Peter D. Inskip

Cellular-Telephone Use and Brain Tumors

BACKGROUND Concern has arisen that the use of hand-held cellular telephones might cause brain tumors. If such a risk does exist, the matter would be of considerable public health importance, given the rapid increase worldwide in the use of these devices. METHODS We examined the use of cellular telephones in a case-control study of intracranial tumors of the nervous system conducted between 1994 and 1998. We enrolled 782 patients through hospitals in Phoenix, Arizona; Boston; and Pittsburgh; 489 had histologically confirmed glioma, 197 had meningioma, and 96 had acoustic neuroma. The 799 controls were patients admitted to the same hospitals as the patients with brain tumors for a variety of nonmalignant conditions. RESULTS As compared with never, or very rarely, having used a cellular telephone, the relative risks associated with a cumulative use of a cellular telephone for more than 100 hours were 0.9 for glioma (95 percent confidence interval, 0.5 to 1.6), 0.7 for meningioma (95 percent confidence interval, 0.3 to 1.7), 1.4 for acoustic neuroma (95 percent confidence interval, 0.6 to 3.5), and 1.0 for all types of tumors combined (95 percent confidence interval, 0.6 to 1.5). There was no evidence that the risks were higher among persons who used cellular telephones for 60 or more minutes per day or regularly for five or more years. Tumors did not occur disproportionately often on the side of head on which the telephone was typically used. CONCLUSIONS These data do not support the hypothesis that the recent use of hand-held cellular telephones causes brain tumors, but they are not sufficient to evaluate the risks among long-term, heavy users and for potentially long induction periods.

Obesity in Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report from the Childhood Cancer Survivor Study

PURPOSE To determine whether adult survivors (>or= 18 years of age) of childhood acute lymphoblastic leukemia (ALL) are at increased risk for obesity and to assess patient and treatment variables that influence risk. PATIENTS AND METHODS A retrospective cohort of participants of the Childhood Cancer Survivor Study was used to compare 1,765 adult survivors of childhood ALL to 2,565 adult siblings of childhood cancer survivors. Body-mass index (BMI; kilograms per square meter), calculated from self-reported heights and weights, was used to determine the prevalence of being overweight (BMI, 25-29.9) or obese (BMI >or= 30.0). Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for being overweight or obese among ALL survivors relative to the sibling control group. RESULTS The age- and race-adjusted OR for being obese in survivors treated with cranial radiation doses >or= 20 Gy in comparison with siblings was 2.59 for females (95% CI, 1.88 to 3.55; P <.001) and 1.86 for males (95% CI, 1.33 to 2.57; P <.001). The OR for obesity was greatest among females diagnosed at 0 to 4 years of age and treated with radiation doses >or= 20 Gy (OR, 3.81; 95% CI, 2.34 to 5.99; P <.001). Obesity was not associated with treatment consisting of chemotherapy only or with cranial radiation doses of 10 to 19 Gy. CONCLUSION Cranial radiotherapy >or= 20 Gy is associated with an increased prevalence of obesity, especially in females treated at a young age. It is imperative that healthcare professionals recognize this risk and develop strategies to enhance weight control and encourage longitudinal follow-up.

Second Neoplasms in Survivors of Childhood Cancer: Findings From the Childhood Cancer Survivor Study Cohort

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 Hodgkins 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.

Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study

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 Hodgkins 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 Hodgkins lymphoma compared with 49 (19%) controls. 11 (42%) of those who had Hodgkins 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 Hodgkins 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.

Long-Term Neurologic and Neurosensory Sequelae in Adult Survivors of a Childhood Brain Tumor: Childhood Cancer Survivor Study

PURPOSE To describe the neurologic and neurosensory deficits in children with brain tumors (BTs), compare incidence of these deficits with that of a sibling control group, and evaluate the factors associated with the development of these deficits. PATIENTS AND METHODS Detailed questionnaires were completed on 1,607 patients diagnosed between 1970 and 1986 with a primary CNS tumor. Neurosensory and neurologic dysfunctions were assessed and results compared with those of a sibling control group. Medical records on all patients were abstracted, including radiotherapy dose and volume. RESULTS Seventeen percent of patients developed neurosensory impairment. Relative to the sibling comparison group, patients surviving BTs were at elevated risk for hearing impairments (relative risk [RR], 17.3; P = <.0001), legal blindness in one or both eyes (RR, 14.8; P = <.0001), cataracts (RR, 11.9; P = <.0001), and double vision (RR, 8.8; P = <.0001). Radiation exposure greater than 50 Gy to the posterior fossa was associated with a higher likelihood of developing any hearing impairment. Coordination and motor control problems were reported in 49% and 26%, respectively, of survivors. Children receiving at least 50 Gy to the frontal brain regions had a moderately elevated risk for motor problems (RR, 2.0; P <.05). Seizure disorders were reported in 25% of patients, including 6.5% who had a late first occurrence. Radiation dose of 30 Gy or more to any cortical segment of the brain was associated with a two-fold elevated risk for a late seizure disorder. CONCLUSION Children surviving BTs are at significant risk for both early and late neurologic or neurosensory sequelae. These sequelae need to be prospectively monitored.

Sex Disparities in Cancer Incidence by Period and Age

Background: Cancer epidemiology articles often point out that cancer rates tend to be higher among males than females yet rarely is this theme the subject of investigation. Methods: We used the Surveillance, Epidemiology and End Results program data to compute age-adjusted (2000 U.S. standard population) sex-specific incidence rates and male-to-female incidence rate ratios (IRR) for specific cancer sites and histologies for the period 1975 to 2004. Results: The 10 cancers with the largest male-to-female IRR were Kaposi sarcoma (28.73), lip (7.16), larynx (5.17), mesothelioma (4.88), hypopharynx (4.13), urinary bladder (3.92), esophagus (3.49), tonsil (3.07), oropharynx (3.06), and other urinary organs (2.92). Only 5 cancers had a higher incidence in females compared with males: breast (0.01), peritoneum, omentum, and mesentery (0.18), thyroid (0.39), gallbladder (0.57), and anus, anal canal, and anorectum (0.81). Between 1975 and 2004, the largest consistent increases in male-to-female IRR were for cancers of the tonsil, oropharynx, skin excluding basal and squamous, and esophagus, whereas the largest consistent decreases in IRR were for cancers of the lip and lung and bronchus. Male-to-female IRRs varied considerably by age, the largest increases of which were for ages 40 to 59 years for tonsil cancer and hepatocellular carcinoma. The largest decreases in male-to-female IRR by age, meanwhile, were for ages 30 to 49 years for thyroid cancer, ages >70 years for esophageal squamous cell carcinoma, and ages >30 years for lung and bronchus cancer. Conclusion: These observations emphasize the importance of sex in cancer etiopathogenesis and may suggest novel avenues of investigation. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1174–82)

Breast Cancer after Childhood Cancer: A Report from the Childhood Cancer Survivor Study

Context Adult survivors of childhood cancer are at risk for developing breast cancer and other secondary cancer. Knowing the risk factors for breast cancer in these women may help to formulate screening policies for them. Contribution Among 6068 women who survived childhood cancer, 95 developed breast cancer at a median age of 35 years. Childhood sarcoma, chest irradiation, family history of breast cancer, and personal history of thyroid disease increased the risk for breast cancer. Implications Women who survived childhood cancer and had sarcoma, chest irradiation, family history of breast cancer, or personal history of thyroid disease should consider early, vigilant screening for breast cancer. The Editors Women treated with chest radiation therapy for childhood and adolescent Hodgkin disease are at increased risk for developing breast cancer at a young age (1-12). However, case reports and preliminary studies indicate that survivors of childhood cancer other than Hodgkin disease may also be at risk for secondary breast cancer (1, 13, 14). Practitioners caring for the growing population of young female survivors of childhood cancer are challenged with assessing breast cancer risk in order to recommend screening and preventive strategies. Although recent studies have shown that the risk for radiation-induced breast cancer is directly related to dose of chest radiation, specific details of previous treatment are not always available to clinicians and may not affect screening decisions (11, 12). In addition, whether primary cancer diagnosis, previous treatment other than chest radiation, or other well-established breast cancer risk factors contribute to a childhood cancer survivors risk for breast cancer is unknown. Studies of Hodgkin disease survivors have shown that clinical examination and screening mammography can detect early-stage secondary breast cancer in young women (15-17), and although treatment options may be limited by previous therapy, early-stage secondary breast cancer is curable (16, 17). Thus, identifying specific groups of childhood cancer survivors who would benefit from early mammographic screening might reduce the morbidity and mortality of breast cancer in these young women. In this study, we analyzed a large series of women with secondary breast cancer from a cohort of childhood cancer survivors, the Childhood Cancer Survivor Study (CCSS), to describe clinical and pathologic features of breast cancer and to determine breast cancer risk relative to the general population. We hypothesized that breast cancer risk would be modified by previous treatment and factors unrelated to treatment. Thus, in this large cohort of women, we assessed the influence of primary cancer, previous treatment, family cancer history, and menstrual and reproductive history on breast cancer risk. Methods Study Sample: Childhood Cancer Survivors Study The CCSS is a follow-up study of childhood cancer survivors established in 1994. Eligibility criteria included diagnosis at an age younger than 21 years with leukemia, brain tumor, Hodgkin disease, non-Hodgkin lymphoma, renal tumor, neuroblastoma, or soft-tissue or bone sarcoma and survival of at least 5 years after diagnosis. The 20276 eligible participants received a diagnosis from 1 January 1970 to 31 December 1986 at 1 of 25 collaborating institutions (Appendix). Participants (n= 14054) completed a self-report questionnaire, providing information about their medical history, family medical history, reproductive history, and socioeconomic status. Follow-up questionnaires were sent to patients reporting second cancer diagnoses. Information on the cohort was updated in 2000. We used data available as of May 2002 for this analysis. No men in the CCSS reported breast cancer by that date; thus, this analysis was restricted to women. Detailed information on the study methods and cohort characteristics has been reported (18). The human subjects committee at each participating institution approved the CCSS protocol. Clinical Data We abstracted treatment data from medical records, including chemotherapeutic agents and dose, and radiation therapy dose, and site for primary cancer and relapses. We asked participants who self-reported breast cancer to sign a medical release to confirm the diagnosis. We confirmed all cases of breast cancer in this report and obtained the tumor size, histologic characteristics, hormone receptor status, involvement of axillary nodes, and metastatic sites from pathology records. Statistical Analysis We compared survivors who had breast cancer with those who did not have breast cancer with respect to primary cancer diagnosis, age at diagnosis, years of follow-up, and therapy for the primary cancer. We calculated standardized incidence ratios for breast cancer by using age-, sex-, and calendar-yearspecific incidence rates of the general population (Surveillance, Epidemiology, and End Results Program [SEER], National Cancer Institute, Bethesda, Maryland [19]). We considered survivors to be at risk for breast cancer from 5 years after the childhood cancer diagnosis until 1 of the following 3 events: death, breast cancer diagnosis, or completion of the CCSS questionnaire. To make the definition of incidence comparable in the calculation of the observed and expected numbers, we included only the first primary breast cancer diagnosis. We calculated cumulative incidences of breast cancer by attained age (20). We used Poisson multiple regression models for standardized incidence ratios to assess the modification of risk for developing breast cancer by several variables chosen a priori (21). We considered the following risk factors for breast cancer: age at and years since primary cancer diagnosis; age at menarche (<12 years or 12 years); age at first live birth (never, <20 years, 20 to 24 years, or 25 years), as queried in the CCSS questionnaire; history of breast cancer in first-degree female relatives (yes or no); exposure to chest radiation (yes or no); exposure to pelvic radiation (yes or no); family history of sarcoma (yes or no); history of thyroid disease (thyroid nodules, overactive or underactive thyroid, or enlarged thyroid); and exposure to an alkylating agent (alkylating agent score, measured as previously described, accounted for several drug exposures and dose) (22). The Poisson multiple regression incorporated all time-dependent factors by splitting each survivors follow-up period into several time intervals, wherein each factor was assumed constant. We initially evaluated the relative rate of developing breast cancer for each risk factor, adjusting for the exposure to chest radiation (yes or no). We then stratified the analysis by the exposure to chest radiation and assessed the modification of risk with age at and years since primary cancer diagnosis, family history of breast cancer or sarcoma, history of thyroid disease, and exposure to pelvic radiation. The years since primary cancer diagnosis variable was the baseline time factor of the model for which we obtained fitted standardized incidence ratios relative to SEER data. For other variables, we calculated relative rates by comparing standardized incidence ratios across categories of each variable. All significance tests were 2-sided. We used SAS software, version 8 (SAS Institute Inc., Cary, North Carolina), and S-PLUS software, version 6 (Insightful Corp.), for this analysis. Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Cohort Characteristics Of the 20276 survivors eligible for the CCSS cohort, 9062 were women. Of those, 6498 women participated, 6068 of whom had signed medical record release to be eligible for this analysis. Of the 6068 eligible women, 95 women had 111 confirmed cases of breast cancer. Primary cancer diagnosis and age at treatment were similar between participants and nonparticipants (Table 1). Survivors with breast cancer were older at diagnosis of primary cancer and at follow-up than those without breast cancer. As expected, a large proportion of the women with breast cancer (65 of 95 [68%] women) were Hodgkin disease survivors, and all but 2 of the 65 women were known to have received chest radiation therapy. However, 30 of 95 (32%) women with breast cancer were survivors of other childhood cancer, and 20 of 95 (21%) women did not receive chest radiation therapy. The proportion of patients exposed to alkylating agents was similar in both groups (49.5% vs. 49.2%) (Table 1). Table 1. Characteristics of Women Who Did and Did Not Develop Breast Cancer and of Eligible Nonparticipants Since the oldest survivors in this cohort were 51 years of age, all cases of breast cancer were diagnosed in relatively young women (median age at diagnosis, 35 years [range, 20 to 49 years]) (Table 2). However, 19% (18 of 95 women) of the breast cancer cases occurred in women 20 to 29 years of age and 64% (61 of 95 women) of cases occurred in women 30 to 39 years of age. Median time from childhood cancer diagnosis to breast cancer diagnosis was 19 years; however, the range extended from 6 years to 29 years after primary cancer diagnosis (Table 2). Table 2. Clinical and Pathologic Characteristics of Breast Cancer Cases Of the 111 cases of breast cancer, 21 cases were ductal carcinoma in situ (Table 2). Of those 21 cases, 19 were diagnosed in Hodgkin disease survivors and 2 in soft-tissue sarcoma survivors. Table 2 shows the distribution of histologic characteristics in the invasive cases. We determined the stage in 66 of 90 (73%) invasive cases from pathology reports (Table 2). Twenty-six (29%) cases involved axillary lymph nodes, and 5 (6%) cases involved distant metastatic disease. Estrogen receptor status was available in 37 cases, and 76% of those were positive. There was no predominant laterality. Sixteen cases (17%) were bilateral, 5 were syn

History of allergies and autoimmune diseases and risk of brain tumors in adults

To explore a possible influence of the immune system in the development of brain tumors, we evaluated the relationship between history of allergies and autoimmune diseases and risk of brain tumors within a large, hospital‐based case‐control study. Cases (n = 782) were patients recently diagnosed with glioma (n = 489), meningioma (n = 197) or acoustic neuroma (n = 96) at hospitals in Boston, Phoenix and Pittsburgh (USA). Controls (n =799) were patients hospitalized for a variety of nonmalignant conditions and frequency‐matched to cases by hospital, age, sex, race/ethnicity and distance of residence from hospital. Research nurses collected data by personal interview of patients. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression. There was a significant inverse association between glioma and history of any allergies (OR = 0.67, 95% CI = 0.52–0.86) or autoimmune diseases (OR = 0.49, 95% CI = 0.35–0.69). No significant associations were evident for meningioma or acoustic neuroma with history of any allergies. An inverse association was observed between meningioma and history of autoimmune diseases (OR = 0.59, 95% CI = 0.38–0.92). There was a suggestion of interaction between allergies and autoimmune diseases on risk of glioma (p = 0.06), with subjects having both conditions being at lowest risk (OR = 0.24, 95% CI = 0.14–0.42). Among the specific conditions, asthma and diabetes showed the most consistent associations (OR = 0.63, 95% CI = 0.43–0.92 and OR = 0.44, 95% CI = 0.27–0.70, respectively). Our results add to evidence that persons with allergies or autoimmune diseases are at reduced risk of glioma. The basis of the associations is not clear, but they might imply a role of immunologic factors in the development of brain tumors. Published 2002 Wiley‐Liss, Inc.

Radiation Dose and Breast Cancer Risk in the Childhood Cancer Survivor Study

PURPOSE The purpose of this study was to quantify the risk of breast cancer in relation to radiation dose and chemotherapy among survivors of childhood cancer. METHODS We conducted a case-control study of breast cancer in a cohort of 6,647 women who were 5-year survivors of childhood cancer and who were treated during 1970 through 1986. One hundred twenty patients with histologically confirmed breast cancer were identified and were individually matched to four selected controls on age at initial cancer and time since initial cancer. Medical physicists estimated radiation dose to the breast tumor site and ovaries on the basis of medical records. RESULTS The odds ratio for breast cancer increased linearly with radiation dose, and it reached 11-fold for local breast doses of approximately 40 Gy relative to no radiation (P for trend < .0001). Risk associated with breast irradiation was sharply reduced among women who received 5 Gy or more to the ovaries (P = .002). The excess odds ratio per Gy was 0.36 for those who received ovarian doses less than 5 Gy and was 0.06 for those who received higher doses. Radiation-related risk did not vary significantly by age at exposure. Borderline significantly elevated risks were seen for doxorubicin, dactinomycin, dacarbazine, and carmustine. CONCLUSION Results confirm the radiation sensitivity of the breast in girls age 10 to 20 years but do not demonstrate a strong effect of age at exposure within this range. Irradiation of the ovaries at doses greater than 5 Gy seems to lessen the carcinogenic effects of breast irradiation, most likely by reducing exposure of radiation-damaged breast cells to stimulating effects of ovarian hormones.

Risk of Second Primary Thyroid Cancer after Radiotherapy for a Childhood Cancer in a Large Cohort Study: An Update from the Childhood Cancer Survivor Study

Abstract 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.