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Background: Although 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.Methods: 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 with life-table methods and Poisson regression. Chemotherapy-related risks were evaluated separately by categories of radiation dose.Results: 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 of 20 Gy or less, 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 (Ptrend = 0.03). No chemotherapy-related risk was evident for thyroid radiation doses more than 20 Gy.Conclusions: Treatments with alkylating agents increased thyroid cancer risk, but only in the radiation dose range less than 20 Gy, in which cell sparing likely predominates over cell killing.Impact: 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. Cancer Epidemiol Biomarkers Prev; 21(1); 92–101. ©2011 AACR.

Background Eyes with Group D intraocular retinoblastoma have low salvage rates. A pilot study showed safety and efficacy of sub-Tenon's fascia carboplatin with systemic chemotherapy supporting further study. Methods Children with newly diagnosed bilateral intraocular retinoblastoma with at least one remaining Group C or D eye were treated with six courses of carboplatin/etoposide/vincristine (CEV) with sub-Tenon's fascia carboplatin for Group C/D eyes during courses 2-4. Local ophthalmic therapy started at course 3. The primary study objective was to determine the 1-year failure rate of Group D eyes. Results The study closed prematurely due to poor accrual and 22 of 30 patients were evaluable for failure rate, contributing 25 Group D and four Group C eyes. Among the 25 Group D eyes, there were 13 failures within the first year of study enrollment including eight needing external beam radiotherapy (EBR) and five needing enucleation, resulting in 1-year failure rate of 52%. The failure rate was significantly lower than the historical rate of 70% (P = .039). The 1-year eye preservation rate for Group D eyes was 80% (20/25). One-year failure rate for Group C eyes was 25% (1/4); 1-year preservation rate was 100% without need for EBR. Systemic toxicity included Grade 3 hearing loss in two subjects, infections, neutropenia, and thrombocytopenia. Ocular toxicities included periorbital fat atrophy (13/29 = 45% eyes), optic nerve atrophy (1/29 = 3% eyes), and restrictive fibrosis (1/29 = 3% eyes). Conclusions Sub-Tenon's fascia carboplatin plus CEV was partially effective in Group D intraocular retinoblastoma but had unacceptable ocular toxicities.

Background: Survivors of Hodgkin lymphoma (HL) in childhood have an increased risk of subsequent malignant neoplasms (SMNs). Herein, the authors extended the follow-up of a previously reported Late Effects Study Group cohort and identified patients at highest risk for SMNs to create evidence for risk-based screening recommendations. Methods: The standardized incidence ratio was calculated using rates from the Surveillance, Epidemiology, and End Results program as a reference. The risk of SMN was estimated using proportional subdistribution hazards regression. The cohort included 1136 patients who were diagnosed with HL before age 17 years between 1955 and 1986. The median length of follow-up was 26.6 years. Results: In 162 patients, a total of 196 solid SMNs (sSMNs) were identified. Compared with the general population, the cohort was found to be at a 14-fold increased risk of developing an sSMN (95% confidence interval, 12.0-fold to 16.3-fold). The cumulative incidence of any sSMN was 26.4% at 40 years after a diagnosis of HL. Risk factors for breast cancer among females were an HL diagnosis between ages 10 years and 16 years and receipt of chest radiotherapy. Males treated with chest radiotherapy at age

Cranial radiation therapy (CRT) predisposes to GH deficiency and subsequent neoplasms (SNs) of the central nervous system (CNS). Increased rates of SNs have been reported in GH-treated survivors.The objective of the study was to evaluate the association between GH treatment and the development of CNS-SNs.The study was designed with a retrospective cohort with longitudinal follow-up.The setting of the study was multiinstitutional.A total of 12 098 5-year pediatric cancer survivors from the Childhood Cancer Survivor Study, diagnosed with cancer prior to age 21 years, of whom 338 self-reported GH treatment, which was verified through medical record review.INTERVENTIONS included subject surveys, medical records abstraction, and pathological review.Incidence of meningioma, glioma, and other CNS-SNs was measured.Among GH-treated survivors, 16 (4.7%) developed CNS-SN, including 10 with meningioma and six with glioma. Two hundred three survivors without GH treatment (1.7%) developed CNS-SN, including 138 with meningioma, 49 with glioma, and 16 with other CNS-SNs. The adjusted rate ratio in GH-treated compared with untreated survivors for development of any CNS-SN was 1.0 [95% confidence interval (CI) 0.6-1.8, P = .94], for meningiomas, 0.8 (95% CI 0.4-1.7, P = .61), and for gliomas, 1.9 (95% CI 0.7-4.8, P = .21). Factors associated with meningioma development included female gender (P = .001), younger age at primary cancer diagnosis (P.001), and CRT/longer time since CRT (P.001). Glioma was associated with CRT/shorter time since CRT (P.001).There was no statistically significant increased overall risk of the occurrence of a CNS-SN associated with GH exposure. Specifically, occurrence of meningiomas and gliomas were not associated with GH treatment.

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.

Childhood cancer survival rates have continued to increase during the past four decades, so now the expectation is that the approximately 80 % will be cured. For some, this improved survival has been achieved at the expense of long-term complications of surgery, chemotherapy, and radiation. These late effects include neurocognitive deficits, cardiovascular and pulmonary morbidity, endocrine dysfunction, auditory impairment, and reduced fertility, and will be detailed in this chapter. Second malignant neoplasms are another late complication for survivors. The need for long-term follow-up of childhood cancer survivors is necessary in order to identify these late effects and provide survivors with appropriate care and surveillance. Research is also needed in order to learn more about late effects of therapy as childhood cancer survivors’ age, and to identify and further characterize second malignant neoplasms. This information is critical in refining treatment algorithms that are designed to reduce late effects, and to continue to improve survival.

Purpose 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. Results 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 secondary sarcoma (OR = 4.1, 95% CI = 1.8–9.5). A dose–response relation was observed, with elevated risks at doses between 10 and 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 (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. Conclusions 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.

Background: Although 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. Methods: 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 with life-table methods and Poisson regression. Chemotherapy-related risks were evaluated separately by categories of radiation dose. Results: 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 of 20 Gy or less, 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 (Ptrend = 0.03). No chemotherapy-related risk was evident for thyroid radiation doses more than 20 Gy. Conclusions: Treatments with alkylating agents increased thyroid cancer risk, but only in the radiation dose range less than 20 Gy, in which cell sparing likely predominates over cell killing. Impact: 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. Cancer Epidemiol Biomarkers Prev; 21(1); 92–101. ©2011 AACR.

Purpose To evaluate a chemoreduction regimen using systemic vincristine and carboplatin (VC) and local ophthalmic therapies to avoid external-beam radiotherapy (EBRT) or enucleation in patients with Group B intraocular retinoblastoma. Patients and methods Twenty-one patients (25 eyes) were treated with six cycles of VC, accompanied by local ophthalmic therapies after cycle 1. The primary study objective was to determine the 2-year event-free survival (EFS) where an event was defined as the use of systemic chemotherapy in addition to vincristine or carboplatin, EBRT, and/or enucleation. Results All patients had tumor regression after the first cycle of VC and only two patients had progression during therapy. There were seven treatment failures within 2 years of study enrollment, resulting in 2-year EFS of 65% and early study closure in accordance with the statistical design. The 2-year cumulative incidence of enucleation was 15%; for external beam radiation therapy, it was 10%; and for chemotherapy to control progressive disease, it was 10%. All patients sustaining a treatment failure were salvaged with additional therapy. Conclusions For the majority of patients with Group B intraocular retinoblastoma, chemoreduction with VC, without etoposide, in conjunction with local therapy provides excellent opportunity for ocular salvage. Local therapy given with every chemotherapy cycle and incorporation of etoposide may provide improved ocular salvage rates. Central review of group at diagnosis is critical in assigning appropriate therapies.

BACKGROUND 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.

Background To evaluate the occurrence of second malignant neoplasms (SMN) following chemoreduction (CRD) with carboplatin, vincristine, and etoposide (CEV) as frontline therapy in patients with retinoblastoma (RB). Prodecure We conducted a two-institution retrospective chart review of 245 patients with intraocular RB treated with six cycles of vincristine, carboplatin, and etoposide for treatment of intraocular retinoblastoma. Cumulative incidence of SMN was calculated with adjustment for the competing risk of death. Results There were 187 patients with germline retinoblastoma and 58 with non-germline disease. External beam radiotherapy was subsequently utilized in 46 (24%) of germline cases and six (10%) of non-germline cases. Mean follow-up of germline and non-germline patients was 80 and 70 months, respectively. Seven subsequent cancers were found in six patients for an overall incidence of 3% at a mean of 11 years. For germline cases, following CEV alone (n = 156), SMN were found in 4% following the RB diagnosis. We found no SMN in patients with non-germline RB. One patient developed pineoblastoma. SMN included osteosarcoma (n = 3), rhabdomyosarcoma (n = 1), orbital and conjunctival melanoma (n = 1), low-grade glioma (n = 1), and acute promyeloctic leukemia (n = 1). Five of the six patients with a second malignancy survive at mean of 46 months (range 15–71 months). Conclusions At a mean of 11 years, 4% of children with germline RB treated with CEV as frontline therapy developed SMN's. No SMN was found in non-germline patients. Concerns regarding CEV-induced second cancers should not deter clinicians from using life and vision preserving therapy in patients with retinoblastoma. Pediatr Blood Cancer 2012; 59: 121–125. © 2011 Wiley Periodicals, Inc.

Previous investigations of cancer survivors report that the cumulative incidence of subsequent leukemia plateaus between 10 and 15 years after primary therapy. Risk beyond 15 years has not been comprehensively assessed, primarily because of lack of long-term follow-up. Among 5-year survivors from the Childhood Cancer Survivor Study cohort, 13 pathologically confirmed cases of subsequent leukemia occurred ≥ 15 years after primary malignancy, with a mean latency of 21.6 years (range, 15-32 years). Seven were acute myeloid leukemia (2 acute promyelocytic leukemia with t(15;17), 2 with confirmed preceding myelodysplastic syndrome), 4 acute lymphoblastic leukemia (2 pre-B lineage, 1 T cell, 1 unknown), and 2 other. Two acute myeloid leukemia cases had the 7q− deletion. The standardized incidence ratio was 3.5 (95% confidence interval, 1.9-6.0). Median survival from diagnosis of subsequent leukemia was 2 years. This is the first description of a statistically significant increased risk of subsequent leukemia ≥ 15 years from primary diagnosis of childhood cancer.

BACKGROUND:The issues involved in transition from pediatric cancer care to adult-focused care differ from those in other childhood diseases, because malignant disease itself is no longer a problem. However, the potential for fatal outcome places a greater dependence on the pediatric oncology setting and delays this transition process, often beyond adolescence. Adverse long-term physical and psychological effects accompany survival for many of the cured children, and because these effects may not become manifest until adulthood, programs that support transition for childhood cancer survivors require the expertise of many subspecialists.OBJECTIVES:To describe the issues and barriers to successful transition programs for childhood cancer survivors when they are ready for adult-focused care.METHODS:We reviewed the literature and discuss the barriers to transition at the survivor, provider, and health care system levels for survivors of childhood cancer. We also critically assess the elements of successful transition programs.RESULTS:Education of survivors and providers regarding long-term health risks is necessary for a successful transition. This process should be gradual to address the educational needs of survivors, families, and health care professionals, determine “readiness” for transition, and address financial and insurance concerns. Because little is known regarding adverse long-term health-related sequelae beyond the fourth decade of life, research is needed to quantify and reduce the consequences of these morbidities.CONCLUSIONS:Transition programs for pediatric cancer survivors require experts who are knowledgeable regarding the long-term follow-up needs of childhood cancer survivors and who can provide a bridge between pediatric oncology and primary care that is risk based.

Background 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. Methods 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. Results 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. Conclusions 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.

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.

Increases in the number of adult cancer survivors and other issues have forced the oncology community to examine, evaluate, and alter the cancer care paradigm. Pediatric oncologists are grappling with the task of transitioning a growing population of adult survivors of childhood cancer to adult medicine, while oncologists caring for adult cancer survivors are seeking models of follow-up care that are acceptable to patients and providers. Workforce and access-to-care issues suggest that primary care providers will see more cancer survivors in their practices across time, although it is unclear how prepared they are for this task. Translational research is needed to develop evidence-based clinical care and survivorship care plans. A broad picture of the evolving field of adult cancer survivorship is presented. The recent focus on young adult survivors of childhood cancer, an overview of translational research needed to inform the physical and psychosocial care of cancer survivors, and the roles of primary and specialty care providers managing this population is examined. Finally, an overview of evolving treatment summary and care plan initiatives is presented.

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. Cancer 2009;115(18 suppl):4374–84. © 2009 American Cancer Society.

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.

Purpose 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. Results 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. Conclusion 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.

Background Infertility is often a complication for adolescent and young adult males who receive cancer therapy, a problem that might be averted through using cryopreserved sperm. We aim to evaluate feasibility of offering newly diagnosed patients the opportunity to bank sperm and, to determine the beliefs and decision-making processes of patients and their parents who considered sperm banking. Procedure Eligible patients and parents were approached and offered sperm cryopreservation. Semen samples from patients who sequentially attempted sperm banking were analyzed. Questionnaires were then administered to patients and parents who had been approached about sperm banking. Results Semen samples from 68 patients were analyzed. Nine patients were azoospermic; all had been pre-treated with chemotherapy. Fifty patients completed the questionnaire. Parent and patient made the decision together to bank 80% of the time. All sons who attempted to bank and their parents felt they had made the right decision, including those who attempted but failed. Conclusions Viable sperm can be collected successfully from adolescent and young adults who are newly diagnosed with cancer. Semen quality was dramatically reduced by one course of gonadotoxic therapy. Parents and patients want information regarding sperm cryopreservation early. Parents appear to play an important role in the decision to sperm bank. We recommend sperm banking be offered to all eligible patients. Pediatr Blood Cancer 2008;50:594–598. © 2007 Wiley-Liss, Inc.

Recent advances in diagnostic and therapeutic methods in pediatric oncology have led to greater survival rates in children with malignancies. However, major long-term complications can occur that limit the quality of survival, infertility being one of them. Chemotherapy, radiation treatment, surgery, and combinations of these treatments have been implicated in causing infertility, with males being especially sensitive to therapy. Cryopreservation of semen, or sperm banking, is an easy, widely available means to preserve fertility for adolescent and young adult males with cancer. In this article, the pertinent literature is reviewed, and a sperm-banking program is described. Recommendations are offered for institutions attempting to develop a successful program, and the nurse's role in education and facilitation is discussed.

Background Childhood cancer survivors are at increased risk for the development of secondary sarcomas. Exposure to radiation therapy is a known risk factor for the development of these sarcomas. Other risk factors for secondary sarcomas have not been well described for childhood cancer survivors. We analyzed a large cohort of childhood cancer survivors to determine the true incidence of secondary sarcomas and to examine factors associated with the risk of developing secondary sarcomas. Methods The history of secondary sarcomas in 14,372 participants in the Childhood Cancer Survivor Study was determined from self-reports in three questionnaires. Risk of secondary sarcoma was evaluated by use of standardized incidence ratios (SIRs) and excess absolute risks (EARs) as calculated by use of data from the Surveillance, Epidemiology, and End Results Program. Cox regression models were used to estimate hazard ratios of developing subsequent sarcomas. Hazard ratios were reported as relative risks (RRs). Results We identified 108 patients with sarcomas that were diagnosed a median of 11 years after the diagnosis of childhood cancer. The risk of sarcoma was more than ninefold higher among childhood cancer survivors than among the general population (SIR = 9.02, 95% confidence interval [CI] = 7.44 to 10.93). The excess absolute risk of secondary sarcoma was 32.5 per 100,000 person-years (95% CI = 26.1 to 40.3 per 100,000 person-years). Higher standardized incidence ratios and excess absolute risks were associated with young age at primary diagnosis, primary sarcoma diagnosis, and a family history of cancer. In a multivariable model, increased risk of secondary sarcoma was associated with radiation therapy (RR = 3.1, 95% CI = 1.5 to 6.2), with a primary diagnosis of sarcoma (RR = 10.1, 95% CI = 4.7 to 21.8), with a history of other secondary neoplasms (RR = 2.2, 95% CI = 1.1 to 4.5), and with treatment with higher doses of anthracyclines (RR = 2.3, 95% CI = 1.2 to 4.3) or alkylating agents (RR = 2.2, 95% CI = 1.1 to 4.6). Conclusion Childhood cancer survivors appear to be at increased risk for secondary sarcomas compared with general population rates.

Background To develop and validate a method of classifying the intensity of pediatric oncology treatments using four operationally defined categories of treatment intensity. Procedure An earlier version of a rating scale, the intensity of treatment rating (ITR), was revised and validated in two phases. In the Scale Construction phase, three criterion raters revised the ITR items based on consensus and item agreement data from pediatric oncologist raters (N = 15). In the Scale Validation phase, the new ITR-2 items were validated using a second set of pediatric oncologists external to our institution (N = 12). In addition, a third group of raters (N = 16), was employed to assess inter-rater reliabilities for 12 patients at varying levels of treatment intensities. Results Agreement between criterion ratings and the median of external raters for all 34 items on the ITR-2 was very high (r = 0.95, range 0.71–0.91). When the ITR-2 was used to rate 12 patient examples, the inter-rater agreement among pediatric oncologists was also very high (median agreement between criterion-rater pairs: r = 0.87; overall relatedness among 16 raters: rICC = 0.83). Conclusions The revised ITR Scale 2.0 (ITR-2) is a valid and reliable scale for classifying the intensity of pediatric oncology treatments. Pediatr Blood Cancer 2007;48:673–677. © 2007 Wiley-Liss, Inc.

Background Retinoblastoma occurs in approximately 4 per million children per year in the United States, usually before 2 years of age. In developed countries, 95% of children with tumor in one eye can be cured with enucleation, while children with tumor in both eyes require individualized therapy to preserve vision. Although enucleation and radiation are very effective therapies for children with bilateral disease, the resultant visual impairment, cosmetic deformity and risk for new tumors result in morbidity to these children who otherwise have a near normal lifespan. Therefore, since 1994, chemoreduction with vincristine, carboplatin, and etoposide combined with focal treatment, have been used successfully. However, a major concern with the use of carboplatin has been ototoxicity. Procedures To determine whether carboplatin, in the doses and schedule used by us and others to treat retinoblastoma (18.6 mg/kg q 4 weeks for six cycles) results in hearing impairment, we reviewed the records of 248 children with retinoblastoma, 164 of whom had received carboplatin. Children generally received carboplatin, vincristine, and etoposide (CEV) for six cycles of chemotherapy. Results Hearing evaluations prior to initiating therapy were abnormal in 14 patients (5.6%). No patients with normal initial audiograms were found to have abnormal studies following repeated evaluations. Conclusion While ototoxicity is a potential concern in this young patient population, carboplatin in the treatment of retinoblastoma does not appear to produce impairment. Screening can identify children who require frequent audiologic follow-up, but children whose hearing is normal prior to therapy do not require routine surveillance following six cycles of standard CEV therapy. Pediatr Blood Cancer 2008;50:223–226. © 2007 Wiley-Liss, Inc.

Among pediatric non-Hodgkin lymphomas, one of the most frequent types is lymphoblastic lymphoma (LBL). Specific chromosome abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia, but have not been evaluated for prognostic value in pediatric LBL. For the Children's Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, 13 patients were enrolled with cytogenetic analysis of LBL and on treatment protocol CCG-502. Pathology material and karyotypes at initial diagnosis were given central review. The patients were aged 6-13 years (median 9 years), with a male-to-female ratio of 12:1. All patients had advanced disease. Disease relapsed in six patients (event-free survival 54% +/- 14%, median 10.8 years). Chromosome abnormalities were identified in 11 (85%), and translocations at 14q11.2 likely involving the T-cell receptor alpha/delta locus (TCR A/D) occurred in 4 (31%). For patients with relapse, four had translocations t(1;14)(p32;q11.2), t(8;14)(q24.1;q11.2), t(11;14)(p13;q11.2), or t(9;17)(q34;q23), involving breakpoints in the regions of TAL1, MYC, LMO2, and NOTCH1, respectively. Pediatric advanced LBLs have a high frequency of chromosome abnormalities; in this limited study, these often involved translocations at 14q11.2, the site of TCR A/D. Translocations possibly involving TAL1, MYC, LMO2, or NOTCH1 may have contributed to poor outcome. Further studies are warranted in larger cohorts of children and adolescents with LBL to evaluate the prognostic significance.

Among pediatric non-Hodgkin lymphomas, one of the most distinctive types is anaplastic large cell lymphoma (ALCL). Specific chromosomal abnormalities are associated with prognosis in childhood acute lymphoblastic leukemia, but chromosome abnormalities have not been evaluated for prognostic value in pediatric ALCL. For Children's Cancer Group protocol CCG-E-08 Etiologic Study of Non-Hodgkin Lymphoma in Childhood, three patients were enrolled with cytogenetic analysis of ALCL and simultaneously enrolled on treatment protocol CCG-552. Pathology material and karyotypes at initial diagnosis underwent central review. Demographics included ages of 9, 12, and 14 years, and a male/female ratio of 1:2. All patients had advanced disease (stage III). Disease progressed or relapsed in two patients, and one died. Chromosomal abnormalities, including t(2;5)(p23;q35), the ALK/NPM fusion gene, and complex karyotypes with multiple additional abnormalities, were identified in all three patients. In two patients with progressive disease or relapse, additional chromosomal abnormalities at 1q21 and 10q24, possibly involving MCL1 and HOX11/TCL3, respectively, may have contributed to worse outcome. Pediatric ALCL cases frequently have complex karyotypes and usually involve ALK/NPM translocations in this limited study. Additional chromosome abnormalities may be involved in the pathogenesis of ALCL. Further studies are warranted in larger cohorts of children and adolescents with ALCL.

Purpose To evaluate the reliability of the International Classification of Retinoblastoma (ICRB) for predicting treatment success with chemoreduction (CRD). Design Noncomparative interventional case series. Participants Two hundred forty-nine consecutive eyes. Methods All eyes were treated with CRD and were classified according to the ICRB: group A included those eyes with retinoblastoma ≤3 mm; group B included those eyes with retinoblastoma >3 mm, macular location, or minor subretinal fluid; group C included those eyes with retinoblastoma with localized seeds; group D included those eyes with retinoblastoma with diffuse seeds; group E included those eyes with massive retinoblastoma necessitating enucleation. The CRD regimen included vincristine, etoposide, and carboplatin for 6 cycles plus local consolidation with thermotherapy or cryotherapy. Main Outcome Measure Chemoreduction success, defined as avoidance of external beam radiotherapy or enucleation. Results Of the 249 eyes, 23 (9%) were in group A, 96 (39%) were in group B, 21 (8%) were in group C, and 109 (44%) were in group D. In this series, group E eyes were managed with enucleation. Treatment success was achieved in 100% of group A, 93% of group B, 90% of group C, and 47% of group D eyes. Conclusions The ICRB can be of assistance in predicting CRD success for retinoblastoma. Additional treatment methods are necessary to salvage more group D eyes.

Regardless of how one defines survivorship, more than 10 million individuals in the United States have been treated for a malignant disease; about 250,000 were younger than 21 years of age at diagnosis. Thirty years ago, pediatric oncologists recognized that children with cancer might be cured by adding chemotherapy to surgery and radiation. Studies were then begun of complications that could reduce survival or the quality of survival, and that might be associated with previous therapy. The complications were termed late effects, and studies focused on patients who were likely to be cured, or less likely to succumb to the original cancer than they were to experience disabilities. Clinical trials tested whether changes in therapy to reduce complications could maintain the same excellent survival rates. During the last 20 years, articles detailing late effects and the relationship between therapy and outcome have been published. This article reviews the progress made in understanding the outcomes reported and the efforts made to improve the quality of long-term survival for children and adolescents. Several questions remain regarding the long-term complications of therapy. Clinicians need more data regarding the effects of aging to guide them in managing former patients. Caregivers and pediatric cancer survivors who are now adults seek the optimal venue in which to receive care as independent adults. In addition, medical oncologists need to determine whether the models for research and clinical care of survivors created in pediatric oncology can be applied to survivors of adult-onset cancer.

Background Although intra-retinal tumor has long been staged presurgically according to the Reese–Ellsworth (R–E) system, retinoblastoma differs from other pediatric neoplasms in never having had a widely accepted classification system that encompasses the entire spectrum of the disease. Comparisons among studies that consider disease extension, risk factors for extra-ocular relapse, and response to therapy require a universally accepted staging system for extra-ocular disease. Procedure A committee of retinoblastoma experts from large centers worldwide has developed a consensus classification that can encompass all retinoblastoma cases and is presented herein. Patients are classified according to extent of disease and the presence of overt extra-ocular extension. In addition, a proposal for substaging considering histopathological features of enucleated specimens is presented to further discriminate between Stage I and II patients. Results The following is a summary of the classification system developed—Stage 0: Patients treated conservatively (subject to presurgical ophthalmologic classifications); Stage I: Eye enucleated, completely resected histologically; Stage II: Eye enucleated, microscopic residual tumor; Stage III: Regional extension [(a) overt orbital disease, (b) preauricular or cervical lymph node extension]; Stage IV: Metastatic disease [(a) hematogenous metastasis: (1) single lesion, (2) multiple lesions; (b) CNS extension: (1) prechiasmatic lesion, (2) CNS mass, (3) leptomeningeal disease]. A proposal is also presented for substaging of enucleated Stages I and II eyes. Conclusions The proposed staging system is the product of an international effort to adopt a uniform staging system for patients with retinoblastoma to cover the whole spectrum of the disease. Pediatric Blood Cancer 2006;47:801–805. © 2005 Wiley-Liss, Inc.

Background Only a few small studies have assessed the long-term morbidity that follows the treatment of childhood cancer. We determined the incidence and severity of chronic health conditions in adult survivors. Methods The Childhood Cancer Survivor Study is a retrospective cohort study that tracks the health status of adults who received a diagnosis of childhood cancer between 1970 and 1986 and compares the results with those of siblings. We calculated the frequencies of chronic conditions in 10,397 survivors and 3034 siblings. A severity score (grades 1 through 4, ranging from mild to life-threatening or disabling) was assigned to each condition. Cox proportional-hazards models were used to estimate hazard ratios, reported as relative risks and 95% confidence intervals (CIs), for a chronic condition. Results Survivors and siblings had mean ages of 26.6 years (range, 18.0 to 48.0) and 29.2 years (range, 18.0 to 56.0), respectively, at the time of the study. Among 10,397 survivors, 62.3% had at least one chronic condition; 27.5% had a severe or life-threatening condition (grade 3 or 4). The adjusted relative risk of a chronic condition in a survivor, as compared with siblings, was 3.3 (95% CI, 3.0 to 3.5); for a severe or life-threatening condition, the risk was 8.2 (95% CI, 6.9 to 9.7). Among survivors, the cumulative incidence of a chronic health condition reached 73.4% (95% CI, 69.0 to 77.9) 30 years after the cancer diagnosis, with a cumulative incidence of 42.4% (95% CI, 33.7 to 51.2) for severe, disabling, or life-threatening conditions or death due to a chronic condition. Conclusions Survivors of childhood cancer have a high rate of illness owing to chronic health conditions.

Radiation exposure at a young age is a strong risk factor for thyroid cancer. We conducted a nested case-control study of 69 thyroid cancer cases and 265 controls from a cohort of 14,054 childhood cancer survivors to evaluate the shape of the radiation dose-response relationship, in particular at high doses, and to assess modification of the radiation effects by patient and treatment characteristics. We considered several types of statistical models to estimate the excess relative risk (ERR), mainly guided by radiobiological models. A two-parameter model with a term linear in dose and a negative exponential in dose squared provided the best parsimonious description with an ERR of 1.3 per gray (95% confidence interval 0.4-4.1) at doses below 6 Gy and a relative decrease in ERR of 0.2% per unit dose squared with increasing dose, that is, decreases in the ERR/Gy of 53% at 20 Gy and 95% at 40 Gy. Further analyses using spline models suggested that the significant nonlinearity at high doses was characterized most appropriately as a true downturn rather than a flattening of the dose-response curve. We found no statistically significant modification of the dose-response relationship by patient characteristics; however, the linear parameter (i.e., the ERR/ Gy at doses less than 6 Gy) did decrease consistently and linearly with increasing age at childhood cancer diagnosis, from 4.45 for 0-1-year-olds to 0.48 for 15-20-year-olds. In summary, we applied models derived from radiobiology to describe the radiation dose-response curve for thyroid cancer in an epidemiological study and found convincing evidence for a downturn in risk at high doses.

Background Comparison of functional mobility and quality of life is performed in patients with lower-extremity bone sarcoma following either amputation, limb-sparing surgery, or rotationplasty with four different types of outcome measures: (1) an objective functional mobility measure that requires patients to physically perform specific tasks, functional mobility assessment (FMA); (2) a clinician administered tool, Musculoskeletal Tumor Society Scale (MSTS); (3) a patient questionnaire, Toronto Extremity Salvage Scale (TESS); and (4) a health-related quality of life (HRQL) measure, Short Form-36 version 2 (SF-36v.2). Procedure This is a prospective multi-site study including 91 patients with lower-extremity bone sarcoma following amputation, limb-sparing surgery, or rotationplasty. One of three physical therapists administered the quality of life measure (SF-36v.2) as well as a battery of functional measures (FMA, MSTS, and TESS). Results Differences between patients who had amputation, limb-sparing surgery, or rotationplasty were consistently demonstrated by the FMA. Patients with limb sparing femur surgery performed better than those patients with an above the knee amputation but similarly to a small number of rotationplasty patients. Several of the more conventional self-report measures were shown to not have the discriminative capabilities of the FMA in these cohorts. Conclusion In adolescents with lower-extremity bone sarcoma, it may be advantageous to consider the use of a combination of outcome measures, including the FMA, for objective functional mobility assessment along with the TESS for a subjective measure of disability and the SF-36v.2 for a quality-of-life measure. Pediatr Blood Cancer 2007;49:964–969. © 2006 Wiley-Liss, Inc.

The risk of second malignant neoplasm (SMN) was evaluated in 979 children with Hodgkin's disease. This cohort was diagnosed between 1955 and 1979 at one of the institutions of the Late Effects Study Group. Solid tumors, non-lymphocytic leukemia, and non-Hodgkin's lymphoma (NHL) developed in 18, 17, and 3 patients, respectively. The estimated cumulative probability of developing any SMN was 2% at 5 years from diagnosis, 5% at 10 years, and 9% at 15 years. The incidence is ninefold greater than the risk of acquiring cancer in 19 year-olds, the median age at which the diagnosis of SMN was made in this study population. For leukemia and NHL the corresponding probabilities were 1%, 3%, and 4% for the group as a whole but were increased (2%, 6%, and 8%) in patients who had suffered one or more recurrences. In order to analyze the risk of leukemia and NHL associated with alkylating agent chemotherapy, each patient was assigned a score of one for each alkylating agent administered for a 6-month period. Scores of 2, 4, 6, and 8 were associated with probabilities of leukemia or NHL of 2%, 3%, 6%, and 10%, respectively. In a multivariate analysis for leukemia/lymphoma that included AAD score, stage, and splenectomy, the effect of AAD score and splenectomy did not change substantially compared to the univariate results. AAD score remained statistically significant (P = .0001), and splenectomy was of borderline significance (P = .09). Ot the 18 solid tumor SMNs, 15 developed within the field of radiation, and one other developed in tissue irradiated 34 years earlier for hemangioma. This study of a large and unselected group of children with Hodgkin's disease who received a variety of therapies demonstrates that children are as likely as adults to develop acute leukemia after alkylating agents and solid tumors in the field of radiation therapy.

This case describes a twin with bilateral retinoblastoma who developed leiomyosarcoma of the bladder at age 17 and again at 39. At 17-years of age she was diagnosed with a leiomyosarcoma of the bladder after presenting with recurrent urinary tract infections, hematuria, and dysuria. She was treated with partial cystectomy. After a 12-year disease-free interval, she was diagnosed with a second leiomyosarcoma of the bladder. This case supports the relationship between the genetic form of retinoblastoma and leiomyosarcoma and illustrates the necessity for extensive follow-up and well-defined treatment of secondary neoplasms.

Purpose To determine the risk of subsequent carcinomas other than breast, thyroid, and skin, and to identify factors that influence the risk among survivors of childhood cancer. Patients and Methods Subsequent malignant neoplasm history was determined in 13,136 participants (surviving ≥ 5 years postmalignancy, diagnosed from 1970 to 1986 at age < 21 years) of the Childhood Cancer Survivor Study to calculate standardized incidence ratios (SIRs), using Surveillance, Epidemiology, and End Results data. Results In 71 individuals, 71 carcinomas were diagnosed at a median age of 27 years and a median elapsed time of 15 years in the genitourinary system (35%), head and neck area (32%), gastrointestinal tract (23%), and other sites (10%). Fifty-nine patients (83%) had received radiotherapy, and 42 (59%) developed a second malignant neoplasm in a previous radiotherapy field. Risk was significantly elevated following all childhood diagnoses except CNS neoplasms, and was highest following neuroblastoma (SIR = 24.2) and soft tissue sarcoma (SIR = 6.2). Survivors of neuroblastoma had a 329-fold increased risk of renal cell carcinomas; survivors of Hodgkin's lymphoma had a 4.5-fold increased risk of gastrointestinal carcinomas. Significantly elevated risk of head and neck carcinoma occurred in survivors of soft tissue sarcoma (SIR = 22.6), neuroblastoma (SIR = 20.9), and leukemia (SIR = 20.9). Conclusion Young survivors of childhood cancers are at increased risk of developing subsequent carcinomas typical of later adulthood, underscoring the importance of long-term follow-up and risk-based screening. Follow-up of the cohort is ongoing to determine lifetime risk and delineate individual characteristics that contribute to risk.

Summary Background Survivors of malignant disease in childhood who have had radiotherapy to the head, neck, or upper thorax have an increased risk of subsequent primary thyroid cancer, but the magnitude of risk over the therapeutic dose range has not been well established. We aimed to quantify the long-term risk of thyroid cancer after radiotherapy and chemotherapy. Methods In a nested case-control study, 69 cases with pathologically confirmed thyroid cancer and 265 matched controls without thyroid cancer were identified from 14 054 5-year survivors of cancer during childhood from the Childhood Cancer Survivor Study cohort. Childhood cancers were diagnosed between 1970 and 1986 with cohort follow-up to 2000. Findings Risk of thyroid cancer increased with radiation doses up to 20–29 Gy (odds ratio 9·8 [95% CI 3·2–34·8]). At doses greater than 30 Gy, a fall in the dose-response relation was seen. Both the increased and decreased risks were more pronounced in those diagnosed with a first primary malignant disease before age 10 years than in those older than 10 years. Furthermore, the fall in risk remained when those diagnosed with Hodgkin's lymphoma were excluded. Chemotherapy for the first cancer was not associated with thyroid-cancer risk, and it did not modify the effect of radiotherapy. 29 (42%) cases had a first diagnosis of Hodgkin's lymphoma compared with 49 (19%) controls. 11 (42%) of those who had Hodgkin's lymphoma had subsequent thyroid cancers smaller than 1 cm compared with six (17%) of those who had other types of childhood cancer (p=0·07). Interpretation The reduction in radiation dose-response for risk of thyroid cancer after childhood exposure to thyroid doses higher than 30 Gy is consistent with a cell-killing effect. Standard long-term follow-up of patients who have had Hodgkin's lymphoma for detection of thyroid cancer should also be undertaken for survivors of any cancer during childhood who received radiotherapy to the thorax or head and neck region.

During the past 30 years, changes in the treatment of children and adolescents with cancer have led to substantial improvements in survival. Although treatment-related factors have been shown to impact subsequent health status and quality of life, there is limited information on survivors who are now two or more decades after treatment. The Childhood Cancer Survivor Study (CCSS) was established as a resource for investigating the long-term outcomes of a cohort of 5-year survivors of childhood and adolescent cancer, diagnosed between 1970-1986. The CCSS cohort has more than 14,000 active participants, including survivors of leukemia, brain tumors, Hodgkin disease, non-Hodgkin lymphoma, Wilms tumor, neuroblastoma, soft-tissue sarcoma, and bone tumors. Study participants, extensively characterized by their cancer therapy, have provided self-reported sociodemographic- and health-related information. Although the survivor population has been found to be at significantly increased risk of several adverse outcomes, such as late mortality, second cancers, pulmonary complications, pregnancy loss, low birth weight of offspring, and decreased education, the overall proportion of survivors affected is relatively small. Subgroups at high risk of adverse outcomes, defined by treatment-related, demographic, or medical factors, can be identified. The ongoing evaluation of large and diverse cohorts of cancer survivors will aid in further identifying individuals who should be the target of innovative intervention strategies.

The management of retinoblastoma has gradually changed over the past 10 years. Over 95% of children with retinoblastoma in the United States are cured with modern techniques. The challenge remains, however, in maintaining the eye and vision. There is a trend away from enucleation and external beam radiotherapy toward focal conservative treatments involving primary chemoreduction in conjunction with thermotherapy and cryotherapy. This is related to earlier detection of the disease, recognition of more effective chemotherapeutic agents, more focused local treatment modalities, and, most importantly, knowledge of the long-term risks of external beam radiotherapy. Enucleation is still preferable for retinoblastoma that fills most of the eye, especially when the disease is unilateral or when there is concern for tumor invasion into the optic nerve, choroid, or orbit. The orbital integrated implant is placed after enucleation and provides acceptable prosthesis motility and appearance. External beam radiotherapy is still vital for treating advanced retinoblastoma, especially when there is diffuse vitreous or subretinal seeding after failure of other methods and preservation of vision is a priority. The most important recent advance in the management of retinoblastoma is the use of intravenous chemotherapy for tumor reduction, a technique of neoadjuvant chemotherapy termed "chemoreduction." This is followed by tumor consolidation with focal measures such as thermotherapy, cryotherapy, and plaque radiotherapy. This strategy provides reduced tumor volume and often permits consolidation with methods other than radiotherapy. It appears that vision can be preserved in some cases with these methods, avoiding some of the local complications like radiation cataract or macular edema that have been found with radiotherapy techniques. External beam radiotherapy and enucleation can now be avoided in most cases of Reese-Ellsworth groups I (minimal disease) through IV (moderate disease) retinoblastoma. The most advanced stage of retinoblastoma, Reese-Ellsworth group V, continues to provide the greatest difficulty for management, and external beam radiotherapy and enucleation are often employed in addition to chemoreduction to save the child's life. A collaborative prospective study in North America is currently under way to further study the benefits and risks of chemoreduction for minimal, moderate, and advanced retinoblastoma.

Purpose To evaluate retinoblastoma control following chemoreduction. Design Interventional case series. Methods Prospective. Setting Single center trial. Patient population 457 retinoblastomas in 193 eyes of 125 patients. Nonrandomized, noncomparative study. Intervention All patients received intravenous vincristine, etoposide, and carboplatin,. The tumors were managed with chemoreduction alone (group W) or chemoreduction combined with thermotherapy (group X), cryotherapy (group Y), or both thermotherapy and cryotherapy (group Z). Main outcome measure Tumor recurrence in each treatment group. Results Of 457 retinoblastomas, 63 (14%) were in group W, 256 (56%) in group X, 127 (28%) in group Y, and 11 (2%) in group Z. The tumor was located in the macula in 33 (52%) of group W, 109 (43%) of group X, 3 (2%) of group Y, and 9 (1%) of group Z. The mean tumor thickness at initial examination was 7 mm for group W, 4 mm for group X, 2 mm for group Y, and 3 mm for group Z. Using Kaplan-Meier estimates, recur-rence of the individual retinoblastoma at 7 years was found in 45% of group W and 18% for combined groups X, Y, and Z. Risk factors predictive of tumor recurrence by multivariate analysis included macular tumor location for all groups and additionally female gender for group W and increasing tumor thickness for groups X, Y, and Z. Conclusions Chemoreduction alone or combined with cryotherapy or thermotherapy is effective for treatment of retinoblastoma, but tumor recurrence rate is highest for those located in the macula and those with greater thickness.

Background Self-concept was compared between adult survivors of childhood acute lymphoblastic leukemia (ALL) and sibling controls. Adult survivor subgroups at greatest risk for negative self-concept were identified. Procedure Survivors (n = 578) aged ≥18 years, treated before age 20 years on Children's Cancer Group (CCG) ALL protocols, and 396 sibling controls completed a telephone interview and the Harter Adult Self-Perception Profile (ASPP). Results Survivors global self-worth scores were significantly lower than sibling controls (mean 3.09 vs. 3.18; P = 0.022). Unemployed survivors reported lower global self-worth scores than employed (mean 2.77 vs. 3.12; P = 0.0001), whereas employment status was not associated with self-worth in controls. Among survivors, predictors of negative self-concept included unemployment (odds ratio (OR) = 2.87; 95% CI: 1.50–5.50), and believing that cancer treatment limited employability (OR = 3.17; 95% CI: 1.79–5.62). Unemployment increased the odds for negative self-concept among survivors who received combinations of central nervous system (CNS) irradiation (CRT) and intrathecal methotrexate (IT-MTX), except high CRT with no or low dose IT-MTX. Employed survivors who perceived that treatment limited their employability showed increased odds of negative self-concept for all treatment groups compared to those who did not. Minority ethnic group membership was a borderline significant predictor of negative self-concept (OR = 1.79; 95% CI: 0.94–3.33). Conclusions Global self-worth was significantly lower in ALL survivors than sibling controls, however, 81% of survivors had positive self-concept. Survivor subgroups most vulnerable to negative self-concept were the unemployed survivors, believing that cancer treatment affected employability, and ethnic minority group members. Targeted intervention may have greater clinical relevance for these subgroups. © 2003 Wiley-Liss, Inc.

Background Fertility impairments among women treated during childhood for cancer are known to occur after some, but not all, types of anticancer therapy. Although leukemia is the most common cancer of childhood, until now fertility in survivors has not been comprehensively assessed. Procedure We investigated functional impairment of fertility in women who were long-term survivors of acute lymphoblastic leukemia (ALL) with a retrospective cohort study. Proven fertility (defined as ever pregnant) was evaluated by self-report among 182 females treated on protocols of the Children's Cancer Group (age at interview, 22.6 years on average) and 170 controls drawn from among the survivors' female siblings (23.4 years). The interview included psychosocial inventories designed to detect mood problems. Results Significant fertility deficits were noted in female survivors treated with cranial radiotherapy (CRT) at any dose around the time of menarche (relative fertility (RF)) = 0.27, 95% CI = 0.09, 0.82, P = 0.03). Controlling for marital status, mood at interview, and many fertility-related situations did not change the association. Conclusion This study provides evidence for fertility deficits after treatment for ALL with CRT, and, in addition, for the first time, suggests that girls treated around the time of menarche are especially at risk. Clinical confirmation of these results is needed. If gonadal damage occurs in women receiving these treatments, their risk for further sequelae, such as osteoporosis and heart disease, may be significantly raised, requiring active management and intervention. © 2004 Wiley-Liss, Inc.

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. Cancer 2004. © 2004 American Cancer Society.

Historically, the survival of children and adolescents with Burkitt's and Burkitt-like lymphoma had been poor. Recently, short and intensive chemotherapy appears to have improved disease outcome. We therefore reviewed the results of four successive Children's Cancer Group trials conducted on 470 children with disseminated Burkitt's and Burkitt-like lymphoma. Of the patients studied, the median age was 8 years (0-21 years), the male:female ratio was 4:1, 58% had lactate dehydrogenase (LDH) > or = 500 IU/l, 23% had M2 or M3 bone marrow (BM), and 12% demonstrated central nervous system involvement. In a multivariate analysis, the 4-year event-free survival (EFS) in patients > or = 15-years-old compared with or = 500 IU/l compared with LDH < 500 IU/l was 49 +/- 3 versus 71 +/- 4% (P < 0.001). Furthermore, patients treated on the most recent protocol, which was short and more intensive, had a significantly improved survival compared with those on previous trials (4-year EFS 80 +/- 6 versus 54 +/- 2%, P < 0.001). In summary, the outcome for childhood Burkitt's and Burkitt-like lymphoma has recently improved with the use of short and intensive B-cell non-Hodgkin's lymphoma-directed therapy.

This study reviews the common long-term sequalae of childhood cancer and its therapy. It discusses the clinical and research challenges posed by such late effects. The authors address related topics of late effects research and clinical care, methodological issues, barriers and directions for the future.

PURPOSE: To report the results of chemoreduction and focal therapy for retinoblastoma with determination of factors predictive of the need for treatment with external beam radiotherapy or enucleation DESIGN: Interventional case series METHODS: One-hundred three patients with retinoblastoma (158 eyes with 364 tumors) at the Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University in conjunction with the Division of Oncology at Children’s Hospital of Philadelphia from June 1994 to August 1999 were enrolled for this prospective clinical trial. The patients received treatment for retinoblastoma with six planned cycles (one cycle per month) of chemoreduction using vincristine, etoposide, and carboplatin combined with focal treatments (cryotherapy, thermotherapy, or plaque radiotherapy). The two main outcome measures after chemoreduction and focal therapy were the need for external beam radiotherapy and the need for enucleation. The clinical features at the time of patient presentation were analyzed for impact on the main outcome measures using a series of Cox proportional hazards regressions. RESULTS: Using Reese-Ellsworth (RE) staging for retinoblastoma, there were nine (6%) eyes with group I disease, 26 (16%) eyes with group II disease, 16 (10%) eyes with group III disease, 32 (20%) eyes with group IV disease, and 75 (48%) eyes with group V retinoblastoma. All eyes showed initial favorable response with tumor regression. The median follow-up was 28 months (range, 2–63 months). Failure of chemoreduction and need for treatment with external beam radiotherapy occurred in 25% of eyes at 1 year, 27% at 3 years, and no further increase at 5 years. More specifically, external beam radiotherapy was necessary at 5 years in 10% of RE groups I–IV eyes and 47% of RE group V eyes. Multivariate factors predictive of treatment with external beam radiotherapy included non-Caucasian race, male sex, and RE group V disease. Failure of chemoreduction and the need for treatment with enucleation occurred in 13% eyes at 1 year, 29% at 3 years, and 34% at 5 years. More specifically, enucleation was necessary in 15% of RE groups I–IV eyes at 5 years and in 53% of RE group V at 5 years. Multivariate factors predictive of treatment with enucleation included patient age older than 12 months, single tumor in eye, and tumor proximity to foveola within 2 mm. Overall, of the 158 eyes, 50% required external beam radiotherapy or enucleation and 50% were successfully managed without these treatments. No patient developed retinoblastoma metastasis, pinealoblastoma, or second malignant neoplasms over the 5-year follow up. CONCLUSIONS: Chemoreduction offers satisfactory retinoblastoma control for RE groups I–IV eyes, with treatment failure necessitating additional external beam radiotherapy in only 10% of eyes and enucleation in 15% of eyes at 5-year follow-up. Patients with RE group V eyes require external beam radiotherapy in 47% and enucleation in 53% at 5 years.

For the past 30 years, retinoblastoma, a tumor that occurs in only 3 % of children with cancer, has been the subject of extensive molecular biologic research. However, apart from a short period in the 1970s, retinoblastoma has not been studied by any of the pediatric cooperative groups. The past decade has witnessed significant multidisciplinary prospective clinical and biologic studies of this rare pediatric neoplasm. The Children’s Oncology Group (COG) has successfully opened four clinical trials with a fifth recently approved. This chapter will review these ongoing prospective multicenter trials.

PURPOSE: To determine the toxicity and response rate in children treated with dexamethasone, etoposide, cisplatin, high-dose cytarabine, and l-asparaginase (DECAL) for recurrent non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease (HD). PATIENTS AND METHODS: Ninety-seven children with recurrent NHL (n = 68) or HD (n = 29) were enrolled. Treatment consisted of two cycles of DECAL, then bone marrow transplantation or up to four cycles of ifosfamide, mesna, and etoposide alternating with DECAL maintenance therapy. RESULTS: After two cycles of DECAL induction therapy, complete response (CR) or partial response (PR) was reported in 19 (65.5%; 10 CRs and nine PRs) of 29 patients with HD and 29 (41.6%; 23 CRs and six PRs) of 68 patients with NHL. When only 24 patients with HD and 58 patients with NHL who were assessable for response were considered, the response rates were 79.2% (19 of 24 patients) and 50.0% (29 of 58 patients), respectively. Five-year event-free survival was 26% ± 9% and 23% ± 5% in patients with HD and NHL, respectively. Five-year survival was 31% ± 14% and 30% ± 6%, respectively. Although median time to treatment failure was significantly longer in patients with HD (EFS, P = .002; survival, P = .011), this difference did not translate into a higher long-term survival. Grade 3 or 4 toxic effects were observed during induction in 70 (72%) of 97 patients and during maintenance in 45 (70%) of 64 courses of DECAL therapy. Pancytopenia and systemic infections in particular were frequently observed. Other toxic effects were uncommon. Although not a formal part of the therapy or the study design, 42 patients who responded to therapy who underwent bone marrow transplant did not show any benefit from this approach. CONCLUSION: DECAL is an effective and tolerable salvage regimen for treating patients with recurrent NHL and HD.