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The case-cohort design, among many two-phase sampling designs, substantially reduces the cost of an epidemiological study by selecting more informative participants within the full cohort for expensive variable measurements. Despite their benefits, additive hazards models, which estimate hazard differences, have rarely been used for the analysis of case-cohort studies due to the lack of software and application examples. In this paper, we describe a newly developed estimation method that fits the additive hazards models to general two-phase sampling studies along with the R package addhazard that implements it. It allows for missing covariates among cases, cohort stratification, robust variances, and the incorporation of auxiliary information from the full cohort to enhance inference precision. We demonstrate the use of this tool to estimate the association of the risk of coronary heart disease (CHD) with biomarkers high-sensitivity C-reactive protein (hs-CRP) and Lipoprotein-associated phospholipase A2 (Lp-PLA2) by analyzing the Atherosclerosis Risk in Communities Study, which adopted a two-phase sampling design for studying these two biomarkers. We show that the use of auxiliary variables from the full cohort based on calibration techniques improves the precision of the hazard difference being estimated. We observe a synergistic effect of the two biomarkers among participants with lower LDL cholesterol (LDL-C): the CHD hazard rate attributable to the combined action of high hs-CRP and high Lp-PLA2 exceeded the sum of the CHD hazard rate attributable to each one independently by 11.58 (95% CI 2.16-21.01) cases per 1000 person-years. With higher LDL-C, we observe the CHD hazard rate attributable to the combined action of high hs-CRP and medium Lp-PLA2 was less than the sum of their individual effects by 13.42 (95% CI 2.44-24.40) cases per 1000 person-years. This demonstration serves the dual purposes of illustrating analysis techniques and providing insights about the utility of hs-CRP and Lp-PLA2 for identifying the high-risk population of CHD that the traditional risk factors such as the LDL-C may miss. Epidemiologists are encouraged to use this new tool to analyze other case-cohort studies and incorporate auxiliary variables embedded in the full cohort in their analysis.
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1-Alquil-2-acetilglicerofosfocolina Esterase , Doença das Coronárias , Biomarcadores , Proteína C-Reativa/análise , Estudos de Coortes , Doença das Coronárias/epidemiologia , HumanosRESUMO
The infinite dimensional Z-estimation theorem offers a systematic approach to joint estimation of both Euclidean and non-Euclidean parameters in probability models for data. It is easily adapted for stratified sampling designs. This is important in applications to censored survival data because the inverse probability weights that modify the standard estimating equations often depend on the entire follow-up history. Since the weights are not predictable, they complicate the usual theory based on martingales. This paper considers joint estimation of regression coefficients and baseline hazard functions in the Cox proportional and Lin-Ying additive hazards models. Weighted likelihood equations are used for the former and weighted estimating equations for the latter. Regression coefficients and baseline hazards may be combined to estimate individual survival probabilities. Efficiency is improved by calibrating or estimating the weights using information available for all subjects. Although inefficient in comparison with likelihood inference for incomplete data, which is often difficult to implement, the approach provides consistent estimates of desired population parameters even under model misspecification.
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Análise de Sobrevida , Aterosclerose/etiologia , Bioestatística , Feminino , Humanos , Funções Verossimilhança , Modelos Estatísticos , Probabilidade , Modelos de Riscos Proporcionais , Análise de RegressãoRESUMO
PURPOSE: To create clinically useful models that incorporate readily available demographic and cancer treatment characteristics to predict individual risk of heart failure among 5-year survivors of childhood cancer. PATIENTS AND METHODS: Survivors in the Childhood Cancer Survivor Study (CCSS) free of significant cardiovascular disease 5 years after cancer diagnosis (n = 13,060) were observed through age 40 years for the development of heart failure (ie, requiring medications or heart transplantation or leading to death). Siblings (n = 4,023) established the baseline population risk. An additional 3,421 survivors from Emma Children's Hospital (Amsterdam, the Netherlands), the National Wilms Tumor Study, and the St Jude Lifetime Cohort Study were used to validate the CCSS prediction models. RESULTS: Heart failure occurred in 285 CCSS participants. Risk scores based on selected exposures (sex, age at cancer diagnosis, and anthracycline and chest radiotherapy doses) achieved an area under the curve of 0.74 and concordance statistic of 0.76 at or through age 40 years. Validation cohort estimates ranged from 0.68 to 0.82. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups, corresponding to cumulative incidences of heart failure at age 40 years of 0.5% (95% CI, 0.2% to 0.8%), 2.4% (95% CI, 1.8% to 3.0%), and 11.7% (95% CI, 8.8% to 14.5%), respectively. In comparison, siblings had a cumulative incidence of 0.3% (95% CI, 0.1% to 0.5%). CONCLUSION: Using information available to clinicians soon after completion of childhood cancer therapy, individual risk for subsequent heart failure can be predicted with reasonable accuracy and discrimination. These validated models provide a framework on which to base future screening strategies and interventions.
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Antineoplásicos/efeitos adversos , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etiologia , Neoplasias , Sobreviventes/estatística & dados numéricos , Adolescente , Adulto , Antineoplásicos/administração & dosagem , Área Sob a Curva , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Insuficiência Cardíaca/induzido quimicamente , Humanos , Incidência , Masculino , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Países Baixos/epidemiologia , América do Norte/epidemiologia , Distribuição de Poisson , Radioterapia/efeitos adversos , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: The standard treatment of pulmonary metastases in patients with Wilms tumor (WT) includes 12-gray radiotherapy (RT) to the entire chest. To the authors' knowledge, the risk of breast cancer (BC) in a large cohort of female survivors of WT has not previously been reported. METHODS: A total of 2492 female participants in National Wilms Tumor Studies 1 through 4 (1969-1995) were followed from age 15 years through the middle of 2013 for incident BC. The median age at the time of last contact was 27.3 years. The authors calculated cumulative risk at age 40 years (CR40), hazard ratios (HR) by Cox regression, standardized incidence ratios (SIRs) relative to US population rates, and 95% confidence intervals (95% CIs). RESULTS: The numbers of survivors with invasive BC divided by the numbers at risk were 16 of 369 (CR40, 14.8% [95% CI, 8.7-24.5]) for women who received chest RT for metastatic WT, 10 of 894 (CR40, 3.1% [95% CI, 1.3-7.41]) for those who received only abdominal RT, and 2 of 1229 (CR40, 0.3% [95% CI, 0.0-2.3]) for those who received no RT. The SIRs for these 3 groups were 27.6 (95% CI, 16.1-44.2) based on 5010 person-years (PY) of follow-up, 6.0 (95% CI, 2.9-11.0) based on 13,185 PY of follow-up, and 2.2 (95% CI, 0.3-7.8) based on 13,560 PY of follow-up, respectively. The risk was high regardless of the use of chest RT among women diagnosed with WT at age ≥10 years, with 9 of 90 women developing BC (CR40, 13.5% [95% CI, 5.6-30.6]; SIR, 23.6 [95% CI, 10.8-44.8] [PY, 1463]). CONCLUSIONS: Female survivors of WT who were treated with chest RT had a high risk of developing early BC, with nearly 15% developing invasive disease by age 40 years. Current guidelines that recommend screening only those survivors who received ≥20 Gy of RT to the chest might be reevaluated.
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Neoplasias da Mama/epidemiologia , Carcinoma Ductal de Mama/epidemiologia , Neoplasias Renais/epidemiologia , Neoplasias Pulmonares/epidemiologia , Neoplasias Induzidas por Radiação/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Tumor de Wilms/epidemiologia , Adolescente , Adulto , Antibióticos Antineoplásicos/uso terapêutico , Canadá/epidemiologia , Doxorrubicina/uso terapêutico , Feminino , Humanos , Incidência , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Estudos Longitudinais , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundário , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Estados Unidos , Tumor de Wilms/patologia , Tumor de Wilms/terapia , Adulto JovemRESUMO
BACKGROUND: Intra-operative tumor spill increases the risk of local recurrence of Wilms tumor, and adversely impacts relapse-free (RFS) and overall survival (OS) rates. METHODS: Surgical checklists, operative notes, institutional pathology reports, central pathology review and flow sheets of 602 patients registered between August 1986 and September 1994 on National Wilms Tumor Study-4 as randomized, followed or switched and coded as Final Stage II, favorable histology (FH) were reviewed. RFS and OS were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated using the Cox model and tested for statistical significance by the log-rank test. RESULTS: Four hundred ninety-nine patients were found after review to have Stage II, FH Wilms tumor. The 8-year RFS percentages were 85.0% (95% confidence interval (CI): 81.1%, 88.1%) for those with no spill compared to 75.7% (65.8%, 83.2%) for those with spill. The 8-year OS percentages were 95.6% (93.1%, 97.3%) for those with no spill compared to 90.3% (82.2%, 94.9%) for those with spill. The HR for relapse among those with spill was 1.55 ((95%CI: 0.97,2.51), P = 0.067) and the HR for death was 1.94 ((0.92,4.09), P = 0.077). CONCLUSIONS: RFS and OS were lower for patients who had intra-operative tumor spill. The majority of NWTS Stage II, FH patients with intra-operative tumor spill have an overall excellent outcome when treated with two drug chemotherapy (vincristine and actinomycin D) and no abdominal irradiation.
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Neoplasias Renais/cirurgia , Inoculação de Neoplasia , Nefrectomia/efeitos adversos , Tumor de Wilms/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Dactinomicina/administração & dosagem , Intervalo Livre de Doença , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Estadiamento de Neoplasias , Radioterapia , Resultado do Tratamento , Vincristina/administração & dosagem , Tumor de Wilms/mortalidade , Tumor de Wilms/patologiaRESUMO
Standard analyses of data from case-control studies that are nested in a large cohort ignore information available for cohort members not sampled for the sub-study. This paper reviews several methods designed to increase estimation efficiency by using more of the data, treating the case-control sample as a two or three phase stratified sample. When applied to a study of coronary heart disease among women in the hormone trials of the Women's Health Initiative, modest but increasing gains in precision of regression coefficients were observed depending on the amount of cohort information used in the analysis. The gains were particularly evident for pseudo- or maximum likelihood estimates whose validity depends on the assumed model being correct. Larger standard errors were obtained for coefficients estimated by inverse probability weighted methods that are more robust to model misspecification. Such misspecification may have been responsible for an important difference in one key regression coefficient estimated using the weighted compared with the more efficient methods.
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PURPOSE: This study was undertaken to evaluate the incidence of pulmonary disease among patients treated with radiation therapy (RT) for pulmonary metastases (PM) from Wilms tumor (WT). PATIENTS AND METHODS: We reviewed records of 6,449 patients treated on National Wilms Tumor Studies-1, -2, -3, and -4 whose flow sheets or annual status reports documented one of several pulmonary conditions. Cases were fully evaluable if pulmonary function test (PFT) results were available, pulmonary fibrosis was identified on a chest radiograph or was listed as the primary or a contributing factor to death. Partially evaluable cases were those for whom PFT results could not be obtained. We evaluated the relationship between RT factors and the occurrence of pulmonary disease using hazard ratios (HRs) and cumulative incidence, treating death as a competing risk. RESULTS: Sixty-four fully evaluable and 16 partially evaluable cases of pulmonary disease were identified. The cumulative incidence of pulmonary disease at 15 years since WT diagnosis was 4.0% (95% confidence interval [CI] 2.6-5.4%) among fully evaluable and 4.8% (95% CI 3.3-6.4%) among fully and partially evaluable patients who received lung RT for PM at initial diagnosis. Rates of pulmonary disease were substantially higher among those who received lung RT for PM present at initial diagnosis or relapse compared to those who received no RT or only abdominal RT (HR 30.2, 95% CI 16.9-53.9). CONCLUSION: The risk of pulmonary disease must be considered in evaluating the risk:benefit ratio of lung RT for the management of PM from WT.
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Neoplasias Pulmonares/epidemiologia , Fibrose Pulmonar/epidemiologia , Tumor de Wilms/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Incidência , Lactente , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Fibrose Pulmonar/etiologia , Testes de Função Respiratória , Fatores de Risco , Tumor de Wilms/patologia , Tumor de Wilms/radioterapiaRESUMO
PURPOSE: Stage III designation in NWTS-5 (National Wilms Tumor Study-5) was determined by four pathologic criteria: positive lymph nodes (LNs), peritoneal implants, residual disease, and tumor rupture. The objective of this study was to determine the prognostic significance of each of the stage III criteria. PATIENTS AND METHODS: Children with stage III Wilms tumor (WT) treated in NWTS-5 were assessed for event-free (EFS) and overall survival (OS). Sites of relapse and molecular status of tumors are reported. EFS and OS are reported 8 years after diagnosis. RESULTS: There were 569 patients with local stage III favorable-histology (FH) WT in this analysis, of whom 109 had overall stage IV disease. LN involvement alone was the most frequent criterion for stage III designation (38%), followed by microscopic residual disease alone (20%), microscopic residual disease and LN involvement (14%), and spill or soilage alone (9%). The 8-year EFS and OS estimates for all patients with local stage III FHWT were 82% and 91%, respectively. Multivariate analysis demonstrated that both LN involvement (relative risk, 1.89; P = .005) and microscopic residual disease (relative risk, 1.87; P = .007) were predictive of EFS, and OS results were similar. There was no apparent difference in pattern of relapse according to stage III subtype. The rate of loss of heterozygosity was higher (6%) for those with positive LNs than for those without (2%; P = .05). CONCLUSION: LN involvement and microscopic residual are the stage III criteria highly predictive of EFS and OS for patients with stage III FHWT. It is possible that in future studies, patients with different stage III criteria may receive different therapies.
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Neoplasias Renais/patologia , Tumor de Wilms/patologia , Criança , Previsões , Humanos , Neoplasias Renais/mortalidade , Metástase Linfática , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Tumor de Wilms/mortalidadeRESUMO
BACKGROUND: Metastatic lung disease in Wilms tumor (WT) patients was traditionally identified by chest radiograph (CXR). It is unclear whether patients with small lesions, detectable only by computed tomography ("CT-only" lesions), require the more intensive therapy, including doxorubicin and lung irradiation, given to patients with metastases detectable by CXR. PROCEDURES: This study involved 417 patients with favorable histology WT and isolated lung metastases (detected by CXR or CT) who were registered on National Wilms tumor Study (NWTS)-4 or -5. Outcomes by method of detection (CXR vs. CT-only), use of lung radiation, and 2- or 3-drug chemotherapy (dactinomycin and vincristine ± doxorubicin) were determined and compared using the log-rank test. RESULTS: There were 231 patients with lung lesions detected by CXR and 186 by CT-only. Of the patients with CT-only nodules, 37 received only 2 drugs and 101 did not receive lung radiation. Five-year event-free survival (EFS) was greater for patients receiving three drugs (including doxorubicin) with or without lung radiation than for those receiving two drugs (80% vs. 56%; P = 0.004). There was no difference seen in 5-year overall survival (OS) between the 3- and 2-drug subsets (87% vs. 86%; P = 0.91). There were no significant differences in EFS (82% vs. 72%; P = 0.13) or OS (91% vs. 83%; P = 0.46) for patients with CT-only nodules whether they received lung radiation or not. CONCLUSIONS: Our results suggest that patients with CT-only lung lesions may have improved EFS but not OS from the addition of doxorubicin but do not appear to benefit from pulmonary radiation.
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Neoplasias Renais/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Radiografia Torácica , Tomografia Computadorizada por Raios X , Tumor de Wilms/diagnóstico por imagem , Tumor de Wilms/secundário , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/terapia , Masculino , Nefrectomia , Tumor de Wilms/terapiaRESUMO
BACKGROUND: Little is known about treatment outcomes for children who have end-stage renal disease (ESRD) after treatment for Wilms tumor (WT). METHODS: Time-to-transplant, graft failure, and survival outcomes were examined for 173 children enrolled on the National Wilms Tumor Study who developed ESRD. RESULTS: Fifty-five patients whose ESRD resulted from progressive bilateral WT (PBWT) experienced high early mortality from WT that limited their opportunity for transplant (47% at 5 years) and survival (44% at 10 years) in comparison to population controls. The 118 patients whose ESRD was due to other causes (termed "chronic kidney disease"), many of whom had WT-associated congenital anomalies, had transplant (77% at 5 years) and survival (73% at 10 years) outcomes no worse than those for population controls. Graft failure following transplant was comparable for the two groups. Minority children had twice the median time to transplant as non-Hispanic whites and twice the mortality rates, also reflecting population trends. CONCLUSIONS: In view of the continuing high mortality in patients with ESRD, and the dramatic improvement in outlook following kidney transplantation, re-evaluation of current guidelines for a 2-year delay in transplant following WT treatment may be warranted.
Assuntos
Falência Renal Crônica/etiologia , Falência Renal Crônica/mortalidade , Neoplasias Renais/complicações , Transplante de Rim/mortalidade , Tumor de Wilms/complicações , Adolescente , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Humanos , Lactente , Recém-Nascido , Falência Renal Crônica/cirurgia , Neoplasias Renais/cirurgia , Masculino , Análise de Sobrevida , Resultado do Tratamento , Tumor de Wilms/cirurgiaRESUMO
PURPOSE: We assessed risk factors for end stage renal disease in patients with Wilms tumor without known WT1 related syndromes. We hypothesized that patients with characteristics suggestive of a WT1 etiology (early onset, stromal predominant histology, intralobar nephrogenic rests) would have a higher risk of end stage renal disease due to chronic renal failure. We predicted a high risk of end stage renal disease due to progressive bilateral Wilms tumor in patients with metachronous bilateral disease. MATERIALS AND METHODS: End stage renal disease was ascertained in 100 of 7,950 nonsyndromic patients enrolled in a National Wilms Tumor Study during 1969 to 2002. Risk factors were evaluated with cumulative incidence curves and proportional hazard regressions. RESULTS: The cumulative incidence of end stage renal disease due to chronic renal failure 20 years after Wilms tumor diagnosis was 0.7%. For end stage renal disease due to progressive bilateral Wilms tumor the incidence was 4.0% at 3 years after diagnosis in patients with synchronous bilateral Wilms tumor and 19.3% in those with metachronous bilateral Wilms tumor. For end stage renal disease due to chronic renal failure stromal predominant histology had a HR of 6.4 relative to mixed (95% CI 3.4, 11.9; p<0.001), intralobar rests had a HR of 5.9 relative to no rests (95% CI 2.0, 17.3; p=0.001), and Wilms tumor diagnosis at less than 24 months had a HR of 1.7 relative to 24 to 48 months and 2.8 relative to greater than 48 months (p=0.003 for trend). CONCLUSIONS: Metachronous bilateral Wilms tumor is associated with high rates of end stage renal disease due to surgery for progressive Wilms tumor. Characteristics associated with a WT1 etiology markedly increased the risk of end stage renal disease due to chronic renal failure despite the low risk in non-WT1 syndromic cases overall.
Assuntos
Falência Renal Crônica/epidemiologia , Falência Renal Crônica/etiologia , Neoplasias Renais/complicações , Tumor de Wilms/complicações , Pré-Escolar , Genes do Tumor de Wilms , Humanos , Lactente , Neoplasias Renais/genética , Fatores de Risco , Tumor de Wilms/genéticaRESUMO
PURPOSE: This study was undertaken to evaluate the effect of prior treatment with radiation therapy or chemotherapy for unilateral Wilms tumor (WT) diagnosed during childhood on pregnancy complications, birth weight, and the frequency of congenital malformations in live-born offspring. PATIENTS AND METHODS: We reviewed pregnancy outcomes among female survivors and partners of male survivors of WT treated on National Wilms Tumor Studies 1, 2, 3, and 4 by using a maternal questionnaire and a review of both maternal and offspring medical records. RESULTS: We received reports of 1,021 pregnancies with duration of 20 weeks or longer, including 955 live-born singletons, for whom 700 sets of maternal and offspring medical records were reviewed. Rates of hypertension complicating pregnancy (International Classification of Diseases [ICD] code 642), early or threatened labor (ICD-644) and malposition of the fetus (ICD-652) increased with increasing radiation dose in female patients. The percentages of offspring weighing less than 2,500 g at birth and of those having less than 37 weeks of gestation also increased with dose. There was no significant trend with radiation dose in the number of congenital anomalies recorded in offspring of female patients. CONCLUSION: Women who receive flank radiation therapy as part of the treatment for unilateral WT are at increased risk of hypertension complicating pregnancy, fetal malposition, and premature labor. The offspring of these women are at risk for low birth weight and premature (ie, < 37 weeks gestation) birth. These risks must be considered in the obstetrical management of female survivors of WT.
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Complicações Neoplásicas na Gravidez/etiologia , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/radioterapia , Feminino , Seguimentos , Humanos , Hipertensão Induzida pela Gravidez/etiologia , Masculino , Gravidez , Resultado da Gravidez , Lesões por Radiação/etiologia , SobreviventesRESUMO
OBJECTIVE: To determine the event-free survival (EFS) and overall survival (OS) of children with very low risk Wilms tumor (VLRWT) treated with surgery only. BACKGROUND: Previous studies suggested that postoperative chemotherapy had not improved the prognosis of children with VLRWT. A total of 77 children <24 months of age with small (<550 g) Stage I favorable histology Wilms tumors were treated with surgery only. This study was closed based on stopping rules to ensure that the 2-year EFS was > or =90%. METHODS: A total of 77 children were assessed for EFS and OS. Of these patients, 21 enrolled at the time of closure were recalled, treated with dactinomycin and vincristine (regimen EE4A), and censored for analysis thereafter. About 111 children subsequently treated with EE4A were available for comparison. RESULTS: Median follow-up of surviving patients was 8.2 years for surgery only (range, 1.9-11.8 years) and 5.2 years for the EE4A group (range, 1.6-8.9 years). The estimated 5-year EFS for surgery only was 84% (95% confidence interval [CI]: 73%, 91%); for the EE4A patients it was 97% (95% CI: 92%, 99%, P = 0.002). One death was observed in each treatment group. The estimated 5-year OS was 98% (95% CI: 87%, 99%) for surgery only and 99% (95% CI: 94%, 99%) for EE4A (P = 0.70). CONCLUSION: The surgery-only EFS was lower than anticipated but, coupled with a much higher than anticipated salvage rate of the chemotherapy naive patients whose disease recurred, led to an observed long-term OS equivalent to that seen with 2-drug chemotherapy. This approach to the treatment of patients with VLRWT eliminates the toxic side-effects of chemotherapy for a large majority of patients. A follow-up study is underway to confirm these findings.
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Neoplasias Renais/cirurgia , Tumor de Wilms/cirurgia , Humanos , Lactente , Neoplasias Renais/mortalidade , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Tumor de Wilms/mortalidadeRESUMO
PURPOSE: We undertook this study to determine (1) the frequency with which spilled tumor cells of favorable histology produced intra-abdominal disease in patients treated with differing chemotherapy regimens and abdominal radiation therapy (RT) and (2) the patterns of relapse and outcomes in such patients. METHODS AND MATERIALS: The influence of RT dose (0, 10, and 20 Gy), RT fields (flank, whole abdomen), and chemotherapy with dactinomycin and vincristine (2 drugs) vs. added doxorubicin (three drugs) on intra-abdominal tumor recurrence rates was analyzed by logistic regression in 450 patients. Each patient was considered at risk for two types of failure: flank and subdiaphragmatic beyond-flank recurrence, with the correlation between the two outcomes accounted for in the analyses. RESULTS: The crude odds ratio for the risk of recurrence relative to no RT was 0.35 (0.15-0.78) for 10Gy and 0.08 (0.01-0.58) for 20Gy. The odds ratio for the risk of recurrence for doxorubicin to two drugs after adjusting for RT was not significant. For Stage II patients (NWTS-4), the 8-year event rates with and without spillage, respectively, were 79% and 87% for relapse-free survival (p = 0.07) and 90% and 95% for overall survival (p = 0.04). CONCLUSIONS: Irradiation (10 Gy or 20 Gy) reduced abdominal tumor recurrence rates after tumor spillage. Tumor spillage in Stage II patients reduced relapse-free survival and overall survival, but only the latter was of statistical significance. These data provide a basis for assessing the risks vs. benefits when considering treatment for children with favorable histology Wilms tumor and surgical spillage.
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Neoplasias Abdominais/prevenção & controle , Neoplasias Abdominais/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Renais , Inoculação de Neoplasia , Tumor de Wilms/secundário , Criança , Dactinomicina/administração & dosagem , Doxorrubicina/administração & dosagem , Seguimentos , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/radioterapia , Modelos Logísticos , Estadiamento de Neoplasias , Razão de Chances , Neoplasias Peritoneais/prevenção & controle , Neoplasias Peritoneais/secundário , Dosagem Radioterapêutica , Medição de Risco/métodos , Vincristina/administração & dosagem , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/radioterapiaRESUMO
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.
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Neoplasias Renais/complicações , Segunda Neoplasia Primária/complicações , Tumor de Wilms/complicações , Adolescente , Criança , Estudos de Coortes , Humanos , Incidência , Segunda Neoplasia Primária/classificação , Segunda Neoplasia Primária/patologia , Análise de SobrevidaRESUMO
PURPOSE: This analysis was undertaken to determine the cumulative risk of and risk factors for portal hypertension (PHTN) in patients with Wilms' tumor (WT). METHODS AND MATERIALS: Medical records were reviewed to identify cases of PHTN identified with late liver/spleen/gastric toxicities in a cohort of 5,195 patients treated with National Wilms' Tumor Studies (NWTS) protocols 1 to 4. A nested case control study (5 controls/case) was conducted to determine relationships among doxorubicin, radiation therapy (RT) dose to the liver, patient gender, and PHTN. Conditional logistic regression was used to estimate adjusted hazard ratios (HR) of PHTN associated with these factors. RESULTS: Cumulative risk of PHTN at 6 years from WT diagnosis was 0.7% for patients with right-sided tumors vs. 0.1% for those with left-sided tumors (p = 0.002). Seventeen of 19 cases were evaluable for RT. The majority of cases (16/17 [94%]) received right-flank RT either alone or as part of whole-abdomen RT and received >15 Gy to the liver. Fifteen of 17 (88%) patients received a higher dose to the liver than they would have with modern WT protocols. Controlling for RT dose, the HR was 3.0 for patients who received doxorubicin (p = 0.32) and 2.8 for females (p = 0.15). Controlling for doxorubicin, the 95% lower confidence bound on the HR associating PHTN with a minimum liver RT dose of >15 Gy vs.
Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Hipertensão Portal/etiologia , Neoplasias Renais , Fígado/efeitos da radiação , Tumor de Wilms , Estudos de Casos e Controles , Criança , Pré-Escolar , Terapia Combinada/efeitos adversos , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/radioterapia , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Modelos Logísticos , Masculino , Modelos de Riscos Proporcionais , Dosagem Radioterapêutica , Risco , Baço/efeitos dos fármacos , Baço/efeitos da radiação , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/patologia , Tumor de Wilms/radioterapiaRESUMO
Case-cohort data analyses often ignore valuable information on cohort members not sampled as cases or controls. The Atherosclerosis Risk in Communities (ARIC) study investigators, for example, typically report data for just the 10%-15% of subjects sampled for substudies of their cohort of 15,972 participants. Remaining subjects contribute to stratified sampling weights only. Analysis methods implemented in the freely available R statistical system (http://cran.r-project.org/) make better use of the data through adjustment of the sampling weights via calibration or estimation. By reanalyzing data from an ARIC study of coronary heart disease and simulations based on data from the National Wilms Tumor Study, the authors demonstrate that such adjustment can dramatically improve the precision of hazard ratios estimated for baseline covariates known for all subjects. Adjustment can also improve precision for partially missing covariates, those known for substudy participants only, when their values may be imputed with reasonable accuracy for the remaining cohort members. Links are provided to software, data sets, and tutorials showing in detail the steps needed to carry out the adjusted analyses. Epidemiologists are encouraged to consider use of these methods to enhance the accuracy of results reported from case-cohort analyses.
Assuntos
Estudos de Coortes , Doença da Artéria Coronariana/epidemiologia , Métodos Epidemiológicos , Biomarcadores/análise , Calibragem , Doença da Artéria Coronariana/etnologia , Doença da Artéria Coronariana/genética , Feminino , Genótipo , Humanos , Modelos Lineares , Masculino , Observação , Modelos de Riscos Proporcionais , Fatores de Risco , Estudos de AmostragemRESUMO
OBJECTIVE: This study examined the association between pre-conception and in utero maternal medical radiation exposure and Wilms tumor, using data from a large population-based case-control study. METHODS: Cases were identified from the National Wilms Tumor Study Group. Controls were identified by random digit dialing and frequency matched to child's age and geographic area of residence in the United States and Canada. Interview data from 512 cases and 509 controls were analyzed using multivariable logistic regression. Odds ratios (OR) and 95% confidence intervals (CI) for Wilms tumor and exposure to: (1) maternal X-ray alone and; (2) all medical radiation types (X-ray, CT, RT, Nuclear scans, Fluoroscopy) combined, for the period from two years before conception until child birth were estimated after adjustment for age, geographic area, maternal education, and household income. RESULTS: We found no consistent association between the risk of Wilms tumor and either maternal X-ray exposure (OR 0.9, 95% CI 0.7-1.3) or all medical radiation types combined (OR 0.9, 95% CI 0.7-1.2). No meaningful associations were seen for analysis of gonadal or non-gonadal radiation exposure. CONCLUSION: Our study did not find any consistent pattern of association between Wilms tumor and maternal radiation exposure during pre-pregnancy or pregnancy period. In view of the negative findings from the largest case control study of this question to date, the reduced doses of biological radiation during pregnancy, and the requirements for an improved study design, we believe that future studies of this exposure may not be a priority for research on Wilms tumor.