Richard K. Severson

Incidence of cancer in children in the United States : sex-, race-, and 1-year age-specific rates by histologic type

Background. Rates of cancer in children usually are presented in 5‐year age groups, despite large variations of incidence within these groups. The purpose of this report is to provide histology‐specific incidence rates within single‐year age groups, stratified by sex and race, among children.

Epidemiologic Evaluation of Measurement Data in the Presence of Detection Limits

Quantitative measurements of environmental factors greatly improve the quality of epidemiologic studies but can pose challenges because of the presence of upper or lower detection limits or interfering compounds, which do not allow for precise measured values. We consider the regression of an environmental measurement (dependent variable) on several covariates (independent variables). Various strategies are commonly employed to impute values for interval-measured data, including assignment of one-half the detection limit to nondetected values or of “fill-in” values randomly selected from an appropriate distribution. On the basis of a limited simulation study, we found that the former approach can be biased unless the percentage of measurements below detection limits is small (5–10%). The fill-in approach generally produces unbiased parameter estimates but may produce biased variance estimates and thereby distort inference when 30% or more of the data are below detection limits. Truncated data methods (e.g., Tobit regression) and multiple imputation offer two unbiased approaches for analyzing measurement data with detection limits. If interest resides solely on regression parameters, then Tobit regression can be used. If individualized values for measurements below detection limits are needed for additional analysis, such as relative risk regression or graphical display, then multiple imputation produces unbiased estimates and nominal confidence intervals unless the proportion of missing data is extreme. We illustrate various approaches using measurements of pesticide residues in carpet dust in control subjects from a case–control study of non-Hodgkin lymphoma.

Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium

Some autoimmune disorders are increasingly recognized as risk factors for non-Hodgkin lymphoma (NHL) overall, but large-scale systematic assessments of risk of NHL subtypes are lacking. We performed a pooled analysis of self-reported autoimmune conditions and risk of NHL and subtypes, including 29 423 participants in 12 case-control studies. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) in a joint fixed-effects model. Sjögren syndrome was associated with a 6.5-fold increased risk of NHL, a 1000-fold increased risk of parotid gland marginal zone lymphoma (OR = 996; 95% CI, 216-4596), and with diffuse large B-cell and follicular lymphomas. Systemic lupus erythematosus was associated with a 2.7-fold increased risk of NHL and with diffuse large B-cell and marginal zone lymphomas. Hemolytic anemia was associated with diffuse large B-cell NHL. T-cell NHL risk was increased for patients with celiac disease and psoriasis. Results for rheumatoid arthritis were heterogeneous between studies. Inflammatory bowel disorders, type 1 diabetes, sarcoidosis, pernicious anemia, and multiple sclerosis were not associated with risk of NHL or subtypes. Thus, specific autoimmune disorders are associated with NHL risk beyond the development of rare NHL subtypes in affected organs. The pattern of associations with NHL subtypes may harbor clues to lymphomagenesis.

Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium

BACKGROUND Common genetic variants in immune and inflammatory response genes can affect the risk of developing non-Hodgkin lymphoma. We aimed to test this hypothesis using previously unpublished data from eight European, Canadian, and US case-control studies of the International Lymphoma Epidemiology Consortium (InterLymph). METHODS We selected 12 single-nucleotide polymorphisms for analysis, on the basis of previous functional or association data, in nine genes that have important roles in lymphoid development, Th1/Th2 balance, and proinflammatory or anti-inflammatory pathways (IL1A, IL1RN, IL1B, IL2, IL6, IL10, TNF, LTA, and CARD15). Genotype data for one or more single-nucleotide polymorphisms were available for 3586 cases of non-Hodgkin lymphoma and for 4018 controls, and were assessed in a pooled analysis by use of a random-effects logistic regression model. FINDINGS The tumour necrosis factor (TNF) -308G-->A polymorphism was associated with increased risk of non-Hodgkin lymphoma (p for trend=0.005), particularly for diffuse large B-cell lymphoma, the main histological subtype (odds ratio 1.29 [95% CI 1.10-1.51] for GA and 1.65 [1.16-2.34] for AA, p for trend <0.0001), but not for follicular lymphoma. The interleukin 10 (IL10) -3575T-->A polymorphism was also associated with increased risk of non-Hodgkin lymphoma (p for trend=0.02), again particularly for diffuse large B-cell lymphoma (p for trend=0.006). For individuals homozygous for the TNF -308A allele and carrying at least one IL10 -3575A allele, risk of diffuse large B-cell lymphoma doubled (2.13 [1.37-3.32], p=0.00083). INTERPRETATION Common polymorphisms in TNF and IL10, key cytokines for the inflammatory response and Th1/Th2 balance, could be susceptibility loci for non-Hodgkin lymphoma. Moreover, our results underscore the importance of consortia for investigating the genetic basis of chronic diseases like cancer.

Infant Cancer in the U.s.: Histology-specific Incidence and Trends, 1973 to 1992

Background Many cancers in infants demonstrate unique epidemiologic, clinical, and genetic characteristics compared with cancers in older children. Few epidemiologic reports, however, have focused on this important age group. Methods: Population-based data from the Surveillance, Epidemiology, and End Results (SEER) program were used to estimate relative frequency, incidence rates, and average annual percentage change of rates among children in their first year of life (infants) who were diagnosed with a malignant neoplasm from 1973 to 1992(N= 1461). Results: The greatest proportion of cases (12%) was diagnosed during the first month of life, with extracranial neuroblastoma accounting for 35% of this total. Overall, the average annual incidence rate was 223/1,000,000 infants. Extracranial neuroblastoma was the most common infant malignancy (58/1,000,000 infants per year), followed by leukemias (37/1,000,000), brain and central nervous system (CNS) tumors (34/1,000,000), and retinoblastoma (27/1,000,000). White infants had a 32% higher incidence rate than black infants. The average annual percentage increase in rates for all cancer from 1973 to 1992 was 2.9% (95% CI: 1.9%, 3.8%). For neoplasms with at least 100 cases, increasing trends were greatest for retinoblastoma (4.6%), CNS (4.1 %), and extracranial neuroblastoma (3.4%). Conclusions: Incidence rates increased notably over the study period. Future studies should consider the unique presentation of infants with cancer when developing new hypotheses related to cancer etiology and gene-environment interactions.

National cancer clinical trials: Children have equal access; adolescents do not

PURPOSE To determine whether adolescents with cancer, who in comparison to younger patients have a higher cancer incidence and lower mortality reduction, have equal access to national cancer clinical trials. METHODS The ethnic/racial distribution of 29,859 subjects < 20 years of age entered onto National Cancer Institute-sponsored clinical trials between January 1, 1991, and June 30, 1994, was compared with the expected distribution of patients of the same age in the United States. RESULTS The Childrens Cancer Group and Pediatric Oncology Group had 29,134 (97.6%) of the total study entries among < 20-year-old subjects during the 3.5 years of surveillance. The adult cooperative groups accounted for < 3% of the clinical trials entries in the 15-19-year age range. When analyzed nationally by region, the under-representation of the older adolescent subjects was universal. From other analyses, the two pediatric cooperative groups were estimated to have registered > 94% of the children < 15 years of age who were expected to have been diagnosed to have cancer, but only 21% of the cancer patients in the 15-19-year age group. CONCLUSIONS The national pediatric cancer cooperative groups allow the majority of American children < 15 years of age and their families equal opportunity to access clinical cancer trials, regardless of race or ethnicity. Among patients 15-19 years of age, however, > 75% are not being enrolled by any cooperative group sponsored by the National Cancer Institute. Thus, older adolescents are disadvantaged with respect to access to the national clinical trials, regardless of their race or ethnicity.

Bilateral Risk for Subsequent Breast Cancer After Lobular Carcinoma-In-Situ: Analysis of Surveillance, Epidemiology, and End Results Data

PURPOSE Noninvasive lesions involving the lobules of the breast are increasingly diagnosed as incidental microscopic findings at the time of lumpectomy or core-needle biopsy. We investigated the incidence rates of invasive breast cancer (IBC) after a diagnosis of lobular carcinoma-in-situ (LCIS) by using Surveillance, Epidemiology, and End Results (SEER) data. PATIENTS AND METHODS Patients (N = 4,853) having a diagnosis of primary LCIS in the time period of 1973 to 1998 were identified using the SEER Public Use CD-ROM data. The database was then searched for patients with subsequent primary IBC occurrences (n = 350). The clinical and pathologic characteristics of patients with subsequent primary IBCs were compared with the characteristics of patients with primary IBCs attained during the same time period (N = 255,114). RESULTS The incidence of IBC increased over time from diagnosis of LCIS, with 7.1% +/- 0.5% incidence of IBC at 10 years. IBCs detected after partial mastectomy occurred in either breast (46% ipsilateral and 54% contralateral); however, after mastectomy, most IBCs were contralateral (94.7%). IBCs occurring after LCIS more often represented invasive lobular histology (23.1%) compared with primary IBCs (6.5%). The standardized incidence ratio (the ratio of observed to expected cases) for developing IBC was 2.4 (95% CI, 2.1 to 2.6) adjusted for age and year of diagnosis. CONCLUSION LCIS is associated with increased risk of subsequent invasive disease, with equal predisposition in either breast. The minimum risk of developing IBC after LCIS is 7.1% at 10 years.

Sarcoma as a second malignancy after treatment for breast cancer

BACKGROUND Second malignant neoplasms may be a consequence of radiotherapy for the treatment of breast cancer. Prior studies evaluating sarcomas as second malignant neoplasms in breast cancer patients have been limited by the numbers of patients and relatively low incidence of sarcoma. Using data from the Surveillance, Epidemiology and End Results registries, we evaluated the influence of radiation therapy on the development of subsequent sarcomas in cases with primary breast cancer. METHODS Cases with primary invasive breast cancer (n = 274,572) were identified in the Surveillance, Epidemiology and End Results Cancer Incidence Public-Use Database (1973-1997). The database was then queried to determine the cases developing subsequent sarcomas (n = 263). Eighty-seven of these cases received radiation therapy, and 176 had no radiation therapy. The cumulative incidence of developing secondary sarcoma and the survival post developing secondary sarcoma were determined by the Kaplan-Meier method. RESULTS The occurrence of sarcoma was low, regardless of whether cases received or did not receive radiation therapy: 3.2 per 1,000 (SE [standard error] = 0.4) and 2.3 per 1,000 (SE = 0.2) cumulative incidence at 15 years post diagnosis, respectively (p = 0.001). Of the sarcomas occurring within the field of radiation, angiosarcoma accounted for 56.8%, compared to only 5.7% of angiosarcomas occurring in cases not receiving radiotherapy. The cumulative incidence of angiosarcoma at 15 years post diagnosis was 0.9 per 1,000 for cases receiving radiation (SE = 0.2) and 0.1 per 1,000 for cases not receiving radiation (SE < 0.1). Overall survival was poor for cases of sarcoma after breast cancer (27-35% at 5 years), but not significantly different between patients receiving or not receiving radiation therapy for their primary breast cancer. CONCLUSIONS Radiotherapy in the treatment of breast cancer is associated with an increased risk of subsequent sarcoma, but the magnitude of this risk is small. Angiosarcoma is significantly more prevalent in cases treated with radiotherapy, occurring especially in or adjacent to the radiation field. The small difference in risk of subsequent sarcoma for breast cancer patients receiving radiotherapy does not supersede the benefit of radiotherapy.

Cigarette Smoking and Risk of Non-Hodgkin Lymphoma: A Pooled Analysis from the International Lymphoma Epidemiology Consortium (InterLymph)

Background: The International Lymphoma Epidemiology Consortium (InterLymph) provides an opportunity to analyze the relationship between cigarette smoking and non-Hodgkin lymphoma with sufficient statistical power to consider non-Hodgkin lymphoma subtype. The results from previous studies of this relationship have been inconsistent, likely due to the small sample sizes that arose from stratification by disease subtype. To clarify the role of cigarette smoking in the etiology of non-Hodgkin lymphoma, we conducted a pooled analysis of original patient data from nine case-control studies of non-Hodgkin lymphoma conducted in the United States, Europe, and Australia. Methods: Original data were obtained from each study and uniformly coded. Risk estimates from fixed-effects and two-stage random-effects models were compared to determine the impact of interstudy heterogeneity. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived from unconditional logistic regression models, controlling for study center, age, sex, and race. Results: In our pooled study population of 6,594 cases and 8,892 controls, smoking was associated with slightly increased risk estimates (OR, 1.07; 95% CI, 1.00-1.15). Stratification by non-Hodgkin lymphoma subtype revealed that the most consistent association between cigarette smoking and non-Hodgkin lymphoma was observed among follicular lymphomas (n = 1452). Compared with nonsmokers, current smokers had a higher OR for follicular lymphoma (1.31; 95% CI, 1.12-1.52) than former smokers (1.06; 95% CI, 0.93-1.22). Current heavy smoking (≥36 pack-years) was associated with a 45% increased OR for follicular lymphoma (1.45; 95% CI, 1.15-1.82) compared with nonsmokers. Conclusions: Cigarette smoking may increase the risk of developing follicular lymphoma but does not seem to affect risk of the other non-Hodgkin lymphoma subtypes we examined. Future research is needed to determine the biological mechanism responsible for our subtype-specific results.

Childhood cancer in the united states: A geographical analysis of cases from the Pediatric Cooperative Clinical Trials Groups

After injuries, cancer is the leading cause of death in children younger than 15 years in the United States. Despite dramatic increases in 5‐year survival rates, more than 100,000 person‐years of life are lost to childhood cancer each year. The exact proportion of pediatric cancer patients who receive care at centers that utilize up‐to‐date therapeutic protocols [such as those affiliated with the Childrens Cancer Group (CCG) or the Pediatric Oncology Group (POG)] remains unknown. The purpose of this study was to estimate the proportion and geographic distribution of childhood cancer patients in the United States who are seen at participating centers of the CCG and the POG.