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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.
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.
A combined cohort of 8,884 North American, 2,893 British and 1,574 Nordic subjects with Wilms tumor (WT) diagnosed before 15 years of age during 1960-2004 was established to determine the risk of secondary malignant neoplasms (SMN). After 169,641 person-years (PY) of observation through 2005, 174 solid tumors (exclusive of basal cell carcinomas) and 28 leukemias were ascertained in 195 subjects. Median survival time after a solid SMN diagnosis 5 years or more from WT was 11 years; it was 10 months for all leukemia. Age-specific incidence of secondary solid tumors increased from approximately 1 case per 1,000 PY at age 15 to 5 cases per 1,000 PY at age 40. The cumulative incidence of solid tumors at age 40 for subjects who survived free of SMNs to age 15 was 6.7%. Leukemia risk, by contrast, was highest during the first 5 years after WT diagnosis. Standardized incidence ratios (SIRs) for solid tumors and leukemias were 5.1 and 5.0, respectively. Results for solid tumors for the 3 geographic areas were remarkably consistent; statistical tests for differences in incidence rates and SIRs were all negative. Age-specific incidence rates and SIRs for solid tumors were lower for patients whose WT was diagnosed after 1980, although the trends with decade of diagnosis were not statistically significant. Incidence rates and SIRs for leukemia were highest among those diagnosed after 1990 (p-trend = 0.003). These trends may reflect the decreasing use of radiation therapy and increasing intensity of chemotherapy in modern protocols for treatment of WT.
OBJECTIVE - To examine the risk factors for urothelial carcinoma (UC) involvement of the prostate in patients undergoing radical cystoprostatectomy (RCP) for bladder cancer, as such involvement has both prognostic and therapeutic implications.
PATIENTS AND METHODS - We examined 308 consecutive men from 1998 to 2005 who had RCP for UC of the bladder, with whole-mount processing of their prostate. Prostatic involvement was categorized by site of origin (the bladder or the prostatic urethra) and, in the case of prostatic urethral origin, by depth of invasion, i.e. dysplasia/carcinoma in situ (CIS), involving the prostatic urethra, prostatic ductal invasion or prostatic stromal invasion. The impact of pathological characteristics was evaluated.
RESULTS - In all, 121 (39.3%) patients had some form of urothelial involvement of the prostate, of whom 59 (48.8%) had dysplasia/CIS of the prostatic urethra, 20 (16.5%) had ductal involvement and 32 (26.4%) had stromal involvement. Multivariate analysis showed that bladder CIS (odds ratio 2.0, 95% confidence interval, 1.2-3.6, P = 0.012) and trigonal involvement of bladder tumours (2.0, 1.1-3.7, P = 0.028) were independent risk factors for urothelial involvement of the prostate.
CONCLUSION - There was prostatic involvement with UC in nearly 40% of patients undergoing RCP. In this study CIS and trigonal involvement were independent predictors of risk, but were not adequate enough to accurately identify most patients who have UC within their prostate; further prospective studies are needed to more accurately predict risk factors and depth of invasion.
Therapy-related acute myeloid leukemia (t-AML) is a rare but fatal complication of cytotoxic therapy. Whereas sporadic cancer results from interactions between complex exposures and low-penetrance alleles, t-AML results from an acute exposure to a limited number of potent genotoxins. Consequently, we hypothesized that the effect sizes of variants associated with t-AML would be greater than in sporadic cancer, and, therefore, that these variants could be detected even in a modest-sized cohort. To test this, we undertook an association study in 80 cases and 150 controls using Affymetrix Mapping 10K arrays. Even at nominal significance thresholds, we found a significant excess of associations over chance; for example, although 6 associations were expected at P less than .001, we found 15 (P(enrich) = .002). To replicate our findings, we genotyped the 10 most significantly associated single nucleotide polymorphisms (SNPs) in an independent t-AML cohort (n = 70) and obtained evidence of association with t-AML for 3 SNPs in the subset of patients with loss of chromosomes 5 or 7 or both, acquired abnormalities associated with prior exposure to alkylator chemotherapy. Thus, we conclude that the effect of genetic factors contributing to cancer risk is potentiated and more readily discernable in t-AML compared with sporadic cancer.
Previous studies identified radiation therapy as a key modifier of basal cell carcinoma (BCC) risk in survivors of hematopoietic cell transplantation (HCT). In the present analysis, risk of BCC was analyzed in relation to age at transplant, attained age, race, total-body irradiation (TBI), and radiation fractionation in 6,306 patients who received HCT at ages 0-65 years after conditioning regimens with (n = 3870) or without (n = 2436) TBI, and who were followed from 100 days to 36.2 years after HCT. While age-specific BCC rates in the unirradiated patient population were higher than those reported for two non-patient populations, the general characteristics were similar; rates increased with attained age, were eightfold lower for non-white patients, and were higher in more recent birth cohorts. After adjusting for these effects, risk in unirradiated patients did not vary significantly with age at HCT. The additional BCC risk associated with radiation exposure was largest for the youngest ages at exposure to radiation, with relative risks exceeding 20 for those transplanted at ages less than 10 years, and decreased with increasing age at exposure until age 40 years, above which no excess risk was identified. Relative risk in the irradiated population did not vary significantly with attained age, dose fractionation or race. Risks per unit dose in HCT patients were similar to other populations exposed under clinical settings to similar radiation doses and were more than 10-fold lower than seen in the atomic bomb survivors, 97% of whom were exposed to doses <1 Sv.
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.
The treatment of pediatric malignancies represents one of the success stories of modern medicine. As survival has increased, the focus is now on minimizing harmful effects of treatment. There continue to be late toxicities and secondary malignancies of the genitourinary (GU) system for childhood cancer survivors related to the specific therapeutic exposures. A systematic approach is important for prevention and treatment of these adverse late GU effects.
Transplant recipients have been reported to have an increased risk of solid cancers but most studies are small and have limited ability to evaluate the interaction of host, disease, and treatment-related factors. In the largest study to date to evaluate risk factors for solid cancers, we studied a multi-institutional cohort of 28 874 allogeneic transplant recipients with 189 solid malignancies. Overall, patients developed new solid cancers at twice the rate expected based on general population rates (observed-to-expected ratio 2.1; 95% confidence interval 1.8-2.5), with the risk increasing over time (P trend < .001); the risk reached 3-fold among patients followed for 15 years or more after transplantation. New findings showed that the risk of developing a non-squamous cell carcinoma (non-SCC) following conditioning radiation was highly dependent on age at exposure. Among patients irradiated at ages under 30 years, the relative risk of non-SCC was 9 times that of nonirradiated patients, while the comparable risk for older patients was 1.1 (P interaction < .01). Chronic graft-versus-host disease and male sex were the main determinants for risk of SCC. These data indicate that allogeneic transplant survivors, particularly those irradiated at young ages, face increased risks of solid cancers, supporting strategies to promote lifelong surveillance among these patients.
BACKGROUND - The growing number of individuals surviving childhood cancer has increased the awareness of adverse long-term sequelae. One of the most worrisome complications after cancer therapy is the development of second malignant neoplasms (SMNs).
METHODS - The authors describe the incidence of solid organ SMN in survivors of pediatric malignant bone tumors who were treated on legacy Children's Cancer Group/Pediatric Oncology Group protocols from 1976 to 2005. This retrospective cohort study included 2842 patients: 1686 who were treated for osteosarcoma (OS) and 1156 who were treated for Ewing sarcoma (ES).
RESULTS - The cohort included 56% boys/young men and 44% girls/young women, and the median age at primary diagnosis was 13 years. The median length of follow-up was 6.1 years (range, 0-20.9 years). In this analysis, 64% of patients were alive. Seventeen patients with solid organ SMN were identified. The standardized incidence ratio was 2.9 (95% confidence interval [CI], 1.4-5.4) for patients who were treated for OS and 5.0 (95% CI, 2.6-9.4) for patients who were treated for ES. The median time from diagnosis to development of solid SMN was 7 years (range, 1-13 years). The 10-year cumulative incidence of solid organ SMN for the entire cohort was 1.4% (95%CI 0.6%-2%).
CONCLUSIONS - The magnitude of risk of solid SMNs was modest after treatment for malignant bone tumors. However, radiation-related solid SMNs will increase with longer follow-up. Because nearly 33% of patients die from their disease, recurrence remains the most significant problem. The development of improved therapies with fewer long-term consequences is paramount. Follow-up should focus on monitoring for both recurrence of primary malignancies and development of SMNs.