulting from new germline RB1 mutation 
Cancer causes & control : CCC  2012;24(2):343-355.
We conducted a case-control study to examine the role of parents’ nutrient intake before their child’s conception in the child’s risk of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation.
Parents of 206 cases from 9 North American institutions and 269 friend and relative controls participated; fathers of 182 cases and 223 controls and mothers of 202 cases and 260 controls provided useable information in telephone interviews on their diet in the year before the child’s conception. We also asked parents about supplements, a significant source of nutrients in users.
Father’s intake of dairy-associated nutrients and his use of calcium supplements were associated with decreased risk while his intake of copper, manganese, and vitamin E was associated with increased risk. Mother’s use of multivitamins close to conception was associated with lower risk as was her intake of several micronutrients found in these supplements. In analyses to elucidate the primary factor from multiple correlated factors, the most robust findings were for father’s calcium intake (adjusted OR=0.46 – 0.63 for 700 mg increase) and calcium supplement use (OR=0.35 – 0.41) and mother’s multivitamin use (ORs 0.28 – 0.48).
There are few directly relevant studies but some data indirectly support the biologic plausibility of the inverse associations with father’s calcium intake and mother’s use of multivitamins; however, we cannot rule out contributions of bias, confounding, or chance. Our findings provide a starting point for further investigation of diet in the etiology of retinoblastoma and new germline mutation generally.
PMCID: PMC3557550  PMID: 23224327
germline mutation; diet; retinoblastoma; case-control studies; pediatric cancer
3.  Risk Factors Associated with Secondary Sarcomas in Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study 
Childhood cancer survivors have an increased risk of secondary sarcomas. To better identify those at risk, the relationship between therapeutic dose of chemotherapy and radiation and secondary sarcoma should be quantified.
Methods and Materials
We conducted a nested case-control study of secondary sarcomas (105 cases, 422 matched controls) in a cohort of 14,372 childhood cancer survivors. Radiation dose at the second malignant neoplasm (SMN) site and use of chemotherapy were estimated from detailed review of medical records. Odds ratios (ORs) and 95% confidence intervals were estimated by conditional logistic regression. Excess odds ratio (EOR) was modeled as a function of radiation dose, chemotherapy, and host factors.
Sarcomas occurred a median of 11.8 years (range: 5.3-31.3 years) from original diagnosis. Any exposure to radiation was associated with increased risk of subsequent sarcoma (OR = 4.1, 95% CI = 1.8-9.5). A dose-response relation was observed, with elevated risks at doses between 10 - 29.9 Gy (OR = 15.6, 95% CI = 4.5-53.9), 30 - 49.9 Gy (OR = 16.0, 95% CI 3.8-67.8) and >50 Gy (OR = 114.1, 95% CI 13.5-964.8). Anthracycline exposure was associated with sarcoma risk (OR = 3.5, 95% CI = 1.6-7.7) adjusting for radiation dose, other chemotherapy, and primary cancer. Adjusting for treatment, survivors with a first diagnosis of Hodgkin lymphoma (HL; OR=10.7, 95% CI = 3.1-37.4) or primary sarcoma (OR=8.4, 95% CI = 3.2-22.3) were more likely to develop a sarcoma.
Of the risk factors evaluated, radiation exposure was the most important for secondary sarcoma development in childhood cancer survivors; anthracycline chemotherapy exposure was also associated with increased risk.
PMCID: PMC3423483  PMID: 22795729
Childhood cancer survivors; secondary sarcomas; radiation late effects
4.  A Revision of the Intensity of Treatment Rating Scale: Classifying the Intensity of Pediatric Cancer Treatment 
Pediatric blood & cancer  2011;59(1):96-99.
We previously developed a reliable and valid method for classifying the intensity of pediatric cancer treatment. The Intensity of Treatment Rating Scale (ITR-2.0) [1] classifies treatments into four operationally defined levels of intensity and is completed by pediatric oncology specialists based on diagnosis, stage, and treatment data from the medical record. Experience with the ITR-2.0 and recent changes in treatment protocols indicated the need for a minor revision and revalidation.
Five criterion raters reviewed the prior items, independently proposing additions and/or changes in the classification of diseases/treatments. Subsequent to a group discussion of the proposed changes, a revised 43 item ITR was evaluated. Pediatric oncologists (n = 47) completed a two-part online questionnaire. Validity of the classifications was determined by the oncologists classifying each disease/treatment into one of the four levels of intensity. Inter-rater reliability was calculated by having each oncologist classify the treatments of 12 sample patients using the new version which we call the ITR-3.
Agreement between median ratings of the 43 items for the pediatric oncologists and the criterion raters was high (r = 0.88). The median of the raters was either identical (81%) with the criterion ratings or discrepant by one level. Inter-rater reliability was very high when using the ITR-3 to classify 12 sample patients, with a median agreement of 0.90 and an intraclass correlation coefficient (rICC = 0.86).
With these minor modifications and updates, the ITR-3 remains a reliable and valid method for classifying pediatric oncology treatment protocols.
PMCID: PMC3223269  PMID: 21858914
pediatric oncology; measurement; treatment intensity; rating
Annals of internal medicine  2012;156(11):757-260.
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.
To determine the risk and associated risk factors for gastrointestinal subsequent malignant neoplasms (SMN) in childhood cancer survivors.
Retrospective cohort study.
The Childhood Cancer Survivor Study, a multi-center study of childhood cancer survivors diagnosed between 1970 and 1986.
14,358 survivors of a malignancy diagnosed at < 21 years who had survived for 5 or more years from initial diagnosis.
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.
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.
This cohort has not yet attained an age at which gastrointestinal malignancy risk is greatest.
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.
PMCID: PMC3554254  PMID: 22665813
6.  Chemotherapy and thyroid cancer risk: A report from the Childhood Cancer Survivor Study 
While ionizing radiation is an established environmental risk factor for thyroid cancer, the effect of chemotherapy drugs on thyroid cancer risk remains unclear. We evaluated the chemotherapy-related risk of thyroid cancer in childhood cancer survivors, and the possible joint effects of chemotherapy and radiotherapy.
The study included 12,547 five-year survivors of childhood cancer diagnosed during 1970 through 1986. Chemotherapy and radiotherapy information was obtained from medical records, and radiation dose was estimated to the thyroid gland. Cumulative incidence and relative risks were calculated using life-table methods and Poisson regression. Chemotherapy-related risks were evaluated separately by categories of radiation dose.
Histologically confirmed thyroid cancer occurred in 119 patients. Thirty years after the first childhood cancer treatment, the cumulative incidence of thyroid cancer was 1.3% (95% CI, 1.0–1.6) for females and 0.6% (0.4–0.8) for males. Among patients with thyroid radiation doses ≤ 20 Gy, treatment with alkylating agents was associated with a significant 2.4-fold increased risk of thyroid cancer (95% CI, 1.3–4.5; P = 0.002). Chemotherapy risks decreased as radiation dose increased, with a significant decrease for patients treated with alkylating agents (P-trend = 0.03). No chemotherapy-related risk was evident for thyroid radiation doses >20 Gy.
Treatments with alkylating agents increased thyroid cancer risk, but only in the radiation dose range under 20 Gy, where cell sparing likely predominates over cell killing.
Our study adds to the evidence for chemotherapy agent-specific increased risks of thyroid cancer, which to date, were mainly thought to be related to prior radiotherapy.
PMCID: PMC3253948  PMID: 22028399
Thyroid cancer; second cancer; chemotherapy; radiation risk; cohort study
7.  Medical radiation exposure and risk of retinoblastoma resulting from new germline RB1 mutation 
Although ionizing radiation induces germline mutations in animals, human studies of radiation-exposed populations have not detected an effect. We conducted a case-control study of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation, to investigate gonadal radiation exposure of parents from medical sources before their child's conception. Parents of 206 cases from 9 North American institutions and 269 controls participated; fathers of 184 cases and 223 friend and relative controls and mothers of 204 cases and 260 controls provided information in telephone interviews on their medical radiation exposure. Cases provided DNA for RB1 mutation testing. Of common procedures, lower GI series conferred the highest estimated dose to testes and ovaries. Paternal history of lower GI series was associated with increased risk of retinoblastoma in the child (matched odds ratio (OR)=3.6, 95% confidence interval (CI) 1.2, 11.2, 2-sided P=0.02), as was estimated total testicular dose from all procedures combined (OR for highest dose=3.9, 95% CI 1.2, 14.4, P =0.02). Maternal history of lower GI series was also associated with increased risk (OR=7.6, 95% CI 2.8, 20.7, P <0.001) as was estimated total dose (OR for highest dose=3.0, 95% CI 1.4, 7.0, P =0.005). The RB1 mutation spectrum in cases of exposed parents did not differ from that of other cases. Some animal and human data support our findings of an association of gonadal radiation exposure in men and women with new germline RB1 mutation detectable in their children, although bias, confounding, and/or chance may also explain the results.
PMCID: PMC3124307  PMID: 20648557
germline mutation; ionizing radiation; retinoblastoma; case-control studies; pediatric cancer
8.  Risk of Second Primary Thyroid Cancer after Radiotherapy for a Childhood Cancer in a Large Cohort Study: An Update from the Childhood Cancer Survivor Study 
Radiation research  2010;174(6):741-752.
Previous studies have indicated that thyroid cancer risk after a first childhood malignancy is curvilinear with radiation dose, increasing at low to moderate doses and decreasing at high doses. Understanding factors that modify the radiation dose response over the entire therapeutic dose range is challenging and requires large numbers of subjects. We quantified the long-term risk of thyroid cancer associated with radiation treatment among 12,547 5-year survivors of a childhood cancer (leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma, central nervous system cancer, soft tissue sarcoma, kidney cancer, bone cancer, neuroblastoma) diagnosed between 1970 and 1986 in the Childhood Cancer Survivor Study using the most current cohort follow-up to 2005. There were 119 subsequent pathologically confirmed thyroid cancer cases, and individual radiation doses to the thyroid gland were estimated for the entire cohort. This cohort study builds on the previous case-control study in this population (69 thyroid cancer cases with follow-up to 2000) by allowing the evaluation of both relative and absolute risks. Poisson regression analyses were used to calculate standardized incidence ratios (SIR), excess relative risks (ERR) and excess absolute risks (EAR) of thyroid cancer associated with radiation dose. Other factors such as sex, type of first cancer, attained age, age at exposure to radiation, time since exposure to radiation, and chemotherapy (yes/no) were assessed for their effect on the linear and exponential quadratic terms describing the dose–response relationship. Similar to the previous analysis, thyroid cancer risk increased linearly with radiation dose up to approximately 20 Gy, where the relative risk peaked at 14.6-fold (95% CI, 6.8–31.5). At thyroid radiation doses >20 Gy, a downturn in the dose–response relationship was observed. The ERR model that best fit the data was linear-exponential quadratic. We found that age at exposure modified the ERR linear dose term (higher radiation risk with younger age) (P < 0.001) and that sex (higher radiation risk among females) (P = 0.008) and time since exposure (higher radiation risk with longer time) (P < 0.001) modified the EAR linear dose term. None of these factors modified the exponential quadratic (high dose) term. Sex, age at exposure and time since exposure were found to be significant modifiers of the radiation-related risk of thyroid cancer and as such are important factors to account for in clinical follow-up and thyroid cancer risk estimation among childhood cancer survivors.
PMCID: PMC3080023  PMID: 21128798
9.  Subsequent Neoplasms in 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study 
The occurrence of subsequent neoplasms has direct impact on the quantity and quality of life in cancer survivors. We have expanded our analysis of these events in the Childhood Cancer Survivor Study (CCSS) to better understand the occurrence of these events as the survivor population ages.
The incidence of and risk for subsequent neoplasms occurring 5 years or more after the childhood cancer diagnosis were determined among 14 359 5-year survivors in the CCSS who were treated from 1970 through 1986 and who were at a median age of 30 years (range = 5–56 years) for this analysis. At 30 years after childhood cancer diagnosis, we calculated cumulative incidence at 30 years of subsequent neoplasms and calculated standardized incidence ratios (SIRs), excess absolute risks (EARs) for invasive second malignant neoplasms, and relative risks for subsequent neoplasms by use of multivariable Poisson regression.
Among 14 359 5-year survivors, 1402 subsequently developed 2703 neoplasms. Cumulative incidence at 30 years after the childhood cancer diagnosis was 20.5% (95% confidence interval [CI] = 19.1% to 21.8%) for all subsequent neoplasms, 7.9% (95% CI = 7.2% to 8.5%) for second malignant neoplasms (excluding nonmelanoma skin cancer), 9.1% (95% CI = 8.1% to 10.1%) for nonmelanoma skin cancer, and 3.1% (95% CI = 2.5% to 3.8%) for meningioma. Excess risk was evident for all primary diagnoses (EAR = 2.6 per 1000 person-years, 95% CI = 2.4 to 2.9 per 1000 person-years; SIR = 6.0, 95% CI = 5.5 to 6.4), with the highest being for Hodgkin lymphoma (SIR = 8.7, 95% CI = 7.7 to 9.8) and Ewing sarcoma (SIR = 8.5, 95% CI = 6.2 to 11.7). In the Poisson multivariable analysis, female sex, older age at diagnosis, earlier treatment era, diagnosis of Hodgkin lymphoma, and treatment with radiation therapy were associated with increased risk of subsequent neoplasm.
As childhood cancer survivors progress through adulthood, risk of subsequent neoplasms increases. Patients surviving Hodgkin lymphoma are at greatest risk. There is no evidence of risk reduction with increasing duration of follow-up.
PMCID: PMC2907408  PMID: 20634481
10.  Late Recurrence in Pediatric Cancer: A Report From the Childhood Cancer Survivor Study 
An increasing percentage of childhood cancer patients are surviving their disease, but there is limited research on late recurrence. We sought to estimate late recurrence rates for the most common pediatric cancers and to determine risk factors for late recurrence.
The incidence of late recurrences, or first recurrences that occurred more than 5 years after diagnosis, was analyzed for the most common pediatric cancers using data from the Childhood Cancer Survivor Study, a retrospective cohort of 5-year survivors of childhood and adolescent cancers who were diagnosed between 1970 and 1986. A total of 12 795 survivors with no history of recurrence within 5 years after their original cancer diagnosis were included in the analysis, with a total of 217 127 person-years of follow-up. Cumulative incidence of late recurrence at 5, 10, 15, and 20 years after diagnosis was calculated using death as a competing risk. Adjusted relative rates of late recurrence were obtained using multivariable Poisson regression. All statistical tests were two-sided.
Overall, 5-year survivors of pediatric cancers experienced a cumulative incidence of recurrent disease of 4.4%, 5.6%, and 6.2% at 10, 15, and 20 years, respectively. Cumulative incidence varied by diagnosis: Survivors of Ewing sarcoma and astrocytoma had the highest 20-year cumulative incidences at 13.0% (95% confidence interval [CI] = 9.4 to 16.5) and 14.4% (95% CI = 12.3 to 16.6), respectively. In multivariable analysis, the greatest risk factors for late recurrence included diagnosis, combination treatment with chemotherapy and radiation, earlier treatment era, and fewer years since diagnosis (P < .001 for all).
Late recurrence is a risk for some pediatric cancers. By understanding diagnosis-specific risks, patients, families, and their medical providers can be better informed of the probability of cure.
PMCID: PMC2800799  PMID: 19966206
11.  Behaviors Associated with Ultraviolet Radiation Exposure in a Cohort of Adult Survivors of Childhood and Adolescent Cancer. A Report from the Childhood Cancer Survivor Study1 
Cancer  2009;115(18 Suppl):4374-4384.
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.
Participants 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 9,298 survivors and 2,950 sibling controls. Median age at follow-up was 31 years (range: 17–54).
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: RR=0.92, 95%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 to 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.
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.
PMCID: PMC2778206  PMID: 19731349
Skin cancer; sun protection behaviors; survivor; radiation; siblings
12.  Radiation Dose and Breast Cancer Risk in the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2009;27(24):3901-3907.
The purpose of this study was to quantify the risk of breast cancer in relation to radiation dose and chemotherapy among survivors of childhood cancer.
We conducted a case-control study of breast cancer in a cohort of 6,647 women who were 5-year survivors of childhood cancer and who were treated during 1970 through 1986. One hundred twenty patients with histologically confirmed breast cancer were identified and were individually matched to four selected controls on age at initial cancer and time since initial cancer. Medical physicists estimated radiation dose to the breast tumor site and ovaries on the basis of medical records.
The odds ratio for breast cancer increased linearly with radiation dose, and it reached 11-fold for local breast doses of approximately 40 Gy relative to no radiation (P for trend < .0001). Risk associated with breast irradiation was sharply reduced among women who received 5 Gy or more to the ovaries (P = .002). The excess odds ratio per Gy was 0.36 for those who received ovarian doses less than 5 Gy and was 0.06 for those who received higher doses. Radiation-related risk did not vary significantly by age at exposure. Borderline significantly elevated risks were seen for doxorubicin, dactinomycin, dacarbazine, and carmustine.
Results confirm the radiation sensitivity of the breast in girls age 10 to 20 years but do not demonstrate a strong effect of age at exposure within this range. Irradiation of the ovaries at doses greater than 5 Gy seems to lessen the carcinogenic effects of breast irradiation, most likely by reducing exposure of radiation-damaged breast cells to stimulating effects of ovarian hormones.
PMCID: PMC2734395  PMID: 19620485
13.  The Childhood Cancer Survivor Study: A National Cancer Institute–Supported Resource for Outcome and Intervention Research 
Journal of Clinical Oncology  2009;27(14):2308-2318.
Survival for childhood cancer has increased dramatically over the last 40 years with 5-year survival rates now approaching 80%. For many diagnostic groups, rapid increases in survival began in the 1970s with the broader introduction of multimodality approaches, often including combination chemotherapy with or without radiation therapy. With this increase in rates of survivorship has come the recognition that survivors are at risk for adverse health and quality-of-life outcomes, with risk being influenced by host-, disease-, and treatment-related factors. In 1994, the US National Cancer Institute funded the Childhood Cancer Survivor Study, a multi-institutional research initiative designed to establish a large and extensively characterized cohort of more than 14,000 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. This ongoing study, which reflects the single most comprehensive body of information ever assembled on childhood and adolescent cancer survivors, provides a dynamic framework and resource to investigate current and future questions about childhood cancer survivors.
PMCID: PMC2677920  PMID: 19364948
14.  High-Risk Populations Identified in Childhood Cancer Survivor Study Investigations: Implications for Risk-Based Surveillance 
Journal of Clinical Oncology  2009;27(14):2405-2414.
Childhood cancer survivors often experience complications related to cancer and its treatment that may adversely affect quality of life and increase the risk of premature death. The purpose of this manuscript is to review how data derived from Childhood Cancer Survivor Study (CCSS) investigations have facilitated identification of childhood cancer survivor populations at high risk for specific organ toxicity and secondary carcinogenesis and how this has informed clinical screening practices. Articles previously published that used the resource of the CCSS to identify risk factors for specific organ toxicity and subsequent cancers were reviewed and results summarized. CCSS investigations have characterized specific groups to be at highest risk of morbidity related to endocrine and reproductive dysfunction, pulmonary toxicity, cerebrovascular injury, neurologic and neurosensory sequelae, and subsequent neoplasms. Factors influencing risk for specific outcomes related to the individual survivor (eg, sex, race/ethnicity, age at diagnosis, attained age), sociodemographic status (eg, education, household income, health insurance) and cancer history (eg, diagnosis, treatment, time from diagnosis) have been consistently identified. These CCSS investigations that clarify risk for treatment complications related to specific treatment modalities, cumulative dose exposures, and sociodemographic factors identify profiles of survivors at high risk for cancer-related morbidity who deserve heightened surveillance to optimize outcomes after treatment for childhood cancer.
PMCID: PMC2677926  PMID: 19289611
15.  Second Neoplasms in Survivors of Childhood Cancer: Findings From the Childhood Cancer Survivor Study Cohort 
Journal of Clinical Oncology  2009;27(14):2356-2362.
To review the reports of subsequent neoplasms (SNs) in the Childhood Cancer Survivor Study (CCSS) cohort that were made through January 1, 2006, and published before July 31, 2008, and to discuss the host-, disease-, and therapy-related risk factors associated with SNs.
Patients and Methods
SNs were ascertained by survivor self-reports and subsequently confirmed by pathology findings or medical record review. Cumulative incidence of SNs and standardized incidence ratios for second malignant neoplasms (SMNs) were calculated. The impact of host-, disease-, and therapy-related risk factors was evaluated by Poisson regression.
Among 14,358 cohort members, 730 reported 802 SMNs (excluding nonmelanoma skin cancers). This represents a 2.3-fold increase in the number of SMNs over that reported in the first comprehensive analysis of SMNs in the CCSS cohort, which was done 7 years ago. In addition, 66 cases of meningioma and 1,007 cases of nonmelanoma skin cancer were diagnosed. The 30-year cumulative incidence of SMNs was 9.3% and that of nonmelanoma skin cancer was 6.9%. Risk of SNs remains elevated for more than 20 years of follow-up for all primary childhood cancer diagnoses. In multivariate analyses, risks differ by SN subtype, but include radiotherapy, age at diagnosis, sex, family history of cancer, and primary childhood cancer diagnosis. Female survivors whose primary childhood cancer diagnosis was Hodgkin's lymphoma or sarcoma and who received radiotherapy are at particularly increased risk. Analyses of risk associated with radiotherapy demonstrated different dose-response curves for specific SNs.
Childhood cancer survivors are at a substantial and increasing risk for SNs, including nonmelanoma skin cancer and meningiomas. Health care professionals should understand the magnitude of these risks to provide individuals with appropriate counseling and follow-up.
PMCID: PMC2738645  PMID: 19255307
16.  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.
Women treated with therapeutic chest radiation may develop breast cancer.
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 include study heterogeneity, design and small sample size.
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.
PMCID: PMC2857928  PMID: 20368650
17.  Impact of CNS Treatment on Mood in Adult Survivors of Childhood Leukemia: A Report From the Children’s Cancer Group 
This study assessed the relationship between CNS treatment and psychologic mood using the Profile of Moods State (POMS), a standardized measure of affect, among a large sample of young adult survivors of childhood acute lymphoblastic leukemia (ALL; N = 555).
Patients and Methods
Survivors of childhood ALL (ages 18 to 33 years at study entry) participated in a structured telephone interview eliciting demographic, health, and behavioral data and the POMS. Treatment data included total dose of CNS irradiation (CRT) and intrathecal methotrexate (MTX) obtained from medical records.
Mood disturbance was reported by 24% of survivors. High-dose CRT and MTX predicted disturbance rates modestly and primarily in combination with education variables. Interactions between educational achievement, a history of attendance in special education classes, and sex were better predictors than treatment type or dose. Non-white males, those younger than 12.5 years of age at diagnosis, and those with negative perceptions of current health and cancer’s impact on employment were also at greater risk for mood disturbance (P < .01 to .001).
Although most survivors are doing well psychologically, a subset of long-term survivors show potentially serious mood disturbance. Mood disturbance seems to be a function of interactions between preexisting individual difference variables (eg, sex, race/ethnicity), treatment factors, and posttreatment educational experiences. Prevention strategies aimed at childhood cancer survivors at greatest risk for mood disturbance may be improved by focus on posttreatment psychosocial and educational supports.
PMCID: PMC1459335  PMID: 14645430
To evaluate individual tumor control following chemoreduction for retinoblastoma.
Prospective nonrandomized single-center case series of 457 retinoblastomas managed with six cycles of chemoreduction (vincristine, etoposide, and carboplatin). The tumors were then managed with chemoreduction alone (group A) or chemoreduction combined with thermotherapy (group B), cryotherapy (group C), or both thermotherapy and cryotherapy (group D). The main outcome measure was development of tumor recurrence.
Of 457 retinoblastomas, 63 (14%) were in group A, 256 (56%) in group B, 127 (28%) in group C, and 11 (2%) in group D. The tumor was located in the macula in 33 (52%) of group A, 109 (43%) of group B, 3 (2%) of group C, and 1 (9%) of group D. Using Kaplan-Meier analysis, recurrence of the individual retinoblastoma at 7 years was found in 45% of group A and in 18% of combined groups B, C, and D. Treatment of the 93 tumor recurrences included thermotherapy, cryotherapy, or plaque radiotherapy in 62 cases (67%) and external beam radiotherapy or enucleation in 31 cases (33%). Risk factors predictive of tumor recurrence by multivariate analysis included macular tumor location for all groups and, additionally, female sex for group A and increasing tumor thickness for groups B, C, and D.
Chemoreduction alone or combined with cryotherapy and/or thermotherapy is effective for treatment of retinoblastoma, but tumor recurrence is greatest for those located in the macula and those with greater thickness. Globe salvage is usually achieved despite tumor recurrence.
PMCID: PMC1280085  PMID: 15747743

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